Genetic Variation in Individuals and Populations II (2024) PDF

Dr. Akhobadze Madona Genetic Variation in Individuals and Populations: Mutation and Polymorphism (II) 2024  Content: Inherited Variation And Polymorphism In Proteins, Genotypes And Phenotypes In Populations, The Hardy-Weinberg Law, Factors That Dist...

Dr. Akhobadze Madona Genetic Variation in Individuals and Populations: Mutation and Polymorphism (II) 2024  Content: Inherited Variation And Polymorphism In Proteins, Genotypes And Phenotypes In Populations, The Hardy-Weinberg Law, Factors That Disturb Hardy-Weinberg Equilibrium, Ethnic Differences In The Frequency Of Various Genetic Diseases Reading: Ch. 9 - Thompson & Thompson Genetics in Medicine, Robert L. Nussbaum, Roderick R. McInnes, 9th Edition Ch. 8 - Emery’s elements of medical genetics, 14th edition INHERITED VARIATION AND POLYMORPHISM IN PROTEINS any one individual is likely Population genetics is the quantitative study of to be heterozygous for the distribution of genetic variation in populations alleles determining and of how the frequencies of genes and genotypes structurally different are maintained polypeptides at or change over time both within and between approximately 20% of all populations. loci when individuals from different ethnic groups are compared, an even greater fraction of proteins has been found to exhibit detectable polymorphism BIOCHEMICAL INDIVIDUALITY striking degree of biochemical individuality exists within the human species in its makeup of enzymes and other gene products each individual, regardless of his or her state of health, has a unique, genetically determined chemical makeup and thus responds in a unique manner to environmental, dietary, and pharmacological influences GENOTYPES AND PHENOTYPES IN POPULATIONS Population genetics is concerned both with genetic factors - as mutation and reproduction environmental and societal factors - selection and migration together determine the frequency and distribution of alleles and genotypes in families and communities GENETIC FACTORS IN HUMAN IMMUNODEFICIENCY VIRUS RESISTANCE Gene CCR5, which encodes a cell surface cytokine receptor that serves as an entry point for certain strains of the human immunodeficiency virus (HIV) that causes the acquired immunodeficiency syndrome (AIDS) 32– base pair deletion in this gene results in an allele (DCCR5) that encodes a nonfunctional protein due to a frameshift and premature termination Individuals homozygous for the DCCR5 allele do not express the receptor on their cell surface and are resistant to HIV infection Loss of function of CCR5 appears to be a benign trait when we refer to the population frequency of an allele, we are considering a hypothetical gene pool as a collection of all the alleles at a particular locus for the entire population  The Hardy-Weinberg Law Geoffrey Hardy- English mathematician Wilhelm Weinberg - German physician - in 1908 calculating genotype frequencies from allele frequencies p is the frequency of allele A q is the frequency of allele a in the gene The chance of AA genotype is p2 aa genotype is q2 Aa genotype is 2pq The Hardy-Weinberg law rests on these assumptions: The population is large and matings are random with respect to the locus in question Allele frequencies remain constant over time because: There is no appreciable rate of mutation. Individuals with all genotypes are equally capable of mating and passing on their genes, that is, there is no selection against any particular genotype There has been no significant immigration of individuals from a population with allele frequencies very different from the endogenous population The Hardy-Weinberg Law the frequency of the three genotypes AA, Aa, and aa is given by the terms of the binomial expansion (p + q)2 = p2 + 2pq + q2 population genotype frequencies from generation to generation will remain constant, at equilibrium, if the allele frequencies p and q remain constant p2 : 2pq : q2 647 : 134 : 7 (p + q)n, p and q represent the frequencies of two alternative alleles at a locus p + q = 1 and n = 2 If a locus has three Alleles (p + q + r)2 Frequencies of Mating Types and Offspring for a Population in Hardy-Weinberg Equilibrium with Parental Genotypes in the Proportion p2 : 2pq : q2 THE HARDY-WEINBERG LAW IN AUTOSOMAL RECESSIVE DISEASE genetic counseling for autosomal recessive disorders such as phenylketonuria (PKU) Heterozygotes are asymptomatic silent carriers, and their population incidence is impossible to measure directly from the phenotype the frequency of PKU is approximately 1/4500 in Ireland Then the frequency of affected individuals = 1/4500 = q2 q = 0.015, and 2pq = 0.029 or approximately 3% carrier frequency in the Irish population is 3% The Hardy-Weinberg Law in X-Linked Disease there are only two possible male genotypes but three female genotypes red-green color blindness, caused by mutations in the series of red and green visual pigment genes on the X chromosome symbol cb for all the mutant colorblindness alleles and the symbol + for the normal allele, with frequencies q and p  FACTORS THAT DISTURB HARD-YWEINBERG EQUILIBRIUM 1. population is large and mating is random - very small