Population Genetics HO AUG 2024 PDF

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These lecture notes cover Population Genetics for MDS244. The lecture notes describe topics such as allele frequency, genotype frequency, Hardy-Weinberg equilibrium, genetic drift, and mutation.

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Population Genetics HO August 24 Population Genetics UNIVERSITY OF LIBERIA A.M. Dogliotti College of Medicine Department of Me...

Population Genetics HO August 24 Population Genetics UNIVERSITY OF LIBERIA A.M. Dogliotti College of Medicine Department of Medical Biochemistry By Mehidi K. Asst. Prof of Biochemistry 2023-24 1 Population Genetics HO August 24 Learning Objectives  After completion of this session you should be able to:  Explain the meaning of allele frequency & genotype frequency  Solve problems concerning genotype & allele frequencies  Estimate genotype frequencies or allele frequencies in recessive, dominant, & sex-linked diseases using the Hardy- Weinberg equation  Know how to apply the Hardy-Weinberg equilibrium  Describe the roles of mutation, natural selection, genetic drift, gene flow, & consanguinity in population genetics  Interpret scenarios about factors responsible for genetic variation in/among populations 2 2 Population Genetics HO August 24 Topics to be Discussed Overview of Population Genetics  Definition  Genotype & Allele Frequencies Hardy-Weinberg Equilibrium  Determining Genotype Frequencies for:  Autosomal Recessive Diseases  Autosomal Dominant Diseases  Sex-Linked Diseases Genetic Variables Affecting Hardy-Weinberg Equilibrium 3 3 Population Genetics HO August 24 Overview of Population Genetics  Definition  Population genetics is the study of genetic variation in populations  Basic concepts of population genetics allow us to understand  how & why the prevalence of various genetic diseases differs among populations  Thesestudies allow us to evaluate the roles of evolutionary factors such as:  natural selection, genetic drift, and gene flow in changing gene frequencies in human populations 4 4 Population Genetics HO August 24  Genotype & Allele Frequencies  An essential step in understanding genetic variation is to measure it in populations  This is done by estimating genotype & allele frequencies  Genotype Frequencies  Thegenotype frequency is the proportion of a given genotype at a specific locus in the population:  In other words, the frequency (f) of homozygous for one allele, heterozygous, & homozygous for the alternative allele: f(AA), f(Aa), and f(aa)  Because these are the only possible genotypes, it naturally follows that: f(AA) + f(Aa) + f(aa) = 1 5 5 Population Genetics HO August 24 Cont’d…  Ifa population was assayed for the presence of a particular genetic polymorphism at a specific locus, and it was determined that  48/100 individuals possessed the AA genotype, 44/100 possessed the Aa genotype, and 8/100 possessed the aa genotype,  then their genotype frequencies would be expressed as:  AA = 0.48  Aa = 0.44  aa = 0.08  Allele Frequencies  The allele frequency is the actual number of alleles at that locus on chromosomes  To continue with the example given above:  The AA genotype has two copies of the A allele  The Aa genotype has one copy of the A allele and one of the a allele  The aa genotype has two copies of the a allele 6 6 Population Genetics HO August 24 Cont’d…  Therefore, to calculate the allele frequency of the A allele in the population cited above, we would take the number of:  AA individuals (48) and realize that they had two copies (2 x 48)  Aa individuals (44)  realize that they had one copy b/c the number of Chr’s in a diploid population of 100 people would be 200 for that Chr,  the formula becomes:  Then, a shortcut for the determination of the allele frequency for “a” becomes 1 - 0. 7 = 0.3  b/c the two allele frequencies added together must always equal 1  Note  Genotype frequencies measure the proportion of each genotype in a population  Allele frequencies measure the proportion of chromosomes that contain a specific allele (of a gene) 7 7 Population Genetics HO August 24  Hardy-Weinberg Equilibrium  Inlarge populations that are mating at random (with respect to a given allele),  there should be a constant & predictable r/s b/n genotype frequencies & allele frequencies  Thisis expressed as the Hardy-Weinberg equilibrium, & if one knows the inheritance pattern of a specific disease & the frequency of that disease,  the equation can be used to calculate the frequency of alleles in that population: p = frequency of the normal allele q = frequency of the disease allele p2 = frequency of genotype AA 2pq = frequency of the heterozygous genotype q2 = frequency of genotype aa  So the Hardy-Weinberg equation results: p2 + 2pq + q2 = 1 8 8 Population Genetics HO August 24 Cont’d…  Determining Genotype Frequencies for Autosomal Recessive Diseases  In a population in which 1% of the individuals have a recessive disease,  what percentage of the individuals are asymptomatic carriers of the disease?  