https://www.wikilectures.eu/api.php?action=feedcontributions&user=Azrael&feedformat=atomWikiLectures - User contributions [en]2024-03-28T20:03:40ZUser contributionsMediaWiki 1.39.1https://www.wikilectures.eu/index.php?title=Interaction_of_non-allelic_genes&diff=26210Interaction of non-allelic genes2017-12-01T18:23:57Z<p>Azrael: Coursebook chapter by Kučera, M.</p>
<hr />
<div>[[File:Interactions.PNG|right|400px]]<br />
In some cases there is a trait made up of more genes. This causes a '''discrepancy in segregation ratios'''. Usually, many genetic textbooks propose interaction between two genes each with two alleles with complete dominance. Segregation ratios in F2 generations of all types of interactions are summarized in the table below.<br />
<br />
'''Dominant epistasis (12:3:1)''' sets up when dominant gene realize its potential regardless of recessive gene. Only when dominant gene has both alleles recessive then recessive gene can realize its phenotype. <br />
<br />
On the contrary '''recessive epistasis (9:3:4)''' occurs when both recessive alleles of one gene produce uniform phenotype regardless of genotype of the second gene. <br />
<br />
In '''complementary factor (9:7)''' when either of both genes is recessive homozygous, then it leads to an identical phenotype regardless of genotype of the other gene. To produce other phenotype, both genes have to have at least one dominant allele.<br />
<br />
'''Polymorphic gene (9:6:1)''' sets up when both genes are responsible for producing same trait. Then genotype aabb does not produce anything, genotypes A-bb and aaB- produce a half of what A-B- produce. All in all, there is a cumulatory effect.<br />
<br />
'''Duplicate gene (15:1)''' is similar to polymorphic gene but there is no cumulation when both genes have a dominant allele. <br />
<br />
'''Inhibitory factor (13:3)''' happens when dominant genotype of one gene and recessive genotype of the other have same phenotype. In F2 generation we then receive two phenotype classes. One with genotypes A-B-, A-bb, aabb and second with genotypes aaB-.<br />
<br />
[[Category:Genetics]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=File:Interactions.PNG&diff=26208File:Interactions.PNG2017-12-01T18:22:55Z<p>Azrael: Overview of allelic interactions.</p>
<hr />
<div>== Summary ==<br />
Overview of allelic interactions. <br />
== Licensing ==<br />
{{wl_license}}</div>Azraelhttps://www.wikilectures.eu/index.php?title=Hemoglobinopathies&diff=26207Hemoglobinopathies2017-12-01T18:14:36Z<p>Azrael: Coursebook chapter by Kučera, M.</p>
<hr />
<div>'''The hemoglobinopathies''' are all genetic diseases of hemoglobin. They fall into two main groups: '''structural''' hemoglobin variants and syndromes with '''abnormal genetic production''' – thalassemias<br />
<br />
==Structural hemoglobin variants==<br />
'''Abnormal hemoglobin variants''' are caused by '''structural defects''' resulting from an altered amino acid sequence in the α or β chains. Clinicians distinguish among genetic variants such as HbS, HbC, or HbM.<br />
<br />
HbS variant is manifested by disease called '''sickle cell disease'''. It is [[Autosomal recessive inheritance in pedigree and experiment, examples of traits in man|autosomal recessive]] inhereted hemolytic anemia with growth disorder, splenomegaly, and „crisis“. Crisis stands for an acute condition with red blood occlusion of capilaries involving limbs, spleen or lungs. This occlusion is triggered by stress conditions such as high altitude. Without medical treatment, this disorder is lethal.<br />
<br />
The genetic defect of sickle cell anemia is substitution of one nucleotide (A>T) resulting into conversion of glutamic acid into valine in 6. position of 146 amino acids long β chain. This mutation produces rod-like aggregation of HbS molecules changing erytrocyte cell morphology into „sickle-like“.<br />
<br />
Similar clinical findings provide '''HbC hemoglobin'''. HbC has lysine substitution of glutamic acid again on 6. position of β chain. Thus, this chain is less soluble and precipitate in erytrocytes.<br />
Methemoglobins (HbM) are forms of hemoglobin which have their affinity of oxygen altered. This mutation fixes Fe3+ variant of iron which can’t bind oxygen. However, reductases convert Fe<sup>3+</sup> form into Fe<sup>2+</sup> form and thus HbM carriers are only cyanotic.<br />
<br />
There are more genetic variants in Hb structure. Such as 2 amino acid substitutions in HbC Harlem or deletion of 5 amino acids in '''Hb Gun Hill'''. On the other hand, '''Hb Constant Spring''' has 31 more amino acids in its peptide chain due to mutation in stop codon. Hb Lepore variant was produced by fusion of δ chain and β chain.<br />
<br />
==Syndromes with abnormal genetic production – thalassemias==<br />
'''Thalassemias''' are common hemoglobin disorders characterized by '''abnormal hemoglobin production'''. There are two main types, alfa thalassemia (defective α chains) and beta thalassemia (β chains). After reduction of production of either chain, there is a relative abundance of the other. This leads to production of abnormal hemoglobin tetramers composed of all 4 same chains (i.e. alfa chains). Consequently, these tetramers have lower capacity for oxygen and higher precipitation rate in erytrocytes. Higher precipitation of these molecules causes destruction of membranes producing hypochromic anemia.<br />
<br />
In alfa thalassemia there is disrupted production of fetal and adult hemoglobin. In severe forms of alfa thalassemia, fetus suffer from oxygen insufficiency and it leads into hydrops state.<br />
Most common genetic factor which leads to alfa thalassemia is deletion. There are four alleles for alfa chain gene. Deletion of one allele is without clinical findings (αα/α-), deletion of two (αα/-- or α-/α-) causes thalassemia minor with mild anemia, deletion of three (α-/--) leads to sever anemia and deletion of four (--/--) is lethal.<br />
<br />
As for '''beta thalassemia''', defects in production of β chain also produce anemia, however, starting 3 months after birth when synthesis of HbF (γ chain) is physiologically subsituted by HbA (α chain). α chains precipitate in abundance in bone marrow causing ineffective erytropoesis. Heterozygotes (β/-) have mild anemia similar to one with iron deficiency ('''thalassemia minor'''). Cases with '''thalassemia major''' have severe anemia and bones changes due to bone marrow enlargement. Contrary to alfa thalassemia‘s, beta thalassemia mutations are based on nonsense, frameshift or splicing mutations.<br />
<br />
[[Category:Genetics]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=Dihybridism&diff=26205Dihybridism2017-12-01T17:56:49Z<p>Azrael: Coursebook chapter by Kučera, M.</p>
<hr />
<div>[[File:Dihybrid cross.png|thumb|right|300px]]<br />
'''Dihybridism''' is a cross between two different lines that differ in two observed traits. According to Mendel’s law of independent assortment, genes for different traits can segregate independently during the formation of gametes. This applies only on genes localized on various somatic chromosomes.<br />
<br />
When crossing, the P generation is either '''AABB x aabb''' or '''AAbb x aaBB'''. In both these examples there is a crossing between dominant homozygote and recessive homozygote for each gene. The offspring F1 of this cross is uniform and heterozygotic for both genes – AaBb.<br />
<br />
In F2 generation Mendel has found a ratio: (3/4 + 1/4) x (3/4 + 1/4) = 9:3:3:1. There are 9/16 subjects with both dominant phenotypes, 6/16 (3/16+3/16) subjects with one dominant and one recessive phenotype and 1/16 subjects with both recessive phenotypes. The segregation ratio for '''backcross is 1:1:1:1'''.<br />
<br />
For estimating a number of phenotypes, a good rule of thumb is 2n where n represents number of genes. Similarly, the number of genotypes in F2 is 3n. Phenotypic segregation ratio in F2 is counted as (3/4 + 1/4)n or (1/2 + 1/2)n when backcrossing.<br />
<br />
[[Category:Genetics]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=Structure_of_populations,_genetic_drift,_importance_for_evolution&diff=25967Structure of populations, genetic drift, importance for evolution2017-10-02T09:34:03Z<p>Azrael: /* Measurement of population substructure using FST */ +Figure</p>
<hr />
<div>'''Population structure (or “population subdivision”)''' – instead of a single, simple population, populations are subdivided in some way. <br />
<br />
'''Metapopulation''' - the overall "population of populations" <br />
<br />
'''Subpopulations''' (local populations, or demes) - the individual component populations (amongst which gene flow is restricted) <br />
<br />
'''Exemple:''' i) European Caucasians would be a (meta)population, with groups within them defined by nationality or religion would be the subpopulations, ii) the citizens of India may be defined as a population, and the different caste groups as its subpopulations.<br />
<br />
In fact, in many real populations, there may not be any obvious substructure at all, and the '''populations are continuous'''. However, even in effectively continuous populations, different areas can have different allelic frequencies, because the '''whole metapopulation is not panmictic'''. Among humans, many '''populations are structured''', but continuously, in space.<br />
<br />
Population are structured when they have deviations from H-W proportions, or deviations from panmixia. If there is inbreeding, or selection, or if migration is important, then populations can be said to be structured in some way. Gene flow (migration) between subpopulations retards the process of genetic differentiation between populations.<br />
<br />
===Random genetic drift===<br />
Gene pool / gametic pool / zygotic pool<br />
In a population, some individuals may by chance not pass on their alleles to next generation, others by chance pass on more than their “fair share”.<br />
<br />
Formation of zygotic pool is a random process allelic frequencies may change/vary in the course of generations (from generation to generation).<br />
<br />
'''Gene(tic) drift is the change of allelic frequencies in the gene pool produced by random causes.''' It depends on the size of population – changes are unpredictable; more visible/ particularly pronounced in small populations.<br />
<br />
Extreme limit – stabilization/fixation of one allele in the small population and elimination of second alternative allele genetic homozygotization. Given enough time, any allele frequency can drift to 1 (fixation) or 0 (extinction). Speed (time T) of fixation is dependent on the size of population and original allelic frequencies.<br />
<br />
T<sub>fixation</sub> = – 4N·(p·lnp + q·lnq)<br />
<br />
[[file:Genetic_drift.png]]<br />
Alleles (mutations) may be lost or fixed within a (small) population (N, number of individuals in this population)<br />
<br />
===Bottleneck===<br />
Many populations go through “bottlenecks” where the size of population is reduced (migration, disease, famine, climate). A small sample from a population may have a non-random distribution of alleles.<br />
<br />
When the population grows, it will have different allele frequencies from the population before bottleneck.<br />
<br />
===Founder effect===<br />
A few individuals colonising a new region can cause a “founder effect” (f.e.) whereby some genes are more common in the colony than the population they came from. F. e. explains extremely high frequencies of some diseases in subpopulations.<br />
<br />
Examples: i) myotonic dystrophy (inherited muscular disease) is much more common in a region of French Canadian immigrants than in Europe, because some of the original settlers were carrying the gene. ii) Tay-Sachs disease (AR inborn error of metabolism with neurologic symptomatology) has high frequency in Ashkenazi Jews (originated from East Europe)<br />
<br />
The possibility of equilibrium between drift and migration<br />
<br />
The former tends to cause differentiation, the latter to homogenize gene frequencies. <br />
*Wright's „Island model“ of population structure (unrealistic, much abused)<br />
*Wright's „Isolation by distance model“ of population structure <br />
<br />
===Measurement of population substructure using F<sub>ST</sub>===<br />
Subdivision into populations with distinct allelic frequencies could even create a heterozygote deficit (this can be considered a sort of inbreeding), F:<br />
<br />
F=1-(2p<sub>av</sub>q<sub>av</sub>/0.5)<br />
<br />
This sort of inbreeding coefficient is called F<sub>st</sub> after Fixation index in the Subpopulation relative to the Total population (p<sub>av</sub>, q<sub>av</sub> – average allelic frequencies of A and a alleles over all subpopulations in a metapopulation).<br />
F<sub>st</sub>can also be shown to be equal to the standardized variance of gene fequency (also called the Wahlund variance) in the k subpopulations, divided by (standardized by) the maximum possible variance, pavqav. The maximum possible variance is the variance when different populations are fixed for A or a.<br />
:where <br />
[[File:PopGenFormula1.png]]<br />
<br />
F<sub>st</sub> is a fraction of total variance, the proportion of genetic variation found between as opposed to within each populations. Thus, (1-F<sub>st</sub>) is the proportion of the total metapopulation genetic variation found within as opposed to between populations. If there is a lot of local fixation or inbreeding, F<sub>st</sub> will be near 1; if very little, F<sub>st</sub> will be low (0.05, for instance, might be a typical value).<br />
<br />
===Evolutionary aspects===<br />
Drift is the major cause of genetic differences between subpopulations. Since the drift is quantifiably effective in small populations only, it had to play the principal role in early stages of human evolution when our populations were small. <br />
<br />
If populations are subdivided, they can evolve apart, somewhat independently. Population structure allows populations to diversify. This is the reason why population structure is a very important part of evolutionary genetics. <br />
<br />
The term “population structure” usually refers to the patterns in neutral genetic variation that result from the past or present departure from panmixia of a population. Understanding past population structure is of interest to evolutionary biologists because it can point to, e.g., potential environmental factors such as climate changes as driving evolutionary forces. <br />
<br />
Gene flow (migration) homogenizes gene frequencies and can reduce local adaptation, by preventing divergence.There could be a complete absence of gene flow between subpopulations because of social, geographic, ecological, or even biological barriers. In such cases, evolutionary changes between subpopulations occur under complete isolation.<br />
<br />
So, new mutations arising in certain subpopulations remain "private", and genetic differentiation between subpopulations occur with a speed governed by mutation rate and the breeding size of subpopulations. <br />
<br />
Population structure has important biomedical consequences either when a number of subpopulational groups is locally adapted to particular environmental conditions (and maladapted when exposed to new environments) or represents a confounding factor in the study of the statistical association between genetic variants and phenotypic traits.<br />
<br />
[[Category:Biology]]<br />
[[Category:Genetics]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=File:PopGenFormula1.png&diff=25966File:PopGenFormula1.png2017-10-02T09:33:24Z<p>Azrael: Population genetics</p>
<hr />
<div>== Summary ==<br />
Population genetics<br />
== Licensing ==<br />
{{cc|by-sa|3.0|cz}}</div>Azraelhttps://www.wikilectures.eu/index.php?title=Structure_of_populations,_genetic_drift,_importance_for_evolution&diff=25965Structure of populations, genetic drift, importance for evolution2017-10-02T09:30:19Z<p>Azrael: Coursebook chapter. Author: Panczak, A.</p>
<hr />
<div>'''Population structure (or “population subdivision”)''' – instead of a single, simple population, populations are subdivided in some way. <br />
<br />
'''Metapopulation''' - the overall "population of populations" <br />
<br />
'''Subpopulations''' (local populations, or demes) - the individual component populations (amongst which gene flow is restricted) <br />
<br />
'''Exemple:''' i) European Caucasians would be a (meta)population, with groups within them defined by nationality or religion would be the subpopulations, ii) the citizens of India may be defined as a population, and the different caste groups as its subpopulations.<br />
<br />
In fact, in many real populations, there may not be any obvious substructure at all, and the '''populations are continuous'''. However, even in effectively continuous populations, different areas can have different allelic frequencies, because the '''whole metapopulation is not panmictic'''. Among humans, many '''populations are structured''', but continuously, in space.<br />
<br />
Population are structured when they have deviations from H-W proportions, or deviations from panmixia. If there is inbreeding, or selection, or if migration is important, then populations can be said to be structured in some way. Gene flow (migration) between subpopulations retards the process of genetic differentiation between populations.<br />
<br />
===Random genetic drift===<br />
Gene pool / gametic pool / zygotic pool<br />
In a population, some individuals may by chance not pass on their alleles to next generation, others by chance pass on more than their “fair share”.<br />
<br />
Formation of zygotic pool is a random process allelic frequencies may change/vary in the course of generations (from generation to generation).<br />