population in which random events can radically alter an allele frequency may not meet this assumption, also when the population contains subgroups whose members choose to marry within their own subgroup 2. allele frequencies are not changing over time, no migration large deviations from the frequency of individuals homozygous for an autosomal recessive condition changes in allele frequency due to mutation, selection, or migration usually cause more minor and subtle deviations from Hardy-Weinberg equilibrium compared to nonrandom mating Exception to Large Population with Random Mating Stratification - population in which there are a number of subgroups that have remained relatively genetically separate during modern times (the U.S.) African American population of the United States and the mutant allele at the β-globin locus responsible for sickle cell disease has no effect on the frequency of autosomal dominant disease, only a minor effect on the frequency of X-linked disease Exception to Large Population with Random Mating Assortative mating - choice of a mate because the mate possesses some particular trait achondroplasia - autosomal dominant disorder, homozygous offspring will have a severe, lethal form of dwarfism Exception to Large Population with Random Mating Consanguinity - increase in the frequency of autosomal recessive disease in genetic isolates, the chance of mating with another carrier is as high as that observed in cousin marriages, a phenomenon known as inbreeding (Tay-Sachs disease in Ashkenazi Jews) Exceptions to Constant Allele Frequencies Genetic Drift in Small Populations - increased fertility or survival of the carriers of a mutation, occurring for reasons unrelated to carrying the mutant allele, allele frequencies can fluctuate from generation to generation by chance Exceptions to Constant Allele Frequencies Mutation and Selection - new mutation would have little effect in the short term on allele frequencies. Whether an allele is transmitted to the succeeding generation depends on its fitness (f), which is a measure of the number of offspring of affected persons who survive to reproductive age. Fitness is the outcome of the joint effects of survival and fertility Coefficient of selection (s), which is a measure of the loss of fitness and is defined as 1 − f, that is, the proportion of mutant alleles that are not passed on and are therefore lost as a result of selection When a genetic disorder limits reproduction so severely that the fitness is zero (s = 1), it is referred to as a genetic lethal  Positive Selection for Heterozygotes (Heterozygote Advantage) heterozygotes for some diseases have increased fitness not only over homozygotes for the mutant allele but also over homozygotes for the normal allele heterozygotes greatly outnumber homozygotes in the population situation in which selective forces operate both to maintain a deleterious allele and to remove it from the gene pool is described as a balanced polymorphism MIGRATION AND GENE FLOW Migration can change allele frequency by the process of gene flow, defined as the slow diffusion of genes across a barrier term migrant is used here in the broad sense of crossing a reproductive barrier, which may be racial, ethnic, or cultural and not necessarily geographical and requiring physical movement from one region to another A number of factors are thought to allow differences in alleles and allele frequencies among ethnic groups to develop Two such factors are genetic drift, including nonrandom distribution of alleles among the individuals who founded particular subpopulations (founder effect) and heterozygote advantage under environmental conditions that favor the reproductive fitness of carriers of deleterious mutations. GENETIC DRIFT explain a high frequency of a deleterious disease allele in a population When a new mutation occurs in a small population, its frequency is represented by only one copy among all the copies of that gene in the population GENETIC DRIFT Random effects of environment or other chance occurrences that are independent of the genotype and operating in a small population can produce significant changes in the frequency of the disease allele These changes are likely to smooth out as the population increases in size. In contrast to gene flow, in which allele frequencies change because of admixture FOUNDER EFFECT When a small subpopulation breaks off from a larger population, the gene frequencies in the small population may be different from those of the population from which it originated because the new group contains a small, random sample of the parent group and, by chance, may not have the same gene frequencies as the parent group  The population of Finland long isolated genetically by geography, language, and culture, has expanded in the past 300 years from 400,000 to about 5 million Choroideremia - X-linked degenerative eye disease, very rare worldwide; only about 400 cases Fully one third of the total number of patients are from a small region in Finland, populated by a large extended family descended from a founding couple born in the 1640s Old Order Amish religious isolate of European descent that settled in