In an autosomal recessive disease, asymptomatic carriers will be heterozygotes  Thus, the question is really asking for f(Aa) = 2pq  To solve this, we start with the information we have, the frequency of diseased individuals, f(aa) = q2  Calculating f(a) or q:  q2 = 0.01  q = 0.1  Because q = 0.1, we can determine p and thus f(A):  p + q =1  p = f(A) = 0.9 9 9 Population Genetics HO August 24 Cont’d…  Usingthe last portion of the Hardy-Weinberg equation, we can calculate f(Aa) or 2pq:  2pq = 2(0.9)(0.1) = 0.18  Thus, 18% of the population are carriers of the disease  Practical Application of Hardy-Weinberg (PBL Session) A simple example is illustrated by the following case – PKU:  Read on Kaplan-Medical-USML Lecture Notes 2021 - page 331  (For Problem Based Learning) 10 10 Population Genetics HO August 24 Cont’d…  Determining Genotype Frequencies for Autosomal Dominant Diseases  In the case of autosomal dominant diseases,  the largest number of affected individuals will be heterozygotes, or 2pq  Usingthe shortcut that the normal alleles in a population far outnumber the disease alleles,  we can approximate the value of p as being close to 1,  then the formula becomes 2q  Ifthe number of diseased individuals in a population is 1/500, then 2q is 1/500, 6  so q2 is the number of homozygous diseased individuals, or 1/10 11 11 Population Genetics HO August 24 Cont’d…  The term q2 represents  the prevalence of homozygous affected individuals who, although much less commonly seen, may have more severe symptoms  For example,  1/500 people in the United States have a form of LDL-receptor deficiency & are at increased risk for cardiovascular disease & myocardial infarction  Taking 2q = 1/500, one can calculate that;  q2 = 1/106, or one in a million live births are homozygous for the condition  Theseindividuals have greatly elevated LDL-cholesterol levels, a much- higher risk for cardiovascular disease than heterozygotes,  are more likely to present with characteristic xanthomas, xanthelasmas, and corneal arcus  In contrast, in Huntington disease (autosomal dominant),  the number of triplet repeats correlates much more strongly with disease severity than does heterozygous or homozygous status 12 12 Population Genetics HO August 24 Cont’d…  Determining Genotype Frequencies for Sex-Linked Diseases  Because males are hemizygous for the X Chr, when applying the Hardy-Weinberg equilibrium to X-linked recessive diseases,  q (disease allele frequency) equals the prevalence of affected males  Therefore, if the number of hemophiliac males in a population is 1/10,000,  this is the allele frequency q  the prevalence of disease in females is therefore q2 or 1/100,000,000,  the prevalence of female carriers is 2q or 1/5,000.  Onceagain, the majority of the recessive alleles are hidden in the female heterozygotes,  but a significant number are expressed in affected males 13 13 Population Genetics HO August 24  Genetic Variables Affecting Hardy-Weinberg Equilibrium  The Hardy-Weinberg equilibrium works  only for populations in which only two alleles are present.  Additionally, in order for the equation to function properly,  several additional assumptions must hold true  Specifically:  There must be no new mutations  There can be no selection pressure for or against alleles  There can be no genetic drift  There can be no gene flow in or out of the population  All of these conditions  change the genotype, & thus the allele frequencies,  disturb the Hardy-Weinberg equilibrium 14 14 Population Genetics HO August 24 Cont’d… A. New Mutations  Spontaneous mutations will alter the allele frequencies & upset the equilibrium  For e.g., if new mutations in a gene occurred frequently, the frequency of the q allele would be ever increasing  The odds of someone having the q allele would be dependent not only on their inherited genotype,  but on mutations incurred within their parents' germline & their own development  In some cases, a new mutation can be introduced into a population when someone carrying the mutation is one of the early founders of the community  this is referred to as a founder effect  As the community rapidly expands through generations, the frequency of the mutation can be affected by:  natural selection, genetic