7 POPULATION GENETICS 7.1 INTRODUCTION Most humans are susceptible to HIV infection. However, some people seem to be able to avoid infection despite repeated exposure. Some resistance is due to a rare allele of a gene that codes for the CCR5 protein. CCR5 is a cell surface protein that is a co-receptor for the HIV virus when it binds to the cell membrane of macrophages and T cells. Some people have a form of the gene encoding CCR5 that includes a 32-bp deletion that results in a dysfunctional protein. The allele is called CCR5-Δ32. Individuals who inherit two copies of the deleted allele have no CCR5 co-receptors on the cell membrane of white blood cells. These homozygotes are highly resistant to HIV infection. Will the global HIV epidemic result in increasing frequencies of the CCR5-Δ32 allele? If so, how soon will this happen? Also, northern European populations carry a higher frequency of this allele than do Asian or African populations. Is this difference due to chance, or due to the fact that CCR5-Δ32 also increased resistance to some previous epidemic that occurred in Northern Europe (plague, smallpox, etc.)? These are kinds of questions that population genetics is designed to answer. This discipline describes the behavior of alleles in populations by focusing on the forces that can cause allele frequencies to change over time. “Allele frequency change over time” is simply a definition of “evolution”. So population genetics is that branch of genetics that is concerned with the evolutionary processes of natural selection, genetic drift, mutation, migration, and non-random mating. Population genetic approaches can be used to understand the consequences of these processes individually or in combination. Review: A population is a group of organisms of the same species living within a prescribed geographical area. The area is usually determined to be of a size within which individuals are likely to find mates. Geographically widespread species are often subdivided into more or less distinct breeding groups that live within limited geographical areas. These groups are called subpopulations. For example, Ponderosa pine in Southeastern Arizona and Northern Mexico could be considered a single population. Individual pines in Arizona live at high altitudes, but not in desert surrounding the mountains. If there is only rare migration (pollen dispersal) between groups in different mountain ranges, each mountain range would have its own local subpopulation of pines. Humans were probably once subdivided into local populations. Now, for the most part, we exist in a global population (with the exception of a few fairly isolated subpopulations). The complete set of genetic information contained within the individuals in a population is called the ge ne pool. The gene pool includes all genetic loci and all the alleles for each locus present in the population. The gene pool of a population can be described and characterized by certain statistical properties: Allele frequency (gene frequency) is the proportion of all alleles at a locus that are of a specified type. Polymorphism is the proportion of all genetic loci that exist in more than one allelic form. Humans, P=0.32, D. melanogaster, H=0.42. Heterozygosity is the proportion of individuals that are heterozygous (as opposed to homozygous) for alternate alleles at a specific locus. Humans: H=0.06, D. melanogaster, H=0.14 Both heterozygosity and polymorphism are used as measures of genetic variation within populations. Different alleles within populations can be identified by phenotypic effects (color, size, shape variants, disorders like color blindness or Huntington's disease), by variation in protein structure (standard blood-type assays, protein electrophoresis), or by variation in DNA sequence (restriction site variation, variation in number of repeats in repetitive DNA segments, DNA sequence variation)We will begin our discussion of population genetics by considering an analysis of a local population with respect to a phenotype determined by two alleles at a single locus. The human MN blood group is an extremely simple system. It is characterized by a single locus with only two alleles, M and N (sometimes referred to as LM and LN). The alleles are codominant (both alleles are detectable in heterozygotes). blood types (phenotypes) Genotypes M M M (or LM LM) MN M N N N N ALLELE & GENOTYPE FREQUENCIES IN SURVEY OF BRITISH POPULATION: Phenotype Genotype # M alleles # N alleles 298 M 298 MM 596 0 489 MN 489 MN 489 489 213 N 213 NN 0 426 Total 1000 1000 1085 915 Genotype frequency is relative proportion of genotype: Proportion of MM genotype = 298/1000 = 0.298 Proportion of MN genotype = 489/1000 = 0.489 Proportion of NN genotype = 213/1000 = 0.213 Total = 1.000 The allele frequency of the M allele is the relative proportion of the allele: Proportion of M allele =1085/2000=0.5425 Proportion of N allele = 915/2000 =0.4575 Total=1.000 If we let p = the allele frequency of M and q= the allele frequency of N, then q = 1-p. 7.2 THE HARDY-WEINBERG PRINCIPLE We can use knowledge of allele frequencies to make inferences about patterns of mating, selection on certain alleles, migration between populations, etc. Allele frequencies are more useful than genotype frequency because alleles rarely undergo mutation in a single generation, so are stable in their transmission from one generation to the next. In contrast, genotypes are not permanent. They are broken up by the processes of segregation and recombination that take place during meiosis. Furthermore, we can deduce the expected genotype frequencies in the next generation from knowledge of only the allele frequencies in the previous generation. First, consider that for diploid organism with two different alleles at a locus, a gamete has an equal chance of containing either of the two alleles (equal segregation--Mendel's first law). individual gamete types gamete contribution gamete frequency 0.298 MM all M 0.298 M gametes 0.5425 M gametes 0.489 MN 1/2 M 0.2445 M gametes 1/2 N 0.2445 N gametes 0.4575 N gametes 0.213 NN all N 0.213 N gametesNext assume random mating of individuals with respect to MN blood type (usually a very reasonable assumption, as people do not usually chose their spouses based on MN blood type!). Random mating is equivalent to random union of gametes. One Generation of