<br />
'''Gene(tic) drift is the change of allelic frequencies in the gene pool produced by random causes.''' It depends on the size of population – changes are unpredictable; more visible/ particularly pronounced in small populations.<br />
<br />
Extreme limit – stabilization/fixation of one allele in the small population and elimination of second alternative allele genetic homozygotization. Given enough time, any allele frequency can drift to 1 (fixation) or 0 (extinction). Speed (time T) of fixation is dependent on the size of population and original allelic frequencies.<br />
<br />
T<sub>fixation</sub> = – 4N·(p·lnp + q·lnq)<br />
<br />
[[file:Genetic_drift.png]]<br />
Alleles (mutations) may be lost or fixed within a (small) population (N, number of individuals in this population)<br />
<br />
===Bottleneck===<br />
Many populations go through “bottlenecks” where the size of population is reduced (migration, disease, famine, climate). A small sample from a population may have a non-random distribution of alleles.<br />
<br />
When the population grows, it will have different allele frequencies from the population before bottleneck.<br />
<br />
===Founder effect===<br />
A few individuals colonising a new region can cause a “founder effect” (f.e.) whereby some genes are more common in the colony than the population they came from. F. e. explains extremely high frequencies of some diseases in subpopulations.<br />
<br />
Examples: i) myotonic dystrophy (inherited muscular disease) is much more common in a region of French Canadian immigrants than in Europe, because some of the original settlers were carrying the gene. ii) Tay-Sachs disease (AR inborn error of metabolism with neurologic symptomatology) has high frequency in Ashkenazi Jews (originated from East Europe)<br />
<br />
The possibility of equilibrium between drift and migration<br />
<br />
The former tends to cause differentiation, the latter to homogenize gene frequencies. <br />
*Wright's „Island model“ of population structure (unrealistic, much abused)<br />
*Wright's „Isolation by distance model“ of population structure <br />
<br />
===Measurement of population substructure using F<sub>ST</sub>===<br />
Subdivision into populations with distinct allelic frequencies could even create a heterozygote deficit (this can be considered a sort of inbreeding), F:<br />
<br />
F=1-(2p<sub>av</sub>q<sub>av</sub>/0.5)<br />
<br />
This sort of inbreeding coefficient is called F<sub>st</sub> after Fixation index in the Subpopulation relative to the Total population (p<sub>av</sub>, q<sub>av</sub> – average allelic frequencies of A and a alleles over all subpopulations in a metapopulation).<br />
F<sub>st</sub>can also be shown to be equal to the standardized variance of gene fequency (also called the Wahlund variance) in the k subpopulations, divided by (standardized by) the maximum possible variance, pavqav. The maximum possible variance is the variance when different populations are fixed for A or a.<br />
:where <br />
F<sub>st</sub> is a fraction of total variance, the proportion of genetic variation found between as opposed to within each populations. Thus, (1-F<sub>st</sub>) is the proportion of the total metapopulation genetic variation found within as opposed to between populations. If there is a lot of local fixation or inbreeding, F<sub>st</sub> will be near 1; if very little, F<sub>st</sub> will be low (0.05, for instance, might be a typical value).<br />
<br />
===Evolutionary aspects===<br />
Drift is the major cause of genetic differences between subpopulations. Since the drift is quantifiably effective in small populations only, it had to play the principal role in early stages of human evolution when our populations were small. <br />
<br />
If populations are subdivided, they can evolve apart, somewhat independently. Population structure allows populations to diversify. This is the reason why population structure is a very important part of evolutionary genetics. <br />
<br />
The term “population structure” usually refers to the patterns in neutral genetic variation that result from the past or present departure from panmixia of a population. Understanding past population structure is of interest to evolutionary biologists because it can point to, e.g., potential environmental factors such as climate changes as driving evolutionary forces. <br />
<br />
Gene flow (migration) homogenizes gene frequencies and can reduce local adaptation, by preventing divergence.There could be a complete absence of gene flow between subpopulations because of social, geographic, ecological, or even biological barriers. In such cases, evolutionary changes between subpopulations occur under complete isolation.<br />
<br />
So, new mutations arising in certain subpopulations remain "private", and genetic differentiation between subpopulations occur with a speed governed by mutation rate and the breeding size of subpopulations. <br />
<br />
Population structure has important biomedical consequences either when a number of subpopulational groups is locally adapted to particular environmental conditions (and maladapted when exposed to new environments) or represents a confounding factor in the study of the statistical association between genetic variants and phenotypic traits.<br />
<br />
[[Category:Biology]]<br />
[[Category:Genetics]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=File:Genetic_drift.png&diff=25964File:Genetic drift.png2017-10-02T09:26:17Z<p>Azrael: Genetic drift - time to fixation</p>
<hr />
<div>Genetic drift - time to fixation</div>Azraelhttps://www.wikilectures.eu/index.php?title=Genetic_aspects_of_populations,_Hardy-Weinberg_equilibrium&diff=25963Genetic aspects of populations, Hardy-Weinberg equilibrium2017-10-02T08:29:21Z<p>Azrael: Coursebook chapter. Author: Panczak, A.</p>
<hr />
<div>===Population===<br />
'''What is a population from genetic point-of-view?''' It is a group of '''interbreeding individuals of the same species''' that inhabit the same space (prescribed geographical area) and time. The key to a population is that they must be able to interbreed. <br />
<br />
'''Within any given population there is variation (differencies) of/in:'''<br />
*'''phenotypes;''' the proportion of individuals within a population that are of a particular phenotype is phenotype frequency<br />
*'''genotypes;''' the proportion of individuals within a population that are of a particular genotype is genotype frequency<br />
*'''alleles;''' the proportion of all copies of a gene in a population that are of a particular allele type is allelic frequency<br />
<br />
'''The gene pool''' is the sum total of all of the alleles (of one locus) present and carried by the population.<br />
*Gametic gene pool – sum of all alleles in gametes.<br />
*Zygotic gene pool – sum of all alleles in zygotes.<br />
<br />
'''For a gene with 2 alleles, A and a:'''<br />
*N<sub>AA</sub> is the number of AA homozygotes<br />
*N<sub>Aa</sub> is the number of heterozygotes Aa<br />
*N<sub>aa</sub> is the number of aa homozygotes<br />
*N<sub>AA</sub> + N<sub>Aa</sub> + N<sub>aa</sub> = N, number of individuals in population<br />
<br />
Estimating/calculating of allele frequencies in a population <br />
*'''with three distinct phenotypes for a trait (e.g. in MN blood group system)'''<br />
::Let p = frequency of allele A, and q = frequency of a. Then:<br />
::pA = (2N<sub>AA</sub> + N<sub>Aa</sub>) / 2N<br />
::qa = (2N<sub>aa</sub> + N<sub>Aa</sub>) / 2N<br />
::Variant procedure: Calculating allele frequencies from (known) frequencies of genotypes AA, Aa, aa<br />
::pA = f<sub>AA</sub> + ½ f<sub>Aa</sub><br />
::qa = f<sub>aa</sub> + ½ f<sub>Aa</sub><br />
::'''p + q = 1'''<br />
*where (only) two distinct phenotypes exist (i.e., in allelic relation of full dominance/recessivity); estimate of frequency of unfavourable (mutant, deleterious, recessive) allele (Rh blood group system, tasting of PTC or AR diseases)<br />
<br />
[[File:Population_genetics_formula.png]]<br />
<br />
===Genotype frequencies===<br />
If frequency of allele A in a population is p, frequency of allele a in a population is q:<br />
*the probability that both the egg and the sperm contain the A allele is p x p = p<sup>2</sup><br />
*the probability that both the egg and the sperm contain the a allele is q x q = q<sup>2</sup><br />
*the probability that the egg and the sperm contain different alleles is (p x q) + (q x p) = 2pq<br />
<br />
[[File:Population_genetics_square.png]]<br />
===Hardy-Weinberg Equation===<br />
[[File:Hardy Weinberg Equation.png]]<br />
;Hardy-Weinberg law<br />
A population that is not changing genetically is in Hardy-Weinberg equilibrium (1908). It comes if these 5 assumptions are correct:<br />
*Random mating (panmixia)<br />
*Large population size (N approaching infinity)<br />
*No migration between populations<br />
*No (or negligible) mutations<br />
*Natural selection does not affect alleles being considered<br />
<br />
If these assumptions are true, it follows that:<br />
*Allele frequencies remain constant from one generation to the next<br />
*After one (or more) generations of random mating (breeding), the genotype frequencies (for a 2-allele gene with allele frequencies p, q) are in the proportions: '''p<sup>2</sup><sub>(AA)</sub> : 2pq<sub>(Aa)</sub> : q<sup>2</sup><sub>(aa)</sub>''', and population will be in H-W equilibrium. Var.: H-W equilibrium in a large population will be reached after one generation of (random) breeding.<br />
*For a population to be in Hardy Weinberg equilibrium, the observed genotype frequencies must match those predicted by the equation p<sup>2</sup> + 2pq + q<sup>2</sup>.<br />
<br />
;Graphic demonstration of H-W equilibrium<br />
(relation between frequencies of alleles and frequencies of genotypes)<br />
<br />
[[File:Hardy Weinberg Graphical.png]]<br />
<br />
===Multiple alleles===<br />
Multinomial expansion for two alleles a and b with frequencies p and q<br />
p<sup>2</sup> + 2pq + q<sup>2</sup> is a binomial expansion of (p + q)<sup>2</sup><br />
::p<sup>2</sup>(AA) + 2pq(Aa) + q<sup>2</sup>(aa) = (p + q)<sup>2</sup> = (1)<sup>2</sup> = 1<br />
For three alleles a, b and c with frequencies p, q and r, the multinomial expansion is <br />
(p + q + r)<sup>2</sup> which expands into: p<sup>2</sup>+ q<sup>2</sup> + r<sup>2</sup> + 2pq + 2pr +2qr ,<br />
where the first 3 terms being homozygotes and the remaining three heterozygotes.<br />
::'''p + q + r = 1 ''' p<sup>2</sup>+ q<sup>2</sup> + r<sup>2</sup> + 2pq + 2pr +2qr = 1<br />
<br />
[[category:Biology]]<br />
[[category:Genetics]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=File:Hardy_Weinberg_Graphical.png&diff=25962File:Hardy Weinberg Graphical.png2017-10-02T08:27:01Z<p>Azrael: Hardy Weinberg Equilibrium</p>
<hr />
<div>== Summary ==<br />
Hardy Weinberg Equilibrium<br />
== Licensing ==<br />
{{cc|by-sa|3.0|cz}}</div>Azraelhttps://www.wikilectures.eu/index.php?title=File:Hardy_Weinberg_Equation.png&diff=25961File:Hardy Weinberg Equation.png2017-10-02T08:22:42Z<p>Azrael: Hardy Weinberg Equation</p>
<hr />
<div>== Summary ==<br />
Hardy Weinberg Equation<br />
== Licensing ==<br />
{{cc|by-sa|3.0|cz}}</div>Azraelhttps://www.wikilectures.eu/index.php?title=File:Population_genetics_square.png&diff=25960File:Population genetics square.png2017-10-02T08:14:51Z<p>Azrael: Population genetics</p>
<hr />
<div>== Summary ==<br />
Population genetics<br />
== Licensing ==<br />
{{cc|by-sa|3.0|cz}}</div>Azraelhttps://www.wikilectures.eu/index.php?title=File:Population_genetics_formula.png&diff=25959File:Population genetics formula.png2017-10-02T08:07:15Z<p>Azrael: Population genetics</p>
<hr />
<div>== Summary ==<br />
Population genetics<br />
== Licensing ==<br />
{{cc|by-sa|3.0|cz}}</div>Azraelhttps://www.wikilectures.eu/index.php?title=Characteristics_of_cancer_cells&diff=25940Characteristics of cancer cells2017-07-26T14:10:54Z<p>Azrael: Coursebook chapter. Authors: Vodenkova, S.; Jiraskova, K.</p>
<hr />
<div>==Cancer cells==<br />
*one of the fundamental features of cancer is tumor clonality (the tumors development from single cell)<br />
*increased ability to survive (they often gain resistance to apoptosis)<br />
* aberrant regulation of cell cycle (mainly is affected transition between G1- and S-phase)<br />
*grow and divide at an abnormally rapid rate<br />
*decreased need of hormones and growth factors coming from outside of the cell<br />
* poorly differentiated<br />
*abnormal membranes, cytoskeletal proteins, and morphology<br />
* a high number of chromosomal breaks and numerous chromosomal aberrations<br />
*presence of so-called tumor neoantigens<br />
* some transformed cells have ability of autocrine stimulation (usually via growth factors)<br />
*intercellular communication and the relationship between tumor cells and neighboring cells is disrupted<br />
* a failure to fix to a solid cell surface<br />
<br />
==Cancer stem cells (CSC)==<br />
*a type of cancer cell with some characteristics of stem cell<br />
*are able to proliferate and change themselves to any type of cancer cell in a given tumor<br />
* it is believed that they occur in all cancer types<br />
* are most often resistant to chemotherapy, therefore subsequent relapse of cancer can appear<br />
* they account for a small percentage of all cells in tumor – they differ from other cancer cells by the presence of special surface markers on their plasma membranes<br />
<br />
==Cancer Cell Development==<br />
*3 main classes of genes important in controlling cell growth & play a role in cancer cell development<br />
Oncogenes<br />
* cause cells to grow out of control, promote cancer cell growth<br />
*damaged/mutated versions of normal genes called proto-oncogenes<br />
* mutations can be inherited or caused by exposure to a carcinogen in the environment<br />
* mutations are dominant (defect in 1 copy of gene can lead to cancer)<br />
===Tumor suppressor genes===<br />
* normally protect against cancer (act as brakes and help stop cell growth and control cell death)<br />
* damaged/missing - cell growth, cell division and cell death (apoptosis) may not be controlled<br />
* nearly 50% of all cancers are thought to involve a damaged or missing tumor suppressor gene (e.g. p53, APC, Rb)<br />
* mutations are recessive (both copies of gene need to have a defect to be at risk of developing cancer)<br />
===DNA repair genes===<br />
* responsible for repairing damaged genes<br />
* fix mistakes (mutations) that commonly occur when DNA is being copied<br />
* damaged genes → mutations may not be repaired and will build up<br />
* mutations are recessive<br />
<br />
==Forms of cancer==<br />
*Sarcoma affecting mesenchymal tissue (muscle, connective tissue, bone).<br />
*Carcinoma affect epithelial tissue.<br />
*Hematopoietic and lymphoid malignant neoplasms (Leukaemia and Lymphoma).<br />
<br />
==Steps of cancer development==<br />
* cells gradually become malignant through a progressive series of alterations (several steps and several genetic mutations are usually required)<br />
* development of cancer is a multistep and multifactorial process and can take a long time (several years) for cancer to develop<br />
* indication of the multistep development of cancer is that most cancers develop in a late life-period<br />
(The incidence of colon cancer increases more than tenfold between the ages of 30 and 50 and another tenfold between 50 and 70. Dramatic increase of cancer incidence with age suggests that most cancers develop as a consequence of multiple abnormalities, which accumulate over periods of many years).<br />
<br />
===Initiation===<br />
* genetic alteration leading to abnormal proliferation of a single cell<br />
* cell proliferation then leads to the outgrowth of a population of clonally derived tumor cells<br />
* ability to spot mutations and either destroy itself (by apoptosis) or fix the mutations → if the repair fails and more mutations occur, the damaged cell is more likely to become cancerous<br />
* initial change may be caused by carcinogens (chemicals, smoking, exposure to radiation) but often the cause is unknown and may be a random<br />
===Promotion===<br />
* further and repeated damage needs to occur before cancer develops<br />
===Progression===<br />
* additional mutations occur within cells of the tumor population<br />
* mutations confer a selective advantage to the cell (rapid growth, descendants become dominant within the tumor population)<br />
* clonal selection - new clone of tumor cells has evolved on the basis of its increased growth rate or other properties (such as survival, invasion, or metastasis) that confer a selective advantage<br />
* transformation – different cell behavior, grow and function → turn into a cancer cell<br />
* fast-growing cancer cell may double over 1–4 weeks, a slower growing one over 2–6 months<br />
* as cancer cells grow, they can group together to form a lump (tumor)<br />
===Metastasis===<br />
* as cancer cells divide, they can invade surrounding tissue<br />
* can also break away from the original (primary) tumor and enter the bloodstream or lymphatic system<br />
* cancer cells escaping detection by the immune system → can be carried by the blood and lymph to distant parts of the body → metastasize<br />
<br />
==Hallmarks of cancer==<br />
* uncontrolled growth of cancer cells results from accumulated abnormalities affecting many of the cell regulatory mechanisms<br />
* cancer cells typically display abnormalities in the mechanisms that regulate normal cell proliferation, differentiation, and survival<br />
