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Congratulation for Your Success Population Genetics - Drift Mohammad Keramatipour MD, PhD [email protected] M Keramatipour 1 M Keramatipour Welcome To Medical Genetics 2 Today’s Lecture Overview of basic concepts Allele frequency Genotype frequency The Th H Hardy Hardyd -Weinberg W i b L Law Medical applications Factors that change allele frequencies in population Genetic drift ¾ Definition ¾ Effects ¾ Factors affecting drift M Keramatipour 3 M Keramatipour Population Genetics: History 4 Basic Definitions Genes, Alleles, Genotype, and Phenotype !! Emerged in the 1920s 1920s and 1930 1930ss Main M i contributors: t ib t Si Sir R Ronald ld Fi Fisher, h S Sewallll W Wright, i ht JJ. B B. Population Genetics: Genetics: is the study of: ¾ Genetic variation in population and the factors that change or maintain such variation (over many generation) ¾ Distribution of genes/alleles and inherited traits S. Haldane Direct extension of Mendelian genetics, molecular genetics, and the idea of Darwin Population Population:: is a group of interbreeding individuals who Focus changes from individual to population share a gene pool The central issue: genetic variation Gene G pooll: consists pool: i t off allll genes ((or alleles) ll l ) iin a population l ti M Keramatipour 5 M Keramatipour 6 Human Population Human Population Establishment of genetic diversity & development of ethnic Genetic diversity in human population ¾ Human chromosome and their loci are identical among us ¾ Alleles & their frequencies vary among population groups groups:: groups ¾ Mutation ¾ Natural selection ¾ Reproductive isolation 8 Disease causing g alleles 8 Neutral DNA polymorphism DNA polymorphism ¾ Definition Main racial divisions in human population: ¾ Caucasian (European) ¾ Blacks (African) ¾ Asian 8 Polymorphic genes 8 Monomorphic genes ¾ Different frequencies q of alleles and genotypes Average heterozygosity in individual M Keramatipour 7 Allele & Genotype Frequencies Driving genotype frequencies from allele frequency ¾ Assume A a population l ti 8 Gene pool 8 Assume a gene with two alleles 8 Allele A = 70% 70% 8 Allele a = 30% 30% Driving g allele frequency y from g genotype y frequency: y ¾ Example: assume a population with following genotype at locus X with two alleles, B & b - BB: BB 350 - Bb: 400 - bb: 250 - Calculate the allele and genotype frequencies? ¾ Calculate the genotype frequencies 8 AA, Aa, Aa, & aa 9 M Keramatipour HardyHardy -Weinberg Law 10 HardyHardy -Weinberg Law Driving genotype frequencies from allele frequencies? 1908: 1908: Harold Hardy & Wilhelm Weinberg ¾ Introduction of a mathematical expression that: 8 Relate the allele and genotype frequencies in populations 8 Predicts g genetic stability y over the course of many y generations: Hardy Hardyy-Weinberg g law: ((for a locus with two alleles A and a with frequencies p and q respectively) ¾ The frequency of the three genotypes AA, AA Aa Aa,, and aa are given by the terms of the binomial expansion of (p+q p+q))2 = p2 + 2pq + q2 ÁStability of allele and genotype frequencies ÁRefer to as “equilibrium” equilibrium ÁUnder a given set of conditions ¾ Whatever allele frequencies happen to be present in the population will result in genotype frequencies of p2:2pq:q2, and these relative genotype frequencies will remain constant from generation to generation as long as the allele q (p and q) (p q) remain constant frequencies Later development: ¾ Understanding changes in gene/allele frequencies within a population when such equilibrium is violated M Keramatipour 8 Allele & Genotype Frequencies Fundamental characteristics of a population: ¾ Allele frequency ¾ Genotype frequency 8 How can we drive such p parameters in a p population?? p M Keramatipour M Keramatipour ¾ In general, the genotype frequencies for any known number of alleles with allele frequencies p1, p2, ….,p ….,pn can be derived from expansion of (p1 + p2 + ….pn)2 ….p 11 M Keramatipour 12 Assumptions of HardyHardy-Weinberg Law HardyHardy -Weinberg Equilibrium A population in HardyHardy-Weinberg Equilibrium Equilibrium? ? Hardy Hardy--Weinberg law is based upon following A population in disequilibrium disequilibrium? ? assumptions: ¾ Large L population l ti size i No population satisfy HardyHardy-Weinberg equilibrium ¾ Random mating completely Because of large size of human population we consider our population in HardyHardy-Weinberg equilibrium This Thi law l is i used d to d determine i the h ffrequencies i off di disease genes which is critical in genetic counseling specially for autosomal recessive disorders ¾ Constant allele frequencies 8 No mutation 8 No selection 8 No migration M Keramatipour 13 M Keramatipour Population in Equilibrium?? 