drift, & consanguinity 15 15 Population Genetics HO August 24  Clinical Correlate  Branched Chain Ketoacid Dehydrogenase Deficiency  Branched chain ketoacid dehydrogenase deficiency (maple syrup urine disease)  occurs in 1/176 live births in the Mennonite community of Lancastershire, Pennsylvania  In the U.S. population at large, the disease occurs in only 1/180,000 live births  The predominance of a single mutation (allele) in the branched chain dehydrogenase gene in this group suggests a common origin of the mutation  This may be due to a founder effect  Note  The 4 evolutionary factors responsible for genetic variation in populations are:  Mutation  Natural selection  Genetic drift  Gene flow 16 16 Population Genetics HO August 24 Cont’d… B. Selection Pressure (Natural Selection)  Evolutionary selection for or against alleles can alter both the genotype & allele frequencies 1. Negative Selection  Inthe case of negative selection, if individuals with the disease (q2 ) die before reproducing or are less able to reproduce,  the allele frequency (q) will steadily decline 2. Heterozygote Advantage  Ifthere is a positive survival advantage for heterozygote carriers compared with normal individuals,  referred to as a "heterozygote advantage,"  then the allele frequency (q) may increase 17 17 Population Genetics HO August 24 Cont’d…  Natural selection acts upon genetic variation,  increasing the frequencies of alleles that promote survival or fertility (referred to as fitness) &  decreasing the frequencies of alleles that reduce fitness  The reduced fitness of most disease-producing alleles helps explain why most genetic diseases are relatively rare  Dominant diseases, in which the disease-causing allele is more readily exposed to the effects of natural selection,  tend to have lower allele frequencies than do recessive diseases, where the allele is typically hidden in heterozygotes  There is now evidence for heterozygote advantages for several other recessive diseases that are relatively common in some populations. E.g., include:  Cystic fibrosis (heterozygote resistance to typhoid fever)  Hemochromatosis (heterozygote advantage in iron-poor environments)  Glucose-6-phosphate dehydrogenase deficiency, hemolytic anemia (heterozygote resistance to malaria) 18 18 Population Genetics HO August 24  Clinical Correlate  Sickle Cell Disease and Malaria  Sickle cell disease affects 1/600 African Americans & up to 1/50 individuals in some parts of Africa  How could this highly deleterious disease-causing mutation become so frequent, especially in Africa?  Theanswer lies in the fact that the falciparum malaria parasite, which has been common in much of Africa,  does not survive well in the erythrocytes of sickle cell heterozygotes  These individuals, who have no clinical signs of sickle cell disease,  are thus protected against the lethal effects of malaria  Consequently, there is a heterozygote advantage for the sickle cell mutation,  it maintains a relatively high frequency in some African populations 19 19 Population Genetics HO August 24 Cont’d… C. Genetic Drift  Within a small population, allele frequencies can change by random chance  For e.g., in a heterozygote cross the probability of having a homozygous child (aa) is 25%  However, if a heterozygote cross results in four children, three of whom are homozygous recessive (aa),  then the allele frequency of a, f(a), increases  The effect of genetic drift is minimal in large populations, but can have a significant impact on allele frequency in small populations  If an affected person moves into a small, unaffected population,  this, too, can dramatically change the allele frequency (the "founder effect")  Mutation rates & founder effects act along with genetic drift to make certain genetic diseases more common (or rarer) in small, isolated  populations than in the world at large  Consider the pedigrees (very small populations) shown in Fig-1 20 20 Population Genetics HO August 24 Genetic drift begins. In both examples the frequency of affected persons in generation III is 2/3, higher than the 1/2 predicted by statistics Fig-1: Genetic Drift in Two Small Populations (Illustrated with a Dominant Disease) 21 21 Population Genetics HO August 24 Cont’d…  Ifthe woman and the affected man (II-5) in the top panel had 1,000 children rather than 6, Fig-1  the prevalence of the disease in their offspring (Generation III) would be closer to 1/2, the statistical mean  Although genetic drift affects populations larger than a single family, this example illustrates two points:  When a new mutation or a founder effect occurs in a small population,  genetic drift can make the