* cancer cells never differentiate - continue to divide, cause more damage, and invade new tissue<br />
<br />
===Uncontrolled proliferation===<br />
*normal cells display density-dependent inhibition of cell proliferation = proliferate until they reach a finite cell density → become quiescent (arrested in the G0 stage of the cell cycle)<br />
* cancer cells proliferation is not sensitive to density-dependent inhibition → uncontrolled proliferation (ability to grow on top of other cells in layers resulting in a tumor)<br />
* insensitivity to growth-inhibitory (antigrowth) signals → cancer cells inactivate tumor suppressor genes that normally inhibit growth<br />
<br />
===Reduced requirements for extracellular growth factors===<br />
*self-sufficiency in growth signals = cancer cells can produce growth factors<br />
* abnormal production of growth factors leads to continuous auto-stimulation of cell division<br />
* cancer cells are less dependent on growth factors from other physiologically normal sources<br />
* contributing to the unregulated proliferation of tumor cells<br />
<br />
===Evasion of programmed cell death (apoptosis)===<br />
* normal cells - ability to recognize unrepairable damage and perform a controlled self-destruction for the good of the whole<br />
* cancer cells - allowing their damaged and abnormal features to continue infecting the body<br />
* cancer cells suppress and inactivate genes and pathways that normally enable cells to die<br />
<br />
===Limitless replication potential===<br />
*normal cells - go through senescence through e.g. shortening of telomeres with every cell division<br />
* cancer cells - have telomerase that will sustain the telomere length of the chromosomes rendering the cell virtually immortal even after generations of growth<br />
<br />
===Sustained angiogenesis===<br />
* cancer cells acquire the capacity to draw out their own supply of blood and blood vessels<br />
* ability to form new blood vessels - cancer cells send out chemical signals that promote angiogenesis<br />
* new blood vessels provide the blood supply needed for growth by acting as a type of feeding tube for the delivery of oxygen and nutrients to the cancer cell<br />
* angiogenesis is critical for allowing cancer cells to metastasise or invade neighbouring tissue and distant regions of the body<br />
<br />
===Tissue invasion and metastasis===<br />
* cancer cells acquire the capacity to migrate to other organs, invade other tissues, and colonize these organs, resulting in their spread throughout the body<br />
<br />
[[Category:Genetics]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=Teratogenesis,_teratogens&diff=25939Teratogenesis, teratogens2017-07-24T14:23:13Z<p>Azrael: New coursebook article by A. Šípek</p>
<hr />
<div>==Teratogenesis==<br />
'''Teratogenesis''' is a specific term for '''abnormal''' process (processes) during the prenatal development that leads to developmental errors (in general called '''birth defects''' or congenital malformations - see question 100: [[Inborn errors of development in human, examples, classification]]).<br />
<br />
Teratogenesis is quite complex process which involves different factors - called teratogens - that affect the normal process of prenatal development. Not each of the teratogen exposures actually leads to formation of some defect, there are many other factors that will influence the final result of the exposure:<br />
<br />
*Type of teratogenic factor (its "potency").<br />
*Genotype of the mother and embryo/fetus.<br />
*Species of the particular organism.<br />
*Time factor - length and timing of teratogen exposure (mind so called "preteratogenic period".<br />
*Dose/intensity of teratogenic factor.<br />
*Other/random factors.<br />
<br />
==Teratogens==<br />
Described in detail in Question 99 ([[Environmental mutagens and teratogens]]).<br />
<br />
[[Category:Genetics]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=Environmental_mutagens_and_teratogens&diff=25938Environmental mutagens and teratogens2017-07-24T14:05:47Z<p>Azrael: +cat</p>
<hr />
<div>==Mutagens==<br />
===Physical mutagens===<br />
<br />
Ionizing radiation represents a radiation with shorter wavelength and larger energy in comparison with other type of radiation (X-ray, gamma-ray, cosmic rays). <br />
<br />
Above radiation exhibits high energy and high penetration through the tissues. Ionizing radiation by passing through the tissue colides with atoms with subsequent release of the electrons; along the trace of the radiation free radicals and ions, capable of reacting with biological macromolecules, including DNA, arise (H<sup>+</sup>, OH<sup>-</sup>). Ionizing radiation may directly attack DNA itself. This kind of radiation induces oxidation of DNA bases and disrupts pentose-phosphate bond in DNA helix. Mutagenic effect depends on the amount of arising ions.<br />
Absorbed dose of ionizing radiation is being expressed in Grays [Gy = J/kg].<br />
<br />
Mutagenic effect depends on:<br />
# The dose<br />
# The duration of exposure<br />
# The phase of the cell cycle in the target cell<br />
# The capacity of the DNA repair system<br />
<br />
Ionizing radiation induces gene mutations, chromosomal aberrations and, ultimately, chromosomal translocations. There is no threshold for ionizing radiation, even small quantities may induce mutations. The quantity of radiation, which may duplicate the amount of mutations in humans, is important in genetics for prediction of the risk (especially in the etiology of neoplasia).<br />
<br />
====Ultraviolet radiation====<br />
Damage of DNA molecule induced by UV radiation <br />
UV radiation exhibits lower energy than ionizing radiation, but even UV is capable to cause electron excitation. UV radiation is absorbed by several organic molecules, namely by pyrimidines and purines. UV acts as potent mutagen in unicellular organisms, in more complex organisms it alterates cells on the surface. In humans UV induces or contributes to the induction of skin neoplasia (carcinoma, melanoma). The risk of exposure to UV radiation increases with decreasing ozone content in the atmosphere. UV radiation induces mutations mainly due to generation of hydrated purines and pyrimidine dimers. Thymine alterations are mutagenic due to: a) distortion of DNA double-helical structure hinders the procedure of DNA polymerase along the template with subsequent block of DNA replication; b) in the course of the repair of altered thymines a base mispairing often occurs. The repeated interruption of DNA replication due to thymidine dimers and their incomplete repair cause gaps in newly synthesized DNA chain with subsequent chromosomal breaks. Thymidine dimers may give rise base substitutions and/or deletions.<br />
===Chemical mutagens===<br />
Chemical mutagens are chemicals exerting mutagenic effects. They comprise: a) food stains based on acridine; b) combustion products in cigarette smoke (more than 400 carcinogens and mutagens); c) chemicals in car exhausts; d) monomers in plastics industry (polychlorinated biphenyls, styrene, butadiene, vinyl chloride etc.).<br />
<br />
====Mode of action of chemical mutagens====<br />
# Compounds that are mutagenic only during replication (base analogues and acridine stains).<br />
# Compounds that are mutagenic by attacking DNA unless this is replicated.<br />
# Compounds causing alkylation, deamination and hydroxylation of bases.<br />
<br />
====Base analogues====<br />
These compounds are structurally related to nucleotides and are therefore mis- incorporated into DNA during replication. Their differences in comparison with physiological nucleotides cause base mispairing and mutations. These compounds are employed in investigation of mutagenic processes and as anticancer drugs (2-aminouracil, 5-bromouracil, 5-fluorouracil). <br />
5-bromouracil is analogous to thymin. Br atom replaces methyl group on C5 of pyrimidine and increases a chance of tautomeric shift. If in enol form, 5-BU pairs with guanine. If 5-BU in enol form is incorporated into a new strand, during the following replication 5-BU in keto form pairs with adenine and GC:AT transition arises.<br />
Acridine stains (such as proflavin and acridine blue) induce a shift in the reading frame. Molecules of bases are incorporated in between base pairs and the double-helix conformation of DNA is altered during the replication. During the replication insertion or deletion of one or more bases occurs with all associated phenotype consequences.<br />
====Alkylation compounds ====<br />
Many chemicals may be donors of alkyl groups. Yperit (or its nitroso derivative) was the first reported mutagen. Nitroso guanidine, on the other hand, belongs among the most potent mutagens. Alkylating agents cause mispairing by attaching the functional group (methyl-, ethyl- etc.) to the nucleophilic centers of purines and pyrimidines. Alkylating agents may induce all kinds of mutations and result ultimately in chromosomal aberrations and translocations.<br />
====Deaminating compounds==== <br />
They act via (oxidative) deamination of aminogroup in adenine, guanine and cytosine (as an example: nitrates and nitric acid). Amino- group is converted into keto- group. Deamination alters the ability of bases to form hydrogene bonds. In general, hypoxanthin (deaminated adenine) pairs with cytosine, while uracil pairs with adenine. Deamination results usually in transitions (CG:AT as well as AT:CG). Nitric oxides are generated by combustion of fossil sources and by car exhausts. Nitrates, which are used in canning of smoked meat, are particularly dangerous towards gastrointestinal cells.<br />
====Hydroxylating agents====<br />
May convert cytosin into hydroxy aminocytosine, which pairs with adenine forming CG:AT transition.<br />
<br />
===Biological mutagens===<br />
====Viruses====<br />
In the course of lysogenic cycle viruses may become incorporated into the DNA of the host. Incorporation of virus into the sequence of the gene affects substantially its function, the gene loses its function with subsequent consequences, such as chromosomal breaks, tumors.<br />
====Transposons====<br />
Represent elements capable to transpose from one site of the genome to the other. In human genome there are two classes of transposable elements: LINE (long interspred nuclear element) and SINE (short interspred nuclear element). Their shifts within a genome may have mutagenic effects.<br />
<br />
===Testing of mutagens===<br />
Most mutations negatively affect human health and, additionally, mutagenic compounds are often teratogenic and carcinogenic. Testing of the new compounds for their tentative mutagenic effect is a standard procedure within obligatory atests prior to the compounds is released on market.<br />
====Ames test====<br />
Enables to disclose mutagenic activity, type of the mutations induced and test potential mutagens. For that purpose a special auxotrophic strain ''Salmonela typhimurium'', capable to grow on medium containing histidine, was created. Compounds be tested are added into the medium. By the Ames test we evaluate the emergence of mutations following the transfer on the minimal medium. By adding histidin into the minimal medium the limited amount of cell divisions is allowed and the mutagenic compounds are tested only during the replication. By adding enzymes from liver extract we may stimulate biotransformation of xenobiotics and therefore follow mutagenicity arising after the metabolic activation.<br />
<br />
Currently available scope of methods can test both the mutagenicity and genotoxicity.<br />
<br />
Complex screening for genotoxicity may be carried out on three levels: <br />
# monitoring of environmental pollution;<br />
# monitoring of biological effects (the response of the organism towards genotoxic compounds, exposure levels, effectiveness of the preventive measures); <br />
# genetic monitoring (epidemiological studies regarding spontaneous abortions, incidence of congenital malformations in relation to the genotoxic compounds).<br />
<br />
==Teratogens==<br />
Teratogens are external factors capable to cause (or substantially increase a risk of) congenital malformations. Alike mutagens, teratogens may arbitrarily classified into three major groups: biological teratogens, chemical teratogens and physical teratogens. <br />
<br />
===Classes of teratogens ===<br />
====Biological teratogens ====<br />
Several pathogenic viruses are members of this class. Proven teratogens are following viruses: Rubivirus (rubella), Cytomegalovirus, Herpesviry, Parvovirus B-19, influenza virus, HIV and others, but also bacteria ''Treponema pallidum'' (syphilis) and protozoon ''Toxoplasma gondii'' (toxoplasmosis). Teratogenic risk may also be elevated by serious diseases of the mother, such as diabetes mellitus, phenylketonuria, myasthenia gravis and others.<br />
====Chemical teratogens====<br />
These class of teratogens comprises several industrially and agriculturally employed chemicals (organic solvents, polychlorinated biphenyls, heavy metals etc.). Particularly important group of chemical teratogens is constituted by drugs and medicaments, where prominent teratogens are cytostatics, several antibiotics (namely tetracyclins), antiepileptics (fynytoin, valproate), lithium, warfarin, thalidomide, ACE-inhibitors, steroids, retinoids etc. Teratogenic effects have been spotted in the case of ethyl alcohol (its abuse in gravidity causes foetal alcohol syndrome) and drugs such as pervitin.<br />
====Physical teratogens====<br />
This class of teratogens involves various kinds of radiation (X-rays, gamma-radiation), high temperature and mechanical teratogens .<br />
===Mode of action===<br />
Teratogenic effect has a complex character and a simplification mutagen = teratogen is not applicable. By assessing teratogenic effect we have to take into consideration:<br />
====Factor of the dose====<br />
The dose of the teratogenic agent has a decisive role for its effect. Lower doses may not induce any malformation, or may lead to a moderate or differently located damage.<br />
====Factor of the time====<br />
The sensitivity towards various teratogens is not constant during the pregnancy. In general, the exposure to teratogens during the first trimester of gravidity has the worst prognosis, however, adverse effect exhibits the exposure during the second and third trimester as well. For each teratogen there is so called critical period during which is the fetus most sensitive towards the particular teratogen or during which the target organ/system is most vulnerable. It is not surprising that the effects of the same dose of the same teratogen may be different depending on the phase of gravidity.<br />
Embryo in its early stage of development (embryogenesis) reacts towards teratogens by means All or Nothing. It means that no malformations are fixed within this period; embryo either compensates and restores all the damage or it perishes. In the later period (period of organogenesis) exposure to teratogens induces malformations.<br />
====Genetic and interspecies differences====<br />
Genetic background of individuals significantly predisposes the susceptibility towards teratogens. Although intraspecies variability may not be clearly pronounced, certainly significant is than interspecies variability. This assumption is of importance, particularly with respect to the testing of teratogenic effects. While the same dose of the same teratogen is very effective in humans, it may not be effective at all in rodents (for instance resistance of mice towards teratogenic effects of thalidomide).<br />
<br />
[[Category:Genetics]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=Environmental_mutagens_and_teratogens&diff=25937Environmental mutagens and teratogens2017-07-24T14:05:10Z<p>Azrael: Translated from the Czech version of WikiSkripta (6/2017)</p>
<hr />
<div>==Mutagens==<br />
===Physical mutagens===<br />
<br />
Ionizing radiation represents a radiation with shorter wavelength and larger energy in comparison with other type of radiation (X-ray, gamma-ray, cosmic rays). <br />
<br />
Above radiation exhibits high energy and high penetration through the tissues. Ionizing radiation by passing through the tissue colides with atoms with subsequent release of the electrons; along the trace of the radiation free radicals and ions, capable of reacting with biological macromolecules, including DNA, arise (H<sup>+</sup>, OH<sup>-</sup>). Ionizing radiation may directly attack DNA itself. This kind of radiation induces oxidation of DNA bases and disrupts pentose-phosphate bond in DNA helix. Mutagenic effect depends on the amount of arising ions.<br />
Absorbed dose of ionizing radiation is being expressed in Grays [Gy = J/kg].<br />
<br />
Mutagenic effect depends on:<br />
# The dose<br />
# The duration of exposure<br />
# The phase of the cell cycle in the target cell<br />
# The capacity of the DNA repair system<br />
<br />
Ionizing radiation induces gene mutations, chromosomal aberrations and, ultimately, chromosomal translocations. There is no threshold for ionizing radiation, even small quantities may induce mutations. The quantity of radiation, which may duplicate the amount of mutations in humans, is important in genetics for prediction of the risk (especially in the etiology of neoplasia).<br />
<br />
====Ultraviolet radiation====<br />
Damage of DNA molecule induced by UV radiation <br />