14 Population in Equilibrium?? It is very important to show if a population is in HardyHardy-Weinberg Example: assume a human population of 200 equilibrium or not, in regard to an allele (specially disease casing alleles) How do you show this? ¾ Chi Chi-square square (χ2) test answers this question ¾ In general chi square test can be used to test the validity of a hypothesis by comparing the observed data with expected data based on th hypothesis the h th i M Keramatipour MN blood group frequency in this population: ¾ MM: 168 ¾ MN: 30 ¾ NN: 2 Is this population in equilibrium? 15 Counting Disease Causing Alleles - 1 M Keramatipour 16 Counting Disease Causing Alleles - 2 Using disease incidence to calculate frequency of mutant allele Autosomal dominant conditions: ¾ Assume D is mutant allele with frequency of p and d is the normal allele with frequency of q, q (p is very small and p + q = 1 then we can assume q ≅ 1) Autosomal recessive conditions: ¾ D is the normal allele with p frequency and d is the mutant allele with q frequency ¾ The incidence of the disease (genotype dd) is simply the allele frequency squared (q2) ¾ Homozygous for autosomal dominant conditions are very rare in comparison to heterozygous (p2 << 2pq), so we can ignore p2. In other word,, we can assume all the cases are heterozygote yg ¾ Conversely the allele frequency (q) can be calculated as the square root of the disease incidence (q2) ¾ Frequency of heterozygotes is 2pq and q ≅ 1, so the frequency of heterozygotes which is the observed incidence of the disease is roughly 2p M Keramatipour ¾ The frequency of heterozygote carrier (i.e., the genotype Dd) is 2 2pq 17 M Keramatipour 18 Counting Disease Causing Alleles - 3 Trying Some Examples X-linked conditions: Incidence of FH in a population is 1 in 500 500.. Find the ¾ The frequency of mutant allele (q) for an X-linked X linked recessive is frequency of mutant allele in this population? equal to the frequency of the disease among males Incidence of Tay Tay-Sachs Sachs disease is 1 in 3600 in ¾ The frequency of mutant allele (q) for an X-linked dominant Ashkenazi Jewish births. Calculate the carrier frequency in this population? condition is half of the disease frequency among females M Keramatipour 19 Exceptions to Hardy Hardy-Weinberg Assumptions 20 Exceptions to HardyHardy-Weinberg Assumptions Exceptions to random mating: Assume that a mutant allele and its associated g genotype yp ¾ Stratification is not in Hardy Hardy--Weinberg equilibrium in a given population, what this may tell you? ¾ Assortative Assortative,, & disassortative mating ¾ Consanguinity (inbreeding) (inbreeding), & outbreeding ¾ Maybe underlying assumptions are being violated ¾ The net effect of these exceptions: 8 Excess of homozygotes 8 Deficiency y of heterozygotes yg ¾ Mutation rate, and time ¾ The effect of the mutation (or disease) on survival and reproduction M Keramatipour M Keramatipour 21 M Keramatipour 22 23 M Keramatipour 24 Exceptions to Hardy Hardy-Weinberg .. Exceptions to constant allele frequency ¾ Mutation (the source of new allele) ¾ Neutral forces Genetic drift 8 Migration (gene flow) 8 ¾ Adaptive forces Natural selection 8 Heterozygous superiority or advantage: causes a balanced polymorphism 8 M Keramatipour Genetic Drift Effect of Genetic Drift Drift & drifting: ¾ Random sampling error The net effect of genetic drift: ¾ Random R d fifixation ti or loss l off an allele ll l Genetic Drift: ¾ Random sampling error in allele frequency ?? ¾ The fluctuation in allele frequency in gene pool by chance ¾ Chance / random ?? 8 Survival 8 Reproduction R d ti ¾ Elimination of genetic variation within populations 8 Reducing heterozygosity 8 Increasing homozygosity ¾ Increasing variation between populations ¾ The effect of population size on random sampling error ??? M Keramatipour 25 Genetic Drift and Population Size M Keramatipour 26 Probability of Fixation or Loss The effect of genetic drift is less in large population Population size = N, Mutation rate = r Expected number of new mutation = 2Nr Allele Frequency of the new mutation = 1/2N Probability of fixation is the same as the allele frequency in the population (consistent with random effect of genetic drift) so = 1/2N Probability of loss (elimination) = 1- Probability of fixation = 1 - 1/2N M Keramatipour 27 Effect of Population Size on Fixation 28 How Long Does Fixation Take? Chance of fixation for a new mutation: how many In large population (N is very large), new mutations are generation is it likely to take? more likely to occur But each new mutation has a lower chance of being Again it depends on the number of individuals in the fixed and higher chance of being lost population and it is equal to: t = 4N (t is the average number of generations to achieve fixation)) In small population (N is small), the probability of new mutation is small But the likelihood of fixation is relatively large M