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Genetics: From Genes to Genomes

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1 Genetics: From Genes to Genomes
PowerPoint to accompany Genetics: From Genes to Genomes Fourth Edition Leland H. Hartwell, Leroy Hood, Michael L. Goldberg, Ann E. Reynolds, and Lee M. Silver Prepared by Mary A. Bedell University of Georgia Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition

2 19 Variation and Selection in Populations CHAPTER OUTLINE PART VI
Beyond the Individual Gene and Genome CHAPTER Variation and Selection in Populations CHAPTER OUTLINE 19.1 The Hardy-Weinberg Law: Predicting Genetic Variation in Populations 19.2 Causes of Allele Frequency Changes 19.3 Analyzing Quantitative Variation Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

3 Three subfields of genetics based on the unit object that is the focus of study
Molecular genetics – the unit entity is the gene Formal genetics – the unit entity is the individual organism, defined by genotype Population genetics – the unit entity is a population of interbreeding individuals Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

4 Terms used to describe populations
Population – group of interbreeding individuals of the same species that inhabit the same space at the same time Gene pool – sum total of alleles carried by all members of a population Changes can occur because of mutation, immigration of new individuals into or out of the population, or decreased fitness Microevolution – changes in allele frequencies within a population Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

5 Terms used to describe populations (cont)
Phenotype frequency – proportion of individuals in a population that have a particular phenotype Genotype frequency – proportion of individuals in a population that carry a particular genotype Example: A gene with two alleles (A and B) in a population of 20 individuals 12 are AA 4 are AB 4 are BB Genotype frequencies: AA = 12/20 = 0.6 AB = 4/20 = 0.2 BB = 4/20 = 0.2 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

6 Calculating allele frequencies
Allele frequency – proportion of gene copies in a population that are of a given allele type Example with genotype frequencies: AA = 12/20 = 0.6 AB = 4/20 = 0.2 BB = 4/20 = 0.2 Allele frequencies: in 20 people, there is a total of 40 alleles 12 AA individuals  24 A alleles 4 AB individuals  4 A alleles and 4 B alleles 4 BB individuals  8 B alleles Frequency of A alleles = (24 + 4)/40 = 0.7 Frequency of B alleles = (8 + 4)/40 = 0.3 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

7 From genotype frequencies to allele frequencies
Fig 19.2 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

8 The Hardy-Weinberg law correlates allele and genotype frequencies
Developed independently in 1908 by G.H. Hardy and W. Weinberg Five simplifying assumptions: The population has an infinite number of individuals Individuals mate at random No new mutations appear No migration into or out of the population Genotypes have no effect on ability to survive and transmit alleles to the next generation Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

9 Predicting genotype frequencies in the next generation
Sexually reproducing, diploid organisms Two steps needed to relate genotype frequencies in one generation to the next generation Allele frequencies should be the same in adults as in gametes Allele frequencies in gametes can be used to calculate expected genotype frequencies in zygotes of the next generation Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

10 The Hardy-Weinberg law is a binomial equation
Fig 19.3 In a large population of randomly breeding individuals with no new mutations, no migration, and no differences in fitness based on genotype: p2 + 2pq + q2 = 1 (Equation 19.1) Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

11 Predicting the frequency of albinism: A case study
In a population of 100,000 people: 100 aa albinos, 1800 Aa carriers, 98,100 AA individuals Total A alleles = (2 x 98,100) = 198,000 Total a alleles = (2 x 100) = 2,000 Frequency of A allele = p = 198,000/200,000 = 0.99 Frequency of a allele = q = 2,000/200,000 = 0.01 p2 = (0.99)2 = pq = 2(0.99)(0.01) = q2 = (0.01)2 = Predicted genotypes in the next generation of 100,000 individuals: 100,000 x = 98,010 AA individuals 100,000 x = 1980 Aa individuals 100,000 x = 10 aa individuals Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

12 The population genetics of blue-eye color
Blue-eye color in humans is recessive to brown eyes and arose 6,000 – 10,000 years ago Trait is very common in Europe but rare outside of Europe Geographic differences in proportions of European populations expressing the blue eyes phenotype Fig 19.4a Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