UV radiation exhibits lower energy than ionizing radiation, but even UV is capable to cause electron excitation. UV radiation is absorbed by several organic molecules, namely by pyrimidines and purines. UV acts as potent mutagen in unicellular organisms, in more complex organisms it alterates cells on the surface. In humans UV induces or contributes to the induction of skin neoplasia (carcinoma, melanoma). The risk of exposure to UV radiation increases with decreasing ozone content in the atmosphere. UV radiation induces mutations mainly due to generation of hydrated purines and pyrimidine dimers. Thymine alterations are mutagenic due to: a) distortion of DNA double-helical structure hinders the procedure of DNA polymerase along the template with subsequent block of DNA replication; b) in the course of the repair of altered thymines a base mispairing often occurs. The repeated interruption of DNA replication due to thymidine dimers and their incomplete repair cause gaps in newly synthesized DNA chain with subsequent chromosomal breaks. Thymidine dimers may give rise base substitutions and/or deletions.<br />
===Chemical mutagens===<br />
Chemical mutagens are chemicals exerting mutagenic effects. They comprise: a) food stains based on acridine; b) combustion products in cigarette smoke (more than 400 carcinogens and mutagens); c) chemicals in car exhausts; d) monomers in plastics industry (polychlorinated biphenyls, styrene, butadiene, vinyl chloride etc.).<br />
<br />
====Mode of action of chemical mutagens====<br />
# Compounds that are mutagenic only during replication (base analogues and acridine stains).<br />
# Compounds that are mutagenic by attacking DNA unless this is replicated.<br />
# Compounds causing alkylation, deamination and hydroxylation of bases.<br />
<br />
====Base analogues====<br />
These compounds are structurally related to nucleotides and are therefore mis- incorporated into DNA during replication. Their differences in comparison with physiological nucleotides cause base mispairing and mutations. These compounds are employed in investigation of mutagenic processes and as anticancer drugs (2-aminouracil, 5-bromouracil, 5-fluorouracil). <br />
5-bromouracil is analogous to thymin. Br atom replaces methyl group on C5 of pyrimidine and increases a chance of tautomeric shift. If in enol form, 5-BU pairs with guanine. If 5-BU in enol form is incorporated into a new strand, during the following replication 5-BU in keto form pairs with adenine and GC:AT transition arises.<br />
Acridine stains (such as proflavin and acridine blue) induce a shift in the reading frame. Molecules of bases are incorporated in between base pairs and the double-helix conformation of DNA is altered during the replication. During the replication insertion or deletion of one or more bases occurs with all associated phenotype consequences.<br />
====Alkylation compounds ====<br />
Many chemicals may be donors of alkyl groups. Yperit (or its nitroso derivative) was the first reported mutagen. Nitroso guanidine, on the other hand, belongs among the most potent mutagens. Alkylating agents cause mispairing by attaching the functional group (methyl-, ethyl- etc.) to the nucleophilic centers of purines and pyrimidines. Alkylating agents may induce all kinds of mutations and result ultimately in chromosomal aberrations and translocations.<br />
====Deaminating compounds==== <br />
They act via (oxidative) deamination of aminogroup in adenine, guanine and cytosine (as an example: nitrates and nitric acid). Amino- group is converted into keto- group. Deamination alters the ability of bases to form hydrogene bonds. In general, hypoxanthin (deaminated adenine) pairs with cytosine, while uracil pairs with adenine. Deamination results usually in transitions (CG:AT as well as AT:CG). Nitric oxides are generated by combustion of fossil sources and by car exhausts. Nitrates, which are used in canning of smoked meat, are particularly dangerous towards gastrointestinal cells.<br />
====Hydroxylating agents====<br />
May convert cytosin into hydroxy aminocytosine, which pairs with adenine forming CG:AT transition.<br />
<br />
===Biological mutagens===<br />
====Viruses====<br />
In the course of lysogenic cycle viruses may become incorporated into the DNA of the host. Incorporation of virus into the sequence of the gene affects substantially its function, the gene loses its function with subsequent consequences, such as chromosomal breaks, tumors.<br />
====Transposons====<br />
Represent elements capable to transpose from one site of the genome to the other. In human genome there are two classes of transposable elements: LINE (long interspred nuclear element) and SINE (short interspred nuclear element). Their shifts within a genome may have mutagenic effects.<br />
<br />
===Testing of mutagens===<br />
Most mutations negatively affect human health and, additionally, mutagenic compounds are often teratogenic and carcinogenic. Testing of the new compounds for their tentative mutagenic effect is a standard procedure within obligatory atests prior to the compounds is released on market.<br />
====Ames test====<br />
Enables to disclose mutagenic activity, type of the mutations induced and test potential mutagens. For that purpose a special auxotrophic strain ''Salmonela typhimurium'', capable to grow on medium containing histidine, was created. Compounds be tested are added into the medium. By the Ames test we evaluate the emergence of mutations following the transfer on the minimal medium. By adding histidin into the minimal medium the limited amount of cell divisions is allowed and the mutagenic compounds are tested only during the replication. By adding enzymes from liver extract we may stimulate biotransformation of xenobiotics and therefore follow mutagenicity arising after the metabolic activation.<br />
<br />
Currently available scope of methods can test both the mutagenicity and genotoxicity.<br />
<br />
Complex screening for genotoxicity may be carried out on three levels: <br />
# monitoring of environmental pollution;<br />
# monitoring of biological effects (the response of the organism towards genotoxic compounds, exposure levels, effectiveness of the preventive measures); <br />
# genetic monitoring (epidemiological studies regarding spontaneous abortions, incidence of congenital malformations in relation to the genotoxic compounds).<br />
<br />
==Teratogens==<br />
Teratogens are external factors capable to cause (or substantially increase a risk of) congenital malformations. Alike mutagens, teratogens may arbitrarily classified into three major groups: biological teratogens, chemical teratogens and physical teratogens. <br />
<br />
===Classes of teratogens ===<br />
====Biological teratogens ====<br />
Several pathogenic viruses are members of this class. Proven teratogens are following viruses: Rubivirus (rubella), Cytomegalovirus, Herpesviry, Parvovirus B-19, influenza virus, HIV and others, but also bacteria ''Treponema pallidum'' (syphilis) and protozoon ''Toxoplasma gondii'' (toxoplasmosis). Teratogenic risk may also be elevated by serious diseases of the mother, such as diabetes mellitus, phenylketonuria, myasthenia gravis and others.<br />
====Chemical teratogens====<br />
These class of teratogens comprises several industrially and agriculturally employed chemicals (organic solvents, polychlorinated biphenyls, heavy metals etc.). Particularly important group of chemical teratogens is constituted by drugs and medicaments, where prominent teratogens are cytostatics, several antibiotics (namely tetracyclins), antiepileptics (fynytoin, valproate), lithium, warfarin, thalidomide, ACE-inhibitors, steroids, retinoids etc. Teratogenic effects have been spotted in the case of ethyl alcohol (its abuse in gravidity causes foetal alcohol syndrome) and drugs such as pervitin.<br />
====Physical teratogens====<br />
This class of teratogens involves various kinds of radiation (X-rays, gamma-radiation), high temperature and mechanical teratogens .<br />
===Mode of action===<br />
Teratogenic effect has a complex character and a simplification mutagen = teratogen is not applicable. By assessing teratogenic effect we have to take into consideration:<br />
====Factor of the dose====<br />
The dose of the teratogenic agent has a decisive role for its effect. Lower doses may not induce any malformation, or may lead to a moderate or differently located damage.<br />
====Factor of the time====<br />
The sensitivity towards various teratogens is not constant during the pregnancy. In general, the exposure to teratogens during the first trimester of gravidity has the worst prognosis, however, adverse effect exhibits the exposure during the second and third trimester as well. For each teratogen there is so called critical period during which is the fetus most sensitive towards the particular teratogen or during which the target organ/system is most vulnerable. It is not surprising that the effects of the same dose of the same teratogen may be different depending on the phase of gravidity.<br />
Embryo in its early stage of development (embryogenesis) reacts towards teratogens by means All or Nothing. It means that no malformations are fixed within this period; embryo either compensates and restors all the damage or it perishes. In the later period (period of organogenesis) exposure to teratogens induces malformations.<br />
====Genetic and interspecies differences====<br />
Genetic background of individuals significantly predisposes the susceptibility towards teratogens. Although intraspecies variability may not be clearly pronounced, certainly significant is than interspecies variability. This assumption is of importance, particularly with respect to the testing of teratogenic effects. While the same dose of the same teratogen is very effective in humans, it may not be effective at all in rodents (for instance resistance of mice towards teratogenic effects of thalidomide).</div>Azraelhttps://www.wikilectures.eu/index.php?title=Apoptosis_and_Necrosis&diff=25936Apoptosis and Necrosis2017-07-24T13:43:06Z<p>Azrael: Coursebook chapter. Author: Kábelová, A.</p>
<hr />
<div>'''Apoptosis''' is a highly regulated cellular process leading to elimination of excessive, damaged, or unwanted cells. Apoptosis is a physiological mechanism that occurs in multicellular organisms during their ontogenesis, it has also important role in the maturity and it is considered as a type of programmed cell death (PCD) termed PCD-I. The term “apoptosis” is derived from the Greek word describing the falling off of leaves from tree.<br />
<br />
==Apoptosis vs. necrosis== <br />
Apoptosis is an active (requires energy from ATP hydrolysis) and genetically programmed process leading to cell death, that is carried out by proteolytic enzymes called caspases. It can also be characterized by distinct morphological changes. These include chromatin condensation followed by its clustering in cell nucleus periphery, chromosomes loosing from nucleus membrane and activation of endonucleases. Activated endonucleases cleave DNA that takes place between nucleosomes resulting in formation of 180 bp-long DNA fragments and other multiplies of this length. These DNA fragments characteristically organize in electrophoretic gel according to a certain molecular weight to form a typical DNA-ladder (see picture). Cell nucleus, other membrane organelles, and cytoskeleton are degraded and enclosed by cell membranes. The cell connections are disrupted, apoptotic cell is separated from neighboring cells and shrinks. Eventually, the plasmatic membrane forms blebs and the cell breaks up into small membrane-bound fragments termed apoptotic bodies. Apoptotic bodies contain structurally intact cell-like organelles as well as portions of the nucleus and other membrane organelles. Subsequently, the apoptotic bodies are quickly recognized and removed by the process of phagocytosis by neighboring cells without causing an inflammatory reaction.<br />
<br />
Compared to apoptosis, the process called necrosis is pathological and accidental mode of cell death. It is a passive (does not need energy from ATP hydrolysis), more chaotic, unplanned and non-programmed type of cell death. It typically mediates cell demise in response to sudden and irreversible cell damage (hyperthermia, hypoxia, detergents, toxic substances or direct cell trauma) and it does not occur during normal development. Mechanistically, necrosis is typically not regulated by Bcl-2 family proteins and its progression is independent on caspases activity. During necrosis, the cells lose the integrity of plasmatic membrane and absorb extracellular fluid, which causes irreversible swelling of the cytoplasm and organelles. Finally, plasmatic membrane ruptures and noxious cell content pours out into extracellular matrix. The rest of necrotic cells is not targeted by phagocytes and engulfed, so the cell content can spread quickly throughout the body and cause immediate reactions in surrounding tissues, leading to local inflammation response accompanied with edemas or even to systemic response. The main differences in the process of apoptotic and necrotic cell death are summarized in Table 1.<br />
Moreover, under some pathological conditions both types of cell death may be found and both pathways can switch between each other (e. g. the cell death begins as the apoptosis but due to the lack of energy or caspase mutation cannot be finished, so the necrotic pathway turns on and accomplishes the process of cell death. The decision of the cell to die by necrosis or apoptosis depends largely on the severity of the insult.<br />
<br />
==The role of apoptosis in health and disease==<br />
Apoptosis is a physiological, genetically programmed process that takes part especially in ontogenesis but also in postnatal development of multicellular organisms. It participates in elimination of cells that could be potentially harmful to organisms. It also has an important role in morphogenesis and in maintaining a natural balance between cell proliferation and cell death - tissues homeostasis. Dysregulations of the apoptotic pathway, can cause developmental disorders and many health complications. <br />
<br />
===Apoptosis in ontogenesis===<br />
A general principle of development in human embryogenesis is emerging: excess numbers of cells are made, and then surplus or unwanted cells are removed by apoptosis during the formation of functional organs development and gamete formation. Apoptosis is one of key mechanisms responsible for proper gamete (spermatozoid and oocyte) maturation and embryonic development. <br />
As for morphogenesis, massive apoptosis can be found e.g. at bodies’ cavity forming during human ontogenesis. Another example represents development of fingers. First, there is form like a spade and individual fingers are created when cells between them die by apoptotic cell death. Ineffective apoptosis induction results in syndactyly, which is a disease when fingers are not properly separated. It can be either genetically determined (90% of cases) or caused by teratogens.<br />
<br />
Next, apoptosis also eliminates other structures that are no longer needed, such as tale in tadpole during its transformation to frog. Similarly, differentiation of male and female genital is also strictly dependent on apoptosis. In early embryo, both genitals basis Müllerian and Wolffian ducts are firstly formed. In the men, the production of anti-Müllerian hormone by Sertoli cells in the testes leads to atrophy of the Müllerian ducts, while in women the absence of this hormone causes apoptotic degradation of Wolffian ducts.<br />
<br />
Apoptosis has also a very important role in T-lymphocytes maturation in thymus. Newly derived T-lymphocytes are exposed to a wide variety of self-antigens and undergo two types of selection - positive and negative selection. During the negative selection auto-reactive T-lymphocyte cells, having receptors interacting with own molecules (that are potentially dangerous to organism), are removed by apoptosis. T-lymphocytes that binds too weakly to self-HLA antigens undergo apoptosis too; this process is called positive selection. Both selections finally result in remaining only of those cells which carry adequate affinity to HLA molecules. The positive and negative selections lead to death of almost 95% of T-lymphocytes. <br />
<br />
Neural apoptotic cell death has a pivotal role in both the development and pathophysiology (see chapter) of the nervous system. In the developing nervous system apoptosis is observed as early as neural tube formation and persists throughout terminal diferentiation of the neural network. More than 50% of neurons are lost during development as a result of limiting trophic support from the target tissue they are destined to innervate. <br />
<br />
Besides described situations, apoptosis is also necessary in development of kidneys, heart, lungs and teeth thus we can even consider this to be as important for proper embryo development as cell proliferation and cell differentiation.<br />
<br />
===Apoptosis in adult organisms===<br />
In humans is the process of apoptosis in balance with cell proliferation to maintain the constant number of cells in various tissues and thus prevent growing and shrinking of organs (see picture). In mature organisms keeps apoptosis its function in tissues responding cyclically to hormones changes (endometrium, prostate, breast cells). It is also necessary in elimination of senescent or damaged cells in renewing tissues and cell systems as intestinal epithelium, skin epithelium, bone marrow, red blood cells etc. Very important role of apoptosis is in elimination of damaged, infected, and mutated cell, which can potentially lead to pathology, e. g. to tumor development.<br />
<br />