Pennsylvania and gave rise to a number of small, genetically isolated subpopulations throughout the United States and Canada have large families and a high frequency of consanguineous marriage specific rare autosomal recessive syndromes such as the Ellisvan Creveld syndrome of short-limbed dwarfism, polydactyly, abnormal nails and teeth, and high incidence of congenital heart defects  The French-Canadian population of Canada Hereditary type I tyrosinemia autosomal recessive condition causes hepatic failure and renal tubular dysfunction due to deficiency of fumarylacetoacetase, an enzyme in the degradative pathway of tyrosine hyperornithinemia with gyrate atrophy of the choroid and retina - autosomal recessive condition caused by deficiency of ornithine aminotransferase and leading to loss of vision in young adulthood ETHNIC DIFFERENCES IN THE FREQUENCY OF VARIOUS GENETIC DISEASES The human species of more than 8 billion members are separated into many subpopulations, or ethnic groups, distinguishable by appearance, geographical origin, and history ancestry informative markers (AIMs) 25,000 genes and their location and order on the chromosomes are nearly identical in all humans, extensive polymorphism exists between individuals in a population Most variation is found in all human populations, at similar frequencies CHEMICAL INDIVIDUALITY British physician - Archibald Garrod ABO and Rh blood groups important in determining compatibility for blood transfusions The major histocompatibility complex (MHC) that plays an important role in transplantation medicine the variant protein products of various polymorphic alleles are often what is responsible for different phenotypes and likely to dictate how genetic variation at a locus affects the interaction between an individual and the environment. BLOOD GROUPS AND THEIR POLYMORPHISMS The first instances of genetically determined protein variation were detected in antigens found in blood, the so-called blood group antigens Numerous polymorphisms are known to exist in the components of human blood, especially in the ABO and Rh antigens of red blood cells. the ABO and Rh systems are important in blood transfusion, tissue and organ transplantation, and hemolytic disease of the newborn THE ABO SYSTEM Human blood can be assigned to one of four types according to the presence on the surface of red blood cells of two antigens A and B the presence in the plasma of the two corresponding antibodies anti-A and anti-B THE ABO SYSTEM four major phenotypes: O, A, B, and AB Type A persons have antigen A on their red blood cells type B persons have antigen B type AB persons have both antigens A and B type O persons have neither THE ABO SYSTEM reciprocal relationship, in an individual, between the antigens present on the red blood cells and the antibodies in the serum When the red blood cells lack antigen A, the serum contains anti-A when the cells lack antigen B, the serum contains anti-B The reason is uncertain, but formation of anti-A and anti-B is believed to be a response to the natural occurrence of A-like and B-like antigens in the environment THE ABO SYSTEM determined by a locus on chromosome 9 multiallelism in which three alleles, two of which (A and B) are inherited as a codominant trait and the third of which (O) is inherited as a recessive trait, determine four phenotypes. The A and B antigens are made by the action of the A and B alleles on a red blood cell surface glycoprotein called H antigen THE ABO SYSTEM B allele codes for a glycosyltransferase that preferentially recognizes the sugar d-galactose and adds it to the end of an oligosaccharide chain contained in the H antigen - creating the B antigen A allele preferentially recognizes N-acetylgalactosamine instead of d-galactose and adds N-acetylgalactosamine to the precursor - creating the A antigen O codes for a mutant version of the transferase that lacks transferase activity and does not detectably affect H substance at all THE O ALLELE has a single–base pair deletion in the ABO gene coding region, which causes a frameshift mutation that eliminates the transferase activity in type O individuals ABO blood group typing is being performed directly at the genotype rather than at the phenotype level, especially when there are technical difficulties in serological analysis, as is often the case in forensic investigations or paternity testing MEDICAL IMPORTANCE OF THE ABO blood transfusion and tissue or organ transplantation compatible and incompatible combinations Compatible combination - the red blood cells of a donor do not carry an A or a B antigen that corresponds to the antibodies in the recipient’s serum. theoretically there are universal donors (group O) and universal recipients (group AB), patient is given blood of his or her own ABO group, except in emergencies presence of anti-A and anti-B explains the failure of many of the early attempts to transfuse blood antibodies can cause immediate destruction of ABO-incompatible cells THE RH SYSTEM hemolytic disease of the newborn and in transfusion incompatibilities comes from Rhesus monkeys that were used in the experiments that led to the discovery of the system the population