13 A SNP located in an enhancer of the OCA2 gene is associated with blue eye color
The SNP rs is located in an intron of the HERC2 gene Fig 19.4b Haplotype structure of SNP alleles at the OCA2-HERC2 region Fig 19.4c Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

14 Frequencies of the A and G alleles of the SNP rs12913832 in different populations
p = rs A q = rs G Fig 19.4d Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

15 Use of the Hardy-Weinberg equation with mixed populations
Example: Blue-eye phenotype in a population derived from 100 people from northern Finland and 100 people from Yakuts of eastern Siberia p = frequency of rs A q = frequency of rs G In Finnish population of 100 people, q = 0.84 q2 = (0.84)2 = pq = 2 (0.16)(0.84) = estimated to be GG (blue eyes) 27 estimated to be GA (brown-eyed carriers) In Yakut population of 100 people, q = 0.10 q2 = (0.1)2 = pq = 2 (0.9)(0.1) = estimated to be GG (blue eyes) 18 estimated to be GA (brown-eyed carriers) Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

16 Blue eyes vs. brown eyes in a mixed population (cont)
Total population = 100 Finns Yakuts = 200 Total GG (blue eyes) = 71 Finns + 1 Yakut = 72 Total GA (carriers) = 27 Finns + 18 Yakuts = 45 Total number of G alleles = (2 x 72) + 45 = 189 Frequency of G alleles = q = 189/400 = 0.47 Expected frequency of offspring with blue eyes (GG) from these 100 Finns and 100 Yakuts: q2 = (0.47)2 = 0.22 If 200 offspring, then 0.22 x 200 = 44 with blue eyes Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

17 Properties of populations described by Hardy-Weinberg equilibrium
Conservation of allele proportions Even though the genotype frequencies can change in the second generation, there will be no change in allele frequencies A stratified population formed from two (or more) distinct populations will become balanced in a single generation At Hardy-Weinberg equilibrium, genotype frequencies will be p2, 2pq, and q2 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

18 Hardy-Weinberg provides a starting point for modeling population deviations
Natural populations rarely meet the simplified assumptions of Hardy-Weinberg New mutations at each locus arise occasionally No population is infinitely large Migrations of small groups of individuals does occur Mating is not random There are genotype-specific differences in fitness Hardy-Weinberg equation is useful for estimating population changes through a few generations Not as useful for predicting long-term changes, but does provide a foundation for modeling Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

19 Using Monte Carlo simulations to model long-term changes in allele frequencies
Monte Carlo simulations use a computer program to model possible outcomes of randomly chosen matings over a designated number of generations Starting population has a defined number of individuals that are homozygous and heterozygous Mating pairs are chosen through a random-number generating program Genotypes of offspring at each generation are based on probabilities Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

20 Using Monte Carlo simulations to model long-term changes in allele frequencies (cont)
At each generation in the simulation: Total offspring number and parental population size are equal Parental generation is discarded and offspring serve as parents of next generation Multiple, independent simulations are performed Each simulation represents a possible pathway of genetic drift Change in allele frequencies as a consequence of random inheritance from one generation to the next Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

21 Modeling genetic drift in populations of different sizes
Six Monte Carlo simulations run with two initial populations of heterozygous individuals In these simulations, there was no selection (a) Initial population has 10 individuals (b) Initial population has 500 individuals Fig 19.5 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

22 Population size and time to fixation
Fixation – when only one allele in a population has survived and all individuals are homozygous for that allele No further changes can occur (in the absence of migration or mutation) At each generation, changes in allele frequencies are relatively small Over many generations, there can be large changes in allele frequency In populations with 2 alleles present at equal frequencies, median number of generations to fixation is roughly equal to the total number of gene copies in breeding individuals e.g. Population of 10, median fixation time is 20 generations Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

23 Founder effects and population bottlenecks
Founder effects – occur when a few individuals separate from a larger populations and establish a new population Founder allele frequencies can be different from original population Population bottlenecks – large proportion of individuals die (e.g. from environmental disturbances) Survivors are equivalent to a founder population Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

24 Natural selection acts on differences in fitness to alter allele frequencies
Fitness – individual's relative ability to survive and transmit its genes to the next generation (a statistical measurement) Cannot be measured in individuals in a population But, can be measured in all individuals of the same genotype in a population Two basic components: viability and reproductive success Natural selection – the process that progressively eliminates individuals whose fitness is lower Individuals whose fitness is higher become the parents of the next generation Occurs in all natural populations Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