allele more or less prevalent than statistics alone would predict  A relatively large population in Hardy-Weinberg equilibrium for an allele or many alleles can be affected by population “bottlenecks”  in which natural disaster or large-scale genocide dramatically reduces the size of the population  genetic drift may then change allele frequencies & a new Hardy- Weinberg equilibrium is reached 22 22 Population Genetics HO August 24 Cont’d… D. Gene Flow  In a given population, migration of one group of people into or out of that population may change allele frequencies,  especially if a particular allele is more or less prevalent in the migrating population  Through time, gene flow within a population tends to make the people that make up that population more similar genetically to one another  As with genetic drift, the effect of gene flow is more pronounced in small populations E. Consanguinity  A consanguineous union occurs between mating individuals descended from a common ancestor  Such unions are more likely to produce offspring with recessive diseases  b/c of the likelihood of shared disease-causing mutations  Statistically speaking:  Siblings share 1/2 of their genes  First cousins share 1/8 of their genes  Second cousins share 1/32 of their genes 23 23 Population Genetics HO August 24 Cont’d…  Consanguinity and Its Health Consequences  Consanguinity refers to the mating of individuals who are related to one another  typically, a union is considered to be consanguineous if it occurs b/n individuals related at the second-cousin level or closer  Fig-2 illustrates a pedigree for a consanguineous union  Because of their mutual descent from common ancestors, relatives are more likely to share the same disease-causing genes  Statistically,  Siblings (II-2 and II-3 or II-4) share 1/2 of their genes  First cousins (III-3 and III-4) share 1/8 of their genes (1/2 × 1/2 × 1/2)  Second cousins (IV-1 and IV-2) share 1/32 of their genes (1/8 × 1/2 × 1/2)  These numbers are referred to as the coefficients of relationship  Thus, if individual III-1 carries a disease-causing allele, there is  a 1/2 chance that individual III-3 (his brother) has it &  a 1/8 chance that individual III-4 (his first cousin) has it 24 24 Population Genetics HO August 24 Cont’d…  Consequently, there is an increased risk of genetic disease in the offspring of consanguineous matings  Dozensof empirical studies have examined the health consequences of consanguinity,  particularly first-cousin matings  These studies show that  the offspring of first-cousin matings are  twice as likely to present with a genetic disease as are the offspring of unrelated matings  The frequency of genetic disease increases further in the offspring of closer unions  e.g., uncle/niece or brother/sister matings 25 25 Population Genetics HO August 24 Fig-2: A Pedigree Illustrating Consanguinity 26 26 Population Genetics HO August 24 Review Questions 1. A population has been assayed for a 4-allele polymorphism, & the following genotype counts have been obtained:   On the basis of these genotype counts, what are the gene frequencies of alleles 1 & 2? A. 0.38, 0.28 B. 0.19, 0.14 C. 0.095, 0.07 D. 0.25, 0.25 E. 0.38, 0.20 27 27 Population Genetics HO August 24 Cont’d… 2. Which of the following best characterizes Hardy-Weinberg equilibrium? A. Consanguinity has no effect on Hardy-Weinberg equilibrium. B. Genotype frequencies can be estimated from allele frequencies, but the reverse is not true. C. Natural selection has no effect on Hardy-Weinberg equilibrium. D. Once a population deviates from Hardy-Weinberg equilibrium, it takes many generations to return to equilibrium. E. The frequency of heterozygous carriers of an autosomal recessive mutation can be estimated if one knows the incidence of affected homozygotes in the population 28 28 Population Genetics HO August 24 Cont’d… 3. In a genetic counseling session, a healthy couple has revealed that they are first cousins and that they are concerned about health risks for their offspring.  Which of the following best characterizes these risks? A. Because the couple shares approximately half of their genes, most of the offspring are likely to be affected with some type of genetic disorder. B. The couple has an increased risk of producing a child with an autosomal dominant disease. C. The couple has an increased risk of producing a child with an autosomal recessive disease. D. The couple has an increased risk of producing a child with Down syndrome. E. There is no known increase in risk for the offspring. 