Population Genetics

Review: 1859: Darwin and the birth of modern biology (explaining why living things are as they are) – Heritable Traits and Environment  Evolution

Review: 1859: Darwin and the birth of modern biology (explaining why living things are as they are) – Heritable Traits and Environment  Evolution Mendel: Heredity works by the transmission of particles (genes) that influence the expression of traits

Review: 1859: Darwin and the birth of modern biology (explaining why living things are as they are) – Heritable Traits and Environment  Evolution Mendel: Heredity works by the transmission of particles (genes) that influence the expression of traits Avery, McCarty, and MacLeod: Genes are DNA

Review: 1859: Darwin and the birth of modern biology (explaining why living things are as they are) – Heritable Traits and Environment  Evolution Mendel: Heredity works by the transmission of particles (genes) that influence the expression of traits Avery, McCarty, and MacLeod: Genes are DNA Watson and Crick: Here’s the structure of DNA

Review: 1859: Darwin and the birth of modern biology (explaining why living things are as they are) – Heritable Traits and Environment  Evolution Mendel: Heredity works by the transmission of particles (genes) that influence the expression of traits Avery, McCarty, and MacLeod: Genes are DNA Watson and Crick: Here’s the structure of DNA Modern Genetics: Here’s how DNA influences the expression of traits from molecule to phenotype throughout development

Review: 1859: Darwin and the birth of modern biology (explaining why living things are as they are) – Heritable Traits and Environment  Evolution Mendel: Heredity works by the transmission of particles (genes) that influence the expression of traits How does evolution work at a genetic level? Population Genetics and the Modern Synthesis Avery, McCarty, and MacLeod: Genes are DNA Watson and Crick: Here’s the structure of DNA Modern Genetics: Here’s how DNA influences the expression of traits from molecule to phenotype throughout development

Review: 1859: Darwin and the birth of modern biology (explaining why living things are as they are) – Heritable Traits and Environment  Evolution Mendel: Heredity works by the transmission of particles (genes) that influence the expression of traits How does evolution work at a genetic level? Population Genetics and the Modern Synthesis Avery, McCarty, and MacLeod: Genes are DNA Watson and Crick: Here’s the structure of DNA Modern Genetics: Here’s how DNA influences the expression of traits from molecule to phenotype throughout development How can we describe the patterns of evolutionary change through DNA analyses? Evolutionary Genetics

The Modern Synthesis The Darwinian Naturalists The Mutationists Ernst Mayr Selection is the only mechanism that can explain adaptations; mutations are random and cannot explain the non-random ‘fit’ of organisms to their environment T. H. Morgan R. Goldschmidt The discontinuous variation between species can only be explained by the discontinuous variation we see expressed as a function of new mutations; the probabilistic nature of selection is too weak to cause the evolutionary change we see in the fossil record

The Modern Synthesis Sewall Wright Random chance was an important source of change in small populations J. B. S. Haldane Developed mathematical models of population genetics with Fisher and Wright R. A. Fisher Multiple genes can produce continuous variation, and selection can act on this variation and cause change in a population Theodosius Dobzhansky Described genetic differences between natural populations; described evolution as a change in allele frequencies.

Population Genetics I. Basic Principles

Population Genetics I. Basic Principles A. Definitions: - Population: a group of interbreeding organisms that share a common gene pool; spatiotemporally and genetically defined - Gene Pool: sum total of alleles held by individuals in a population - Gene/Allele Frequency: % of genes at a locus of a particular allele - Gene Array: % of all alleles at a locus: must sum to 1. - Genotypic Frequency: % of individuals with a particular genotype - Genotypic Array: % of all genotypes for loci considered = 1.

Population Genetics I. Basic Principles A. Definitions: B. Basic computations: 1. Determining the Gene and Genotypic Array: AA Aa aa Individuals 60 80 (200)

Population Genetics I. Basic Principles A. Definitions: B. Basic computations: 1. Determining the Gene and Genotypic Array: AA Aa aa Individuals 60 80 (200) Genotypic Array 60/200 = 0.30 80/200 = .40 = 1

Population Genetics I. Basic Principles A. Definitions: B. Basic computations: 1. Determining the Gene and Genotypic Array: AA Aa aa Individuals 60 80 (200) Genotypic Array 60/200 = 0.30 80/200 = .40 = 1 ''A' alleles 120 200/400 = 0.5

Population Genetics I. Basic Principles A. Definitions: B. Basic computations: 1. Determining the Gene and Genotypic Array: AA Aa aa Individuals 60 80 (200) Genotypic Array 60/200 = 0.30 80/200 = .40 = 1 ''A' alleles 120 200/400 = 0.5 'a' alleles

Population Genetics I. Basic Principles A. Definitions: B. Basic computations: 1. Determining the Gene and Genotypic Array 2. Short Cut Method: - Determining the Gene Array from the Genotypic Array a. f(A) = f(AA) + f(Aa)/2 = .30 + .4/2 = .30 + .2 = .50 b. f(a) = f(aa) + f(Aa)/2 = .30 + .4/2 = .30 + .2 = .50 KEY: The Gene Array CAN ALWAYS be computed from the genotypic array; the process just counts alleles instead of genotypes. No assumptions are made when you do this.