Keramatipour M Keramatipour Allele fixation will take much longer in large population 29 M Keramatipour 30 Factors Slowing The Effects of Drift Points to Remember !!! Genetic drift ultimately operates in a directional manner Large g p population p size with regard to allele frequency (fixation or elimination) Migration between subpopulations Mutation Over time genetic drift will cause fixation of one allele for any gene so heterozygosity and polymorphism go to zero ((if g genetic drift is the only y force operating p g within a population) Natural selection (heterozygote advantage ??) The impact of genetic drift is more significant in smaller population M Keramatipour 31 Medical Implication 32 Common Form of Genetic Drift Founder effect ¾ Definition ¾ Different allele frequencies than the original population ¾ Less genetic variation than the original population ¾ Examples 8 Huntington disease in the region of Lake Maracaibo, Venezuela Ethnic differences in the frequency of various genetic diseases ¾ Differences in allele frequencies in different populations, why? ¾ Why some deleterious alleles are relatively common in certain populations? Two main factors: ¾ Genetic drift 8 Founder effect 8 The bottleneck effect ¾ Heterozygote H advantage d M Keramatipour M Keramatipour 8 Type I tyrosinemia in Lac Saint Jean region of Quebec (a French--Canadian subpopulation) French ÁFrequency 1/685 685,, versus 1/100 000 in other part of Quebec ÁAll due to same mutation in fumarylacetoacetase enzyme (a splice donor site mutation in intron 12 12)) 33 Founder Effect: Finland M Keramatipour 34 Finland Population: An Example Finish population: ¾ Develop from 400000 to 5 million during the last 300 years ¾ Distinctive pattern of singlesingle-gene disorders ¾ High g frequencies of at least 20 singlesingle g -g gene disorders 8 Choroideremia Choroideremia:: X X--linked degenerative eye disease X-linked choroideremia Hyperornithinemia Á400 reports all over the world Á1/3 from f a smallll population l ti iin Fi Finland l d ÁA family descendent from a couple born in the 1640 1640ss 8 Hyperornithinemia yp with gy gyrate atrophy p y of the choroid and retina ÁAR disease with deficiency of ornithine aminotransferase ÁSpecific mutation mutation, not seen in other part of the world 8 PKU is very rare in Finland M Keramatipour 35 M Keramatipour 36 AR Diseases in Different Population Founder Effect More example: ¾ Ellis Ellis--van Creveld Syndrome (recessive form of dwarfism) in Old Order Amish of Lancaster County, Pennsylvania ¾ Tay-Sachs Tay Sachs disease in Ashkenazi Jewish M Keramatipour 37 M Keramatipour 38 39 M Keramatipour 40 Common Forms of Genetic Drift The bottleneck effect ¾ Same effect as founder effect 8 Reduced population size 8 Reduced R d d gene pooll 8 Different allele frequencies ¾ Example: ¾ Probably modern human !!! ¾ The African cheetah population M Keramatipour ∆CCR CCR5 5 Allele Frequencies Drift vs. Heterozygote Advantage Heterozygote advantage ¾ Balanced polymorphism ¾ Example: 8 Malaria & hemoglobinopathies g Drift versus heterozygote advantage ¾ Which one is responsible for increased frequency of some deleterious alleles? ¾ Difficult Diffi lt tto fifind d out!!, t!! example: l ¾ CCR CCR5 5: a cell surface cytokine receptor, entry point for some strains of HIV 8 ∆CCR CCR5 5 allele frequency?? M Keramatipour 41 M Keramatipour 42 Conceptual Questions Conceptual Questions Regarding genetic drift, specify the True or False In genetic drift, what is drifting? Why is this an statements: ¾ Over the long run, genetic drift will lead to allele fixation or loss. ¾ When a new mutation occurs within a population, genetic drift is more likely g y to cause the loss of the new allele rather than the fixation of the new allele. ¾ Genetic drift promotes genetic diversity between populations. ¾ Genetic drift promotes genetic diversity in large populations. M Keramatipour appropriate term to describe this phenomenon? Why is genetic drift more significant in small populations? Why does it take longer for genetic drift to cause allele fixation in large population than in small ones? Describe what happens to allele frequencies during the bottleneck effect effect. Discuss the relevance of this effect with regard to species that are approaching extinction. 43 Practical Examples M Keramatipour 44 Thank you for listening, any comments? A group of four birds flies to a new location and initiated the formation of a new colony. Three of them are homozygous DD DD,, and one bird is heterozygous Dd (for a particular locus). ¾ What is the probability that the d allele will become fixed in the population? ¾ If fixation occurs, how long will it take? ¾ How will the growth of the population, from generation to generation, affect the answers to parts a and b? Briefly explain please. M Keramatipour 45 M Keramatipour 46