Apoptosis also has an important role in immune response as it is essential for the T-lymphocyte activity. First, T-lymphocyte is activated and it begins to overexpress Fas ligand (FasL) on its plasma membrane. Next, the lymphocyte kills target cells mentioned above by the activation of death receptor pathway. It starts by binding of Fas receptor on the target cell with FasL on the T-lymphocyte, which enables the forming of the death-induced signaling complex (DISC), recruitment of procaspases 8 and 10 and their activation (see chapter). Besides, apoptosis is also observed in mature peripheral T-lymphocyte, to downregulate the number of reactive cells and to terminate the immune response. <br />
Moreover, apoptosis often occurs in B-lymphocytes during their activation. The activated B-lymphocyte requires the signal from helper T-lymphocyte to initiate the formation of immunoglobulin. In case B-lymphocyte does not receive this signal it can undergo apoptosis. This process ensures that there will not be produced any needful antigens in case of stimulation of B-lymphocyte by some accidental antigen which was not detected by T-lymphocyte. <br />
<br />
===Apoptosis associated with diseases===<br />
Too little or too much apoptosis, or apoptosis occurring in the wrong place and/or at the wrong time can result in pathology including autoimmune diseases, viral and bacterial infections, neurodegenerative, and cardiovascular disorders, or cancer. Furthermore, dysregulated apoptosis signaling may impinge on other age-related disorders such as osteoporosis, atherosclerosis and perhaps on the process of aging itself. <br />
<br />
Recently, these findings have led to the development of therapeutic approaches based on regulation of apoptosis, some of which are in clinical trials or have entered medical practice.<br />
<br />
====Cancer====<br />
Apoptosis prevents malignant transformation whereas decreased apoptosis can predispose human to cancer. Based on the role of apoptosis in maintaining tissue homeostasis, it is not surprising that alterations of apoptosis play an important role in cancer development, including hyperplasia, neoplastic transformation, tumor expansion, neovascularization, and metastasis. Moreover, defects in the apoptotic pathways are responsible for resistance of cancer cells to cancer therapy. New therapeutic approaches are very often attempting to re-activate these pathways bypassing the apoptotic block. <br />
Deregulations of apoptotic pathway leading to its decrease and thus cancer cell survival can result from modulation of the activity of various proteins (inhibiting the activity of tumor suppressor genes, such as Rb and p53 or increasing the activity of proto-oncogenes, such as Bcl-2, Fos and Myc). For example, mutations in r p53 protein are the most common chromosomal aberrations in human cancer. On the other hand, decreased activation of proapoptotic Bcl-2 members, such as Bax or Bak can be found in cancers cells too. In addition, there are often mutations in genes encoding caspases or proteins that regulate caspases activity such as IAPs, Apaf-1, or Smac (see below). <br />
<br />
====Neurological diseases====<br />
Apoptosis plays a key role in central and peripheral nervous system development and up to 50% of neurons die before embryonic development is complete (see above). It has become apparent that excessive or inadvertent apoptosis also plays role in the pathogenesis of several diseases, including neurodegenerative diseases and acute injury. Unnaturally high rate of apoptosis is typical for the pathogenesis of Alzheimer’s, Parkinson’s and Huntington’s diseases, spinal muscular atrophy or amyotrophic lateral sclerosis. <br />
<br />
====Autoimmune disease====<br />
A common feature of autoimmune diseases is altered tolerance to self-antigens and generation of autoantibodies. Immune homeostasis and maintenance of immune tolerance are strongly dependent on apoptosis, moreover defective clearance of dying cells results in persistence of auto antigens, therefore autoimmune diseases can arise both from defective clearance of auto reactive cells or by delayed elimination of auto antigens.<br />
<br />
The activation of T-lymphocyte is known to lead to the upregulation of Fas receptor and Fas ligand and to the susceptibility of these cells to Fas-mediated killing (so called AICD). AICD is essentially a mechanism for switching off the immune response and serves to limit the intensity of immune responses. Some chronic inflammatory disease, such as asthma, could result from an escape of activated T-lymphocytes from Fas/Fas ligand-mediated cell death. This indicates that accelerated induction of apoptosis in T-lymphocyte can limit auto antigen-driven immune response and could be a novel strategy for the treatment of autoimmune disease.<br />
<br />
====Infectious diseases====<br />
Pathogenic microorganisms (bacteria, protozoa) and viruses, once present inside a host must avoid their detection and destruction. Several pathogens can trigger or inhibit apoptosis in eukaryotic host cells thus escaping the activity of immune system. On the other hand, the host can use apoptosis to defend himself from spreading of pathogens. Thus apoptosis has a fundamental role in intracellular pathogen propagation.<br />
<br />
Considering viral infection, it causes induction of apoptosis in the host cell in normal conditions by the recognizing of the virus in the cell by immune system. The elimination of the host cell by the apoptotic process reduces production and spreading of new virions and it represents a key defense mechanism preventing viral propagation. Viruses have therefore developed several strategies to inhibit or delay apoptotic cell death. For example, adenoviruses in the host cell produce a protein E1B 19K, a viral homologue of anti-apoptotic protein Bcl-2. Next, another adenovirus protein termed RID (receptor internalization and degradation) mediates internalization of the cell surface Fas and subsequent destruction inside lysosomes, which allow cells to resist Fas-mediated death and promote survival of the virus.<br />
<br />
On the other hand, some pathogens, especially bacteria induce apoptosis to kill cells of the immune system. For example macrophage undergo apoptosis upon infection with Salmonella, Shigella or Yersinia. It has been implicated that the induction of macrophage death is important to initiate infection, promotes bacterial survival and to enable escape from the host immune responses. <br />
<br />
==The course of apoptosis==<br />
The process of apoptosis can by divided in several stages that include:<br />
# receiving an apoptotic signal that <br />
# turning on the cascade of intracellular activities leading to cell decomposition and apoptotic bodies formation, which are eventually <br />
# removed by phagocytosis.<br />
<br />
===Apoptotic signal===<br />
Apoptosis is regulated by three fundamentals different pathways. First, many cells in multicellular organisms require specific signals from other cells to stay alive. This mechanism ensures cell proliferation and survival only in the right time and the right place. In the absence of such survival signals, often referred to as trophic factors, these cells activate apoptotic program. Next way is receiving of specific signal that induce apoptosis in particular cell. Besides these two physiologically regulated initiations of apoptotic pathway, apoptosis can be triggered by many other non-physiological conditions, including DNA damage caused by radiation or chemical substances, oxidative stress, hypoxia or by presence of foreign agents in cytosol (bacteria, viruses, toxic substances). According to extra or intracellular origin of apoptotic signals we can distinguish apoptosis stimuli to two different apoptotic signaling pathways leading to cell death - intrinsic or extrinsic apoptotic pathway. <br />
<br />
===The extrinsic pathway of apoptosis===<br />
The extrinsic apoptotic pathway is triggered by extracellular apoptosis stimuli, particularly by specific ligands binding to so called death receptors, or receptors with death domain, (DRs). DRs are members of the tumor necrosis factor (TNF) superfamily and include Fas (see above, also called CD95 and Apo1), TNF receptor-1 (TNFR1), TNF-related apoptosis-inducing ligand receptor 1 (TRAIL-R1, also called DR4) and receptor 2 (TRAIL-R2, also called DR5). These receptors are characterized by the presence of up to six cysteine-rich domains (CRD), that define their ligand specificity and by the presence of death domain (DD) in their C-terminal intracellular tail, which is essential for apoptosis induction. The binding of specific ligands (Fas ligand, TNF, TRAIL) to the death receptor causes its homodimerization and recruitment of adapter proteins, e. g. FADD, to the DD. Adapter proteins causes the recruitment of inactive procaspase-8 or -10 to the intracellular site of DRs and its dimerization and activation. Active initiator caspases-8 and -10 can then cleave and activate executioner caspases-3, -6 and -7. <br />
===The intrinsic apoptotic pathway ===<br />
The intrinsic apoptotic pathway is activated in response to cellular stress induced by many stimuli such as oxidative stress, hypoxia, DNA damage, accumulation of unfolded proteins, cytoskeletal disruption, but also growth factors deprivation, and many others. This pathway is also known as mitochondrial apoptotic pathway because it depends on pro-apoptotic factors released from mitochondria that subsequently activate caspases. <br />
The intrinsic and extrinsic apoptotic pathways are not orchestrated separately, but they rather cooperate and complement with each other to amplify the apoptotic signal. <br />
====Bcl-2 family proteins====<br />
Initiation of intrinsic apoptotic pathway is regulated by Bcl-2 (B-cell lymphoma) family proteins that count at least fifteen different members in mammalian cells. These proteins can be divided in the two antagonistic groups according to their function in apoptosis induction. Bax, Bak, Bid or Bim are pro-apoptotic Bcl-2 proteins, while Bcl-2, Bcl-xL, or Mcl-2 have anti-apoptotic function. <br />
Bcl-2 family members possess up to four conserved α-helical domains, designated BH1, BH2, BH3 and BH4. Pro-apoptotic Bcl-2 family proteins differ in numbers of BH (Bcl-2 homology) domains and can be divided into multi-domain proteins having three domains and BH3-only proteins, anti-apoptotic Bcl-2 family proteins are all multi-domain having four domains. Some of these proteins also contain hydrophobic helical transmembrane domain on their C-terminal for anchoring these proteins to cellular membranes (see picture). <br />
<br />
Bcl-2 family proteins activity can be regulated by phosphorylation mediated by cell kinases. Very important way of regulation is also carried out by homodimeric or heterodimeric interactions of individual members belonging to this protein family that are performed by their BH domains. Concurrent inhibition of the activity of anti-apoptotic Bcl-2 proteins and increased activation of pro-apoptotic Bcl-2 proteins is a key mechanism in initiation of intrinsic apoptotic pathway. <br />
<br />
====The role of mitochondria in the intrinsic apoptotic pathway====<br />
The Bcl-2 family proteins are primarily involved in the regulation of mitochondrial membrane integrity. When apoptotic signaling inactivates anti-apoptotic Bcl-2 proteins, it then enables activation of pro-apoptotic Bcl-2 proteins (Bax, Bak). Activated Bax and Bak increase the permeabilization of the outer leaf of membrane leading to decrease of mitochondrial membrane potential by opening of permeability transition pore (PTP) or by pores made directly of pro-apoptotic proteins Bax and Bak.<br />
Increased permeability of mitochondrial membrane leads to the translocation of proapoptotic molecules (cytochrome c and SMAC/Diablo) from intermembrane space of mitochondria to cytosol and facilitates progress of the apoptotic cascade.<br />
Cytochrome c is probably most important protein released from mitochondria. It can be found in intermembrane space of mitochondria to be essential component of the electron transport chain. During apoptosis, translocated cytochrome c, protein Apaf-1, dATP and procaspase-9 form a heptameric complex called apoptosome and allows auto-cleavage and activation of procaspase-9. <br />
<br />
====Caspases====<br />
Caspases are the executive proteins that play key role in both intrinsic and extrinsic apoptotic pathways. They belong to the family of endoproteases that hydrolyze peptide bonds. They have cysteine residue in their active site and the cleavage occurs only after aspartic acid residues present in their substrate. At the time, it is known at least fifteen different caspases in mammals. <br />
Caspases involved in apoptosis can be divided into two groups: initiator caspases, (caspase-9, -8 and -10) and executioner caspases (caspase-3, -6 and -7). The main function of initiator caspases is to cleave and thus activate the executioner caspases. As to executioner caspases, once activated, they can cleave death substrates Death substrates are proteins that ensure cell compactness such as proteins of nuclear lamina, cytoskeletal proteins, or inhibitors of endonucleases cleaving DNA to fragments (described above). Briefly to the caspase-driven cascade, one molecule of activated executioner caspase can activate other molecules of executioner as well as initiator caspases, leading to an accelerated feedback loop of caspase activation. <br />
<br />
Caspase-3 is most important executioner caspase responsible for activation of essential enzyme CAD (Caspase-activated DNase). CAD is normally inhibited by death substrate ICAD (Inhibitor of caspase-activated DNase), after its cleavage by caspase-3 CAD is activated. This protein breaks up the DNA during apoptosis at inter-nucleosomal linker sites between nucleosomes. <br />
Executioner caspases-3 and -7 have a similar substrate specifity and are partially replaceable. Categorization of caspases-1, -2, -4, -5 and -12 is still somehow unclear, they can for instance participate in forming of pro-inflammatory cytokines during inflammatory response (see picture).<br />
<br />
Caspases are initially produced as inactive monomeric zymogenes, termed procaspases. Activation of caspases is strictly regulated and occurs only during apoptosis, because the process of apoptosis is irreversible from the point, when caspases are activated. Dimerization of procaspases followed by auto-cleavage represents basal way of regulation of their activation. Caspase activity can be also regulated by IAP (Inhibitors of apoptosis) family proteins (XIAP, cIAP survivin, livin), that bind and inactivate caspases, which finally blocks progression of apoptosis. Interestingly, regulatory mitochondrial proteins SMAC/Diablo and HTRA2/Omi bind proteins from the IAP family and neutralize their inhibiting function and thus progression of apoptosis. <br />
<br />
====The role of endoplasmic reticulum in intrinsic apoptotic pathway====<br />
Except of mitochondria, endoplasmic reticulum (ER) is another cell organelle which can participate significantly in activation of intrinsic apoptotic pathway. In ER, the apoptotic signal leads to accumulation of unfolded or misfolded proteins, which in turn activate the signaling pathway called UPR (unfolded protein response). During UPR, the expression of proteins that can help proteins to maintain their native structure and thus restore the function of ER is increased in cells. When the ER damage is irreversible, the Ca2+ translocate from the ER lumen to cytosol Releasing Ca2+ from the ER can be regulated by Bcl-2 family proteins too, especially by inactivated protein Bcl-2, that can stimulate opening of channels linked to inositol-1,4,5-triphosphate receptor (IP3R) and release Ca2+ ions. The dimer of pro-apoptotic proteins Bax and Bak can also directly penetrate ER membrane to form pores. Cytosolic Ca2+ can subsequently stimulate the translocation of proapoptotic molecules to cytosol or activate Ca2+-dependent enzymes (caspase-4, -12, calpain) which can finally activate apoptotic pathway.<br />
Cytochrome c or caspase-3 activated in the intrinsic apoptotic pathway can also stimulate the release of Ca2+ from ER to amplify the apoptotic signal in cells. <br />
<br />
===Elimination of the apoptotic cell ===<br />
Apoptotic bodies formed in the final stages of apoptosis change plasmatic membrane composition and display phagocytogenic molecules, such as phosphatidylserine, on their cell surface. In physiological condition, phosphatidylserine is strictly localized in the inner leaf of the plasma membrane. During apoptosis, phosphatidylserine is redistributed to the outer leaf of the plasmatic membrane by an enzyme known as scramblase. The cells labeled by phosphatidylserine are then quickly recognized by phosphatidylserine receptor on the phagocyte cells and are engulfed by neighboring cells, macrophages or other phagocyting cells without causing an inflammatory response. The removal of apoptotic cells by neighboring phagocyting cells is sometimes termed efferocytosis. <br />
<br />
==Links==<br />
===References===<br />
*{{Cite<br />
| type = academic_publication<br />
| surname1 = KÁBELOVÁ<br />
| name1 = Adéla<br />
| source_name = Úloha autofagie a vybraných izotypů beta-tubulinu v rezistenci k taxanům u nádorových linií prsu<br />
| location = Praha<br />
| institute = Univerzita Karlova, Přírodovědecká fakulta, Katedra buněčné biologie<br />
| year = 2015<br />
}}<br />
*{{Cite<br />
| type = article<br />
| surname1 = Cohen<br />
| name2 = G M<br />
| article = Caspases: the executioners of apoptosis<br />
| journal = Biochem J<br />
| year = 1997<br />
| volume = 326 ( Pt 1)<br />
| pages = 1-16<br />
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1218630/?tool=pubmed<br />
| issn = 0264-6021<br />
}}<br />
*{{Cite<br />
| type = article<br />
| surname1 = Elmore<br />
| name2 = Susan<br />