Population Genetics I. Basic Principles A. Definitions: B. Basic computations: C. Hardy-Weinberg Equilibrium: 1. If a population acts in a completely probabilistic manner, then: - we could calculate genotypic arrays from gene arrays - the gene and genotypic arrays would equilibrate in one generation

Population Genetics I. Basic Principles A. Definitions: B. Basic computations: C. Hardy-Weinberg Equilibrium: 1. If a population acts in a completely probabilistic manner, then: - we could calculate genotypic arrays from gene arrays - the gene and genotypic arrays would equilibrate in one generation 2. But for a population to do this, then the following assumptions must be met (Collectively called Panmixia = total mixing) - Infinitely large (no deviation due to sampling error) - Random mating (to meet the basic tenet of random mixing) - No selection, migration, or mutation (gene frequencies must not change)

Population Genetics I. Basic Principles A. Definitions: B. Basic computations: C. Hardy-Weinberg Equilibrium: Sources of Variation Agents of Change Mutation N.S. Recombination Drift - crossing over Migration - independent assortment Mutation Non-random Mating VARIATION So, if NO AGENTS are acting on a population, then it will be in equilibrium and WON'T change.

Population Genetics I. Basic Principles A. Definitions: B. Basic computations: C. Hardy-Weinberg Equilibrium: 3. PROOF: - Given a population with p + q = 1. - If mating is random, then the AA, Aa and aa zygotes will be formed at p2 + 2pq + q2 - They will grow up and contribute genes to the next generation: - All of the gametes produced by AA individuals will be A, and they will be produced at a frequency of p2 - 1/2 of the gametes of Aa will be A, and thus this would be 1/2 (2pq) = pq - So, the frequency of A gametes in the gametes will be p2 + pq = p(p + q) = p(1) = p - Likewise for the 'a' allele (remains at frequency of q). - Not matter what the gene frequencies, if panmixia occurs than the population will reach an equilibrium after one generation of random mating...and will NOT change (no evolution)

Initial genotypic freq. Population Genetics I. Basic Principles A. Definitions: B. Basic computations: C. Hardy-Weinberg Equilibrium: AA Aa aa Initial genotypic freq. 0.4 0.2 1.0 Gene freq. Genotypes, F1 Gene Freq's Genotypes, F2

Initial genotypic freq. Population Genetics I. Basic Principles A. Definitions: B. Basic computations: C. Hardy-Weinberg Equilibrium: AA Aa aa Initial genotypic freq. 0.4 0.2 1.0 Gene freq. f(A) = p = .4 + .4/2 = 0.6 f(a) = q = .2 + .4/2 = 0.4 Genotypes, F1 Gene Freq's Genotypes, F2

Initial genotypic freq. Population Genetics I. Basic Principles A. Definitions: B. Basic computations: C. Hardy-Weinberg Equilibrium: AA Aa aa Initial genotypic freq. 0.4 0.2 1.0 Gene freq. f(A) = p = .4 + .4/2 = 0.6 f(a) = q = .2 + .4/2 = 0.4 Genotypes, F1 p2 = .36 2pq = .48 q2 = .16 = 1.00 Gene Freq's Genotypes, F2

Initial genotypic freq. Population Genetics I. Basic Principles A. Definitions: B. Basic computations: C. Hardy-Weinberg Equilibrium: AA Aa aa Initial genotypic freq. 0.4 0.2 1.0 Gene freq. f(A) = p = .4 + .4/2 = 0.6 f(a) = q = .2 + .4/2 = 0.4 Genotypes, F1 p2 = .36 2pq = .48 q2 = .16 = 1.00 Gene Freq's f(A) = p = .36 + .48/2 = 0.6 f(a) = q = .16 + .48/2 = 0.4 Genotypes, F2