25 Natural selection often acts through environmental conditions
Natural selection in giraffes on the savannah During long droughts, longer necks are needed to reach tree leaves Giraffes with longer necks had higher fitness than giraffes with short necks Fig 19.6 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

26 Modifications to Hardy-Weinberg
In populations undergoing selection, each genotype has a relative fitness e.g. Population with two allele (R and r) Relative fitness (ω) of each genotype (RR, Rr, and rr): ωRR ωRr ωrr Relative frequencies of each genotype at adulthood: p2ωRR 2pqωRr q2ωrr Individual fitness for each genotype is arbitrary Average fitness of the population: = p2ωRR + 2pqωRr + q2ωrr ω (Equation 19.4a) Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

27 Changes in allele frequencies caused by selection
Fig 19.7 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

28 Calculating the changes in allele frequencies due to selection
p' and q' represent allele frequencies after one generation of selection q' (Equation 19.5) Δq = q' – q = s = selection coefficient Varies from 0 (no selection) to 1 (complete selection) If s = 0, Δq is always negative Rate of decrease depends on the allele frequencies As q approaches 0, rate of decrease gets slower (Fig 19.8) (Equation 19.7) Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

29 Predicted and observed decrease in the frequency of a lethal recessive allele over time
Fig 19.8 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

30 An example of Monte Carlo modeling of natural selection
Population with 500 individuals (1 Rr, 499 rr) ωRR = 1.00 ωRr = 0.98 ωrr = 0.98 Six simulations: In three simulations, R allele goes extinct in <100 generations In three simulations, R allele moves to fixation Fig 19.9 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

31 The fitness of alternative genotypes in different environments
H. sapiens migrated out of Africa 70,000 years ago Exposure to ultraviolet rays from sun decreases with increasing distance from equator Affects vitamin D production and skin cancer incidence Close to equator, dark skin protects against skin cancer Farther from equator, lighter skin allows more UV for sufficient vitamin D production Skin pigmentation is a complex quantitative trait and is determined by alleles at many genes Alleles of several genes show strong associations with different populations around the world (Fig 19.10) Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

32 Geographic distribution of allele frequencies at two skin pigmentation loci
Distribution of KITLG alleles Distribution of SLC24A5 alleles Fig 19.10a Fig 19.10b Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

33 Genetic response to cultural innovations
Lactase gene (LCT) required to digest milk In pre-agricultural societies, lactase isn't required after weaning LCT expression is turned off after weaning After cattle domestication (Turkey, ~8,000 years ago), ability to digest milk conferred a survival advantage ~ 5,000 years ago, a DNA alteration in an LCT regulatory sequence occurred Allows LCT expression at high level throughout life Different modern populations around the world vary in LCT allele frequencies (Fig 19.10d) Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

34 Frequency of the sickle-cell allele across Africa where malaria is prevalent
Sickle-cell anemia is a recessive trait caused by mutations in the β-globin locus Heterozygous advantage – individuals that are carriers of sickle-cell are resistant to malaria Fig 19.11 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

35 Balancing selection maintains deleterious alleles in a population
For the β-globin locus, B1 is the normal allele and B2 is a recessive disease allele Relative fitness for B1B2 = 1 Selection coefficient for B1B1 = 1 – s1 Selection coefficient for B2B2 = 1 – s2 Changes in allele frequency resulting from selection Δq = (Equation 19.8) Equilibrium frequency of B2 (qe) is reached when: qe = (Equation 19.9) Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

36 A comprehensive example: Human behavior can affect evolution of pathogens and pests
Evolution of drug resistance in bacterial pathogens e.g. Tuberculosis and evolution of multi-drug resistant strains of TB Factors contributing to rapid evolution of resistance Short generation time and rapid reproduction Large population densities Strong selection imposed by antibiotics Gene transfer between bacteria Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

37 The evolution of resistance in TB bacteria
Repeated cycles of antibiotic treatment coupled with premature cessation of treatment At beginning of treatment, occasional mutations in bacteria can occur that confer resistance If antibiotic treatment is prematurely terminated, the drug-resistant bacteria can proliferate Fig 19.12 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