| article = Apoptosis: a review of programmed cell death<br />
| journal = Toxicol Pathol<br />
| year = 2007<br />
| number = 4<br />
| volume = 35<br />
| pages = 495-516<br />
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2117903/?tool=pubmed<br />
| issn = 0192-6233<br />
}}<br />
*{{Cite<br />
| type = article<br />
| surname1 = Favaloro<br />
| name2 = Bartolo<br />
| surname2 = Allocati<br />
| name2 = Nerino<br />
| surname3 = Graziano<br />
| name3 = Vincenzo<br />
| others = yes<br />
| article = Role of apoptosis in disease<br />
| journal = Aging Albany NY<br />
| year = 2012<br />
| number = 5<br />
| volume = 4<br />
| pages = 330-49<br />
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3384434/?tool=pubmed<br />
| issn = 1945-4589<br />
}}<br />
* {{Cite<br />
| type = article<br />
| surname1 = Meier<br />
| name2 = P<br />
| surname2 = Finch<br />
| name2 = A<br />
| surname3 = Evan<br />
| name3 = G<br />
| article = Apoptosis in development<br />
| journal = Nature<br />
| year = 2000<br />
| number = 6805<br />
| volume = 407<br />
| pages = 796-801<br />
| url = http://www.ncbi.nlm.nih.gov/pubmed/11048731<br />
| issn = 0028-0836<br />
}}<br />
[[Category:Genetics]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=Apoptosis,_genetic_control_and_importance_in_development&diff=25935Apoptosis, genetic control and importance in development2017-07-24T13:32:56Z<p>Azrael: redirect</p>
<hr />
<div>#REDIRECT [[Apoptosis]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=Apoptosis,_clinical_outcomes_of_its_dysregulation&diff=25934Apoptosis, clinical outcomes of its dysregulation2017-07-24T13:32:46Z<p>Azrael: redirect</p>
<hr />
<div>#REDIRECT [[Apoptosis]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=Autosomal_recessive_inheritance_in_pedigree_and_experiment,_examples_of_traits_in_man&diff=25933Autosomal recessive inheritance in pedigree and experiment, examples of traits in man2017-07-24T13:27:55Z<p>Azrael: typo</p>
<hr />
<div>===Characteristics of AR pedigrees===<br />
*the trait is often found in clusters of siblings but not in their parents and offspring <br />
*males and females are equally likely to be affected (in a population, equally, the proportion of affected males should be equal to the proportion of affected females)<br />
*parents could be relatives (the couple related by blood, such as first cousins)<br />
<br />
===Examples of pedigrees===<br />
[[File:AR-Pedigrees.jpg]]<br />
<br />
===AR disease/trait examples===<br />
*Cystic fibrosis (mucoviscidosis), <br />
*phenylketonuria,<br />
*sickle cell anemia,<br />
*albinism.<br />
<br />
===Important about AR inheritance in pedigree===<br />
[[File:Autosomal recessive inheritance.jpg|Monohybridism (hybridization experiment) in AR inheritance|thumb|right]][[File:AR experiment.jpg|thumb|right]] [[File:AR backcross.jpg|thumb|right]] <br />
All individuals with the defect/disease in pedigrees (and in population) are homozygotes of recessive defective (deleterious, nonactive, affected, mutated etc.) alleles, aa. Two copies of a disease allele are needed for an individual to express the phenotype. The parents of an affected (suffering with an AR disease) individual are healthy (not affected by this AR disease) but are disease carriers. <br />
Typically, once a child in a family is born with AR trait/disease we may suppose parents as carriers (heterozygotes Aa) and there is a 25% (1/4) chance (probability, risk) that anyone next offspring will inherit two copies of the disease allele and will therefore have the disease phenotype. N.B.: There is a 50% (1/2) chance that the offspring of carrier parents will inherit one copy of the disease allele and will be a carrier, and there is a 25% probability the offspring will inherit healthy (normal, wild-type etc.) allele from both parents (will be a homozygote AA) and will not express the disease phenotype or be a disease carrier. This AA individual would not be at risk for passing the disorder on to his/her offspring.<br />
<br />
Many AR diseases (disorders) are seen more frequently in individuals of certain ethnic origin than others because these individuals are descendants of the same ancestors. However, because these common ancestors are generally more distantly related to these individuals, couples of the same ethnic background would generally have fewer genes in common than consanguineous couples<br />
<br />
===AR inheritance in hybridization experiment===<br />
In experimental procedure, pure lines (e.g. inbred strains) are choosen showing difference in a character (purple versus white flowers, yellow versus green seeds/pies, colour versus albino coat/fure). Parental generation pairs are formed combining one individual from one and an individual from the other line. They are crossed for obtaining F1 hybrids, these are phenotypically uniform, all expressing one or the other form of the trait (character). By intercrossing the F1 individuals the F2 generation is obtained, where phenotypes are segregating in ratio 3 to one (one vs. the other form of the trait). This 1/4 correspond to recessive phenotype (not seen in the uniform F1 generation) and, retrospectively, also allow to decide which one line (strain) in P generation expressed the recessive form of the trait. <br />
<br />
In a general population with uniform (wild) phenotype, an individual with an exceptional (newly appearing) form of the phenotype can be tested by hybridization experiment, too, if he/she/it express the dominant or recessive form of the trait. <br />
<br />
If this new, different form of a trait is recessive (i.e. new phenotype individual is a homozygote nn), then this hybridization test (crossing with any individual with normal, common, wild phenotype in the population) represents de facto: <br />
<br />
# most probably, a parental cross (wild phenotype individual is a homozygote NN) which leads to uniform (F1) hybrids expressing the wild phenotype, or <br />
# rarely, a backcross (in case that the wild phenotype individual is a hidden, “silent” heterozygote Nn) resulting in phenotypic ratio 1 to 1 .<br />
<br />
'''Experimental cross''' in a population (AR inheritance) – new, spontaneous mutant is recessive homozygote, and wild-type phenotype individuals are (most probably) dominant homozygotes<br />
<br />
<br />
'''Backcross''' (experimental test-cross) in AR inheritance – rarely, wild-type phenotype individuals are heterozygotes (by the way, they had to be at least two of them, of opposite gender in preceding generation of the population; it is the only way how a homozygote recessive could appear in the present generation of the population)<br />
<br />
<br />
[[Category:Genetics]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=Autosomal_dominant_inheritance_in_pedigree_and_experiment,_examples_of_traits_in_man&diff=25932Autosomal dominant inheritance in pedigree and experiment, examples of traits in man2017-07-24T13:27:44Z<p>Azrael: typo</p>
<hr />
<div>===Characteristics of AD pedigrees===<br />
*direct transmission from an affected parent to an affected child (= does not skip generations) <br />
*males and females are equally likely to be affected<br />
*both males and females transmit the disease<br />
*transmission from father to son<br />
===Examples of pedigrees===<br />
[[File:AD-Pedigrees.jpg]]<br />
<br />
===Examples===<br />
[[File:Autosomal dominant inheritance.jpg|thumb|right]][[File:Backcross in AD.jpg|thumb|right]]<br />
*achondroplasia,<br />
*brachydactyly,<br />
*polycystic kidney disease,<br />
*familial hypercholesterolemia,<br />
*dentinogenesis imperfecta, <br />
*osteogenesis imperfecta,<br />
*dysostosis cleidocranialis<br />
<br />
;Important about AD inheritance in pedigree (!!)<br />
'''Many, maybe majority of human traits/diseases with AD inheritance (e.g. dysmorfogenetic syndromes), are AD but with incomplete dominance. Thus, all individuals with the defect/disease in pedigrees (and in population) are heterozygotes Aa. The defect/disease is much more severe in homozygous individuals (AA), often with lethal effect in homozygous fetuses.''' <br />
<br />
===AD inheritance in hybridization experiment===<br />
In experimental procedure, pure lines (e.g. inbred strains) are chosen showing difference in a character (purple versus white flowers, yellow versus green seeds/pies, colour versus albino coat/fure). Parental generation pairs are formed combining one individual from one and an individual from the other line. They are crossed for obtaining F1 hybrids. By intercrossing the F1 individuals the F2 generation is obtained, where phenotypes are segregating in ratio 3 to one (dominant vs. recessive form of the trait). These 3/4 are corresponding to phenotype of F1 hybrids – the F1 generation express the dominant form of the trait as well. <br />
<br />
In a general population with uniform (wild) phenotype, an individual with an exceptional (newly appearing) form of the phenotype can be tested by hybridization experiment, too, if he/she/it express the dominant or recessive form of the trait. If this new, different form of a trait is dominant, then this hybridization test (crossing with anyone individual with normal, common, wild phenotype in the population) represents de facto a backcross repeatedly resulting in phenotypic ratio 1 to 1.<br />
<br />
[[Category:Genetics]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=Gonosomal_inheritance_in_pedigree_and_experiment,_examples_of_traits_in_man&diff=25931Gonosomal inheritance in pedigree and experiment, examples of traits in man2017-07-24T13:27:28Z<p>Azrael: Coursebook chapter. Author: Panczak, A.</p>
<hr />
<div>'''Two subtypes:'''<br />
*gonosomal (X-linked) recessive, GR<br />
*gonosomal (X-linked) dominant, GD<br />
<br />
==Gonosomal recessive - GR==<br />
===Characteristics of GR pedigrees===<br />
*males are much more likely to be affected <br />
*affected males get the disease from their mothers – healthy carriers <br />
*no transmission from father to son<br />
*transmission from an affected grandfather to his grandsons <br />
<br />
===Examples of GR pedigrees===<br />
[[File:XL-pedigrees.jpg]]<br />
<br />
===GR disease/trait examples===<br />
*hemophilia A, hemophilia B,<br />
*Duchenne muscular dystrophy,<br />
*color blindness,<br />
*anhidrotic ectodermal dysplasia<br />
<br />
==Gonosomal dominant - GD==<br />
<br />
===Characteristics of GD (X-linked Dominant) pedigrees===<br />
*Only one copy of a disease allele on the X chromosome is required (and sufficient) for an individual to be susceptible to an X-linked dominant disease <br />
*Both males and females can be affected, although males may be more severely affected because they only carry one copy of genes found on the X chromosome <br />
*Some X-linked dominant disorders are (even) lethal in males (in male fetuses).<br />
*When a female is affected, each pregnancy will have a one in two (50%) chance for the offspring to inherit the disease allele. <br />
*When a male is affected, all his daughters will be affected, but none of his sons will be affected.<br />
*Transmission from an affected grandfather to his grandsons <br />
<br />
===GD disease examples===<br />
*vitamin D-resistant (hypophosphatemic) rickets,<br />
*incontinentia pigmenti,<br />
*Alport syndrome,<br />
*amelogenesis imperfekta (X-linked)<br />
<br />
<br />
==X linked inheritance in hybridization experiment ==<br />
===The white (w) locus in Drosophila===<br />
A single white-eyed male fly was isolated in the laboratory of T. H. Morgan in 1910, and they studied genetic crosses using this white mutant.<br />
<br />
# When the white male was crossed to wild type (i.e. red-eyed) females, all the progeny were red-eyed. From it they concluded the white mutation was recessive.<br />
# When the F1 generation members were crossed with one another, 1/4 of the (F2) progeny were white- eyed. But … The white phenotype was only seen in males.<br />
<br />
;Schedule is explaining the experimental procedure:<br />
Supposed the white gene is located on the X chromosome, the original male is hemizygous for w allele (genotype XwY). The original cross is represented as XwY x X+X+, and all progeny are wild-type in phenotype.<br />
<br />
[[File:XL-experiment1.jpg]]<br />
<br />
If F1 siblings are now crossed, X+Y x XwX+, all females are phenotypically normal, and 1/2 of the males are white (1/4 of total progeny) in F2 generation.<br />
<br />
[[File:XL-experiment2.jpg]]<br />
<br />
In a backcross (Bc), when white males are crossed to heterozygous females, XwY x XwX+, equal numbers of white males and females are observed in the progeny; 1/2 progeny are white-eyed.<br />
<br />
[[File:XL-experiment3.jpg]]<br />
<br />
In reverse backcross, when white females are crossed to wild-type males, XwXw x X+Y, white female parents give rise to white progeny males.<br />
<br />
[[File:XL-experiment4.jpg]]<br />
[[Category:Genetics]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=File:XL-experiment4.jpg&diff=25930File:XL-experiment4.jpg2017-07-24T13:26:00Z<p>Azrael: {{File
|description = X-linked inheritance - experiment
|source = Archive of Aleš Panczak, MD
|date = 2017-07-24
|author = Aleš Panczak, MD
|license = {{cc|by-sa|3.0}}
}}
Category:Genetics
Category:Images</p>
<hr />
<div>{{File<br />
|description = X-linked inheritance - experiment<br />
|source = Archive of Aleš Panczak, MD<br />
|date = 2017-07-24<br />
|author = Aleš Panczak, MD<br />
|license = {{cc|by-sa|3.0}}<br />
}}<br />
[[Category:Genetics]]<br />
[[Category:Images]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=File:XL-experiment3.jpg&diff=25929File:XL-experiment3.jpg2017-07-24T13:25:28Z<p>Azrael: {{File
|description = X-linked inheritance - experiment
|source = Archive of Aleš Panczak, MD
|date = 2017-07-24
|author = Aleš Panczak, MD
|license = {{cc|by-sa|3.0}}
}}
Category:Genetics
Category:Images</p>
<hr />
<div>{{File<br />
|description = X-linked inheritance - experiment<br />
|source = Archive of Aleš Panczak, MD<br />
|date = 2017-07-24<br />
|author = Aleš Panczak, MD<br />
|license = {{cc|by-sa|3.0}}<br />
}}<br />
[[Category:Genetics]]<br />
[[Category:Images]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=File:XL-experiment2.jpg&diff=25928File:XL-experiment2.jpg2017-07-24T13:25:00Z<p>Azrael: {{File
|description = X-linked inheritance - experiment
|source = Archive of Aleš Panczak, MD
|date = 2017-07-24
|author = Aleš Panczak, MD
|license = {{cc|by-sa|3.0}}
}}
Category:Genetics
Category:Images</p>
<hr />
<div>{{File<br />
|description = X-linked inheritance - experiment<br />
|source = Archive of Aleš Panczak, MD<br />
|date = 2017-07-24<br />
|author = Aleš Panczak, MD<br />
|license = {{cc|by-sa|3.0}}<br />
}}<br />
[[Category:Genetics]]<br />
[[Category:Images]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=File:XL-experiment1.jpg&diff=25927File:XL-experiment1.jpg2017-07-24T13:24:07Z<p>Azrael: {{File
|description = X-linked inheritance - experiment
|source = Archive of Aleš Panczak, MD
|date = 2017-07-24
|author = Aleš Panczak, MD
|license = {{cc|by-sa|3.0}}
}}
Category:Genetics
Category:Images</p>
<hr />
<div>{{File<br />
|description = X-linked inheritance - experiment<br />
|source = Archive of Aleš Panczak, MD<br />
|date = 2017-07-24<br />
|author = Aleš Panczak, MD<br />
|license = {{cc|by-sa|3.0}}<br />
}}<br />
[[Category:Genetics]]<br />
[[Category:Images]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=File:XL-pedigrees.jpg&diff=25926File:XL-pedigrees.jpg2017-07-24T13:15:03Z<p>Azrael: {{File
|description = X-linked inheritance - Pedigrees
|source = Archive of Aleš Panczak, MD
|date = 2017-07-24
|author = Aleš Panczak, MD
|license = {{cc|by-sa|3.0}}
}}
Category:Genetics
Category:Images</p>
<hr />
<div>{{File<br />
|description = X-linked inheritance - Pedigrees<br />
|source = Archive of Aleš Panczak, MD<br />
|date = 2017-07-24<br />
|author = Aleš Panczak, MD<br />
|license = {{cc|by-sa|3.0}}<br />
}}<br />
[[Category:Genetics]]<br />
[[Category:Images]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=Autosomal_recessive_inheritance_in_pedigree_and_experiment,_examples_of_traits_in_man&diff=25925Autosomal recessive inheritance in pedigree and experiment, examples of traits in man2017-07-24T12:57:54Z<p>Azrael: Coursebook chapter. Author: Panczak, A.</p>
<hr />
<div>===Characteristics of AR pedigrees===<br />
*the trait is often found in clusters of siblings but not in their parents and offspring <br />
*males and females are equally likely to be affected (in a population, equally, the proportion of affected males should be equal to the proportion of affected females)<br />
*parents could be relatives (the couple related by blood, such as first cousins)<br />
<br />
===Examples of pedigrees===<br />
[[File:AR-Pedigrees.jpg]]<br />
<br />
===AR disease/trait examples===<br />
*Cystic fibrosis (mucoviscidosis), <br />
*phenylketonuria,<br />
*sickle cell anemia,<br />
*albinism.<br />
<br />
===Important about AR inheritance in pedigree===<br />
[[File:Autosomal recessive inheritance.jpg|Monohybridism (hybridization experiment) in AR inheritance|thumb|right]][[File:AR experiment.jpg|thumb|right]] [[File:AR backcross.jpg|thumb|right]] <br />
All individuals with the defect/disease in pedigrees (and in population) are homozygotes of recessive defective (deleterious, nonactive, affected, mutated etc.) alleles, aa. Two copies of a disease allele are needed for an individual to express the phenotype. The parents of an affected (suffering with an AR disease) individual are healthy (not affected by this AR disease) but are disease carriers. <br />