is separated into: Rh-positive individuals - who express, on their red blood cells, the antigen Rh D - polypeptide encoded by a gene (RHD) on chromosome 1, Rh-negative individuals - who do not express this antigen THE RH SYSTEM The Rh-negative phenotype usually originates from homozygosity for a nonfunctional allele of the RH-D gene frequency of Rh-negative individuals varies enormously in different ethnic groups 17% of whites and 7% of African Americans are Rh-negative, whereas the frequency among Japanese is 0.5% HEMOLYTIC DISEASE OF THE NEWBORN Rh-negative persons can readily form anti-Rh antibodies after exposure to Rh-positive red blood cells when an Rh-negative pregnant woman is carrying an Rh-positive fetus Normally during pregnancy, small amounts of fetal blood cross the placental barrier and reach the maternal blood stream If the mother is Rh-negative and the fetus Rh-positive, the mother will form antibodies that return to the fetal circulation and damage the fetal red blood cells, causing hemolytic disease of the newborn IN PREGNANT RH-NEGATIVE WOMEN the risk of immunization by Rh-positive fetal red blood cells can be minimized with an injection of Rh immuneglobulin at 28 to 32 weeks of gestation and again after pregnancy Rh immunoglobulin serves to clear any Rh-positive fetal cells from the mother’s circulation before she is sensitized Rh immune globulin is also given after miscarriage, termination of pregnancy, or invasive procedures such as chorionic villus sampling or amniocentesis preventive measure - routine practice in obstetrical medicine The Major Histocompatibility Complex MHC is composed of a large cluster of genes located on the short arm of chromosome 6 Three classes: the class I and class II genes, correspond to the human leukocyte antigen (HLA) genes Discovered by virtue of their importance in tissue transplantation between unrelated individuals encode cell surface proteins that play a critical role in the initiation of an immune response and specifically in the “presentation” of antigen to lymphocytes cannot recognize and respond to an antigen unless it is complexed with an HLA molecule on the surface of an antigen-presenting cell The interaction between MHC class I and class II molecules, foreign proteins, and T-cell receptors. The class I - HLA-A, HLA-B, and HLA-C encode proteins that are an integral part of the plasma membrane of all nucleated cells consists of two polypeptide subunits, a variable heavy chain encoded within the MHC nonpolymorphic polypeptide, β2-microglobulin, that is encoded by a gene outside the MHC, chromosome 15 Peptides derived from intracellular proteins are generated by proteolytic degradation by a large multifunctional protease transported to the cell surface and held in a cleft formed in the class I molecule to display the peptide antigen to cytotoxic T cells The class II - HLA-DP, HLA-DQ, and HLA-DR encode integral membrane cell surface proteins heterodimer, composed of α and β subunits, both of which are encoded by the MHC present peptides derived from extracellular proteins that had been taken up into lysosomes and processed into peptides for presentation to T cells Other gene loci are functionally unrelated to the HLA class I and class II genes and do not function to determine histocompatibility or immune responsiveness. Some are associated with diseases, such as congenital adrenal hyperplasia caused by deficiency of 21-hydroxylase, and hemochromatosis, a liver disease caused by iron overload  HLA and Disease Association Ankylosing Spondylitis chronic inflammatory disease of the spine and sacroiliac joints risk of developing ankylosing spondylitis is at least 150 times higher for people who have HLA-B27 than for those who do not Less than 5% of B27-positive individuals develop the disease, 20% of B27-positive individuals may have subtle, subclinical manifestations of the disease without any symptoms or disability BONE MARROW TRANSPLANTATION not only can the host reject the graft, but also the graft, which contains immunocompetent lymphocytes, can attack the host in what is known as graft-versus-host disease (GVHD) Survival out to 8 years after bone marrow transplantation for patients with chronic myelogenous leukemia following chemotherapy is 60% if graft host mismatch at no more than one class I or class II locus but falls to 25% when there are both class I and class II mismatches GVHD is also less frequent and severe the better the class I match.  HLA and Disease Association Congenital adrenal hyperplasia Autosomal recessive disorders Due to 21-hydroxylase deficiency Primary hemochromatosis result from mutations in genes that lie within the MHC Affecting such critical processes as immunity against infections and self-tolerance to prevent autoimmunity HLA and Tissue Transplantation determinants of transplant tolerance and graft rejection monozygotic twins, can provide a 100% transplantation success rate without immunosuppressive therapy surviving after 10 years when the recipient and the donor are HLA-identical siblings is 72% but falls to 56% when the donor is a sibling who has only one HLA haplotype in common with the recipient გმადლობთ, ყურადღებისთვის!!!