Initial genotypic freq. Population Genetics I. Basic Principles A. Definitions: B. Basic computations: C. Hardy-Weinberg Equilibrium: AA Aa aa Initial genotypic freq. 0.4 0.2 1.0 Gene freq. f(A) = p = .4 + .4/2 = 0.6 f(a) = q = .2 + .4/2 = 0.4 Genotypes, F1 p2 = .36 2pq = .48 q2 = .16 = 1.00 Gene Freq's f(A) = p = .36 + .48/2 = 0.6 f(a) = q = .16 + .48/2 = 0.4 Genotypes, F2 .36 .48 .16 1.00

Population Genetics I. Basic Principles A. Definitions: B. Basic computations: C. Hardy-Weinberg Equilibrium: D. Utility

Population Genetics I. Basic Principles A. Definitions: B. Basic computations: C. Hardy-Weinberg Equilibrium: D. Utility 1. If no real populations can explicitly meet these assumptions, how can the model be useful?

Population Genetics I. Basic Principles A. Definitions: B. Basic computations: C. Hardy-Weinberg Equilibrium: D. Utility 1. If no real populations can explicitly meet these assumptions, how can the model be useful? It is useful for creating an expected model that real populations can be compared against to see which assumption is most likely being violated.

Example: CCR5 – a binding protein on the surface of white blood cells, involved in the immune response. CCR5-1 = functional allele CCR5 – D32 = mutant allele – 32 base deletion Curiously, homozygotes for D32 are resistant to HIV, and heterozygotes show slower progression to AIDS. Mutant allele interrupts virus’s ability to infect cells.

Example: CCR5 – a binding protein on the surface of white blood cells, involved in the immune response. CCR5-1 = functional allele CCR5 – D32 = mutant allele – 32 base deletion Curiously, homozygotes for D32 are resistant to HIV, and heterozygotes show slower progression to AIDS.

GENOTYPES 32 base-pair deletion, shortening one of the fragments digested with a restriction enzyme

GENOTYPE OBSERVED EXPECTED O - E (O – E)2 (O – E)2/E 1/1 223 224.2 -1.2 1.44 0.006 32/1 57 55.4 1.6 2.56 0.046 32/32 3 3.4 -0.4 0.16 0.047 283 X2 = 0.099 1/1 = 223/283 = 0.788 p = 0.788 + 0.201/2 = 0.89 32/1 = 57/283 = 0.201 32/32 = 3/283 = 0.011 q = 0.011 + 0.201/2 = 0.11 Expected 1/1 = p2 x 283 = (0.792) x 283 = 224.2 Expected 1/32 = 2pq x 283 = (0.196) x 283 = 55.4 Expected 32/32 = q2 x 283 = (0.0121) x 283 = 3.4

So this population is in HWE at this locus So this population is in HWE at this locus. HIV is still rare, and is exerting too small a selective pressure on the whole population to change gene frequencies significantly. This is the percentage of CCR5 delta 32 in different ethnic populations: European Descent: 16% African Americans: 2% Ashkenazi Jews: 13% Middle Eastern: 2-6% Why does the frequency differ in different populations? Drift or Selection?

Allelic frequency of CCR5-d32 in Europe Galvani, Alison P. , and John Novembre. 2005. The evolutionary history of the CCR5-D32 HIV-resistance mutation. Microbes and Infection 7 (2005) 302–309

Spread of the Bubonic Plague Why Europe? - the allele is a new mutation - was it selected for in the past? Spread of the Bubonic Plague

Why Europe? - the allele is a new mutation - was it selected for in the past? Smallpox and CCR5 Smallpox in Europe “In the 18th century in Europe, 400,000 people died annually of smallpox, and one third of the survivors went blind (4). The symptoms of smallpox, or the “speckled monster” as it was known in 18th-century England, appeared suddenly and the sequelae were devastating. The case-fatality rate varied from 20% to 60% and left most survivors with disfiguring scars. The case-fatality rate in infants was even higher, approaching 80% in London and 98% in Berlin during the late 1800s.” Reidel (2005). The WHO certified that smallpox was eradicated in 1979

Relationships Between Smallpox and HIV 1. “Smallpox, on the other hand, was a continuous presence in Europe for 2,000 years, and almost everyone was exposed by direct person-to-person contact. Most people were infected before the age of 10, with the disease's 30 percent mortality rate killing off a large part of the population before reproductive age.” ScienceDaily (Nov. 20, 2003) 2. The HIV epidemic in Africa began as vaccination against smallpox waned in the 1950’s – 1970’s. Perhaps vaccinations for smallpox were working against HIV, too. 3. In vitro studies of wbc’s from vaccinated people had a 5x reduction in infection rate of HIV compared to unvaccinated controls. Weinstein et al. 2010 So, it may have been selected for in Europe, and now confer some resistance to HIV.