29 29 Population Genetics HO August 24 Cont’d… 4. An African American couple has produced two children with sickle cell disease.They have asked why this disease seems to be more common in the African American population than in other U.S. populations.  Which of the following factors provides the best explanation? A. Consanguinity B. Genetic drift C. Increased gene flow in this population D. Increased mutation rate in this population E. Natural selection 30 30 Population Genetics HO August 24 Cont’d… 5. If the incidence of cystic fibrosis is 1/2,500 among a population of Europeans, what is the predicted incidence of heterozygous carriers of a cystic fibrosis mutation in this population? A. 1/25 B. 1/50 C. 2/2,500 D. 1/2,500 E. (1/2,500)2 31 31 Population Genetics HO August 24 Cont’d… 6. A man is a known heterozygous carrier of a mutation causing hyperprolinemia, an autosomal recessive condition. Phenotypic expression is variable & ranges from high urinary excretion of proline to neurologic manifestations including seizures.  Suppose that 0.0025% (1/40,000) of the population is homozygous for the mutation causing this condition.  If the man mates with somebody from the general population, what is the probability that he and his mate will produce a child who is homozygous for the mutation involved? A. 1% (1/100) B. 0.5% (1/200) C. 0.25% (1/400) D. 0.1% (1/1,000) E. 0.05% (1/2,000) 32 32 Population Genetics HO August 24 Cont’d… 7. The incidence of Duchenne muscular dystrophy in North America is about 1/3,000 males. On the basis for this figure, what is the gene frequency of this X-linked recessive mutation? A. 1/3,000 B. 2/3,000 C. (1/3,000)2 D. 1/6,000 E. 1/9,000 33 33 Population Genetics HO August 24  Answers (Kaplan-Medical-USMLE 2021 for Explanation) 1. B 2. E 3. C 4. E 5. A 6. C 7. A 34 34 Population Genetics HO August 24 CASE STUDY  A 20-year-old college student is taking a course in human genetics. She is aware that she has an autosomal recessive genetic disease that has required her lifelong adherence to a diet low in natural protein with supplements of tyrosine and restricted amounts of phenylalanine. She also must avoid foods artificially sweetened with aspartame (Nutrasweet ). She asks her genetics professor about the chances that she would marry a man with the disease producing allele. 35 35 Population Genetics HO August 24 Study Questions 1. A recent study of achondroplasia dwarfism documented 7 new cases out of 250,000 in the US population. In achondroplasia dwarfism, homozygosity is a genetic lethal. What is the allele frequency of the achondroplasia dwarfism disease gene in the U.S. population? 2. Data-mining of the clinical records of a large number of U.S. hospitals indicates that Huntington disorder occurs in the U.S. population at a disease frequency of 1 in 10,000 or 0.0001. In Huntington disorder, homozygosity is not a genetic lethal. What is the allele frequency of the Huntington disease gene in the U.S. population? 36 36 Population Genetics HO August 24 3. A recent study of sickle cell anemia documented 10 new cases out of 6,250 in the African American population. What is the allele frequency (q) of the sickle cell disease gene in the African American population? What is the allele frequency (p) of the sickle cell normal gene in the African American population? What is the frequency of heterozygote carriers in the African American population? 4. A recent study of congenital deafness caused by a connexin 26 mutation documented 1 case out of 4,356 in the Nigeria population. What is the allele frequency (q) of the connexin 26 mutation in the Nigeria population? What is the allele frequency (p) of the connexin 26 normal gene in the Nigeria population? What is the frequency of heterozygote carriers in the Nigeria population? 37 37 Population Genetics HO August 24 5. A recent study of classic Rett syndrome documented 10 new cases out of 180,000 over the last 10 years in the female Mali population. What is the allele frequency (q) of the classic Rett syndrome disease gene in the Mali population? What is the allele frequency (p) of the classic Rett syndrome normal gene in the Mali population? 6. A recent study of Hunter syndrome documented 10 new cases out of 1,000,000 over the last 5 years in the Ethiopia population. What is the allele frequency (q) of the Hunter syndrome disease gene in the Ethiopia population? What is the allele frequency (p) of the Hunter syndrome normal gene in the Ethiopia population? What is the frequency of female heterozygote carriers? 38 38 Population Genetics HO August 24 Table-PG: Summary of Population Genetics 39 39 Population Genetics HO August 24 Table-PG: Summary of Population Genetics….Cont’d 40 40

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