Typically, once a child in a family is born with AR trait/disease we may suppose parents as carriers (heterozygotes Aa) and there is a 25% (1/4) chance (probability, risk) that anyone next offspring will inherit two copies of the disease allele and will therefore have the disease phenotype. N.B.: There is a 50% (1/2) chance that the offspring of carrier parents will inherit one copy of the disease allele and will be a carrier, and there is a 25% probability the offspring will inherit healthy (normal, wild-type etc.) allele from both parents (will be a homozygote AA) and will not express the disease phenotype or be a disease carrier. This AA individual would not be at risk for passing the disorder on to his/her offspring.<br />
<br />
Many AR diseases (disorders) are seen more frequently in individuals of certain ethnic origin than others because these individuals are descendants of the same ancestors. However, because these common ancestors are generally more distantly related to these individuals, couples of the same ethnic background would generally have fewer genes in common than consanguineous couples<br />
<br />
===AR inheritance in hybridization experiment===<br />
In experimental procedure, pure lines (e.g. inbred strains) are choosen showing difference in a character (purple versus white flowers, yellow versus green seeds/pies, colour versus albino coat/fure). Parental generation pairs are formed combining one individual from one and an individual from the other line. They are crossed for obtaining F1 hybrids, these are phenotypically uniform, all expressing one or the other form of the trait (character). By intercrossing the F1 individuals the F2 generation is obtained, where phenotypes are segregating in ratio 3 to one (one vs. the other form of the trait). This 1/4 correspond to recessive phenotype (not seen in the uniform F1 generation) and, retrospectively, also allow to decide which one line (strain) in P generation expressed the recessive form of the trait. <br />
<br />
In a general population with uniform (wild) phenotype, an individual with an exceptional (newly appearing) form of the phenotype can be tested by hybridization experiment, too, if he/she/it express the dominant or recessive form of the trait. <br />
<br />
If this new, different form of a trait is recessive (i.e. new phenotype individual is a homozygote nn), then this hybridization test (crossing with any individual with normal, common, wild phenotype in the population) represents de facto: <br />
<br />
# most probably, a parental cross (wild phenotype individual is a homozygote NN) which leads to uniform (F1) hybrids expressing the wild phenotype, or <br />
# rarely, a backcross (in case that the wild phenotype individual is a hidden, “silent” heterozygote Nn) resulting in phenotypic ratio 1 to 1 .<br />
<br />
'''Experimental cross''' in a population (AR inheritance) – new, spontaneous mutant is recessive homozygote, and wild-type phenotype individuals are (most probably) dominant homozygotes<br />
<br />
<br />
'''Backcross''' (experimental test-cross) in AR inheritance – rarely, wild-type phenotype individuals are heterozygotes (by the way, they had to be at least two of them, of opposite gender in preceding generation of the population; it is the only way how a homozygote recessive could appear in the present generation of the population)<br />
<br />
<br />
[[Category:Genetics]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=File:AR_backcross.jpg&diff=25924File:AR backcross.jpg2017-07-24T12:56:59Z<p>Azrael: {{File
|description = Backcross in AR inheritance
|source = Archive of Aleš Panczak, MD
|date = 2017-07-24
|author = Aleš Panczak, MD
|license = {{cc|by-sa|3.0}}
}}
Category:Genetics
Category:Images</p>
<hr />
<div>{{File<br />
|description = Backcross in AR inheritance<br />
|source = Archive of Aleš Panczak, MD<br />
|date = 2017-07-24<br />
|author = Aleš Panczak, MD<br />
|license = {{cc|by-sa|3.0}}<br />
}}<br />
[[Category:Genetics]]<br />
[[Category:Images]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=File:AR_experiment.jpg&diff=25923File:AR experiment.jpg2017-07-24T12:52:59Z<p>Azrael: {{File
|description = Autosomal recessive inheritance
|source = Archive of Aleš Panczak, MD
|date = 2017-07-24
|author = Aleš Panczak, MD
|license = {{cc|by-sa|3.0}}
}}
Category:Genetics
Category:Images</p>
<hr />
<div>{{File<br />
|description = Autosomal recessive inheritance<br />
|source = Archive of Aleš Panczak, MD<br />
|date = 2017-07-24<br />
|author = Aleš Panczak, MD<br />
|license = {{cc|by-sa|3.0}}<br />
}}<br />
[[Category:Genetics]]<br />
[[Category:Images]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=File:Autosomal_recessive_inheritance.jpg&diff=25922File:Autosomal recessive inheritance.jpg2017-07-24T12:52:18Z<p>Azrael: {{File
|description = Autosomal recessive inheritance
|source = Archive of Aleš Panczak, MD
|date = 2017-07-24
|author = Aleš Panczak, MD
|license = {{cc|by-sa|3.0}}
}}
Category:Genetics
Category:Images</p>
<hr />
<div>{{File<br />
|description = Autosomal recessive inheritance<br />
|source = Archive of Aleš Panczak, MD<br />
|date = 2017-07-24<br />
|author = Aleš Panczak, MD<br />
|license = {{cc|by-sa|3.0}}<br />
}}<br />
[[Category:Genetics]]<br />
[[Category:Images]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=File:AR-Pedigrees.jpg&diff=25921File:AR-Pedigrees.jpg2017-07-24T12:47:58Z<p>Azrael: date</p>
<hr />
<div>{{File<br />
|description = Autosomal recessive inheritance - Examples of pedigrees<br />
|source = Archive of Aleš Panczak, MD<br />
|date = 24-07-2017<br />
|author = Aleš Panczak, MD<br />
|license = {{cc|by-sa|3.0}}<br />
}}<br />
[[Category:Genetics]]<br />
[[Category:Images]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=File:AR-Pedigrees.jpg&diff=25920File:AR-Pedigrees.jpg2017-07-24T12:38:19Z<p>Azrael: {{File
|description = Autosomal recessive inheritance - Examples of pedigrees
|source = Archive of Aleš Panczak, MD
|date =
|author = Aleš Panczak, MD
|license = {{cc|by-sa|3.0}}
}}
Category:Genetics
Category:Images</p>
<hr />
<div>{{File<br />
|description = Autosomal recessive inheritance - Examples of pedigrees<br />
|source = Archive of Aleš Panczak, MD<br />
|date = <br />
|author = Aleš Panczak, MD<br />
|license = {{cc|by-sa|3.0}}<br />
}}<br />
[[Category:Genetics]]<br />
[[Category:Images]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=Autosomal_dominant_inheritance_in_pedigree_and_experiment,_examples_of_traits_in_man&diff=25919Autosomal dominant inheritance in pedigree and experiment, examples of traits in man2017-07-24T12:12:36Z<p>Azrael: Coursebook chapter. Author: Panczak, A.</p>
<hr />
<div>===Characteristics of AD pedigrees===<br />
*direct transmission from an affected parent to an affected child (= does not skip generations) <br />
*males and females are equally likely to be affected<br />
*both males and females transmit the disease<br />
*transmission from father to son<br />
===Examples of pedigrees===<br />
[[File:AD-Pedigrees.jpg]]<br />
<br />
===Examples===<br />
[[File:Autosomal dominant inheritance.jpg|thumb|right]][[File:Backcross in AD.jpg|thumb|right]]<br />
*achondroplasia,<br />
*brachydactyly,<br />
*polycystic kidney disease,<br />
*familial hypercholesterolemia,<br />
*dentinogenesis imperfecta, <br />
*osteogenesis imperfecta,<br />
*dysostosis cleidocranialis<br />
<br />
;Important about AD inheritance in pedigree (!!)<br />
'''Many, maybe majority of human traits/diseases with AD inheritance (e.g. dysmorfogenetic syndromes), are AD but with incomplete dominance. Thus, all individuals with the defect/disease in pedigrees (and in population) are heterozygotes Aa. The defect/disease is much more severe in homozygous individuals (AA), often with lethal effect in homozygous fetuses.''' <br />
<br />
===AD inheritance in hybridization experiment===<br />
In experimental procedure, pure lines (e.g. inbred strains) are chosen showing difference in a character (purple versus white flowers, yellow versus green seeds/pies, colour versus albino coat/fure). Parental generation pairs are formed combining one individual from one and an individual from the other line. They are crossed for obtaining F1 hybrids. By intercrossing the F1 individuals the F2 generation is obtained, where phenotypes are segregating in ratio 3 to one (dominant vs. recessive form of the trait). These 3/4 are corresponding to phenotype of F1 hybrids – the F1 generation express the dominant form of the trait as well. <br />
<br />
In a general population with uniform (wild) phenotype, an individual with an exceptional (newly appearing) form of the phenotype can be tested by hybridization experiment, too, if he/she/it express the dominant or recessive form of the trait. If this new, different form of a trait is dominant, then this hybridization test (crossing with anyone individual with normal, common, wild phenotype in the population) represents de facto a backcross repeatedly resulting in phenotypic ratio 1 to 1.<br />
<br />
[[Category:Genetics]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=File:Backcross_in_AD.jpg&diff=25918File:Backcross in AD.jpg2017-07-24T12:10:05Z<p>Azrael: {{File
|description = Backcross in AD inheritance
|source = Archive of Aleš Panczak, MD
|date = 2017-07-24
|author = Aleš Panczak, MD
|license = {{cc|by-sa|3.0}}
}}
Category:Genetics
Category:Images</p>
<hr />
<div>{{File<br />
|description = Backcross in AD inheritance<br />
|source = Archive of Aleš Panczak, MD<br />
|date = 2017-07-24<br />
|author = Aleš Panczak, MD<br />
|license = {{cc|by-sa|3.0}}<br />
}}<br />
[[Category:Genetics]]<br />
[[Category:Images]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=File:Autosomal_dominant_inheritance.jpg&diff=25917File:Autosomal dominant inheritance.jpg2017-07-24T12:08:58Z<p>Azrael: {{File
|description = Autosomal dominant inheritance
|source = Archive of Aleš Panczak, MD
|date = 2017-07-24
|author = Aleš Panczak, MD
|license = {{cc|by-sa|3.0}}
}}
Category:Genetics
Category:Images</p>
<hr />
<div>{{File<br />
|description = Autosomal dominant inheritance<br />
|source = Archive of Aleš Panczak, MD<br />
|date = 2017-07-24<br />
|author = Aleš Panczak, MD<br />
|license = {{cc|by-sa|3.0}}<br />
}}<br />
[[Category:Genetics]]<br />
[[Category:Images]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=File:AD-Pedigrees.jpg&diff=25916File:AD-Pedigrees.jpg2017-07-24T12:01:28Z<p>Azrael: {{File
|description = Autosomal dominant inheritance - Examples of pedigrees
|source = Archive of Aleš Panczak, MD
|date = 2017-07-24
|author = Aleš Panczak, MD
|license = {{cc|by-sa|3.0}}
}}
Category:Genetics
Category:Images</p>
<hr />
<div>{{File<br />
|description = Autosomal dominant inheritance - Examples of pedigrees<br />
|source = Archive of Aleš Panczak, MD<br />
|date = 2017-07-24<br />
|author = Aleš Panczak, MD<br />
|license = {{cc|by-sa|3.0}}<br />
}}<br />
[[Category:Genetics]]<br />
[[Category:Images]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=Genealogical_method&diff=25915Genealogical method2017-07-24T11:56:13Z<p>Azrael: Coursebook chapter. Author: Panczak, A.</p>
<hr />
<div>[[File:Pedigree-marks.png|thumb|right|300px|Marks used in pedigrees]]<br />
'''Medical Genealogy''' (from Greek: γενεαλογία genealogia from γενεά genea, "generation" and λόγος logos, "knowledge"), is the study of families, family lineages and medical family history. Information about a family is obtained by oral interviews (e.g. by a clinical geneticist, any other physician or a genetic couselor), from medical and historical records, (previous) genetic analysis, and others. The results are displayed and kinship of members of the family are commonly demonstrated in pedigrees or rarely written as narratives. G. serves in basic research of genetic rules in transmission of a trait and, in clinical (medical) genetics, for clinical consulting practice at follow-up of inheritance of various traits.<br />
[[File:Pedigree-lines.png|thumb|right|400px|Pedigree lines]]<br />
==Pedigree==<br />
This is a graphical recording of kinship relations between persons in individual generations. It represents the foundation of genealogical method and bring/provide basic informaion about the occurrence of chosen trait/phenotype. <br />
In the drawing up of a pedigree standard symbols and lines are used (see figures below). More detailed information about the family members is indicated in the legenda (e.g. under or beside the pedigree). The legenda refers to individual members of family through coordinates – generations are numbered by Roman and individuals in a generation by Arabic numerals.<br />
<br />
==Proband==<br />
The person providing the information for construction of pedigree and being interested in evaluation/estimate of the probability (risk) of recurrence of the trait; in the pedigree, this person is labeled with arrow.<br />
[[File:Pedigree-individuals.png|thumb|right|400px|Numbering of individuals in pedigrees]]<br />
<br />
==Genealogy analysis as a method of research==<br />
From biological point of view, genealogy. is considered as one of methods of genetic research. It resides in a selection of families with suitable type of crossing. Afterwards, this genealogy material is subject of logical analysis. In individual families, the effort is made to explain the transmission of traits by schedules used in experimental phenogenetics. <br />
For examination of the type of genetic determination in genealogy, many statistical methods (and now computer programs) have been developped enabling investigate the ratios, the penetrance of followed gene, and estimate the heritability using a collection (date-base) of pedigrees. <br />
<br />
[[Category:Genetics]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=File:Pedigree-individuals.png&diff=25914File:Pedigree-individuals.png2017-07-24T11:48:25Z<p>Azrael: {{File
|description = Individuals in pedigrees
|source = Archive of Aleš Panczak, MD
|date = 2017-07-24
|author = Aleš Panczak, MD
|license = {{cc|by-sa|3.0}}
}}
Category:Genetics
Category:Images</p>
<hr />
<div>{{File<br />
|description = Individuals in pedigrees<br />
|source = Archive of Aleš Panczak, MD<br />
|date = 2017-07-24<br />
|author = Aleš Panczak, MD<br />
|license = {{cc|by-sa|3.0}}<br />
}}<br />
[[Category:Genetics]]<br />
[[Category:Images]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=File:Pedigree-lines.png&diff=25913File:Pedigree-lines.png2017-07-24T11:43:43Z<p>Azrael: {{File
|description = Pedigree lines
|source = Archive of Aleš Panczak, MD
|date = 2017-07-24
|author = Aleš Panczak, MD
|license = {{cc|by-sa|3.0}}
}}
Category:Genetics
Category:Images</p>
<hr />
<div>{{File<br />
|description = Pedigree lines<br />
|source = Archive of Aleš Panczak, MD<br />
|date = 2017-07-24<br />
|author = Aleš Panczak, MD<br />
|license = {{cc|by-sa|3.0}}<br />
}}<br />
[[Category:Genetics]]<br />
[[Category:Images]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=File:Pedigree-marks.png&diff=25912File:Pedigree-marks.png2017-07-24T11:41:06Z<p>Azrael: {{File
|description = Pedigree marks
|source = Archive of Aleš Panczak, MD
|date = 2017-07-24
|author = Aleš Panczak, MD
|license = {{cc|by-sa|3.0}}
}}
Category:Genetics
Category:Images</p>
<hr />
<div>{{File<br />
|description = Pedigree marks<br />
|source = Archive of Aleš Panczak, MD<br />
|date = 2017-07-24<br />
|author = Aleš Panczak, MD<br />
|license = {{cc|by-sa|3.0}}<br />
}}<br />
[[Category:Genetics]]<br />
[[Category:Images]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=Inborn_errors_of_development_in_human,_examples,_classification&diff=25911Inborn errors of development in human, examples, classification2017-07-17T14:29:51Z<p>Azrael: typo</p>
<hr />
<div>Inborn errors of development or congenital malformations or birth defects are specific errors of prenatal development which we can observe in the born children.<br />
<br />
===Ethiology===<br />
*'''Monogenic disorders:''' Marfan syndrome, osteogenesis imperfecta<br />
*'''Chromosomal aberrations:''' down syndrome<br />
*'''Multifactorial:''' hip joint dysplasia, orofacial clefts<br />
*'''Proven teratogens:''' Fetal alcohol syndrome, Gregg syndrome (congenital rubella)<br />
*'''Deformation:''' Amniotic bands syndrome<br />
<br />
===The classical classifications - considering the ethology of the defect===<br />
*'''Malformation''' is caused by an abnormal development of the organ / tissue, that is abnormal from the beginning.<br />
*'''Disruption''' is caused by destructive process, that affects an organ / tissue, that started to develop normally.<br />
*'''Deformation''' is caused by an abnormal physical force, that damages healthy organ / tissue.<br />
*'''Dysplasia''' is caused by an abnormal organization of the cells in the organ / tissue.<br />
<br />
===Classification, considering the multiplicity fo the defect===<br />
*'''Isolated anomaly:''' an anomaly that is not associated with any other conditions (e.g. isolated polydactyly).<br />
*'''Sequence:''' multiple anomalies that result from the pathologic cascade caused by a primary insult (e.g. Potter‘s sequence).<br />
*'''Association:''' selected congenital anomalies that tend to develop all together – in an association (e.g. VATER association).<br />
*'''Syndrome:''' complex of phenotypic traits (anomalies) that are typical for defined clinical diagnosis (e.g. Down syndrome).<br />
<br />
===Examples===<br />
* '''Neural tube defects''' (NTD): anencephaly, spina bifida, encaphalocele<br />
* '''Orofacial clefts'''<br />
* '''Congenital hearth defects'''<br />
* '''Abdominal wall defects''' (omphalocele, gastroshisis)<br />
* '''Limb defects''' (syndactly, polydactyly, reduction limb defects)<br />
<br />
<br />
[[Category:Genetics]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=Inborn_errors_of_development_in_human,_examples,_classification&diff=25910Inborn errors of development in human, examples, classification2017-07-17T14:29:16Z<p>Azrael: New coursebook article by A. Šípek</p>
