Population Genetics 1-2 2023 PDF

Population Genetics I-II Robin T. Varghese, Ph.D. [email protected] Slide credit: Pawel Michalak, Ph. D. Population Genetics I-II Objectives 1. Delineate genetic variation with respect to geographic ancestry and evolution. 2. Derive the Hardy-Weinberg equation and apply to determine genetic ri...

Population Genetics I-II Robin T. Varghese, Ph.D. [email protected] Slide credit: Pawel Michalak, Ph. D. Population Genetics I-II Objectives 1. Delineate genetic variation with respect to geographic ancestry and evolution. 2. Derive the Hardy-Weinberg equation and apply to determine genetic risk by calculating carrier frequency, gene frequency and disease frequency. Demonstrate its use in determining the allelic and phenotypic frequencies within a population. 3. Identify three reasons why allelic frequencies within a population can change slightly with each generation. Give examples where applicable. 4. Distinguish the founder effect and genetic drift; give examples. Population Genetics – is the quantitative description of genetic variation in a population and how gene frequencies and genotypes are maintained or changed. Population Genetics is concerned with: Genetic factors such as rates of mutation and the distribution of new and old genes through reproduction (or failure to reproduce). Environmental/societal factors such as selection, mate choice, behavioral changes, and migration. Population Genetics looks at: • The history and genetic structure of human populations • The flow of alleles between generations and populations • Calculating allele frequencies and assessing risk for certain traits • The frequency of different traits in different populations • Differences in genetic susceptibility to common and uncommon diseases between human populations Definitions • Allelic frequency is the % of an allele in a population. • Genetic equilibrium is the concept that all allele frequencies remain stable from generation to generation. • Gene pool is the complete collection of all alleles in a single locus in a population. • Random mating is when individuals choose a reproductive mate completely by chance. • Assortative mating is a mating pattern in which individuals with specific phenotypes mate with one another more frequently than would be expected under a random mating pattern. • Consanguinity is the property of descending from the same ancestor. Definitions • Fitness is the quantitative representation of individual reproductive success. • Selection is environmental pressure on individuals of a population which results in the enrichment of advantageous or "adaptive" traits and the decline of deleterious traits. • Mutation is an alteration in the genetic material of an organism (this introduces new alleles – many will be deleterious) • Heterozygote advantage describes the case in which the heterozygous genotype has a higher relative fitness than either the homozygous dominant or homozygous recessive genotype. Hardy-Weinberg Equilibrium • p = frequency of dominant allele • q = frequency of recessive allele p+q=1 (p + q)2 = 12 p2 + 2pq + q2 = 1 Application of Hardy-Weinberg 2 p + 2pq + 2 q =1 • p2 = frequency of homozygous dominant (AA) • 2pq = frequency of heterozygotes (Aa) • q2 = frequency of homozygous recessives (aa) Assumptions of Hardy-Weinberg 1. Random mating in a large population 2. Allele frequencies remain constant over time due to: • Negligible rate of new mutations • No selection against a particular genotype • No migration Deviations from the H-W equilibrium can be informative that one of the factors is in play In a certain region of Africa, 16% of the population has sickle cell disease. What percent of the population are carriers (have sickle cell trait) for this allele? What percent of the population will be homozygous for the normal hemoglobin allele? q2 = 0.16 q = 0.4 p+q=1 p + 0.4 = 1 p = 0.6 f heterozygotes = 2pq = 2 (0.6)(0.4) = 0.48 or 48% f homozygous normal = p2 = (0.6)2 = 0.36 or 36% Hardy Weinberg- Sickle Cell Disease example Deleterious alleles persist in a population ? Supposing there is selection against a deleterious allele. Eventually, it will be lost from the population. • • • • • They may be maintained by mutation They may not really reduce fitness Natural selection may not have had time to remove them yet They may be maintained by migration They may be maintained by heterozygote advantage Positive Selection for Heterozygotes (Heterozygote Advantage) Malaria and Sickle Cell Anemia Hardy-Weinberg –CCR5 example • CCR5 encodes a cytokine receptor found on the cell surface of CD4 type T cells. • It is a cofactor for HIV binding and entry into T cells. • HIV leads to AIDS • ΔCCR5 is a 32-base deletion in this gene that leads to a frameshift mutation (nonfunctional protein) • Individuals homozygous for ΔCCR5 do not express the receptor and therefore are resistant to HIV p2 0.170 2pq p 0.009 q2 q Genetic Drift Genetic drift is the change in the frequency of a gene variant (allele) in a population due to the