38 Evolution of pesticide resistance
Large-scale use of DDT and other synthetic insecticides began in 1940s DDT is a nerve toxin in insects Dominant mutations in a single gene confer resistance through detoxification of DDT With insecticide application, strong selection favors heterozygotes By 1984, there were >450 species of mites and insects that had become resistant Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

39 Changes in genotype frequencies in mosquitoes in response to DDT
Use of DDT in Bangkok to control A. aegytpi mosquitoes - began in 1964 and discontinued in 1967 R is dominant, resistance allele; S is susceptibility allele RR genotype confers a fitness cost: In the absence of the insecticide, resistance is subject to negative selection Fig 19.14b Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

40 Analyzing quantitative trait variation
Factors causing continuous variation of quantitative traits Number of genes that determine the trait Genetic and environmental factors that affect penetrance and expressivity of the genes One of the goals of quantitative analysis is to separate the genetics effects from the environmental effects Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

41 Studies of dandelions can help sort out the effects of genes versus the environment
Most dandelion seeds arise from mitotic divisions – all seeds from a single plant are genetically identical Goal is to compare influence of genes and environment on the length of the stem at flowering Fig 19.15a Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

42 Finding the mean and variance of stem length in dandelions
Genetically identical plants grown on hillside: Variation in stem length should be a consequence of environmental interactions (VE) Fig 19.15b Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

43 Genetically identical dandelions grown in two environments
VE for growth in greenhouse < VE for growth on hillside This difference in VE is a measure of the impact of the more diverse environmental conditions on the hillside Fig 19.15c Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

44 Growth of genetically identical and genetically diverse dandelions in a greenhouse
Difference in variance between genetically diverse and identical plants is VG, the genetic variance Fig 19.15d Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

45 Growth of genetically identical and genetically diverse dandelions on a hillside
Total phenotype variance (VP) = VE + VG Fig 19.15e Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

46 Heritability is the proportion of phenotypic variance due to genetic variance
Heritability of a trait is always defined for a specific population in a specific set of environmental conditions Amounts of genetic, environmental, and phenotypic variation may differ among traits (Equation 19.11) Heritability is measured in studies of groups with defined genetic differences Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

47 Measuring the heritability of bill depth in populations of Darwin’s finches
Geospiza fortis on Daphne Major in the Galápagos Islands Correlation between beak size of offspring and the average of the parents' beak sizes (slope of line is 0.82) Fig 19.16a, b Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

48 Results if finch populations had no environmental or no genetic effects
Approximately 82% of variation in bill depth in Darwin's finches is due to genetic variation among individuals (Fig 19.16b, slope of line is 0.82) If the environment had no effect, then heritability would be 1.0 If there was not genetic contribution, then heritability would be 0 Fig 19.16c, d Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

49 Heritability of polygenic traits in humans can be studied using twins
Fig 19.17a Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

50 Concordance of a trait in two children raised in the same family
If the heritability is 0.0, no differences would be observed between monozygotic (MZ), dizygotic (DZ), or unrelated by adoption (UR) Fig 19.17b Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

51 Concordance of a trait in two children raised in the same family (cont)
If the heritability is 1.0, differences would be observed in comparing monozygotic (MZ), dizygotic (DZ), or unrelated by adoption (UR) The extent of difference varies with the trait frequency Fig 19.17b Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

52 A trait's heritability determines its potential for evolution
Heritability quantifies the potential for selection A trait with high heritability has a large potential for evolution Selection differential = S Difference between value for this trait in the parents and value for this trait in the entire population (breeding and non-breeding) Response to selection = R The amount of change in the mean value of a trait that results from selection R = h2S (Equation 19.12) Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

53 Bristle number in parents and offspring in a lab population of D
Bristle number in parents and offspring in a lab population of D. melanogaster This trait has a high heritability: Parents with high bristle numbers have offspring with high bristle numbers Parents with low bristle numbers have offspring with low bristle numbers Fig 19.18 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19

54 Evolution of abdominal bristle number in response to artificial selection in Drosophila
Artificial selection can be imposed on this trait – Flies with high bristle number bred together Flies with low bristle number bred together Fig 19.19 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 19


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