<hr />
<div>Inborn errors of development or congenital malformations or birth defects are specific errors of prenatal development which we can observe in the born children.<br />
<br />
===Ethiology===<br />
*'''Monogenic disorders:''' Marfan syndrome, osteogenesis imperfecta<br />
*'''Chromosomal aberrations:''' down syndrome<br />
*'''Multifactorial:''' hip joint dysplasia, orofacial clefts<br />
*'''Proven teratogens:''' Fetal alcohol syndrome, Gregg syndrome (congenital rubella)<br />
*'''Deformation:''' Amniotic bands syndrome<br />
<br />
===The classical classifications - considering the ethology of the defect===<br />
*'''Malformation''' is caused by an abnormal development of the organ / tissue, that is abnormal from the beginning.<br />
*'''Disruption''' is caused by destructive process, that affects an organ / tissue, that started to develop normally.<br />
*'''Deformation''' is caused by an abnormal physical force, that damages healthy organ / tissue.<br />
*'''Dysplasia''' is caused by an abnormal organization of the cells in the organ / tissue.<br />
<br />
===Classification, considering the multiplicity fo the defect===<br />
*'''Isolated anomaly:''' an anomaly that is not associated with any other conditions (e.g. isolated polydactyly).�<br />
*'''Sequence:''' multiple anomalies that result from the pathologic cascade caused by a primary insult (e.g. Potter‘s sequence).�<br />
*'''Association:''' selected congenital anomalies that tend to develop all together – in an association (e.g. VATER association).�<br />
*'''Syndrome:''' complex of phenotypic traits (anomalies) that are typical for defined clinical diagnosis (e.g. Down syndrome).<br />
<br />
===Examples===<br />
* Neural tube defects (NTD): anencephaly, spina bifida, encaphalocele<br />
* Orofacial clefts<br />
* Congenital hearth defects<br />
* Abdominal wall defects (omphalocele, gastroshisis)<br />
* Limb defects (syndactly, polydactyly, reduction limb defects)<br />
<br />
<br />
[[Category:Genetics]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=Indications_for_chromosome_analysis_in_clinical_genetics&diff=25909Indications for chromosome analysis in clinical genetics2017-07-17T14:14:27Z<p>Azrael: Coursebook chapter. Authors: Mihalova, R</p>
<hr />
<div>===Chromosomal analysis===<br />
*prenatal<br />
*postnatal<br />
<br />
===Indications for prenatal analysis of chromosomes===<br />
*advanced maternal age <br />
*higher than 35 ys in the date of delivery (increased risk of chromosomal aneuploidies, namely M. Down) <br />
*positive screening of congenital anomalies (1st or 2nd trimester maternal serum screening test + increased NT - higher risk of chromosomal abnormalities)<br />
*positive family history <br />
*affected child/fetus in previous pregnancy (with chromosomal abnormality) <br />
*parent - carrier of balanced chromosomal aberration (e.g. translocation)<br />
*patological or atypical ultrasound finding (IUGR – intrauterine growth retardation, microcephaly, hyperechogenic bowel, hydronephrosis, Fallot tetralogy, club foot, polyhydramnios/oligohydramnios, hygroma colli cysticum,...)<br />
*important for differential diagnosis (ultrasound finding could be solitary – usually without chromosomal abnormality or syndromologic – in many cases caused by chromosomal abnormality)<br />
*others (e.g. mother after chemotherapy, in vitro fertilisation pregnancy, …)<br />
<br />
===Indications for postnatal analysis of chromosomes===<br />
# children: <br />
#* craniofacial dysmorphy (flat occiput, epicantus, hypertelorism, cleft lip, cleft palate, malformed ears, craniosynostosis, macroglossia,...)<br />
#*congenital anomalies (heart defects, cryptorchism, NTD – neural tube defects, urogenital defects, agenesis corpus callosum,...) <br />
#*psychomotoric retardation<br />
#*developmental delay, failure to thrive<br />
#*growth retardation, short stature<br />
#*hypotonia<br />
#puberty:<br />
#*amenorhoea<br />
#*gynecomastia<br />
#*developmental defects of secondary sexual features <br />
#adults:<br />
#*infertility/sterility<br />
#*recurrent spontaneous abortions<br />
#*abnormal spermiogram in men<br />
#*positive family history (reproduction loss, affected child, chromosomal aberration in relatives,…) <br />
#*gamete donors<br />
<br />
<br />
[[Category:Genetics]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=Gonosomal_aneuploidy_syndromes_in_man&diff=25908Gonosomal aneuploidy syndromes in man2017-07-17T14:11:43Z<p>Azrael: +cat</p>
<hr />
<div>'''Aneuploidy''' – change in chromosome number by less than a complete set, usually ± 1 chromosome<br />
<br />
'''Trisomy''' – three copies of sex chromosomes<br />
<br />
'''Monosomy''' – one copy of chromosome; monosomy of chromosome X is only monosomy viable in man<br />
<br />
==Clinically important syndromes with gonosomal aneuploidy in man==<br />
===Turner syndrome===<br />
*monosomy of chromosome X; karyotype 45,X<br />
*Frequency 1:2 000-2 500 <br />
*Phenotype (female): <br />
**short stature, broad/shield chest, underdeveloped breast, hygroma colli cysticum (usually detected by ultrasound prenatally), short webbed neck (pterygium colli), palms and feet oedemas (newborns), low posterior hairline <br />
gonadal dysgenesis (rudimentary fibrous ovaries), primary amenorrhoea, average intelligence (not retarded), but frequently learning difficulties <br />
*Therapy: hormonal therapy – growth hormone (height) and sex hormones (sexual features); in vitro fertlilization with oocyte donor <br />
*Life expectancy: usually not limited (more than 90 % of fetuses do not survive, monosomy X is most frequent finding in spontaneous abortions<br />
===Klinefelter syndrome===<br />
* karyotype 47,XXY<br />
*Frequency 1:500-1 000 <br />
*Phenotype (male): <br />
**tall stature, sterility – azoospermia, testicular atrophy, cryptorchism, female pubic hair pattern, poor beard growth, female type of fat distribution, gynaecomastia, average intelligence (not retarded), male psychosexual orientation <br />
<br />
===XXX syndrome („superfemale“)===<br />
*trisomy X; karyotype 47,XXX<br />
*Frequency 1:1 000 <br />
*Phenotype: <br />
**no specific phenotype, average intelligence, normal sexual development, decreased fertility (spontaneous abortions), without higher risk of chromosomal aberrations in offspring, no increased occurrence of congenital disorders <br />
<br />
===XYY syndrome („supermale“)===<br />
* karyotype 47,XYY<br />
*Frequency 1:1 000 <br />
*Phenotype: <br />
** „robust“ growth (proportional), especially height, average intelligence, normal sexual development, normal fertility, without higher risk of chromosomal aberrations in offspring, controversial hypothesis - affected psychosocial development<br />
<br />
[[Category:Genetics]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=Gonosomal_aneuploidy_syndromes_in_man&diff=25907Gonosomal aneuploidy syndromes in man2017-07-17T14:11:01Z<p>Azrael: Coursebook chapter. Authors: Mihalova, R</p>
<hr />
<div>'''Aneuploidy''' – change in chromosome number by less than a complete set, usually ± 1 chromosome<br />
<br />
'''Trisomy''' – three copies of sex chromosomes<br />
<br />
'''Monosomy''' – one copy of chromosome; monosomy of chromosome X is only monosomy viable in man<br />
<br />
==Clinically important syndromes with gonosomal aneuploidy in man==<br />
===Turner syndrome===<br />
*monosomy of chromosome X; karyotype 45,X<br />
*Frequency 1:2 000-2 500 <br />
*Phenotype (female): <br />
**short stature, broad/shield chest, underdeveloped breast, hygroma colli cysticum (usually detected by ultrasound prenatally), short webbed neck (pterygium colli), palms and feet oedemas (newborns), low posterior hairline <br />
gonadal dysgenesis (rudimentary fibrous ovaries), primary amenorrhoea, average intelligence (not retarded), but frequently learning difficulties <br />
*Therapy: hormonal therapy – growth hormone (height) and sex hormones (sexual features); in vitro fertlilization with oocyte donor <br />
*Life expectancy: usually not limited (more than 90 % of fetuses do not survive, monosomy X is most frequent finding in spontaneous abortions<br />
===Klinefelter syndrome===<br />
* karyotype 47,XXY<br />
*Frequency 1:500-1 000 <br />
*Phenotype (male): <br />
**tall stature, sterility – azoospermia, testicular atrophy, cryptorchism, female pubic hair pattern, poor beard growth, female type of fat distribution, gynaecomastia, average intelligence (not retarded), male psychosexual orientation <br />
<br />
===XXX syndrome („superfemale“)===<br />
*trisomy X; karyotype 47,XXX<br />
*Frequency 1:1 000 <br />
*Phenotype: <br />
**no specific phenotype, average intelligence, normal sexual development, decreased fertility (spontaneous abortions), without higher risk of chromosomal aberrations in offspring, no increased occurrence of congenital disorders <br />
<br />
===XYY syndrome („supermale“)===<br />
* karyotype 47,XYY<br />
*Frequency 1:1 000 <br />
*Phenotype: <br />
** „robust“ growth (proportional), especially height, average intelligence, normal sexual development, normal fertility, without higher risk of chromosomal aberrations in offspring, controversial hypothesis - affected psychosocial development</div>Azraelhttps://www.wikilectures.eu/index.php?title=Autosomal_aneuploidy_syndromes_in_man&diff=25906Autosomal aneuploidy syndromes in man2017-07-17T14:07:57Z<p>Azrael: Coursebook chapter. Authors: Mihalova, R</p>
<hr />
<div>'''Aneuploidy''' – change in chromosome number by less than a complete set, usually ± 1 chromosome<br />
<br />
'''Trisomy''' – three copies of particular chromosome<br />
<br />
'''Monosomy''' – one copy of particular chromosome; no autosomal monosomy is viable in man<br />
<br />
==Clinically important (viable) syndromes with autosomal trisomy in man==<br />
===Down syndrome===<br />
*trisomy of chromosome 21; karyotype 47,XX,+21 (girl) or 47,XY,+21 (boy)<br />
*Frequency 1:600-800 (due to effective prenatal diagnostics the frequency is decreased)<br />
*Phenotype: <br />
**constant symptoms - hypotonia in newborns, mental retardation<br />
**variable symptoms - upslanting palpebral fissures, flat face, neck webbing, dysplasia of ears, flat occiput, single palmar crease, epicanthus, macroglossia, short and broad hands, brachydactyly, male hypogenitalism <br />
**Life expectancy is limited variably by: congenital heart defects, defects of other organs, immune system defects, Alzheimer disease, leukemia<br />
===Patau syndrome===<br />
*trisomy of chromosome 13; karyotype 47,XX,+13 or 47,XY,+13<br />
*Frequency 1:15 000-20 000 <br />
*Phenotype: <br />
**severe developmental retardation, congenital heart defects, urogenital defects, microcephaly, craniosynostosis, CNS malformations, microphtalmia (rarely cyclopia), cleft palate, cleft lip, malformed low-set ears, polydactyly<br />
**Life expectancy: approx. 1 month<br />
===Edwards syndrome===<br />
* trisomy of chromosome 18; karyotype 47,XX,+18 or 47,XY,+18<br />
*Frequency 1:5 000-10 000 <br />
*Phenotype: <br />
**severe developmental retardation, failure to thrive, congenital heart defects, kidney defects, malformed low-set ears, hypoplastic nails, digits overlapping, micrognathia, prominent occiput, pedes equinovares (clubfoot), microcephaly<br />
**Life expectancy: approx. 1 year<br />
<br />
Prenatal screening and diagnostics (see questions No. 127 - [[Prenatal screening of inborn errors of development]]; No. 129 - [[Prenatal diagnostics of chromosomal aberrations, possibilities of prevention]]; No. 130 - [[Prenatal diagnostics of inborn errors of development, possibilities of prevention]])<br />
<br />
[[Category:Genetics]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=Etiology_of_chromosomal_aberrations&diff=25905Etiology of chromosomal aberrations2017-07-17T14:00:36Z<p>Azrael: typo, +cat</p>
<hr />
<div>===Chromosomal aberrations===<br />
# Abnormalities in chromosome number<br />
##aneuploidy<br />
##*monosomy<br />
##*trisomy (or tetrasomy, pentasomy...)<br />
##polyploidy <br />
##*triploidy<br />
##*tetraploidy,...<br />
#Abnormalities in chromosome structure<br />
##balanced<br />
##*translocation<br />
##*inversion<br />
##*insertion<br />
##unbalanced<br />
##*deletion (incl. ring chromosome)<br />
##*duplication<br />
##*isochromosome<br />
<br />
===Etiology of congenital chromosomal aberrations===<br />
*Origin of aneuploidies and polyploidies (see question No. 34 – [[Abnormalities in chromosome number, their causes and clinical presentation in man|Abnormalities in chromosome number, their causes and clinical presentations in man]])<br />
*Origin of structural aberrations:<br />
**chromosome breaks and rearrangements during gamete formation (in meiosis) or in pre-gametic mitotic divisions of gonadal cells – resulting in stable products having one centromere and two telomeres <br />
***one centromere is necessary for regular segregation in mitosis (unstable dicentric chromosomes undergo secondary rearrangements)<br />
***telomeres maintain the integrity of the ends of linear chromosome structure (in deleted chromosomes new telomeres are added by **telomere synthesis or by mechanism of telomere capture) <br />
**causes of spontaneous breaks – see below (external effects)<br />
<br />
===Etiology of acquired chromosomal aberrations===<br />
(= chromosome breaks and rearrangements during mitotic divisions of somatic cells)<br />
<br />
External effects (physical, chemical, biological)<br />
**random environmental factors – spontaneous breaks (UV light, ionizing radiation – cosmic rays, medical radiation (X-rays), drugs, viral infections)<br />
**professional exposition (mutagens: chemicals – alkylating agents, intercalation substances...; radiation)<br />
**oncological treatment (chemotherapy, radiotherapy)<br />
<br />
'''Hereditary syndromes of chromosome instability''' <br />
*congenital defects of repair mechanisms - mostly double-strand DNA breaks repair<br />
*rare genetic disorders with AR inheritance, higher predisposition to cancer development<br />
*higher level of chromosome breaks and rearrangements detected in cytogenetic analysis<br />
**ataxia teleangiectasia (defect of ATM gene - important for double-strand DNA breaks repair)<br />
**xeroderma pigmentosum (defect of nucleotide excision repair)<br />
**Bloom syndrome (extreme genome instability, high level of sister chromatid exchanges - SCEs, high frequency of mutations)<br />
**Fanconi anemia<br />
**Nijmegen breakage syndrome<br />
<br />
Methods of analysis of acquired chromosomal aberrations (see question No. 31 – [[Methods of chromosomal examination]])<br />
<br />
[[Category:Genetics]]</div>Azraelhttps://www.wikilectures.eu/index.php?title=Etiology_of_chromosomal_aberrations&diff=25904Etiology of chromosomal aberrations2017-07-17T13:59:58Z<p>Azrael: Coursebook chapter. Authors: Mihalova, R</p>
<hr />
<div>===Chromosomal aberrations===<br />
# Abnormalities in chromosome number<br />
##aneuploidy<br />
##*monosomy<br />
##*trisomy (or tetrasomy, pentasomy...)<br />
##polyploidy <br />
##*triploidy<br />
##*tetraploidy,...<br />
#Abnormalities in chromosome structure<br />
##balanced<br />
##*translocation<br />
##*inversion<br />
##*insertion<br />
##unbalanced<br />
##*deletion (incl. ring chromosome)<br />
##*duplication<br />
##*isochromosome<br />
<br />
===Etiology of congenital chromosomal aberrations===<br />
*Origin of aneuploidies and polyploidies (see question No. 34 – [[Abnormalities in chromosome number, their causes and clinical presentation in man|Abnormalities in chromosome number, their causes and clinical presentations in man]])<br />
*Origin of structural aberrations:<br />
**chromosome breaks and rearrangements during gamete formation (in meiosis) or in pre-gametic mitotic divisions of gonadal cells – resulting in stable products having one centromere and two telomeres <br />
***one centromere is necessary for regular segregation in mitosis (unstable dicentric chromosomes undergo secondary rearrangements)<br />
***telomeres maintain the integrity of the ends of linear chromosome structure (in deleted chromosomes new telomeres are added by **telomere synthesis or by mechanism of telomere capture) <br />
**causes of spontaneous breaks – see below (external effects)<br />
<br />
===Etiology of acquired chromosomal aberrations===<br />
(= chromosome breaks and rearrangements during mitotic divisions of somatic cells)<br />
<br />
External effects (physical, chemical, biological)<br />
**random environmental factors – spontaneous breaks (UV light, ionizing radiation – cosmic rays, medical radiation (X-rays), drugs, viral infections)<br />
**proffessional exposition (mutagens: chemicals – alkylating agents, intercalation substances...; radiation)<br />
**oncological treatment (chemotherapy, radiotherapy)<br />
<br />
'''Hereditary syndromes of chromosome instability''' <br />
*congenital defects of repair mechanisms - mostly double-strand DNA breaks repair<br />
*rare genetic disorders with AR inheritance, higher predisposition to cancer development<br />
*higher level of chromosome breaks and rearrangements detected in cytogenetic analysis<br />
**ataxia teleangiectasia (defect of ATM gene - important for double-strand DNA breaks repair)<br />
**xeroderma pigmentosum (defect of nucleotide excision repair)<br />
**Bloom syndrome (extreme genome instability, high level of sister chromatid exchanges - SCEs, high frequency of mutations)<br />
**Fanconi anemia<br />
**Nijmegen breakage syndrome<br />
<br />
Methods of analysis of acquired chromosomal aberrations (see question No. 31 – [[Methods of chromosomal examination]])</div>Azrael