random redistribution of alleles to the next generation. Chance also plays a role in whether any given individual survives and reproduces. Chance alone can cause allele frequencies to shift from generation to generation. Deviations from the H-W equilibrium Possible effects of random genetic drift in large and small populations. Genetic drift can cause immense losses of genetic variation for small populations Founder Effect The loss of genetic variation that occurs when a new population is established by a very small number of individuals from a larger population Special case of genetic drift Bottleneck Effect Bottleneck effect: extreme example of genetic drift that happens when the size of a population is severely reduced e.g., Famines, earthquakes, disease, violence (war) etc. https://www.khanacademy.org/science/ap-biology/natural-selection/population-genetics/a/genetic-drift-founder-bottleneck Ashkenazi Jewish Disorders The Ashkenazim originate from the Jews who settled along the Rhine River, in Western Germany and in Northern France, and it is estimated that in 1931 they represented 92% of the Jewish population of the world. The holocaust severely reduced the population and forced migrations to many regions of the world. Today there are an estimated 11-12 million Ashkenazim around the world with half of those in the U.S. With little outbreeding this population is enriched in many diseases. • Familial Dysautonomia • Mucolipidosis type IV • Bloom syndrome • Gaucher disease • Fanconi Anemia • Cystic Fibrosis • Niemann Pick disease • Tay-Sachs disease • Canavan disease • Founders' effect and a population genetic bottleneck Isolated populations Genetic Flow Gene pool: 100% brown all individual's b/b Gene pool: 100% green all individual's G/G An individual migrates from one population to the other (and eventually mates) Gene Flow is when genes flow (genetic transfer) from one population to another population. Deviations from the H-W equilibrium Genetic Flow Gene pool: 90% green some individual's G/G, some G/b, some b/b Gene pool: 100% brown all individual b/b Gene Flow is when genes flow (genetic transfer) from one population to another population. An Example of Gene Flow ΔCCR5 Gene The gradual diffusion of genes across reproductive barriers (geographic, racial, ethnic, cultural) Ancient migrations and gene flow Ancient migrations and gene flow dbSNP Derived Allele Ancestral Allele Out of Africa Allele Genotype Count 6670818 G A G AG 1 10800485 C T C CT 1 12416000 A G A AA 2 16845098 C T C CT 1 16965666 G T G GT 1 2.7% Ancestry Informative Markers Ancestry Informative Markers • Alleles that show large differences in allele frequency in populations that originate in different parts of the world. • These markers can assist in charting human migration patterns, documenting historical admixture between populations, and determining genetic diversity among identifiable subgroups. • They can provide a more accurate view of a person’s heritage than self identification and arbitrary categories such as race. • They can be linked to disease causing alleles. Sample Question If 9% of a population have Beta thalassemia (major), what percentage of the population are Carriers for beta thalassemia (heterozygous for Beta-thalassemia) and what percentage of the population are normal (homozygous Dominant)? Consider only two alleles- Beta(normal) and Beta(0) Answer in notes below Sample Question Cystic fibrosis is a recessive condition that affects about 1 in 2,500 babies in the Caucasian population of the United States. Please calculate the following. A. The frequency of the recessive allele in the population. B. The frequency of the dominant allele in the population. C. The percentage of heterozygous individuals (carriers) in the population. Answer in notes below Disorder Recessive Sickle cell anemia ( S/S genotype) Rh (all Rh-negative alleles) Phenylketonuria (all mutant alleles) More examples Population Incidence Allele Frequency 2 U.S. African American Hispanic American U.S. white U.S. African Americans Japanese Scotland Finland Japan q Heterozygote Frequency 2 pq 1 in 11 q 1 in 400 0.05 1 in 40,000 0.005 1 in 101 1 in 6 1 in 14 0.41 0.26 ≈1 in 2 ≈2 in 5 1 in 200 1 in 5300 1 in 200,000 1 in 109,000 0.071 0.014 0.002 0.003 ≈1 in 8 1 in 37 1 in 250 1 in 166 References The hyperlinks embedded within the lecture notes Word document provide ample references for this material. Additional resources are also found below: • Reading Reference: Nussbaum, McInnes and Willard, Chapter 9 • Strachan, T., Goodship, J., Chinnery, P. (2015). Genetics and Genomics in Medicine. New York, NY: Garland Science. • https://www.khanacademy.org/science/biology/her/heredity-and-genetics/v/allelefrequency • https://www.khanacademy.org/science/biology/her/heredity-and-genetics/v/hardyweinberg • https://www.khanacademy.org/science/biology/her/heredity-andgenetics/v/applying-hardy-weinberg • https://www.khanacademy.org/science/biology/her/heredity-andgenetics/v/genetic-drift-bottleneck-effect-and-founder-effect