Selection Dan Graur 1 Conditions for maintaining HardyWeinberg

Selection Dan Graur 1

Conditions for maintaining Hardy-Weinberg equilibrium: 1. 2. 3. 4. 5. random mating no migration no mutation no selection infinite population size 2

2 mathematical approaches to studying genetic changes in populations: Deterministic models Stochastic models 3

Deterministic models assume that changes in allele frequencies from generation to generation occur in a unique manner and can be unambiguously predicted from knowledge of initial conditions. Strictly speaking, this approach applies only when: (1) the population is infinite in size, and (2) the environment either remains constant with time or changes according to deterministic rules. 4

Stochastic models assume that changes in allele frequencies occur in a probabilistic manner, i. e. , from knowledge of the conditions in one generation one cannot predict unambiguously the allele frequencies in the next generation, but can only determine the probabilities with which certain allele frequencies are likely to be attained. 5

Stochastic models are preferable to deterministic ones, since they are based on more realistic assumptions. However, deterministic models are easier mathematically and, under certain circumstances, they yield sufficiently accurate insights. 6

Selection The deterministic approach 7

Natural selection The differential reproduction of genetically distinct individuals (genotypes) within a population. Differential reproduction is caused by differences among individuals in such traits as (1) mortality, (2) fertility (offspring), (3) fecundity (gametes), (4) mating success, and (5) viability of offspring. 8

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Is the fitness of slim men higher than that of fat men? Dixson et al. 2003. Masculine somatotype and hirsuteness as determinants of sexual attractiveness to women. Archives of Sexual Behavior 32: 29– 39. 10

Variability Non-Genetic 11

Arashnia levana Non-genetic variability. 12

Helix aspersa Genetic variability. 13

Variability Non-Genetic Fitness-related Genetic Fitness-unrelated 14

Genetic? No Fitness related? Yes Does selection operate? Hair color 15

Sperm morphology Genetic? Yes Fitness related? Yes Does selection operate? 16

Genetic? Fitness related? Does selection operate? Wealth 17

Darwinian selection requires variation. Lamarkian selection does not require variation. 18

Natural selection is predicated on the availability of genetic variation among individuals in characters related to reproductive success (variation in fitness). 19

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Synonymous and nonsynonymous genetic variability. 21

Evolutionary Success Ryan Kremer Carlos Slim Helú (richest person on earth) 6 children Linus Pauling (Only person to win 2 unshared Nobel prizes) 4 children

The fitness (w) of a genotype is a measure of the individual’s ability to survive and reproduce. The size of a population is constrained by the carrying capacity of the environment. Thus, an individual’s evolutionary success is determined not by its absolute fitness, but by its relative fitness in comparison to the other genotypes in the population. 23

Finite Niche (Carrying) Capacity 24

In nature, the fitness of a genotype is not expected to remain constant for all generations and under all conditions. However, by assigning a constant value of fitness to each genotype, we are able to formulate simple models, which are useful for understanding the dynamics of change in the genetic structure of a population brought about by natural selection. 25

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• We assume that fitness is determined solely by the genetic makeup. • We assume that all loci contribute independently to fitness (i. e. , the different loci do not interact with one another in a manner that affects fitness), so that each locus can be dealt with separately. 27

A very simple model (1): One locus = A Two alleles = A 1 & A 2 The old allele = A 1 The new allele is = A 2 Three genotypes = A 1 A 1, A 1 A 2 & A 2 A 2 Each genotype has a typical fitness (w) We are interested in the fate of A 2 28

A very simple model (2): The fitness of the old genotype (A 1 A 1) is set at 1. The relative fitnesses of the two new possible genotypes (A 1 A 2 & A 2 A 2) are defined comparatively as 1 + s or 1 + t, where s and t are the selection coefficients. 29

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In comparison with A 1, A 2 may deleterious, neutral, or advantageous, and it will be subject to purifying selection, no selection, or positive Darwinian selection, respectively. 31

Genotype A 1 A 1 Fitness w 11 Frequency p 2 A 1 A 2 A 2 A 2 w 12 2 pq w 22 q 2 32

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Change in A 2 allele frequency per generation 34

Genotype A 1 A 1 A 1 A 2 A 2 A 2 Fitness w 11 w 12 w 22 2 pq q 2 Frequency p 2 These are the variables we fiddle with 35

Dominance & Recessiveness At the phenotypic level At the fitness level 36

A 1 dominance Genotype A 1 A 2 A 2 A 2 w 11 w 22 Frequency p 2 2 pq q 2 Fitness A 1 A 1 37

A 1 dominance A 1 A 1 A 1 A 2 A 2 A 2 1 1 1+s A 2 Genotype Fitness 38

A 2 dominance Genotype A 1 A 1 A 1 A 2 A 2 A 2 Fitness w 11 w 22 2 pq q 2 Frequency p 2 39

codominance A 2 dominance A 1 A 1 A 1 A 2 A 2 A 2 1 1+s A 2 Genotype Fitness 40

Codominance (genic selection) Genotype A 1 A 1 Fitness w 11 (w 11 + w 22)/2 w 22 Frequency p 2 A 1 A 2 2 pq A 2 A 2 q 2 41

codominance A 1 A 1 A 1 A 2 A 2 A 2 1 1+s 1 + 2 s A 2 Genotype Fitness 42

codominance A 1 dominance A 2 dominance A 1 = old mutant A 2 = new mutant 43

Selection intensities 44

Initial Frequencies 45

Industrial Melanism 46

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A 2 48

Selection against recessive lethal alleles b-hexosaminidase A is a dimeric lysosomal protein consisting of two a-subunits. It is encoded by a gene on chromosome 15. 49

Selection against recessive lethal alleles b-hexosaminidase-A catalyzes the removal of Nacetylgalactosamine from GM 2 ganglioside, thereby degrading and removing it from the nervous system. 50

Absence of b-hexosaminidase-A Accumulation of GM 2 ganglioside in neurons. 51

Selection against recessive lethal alleles Tay-Sachs disease results from a defect in the HEXA gene encoding the a subunit of b-hexosaminidase A. Warren Tay (1843 -1927) Bernard Sachs (1858 -1944) 52

Tay-Sachs is a recessive… allele 53

Tay-Sachs is a recessive & lethal alleles Symptoms of classical Tay-Sachs disease first appear at 4 to 6 months of age when an apparently healthy baby gradually stops smiling, crawling or turning over, loses its ability to grasp or reach out and, eventually, becomes blind, paralyzed and unaware of its surroundings. Death occurs by age 3 -5. Cherry-red spot from an infant with Tay-Sachs disease. 54

Selection against recessive lethal alleles 55

Inefficiency of selection against recessive allele 56

It is difficult to rid a population of recessive alleles, because they hide behind the back of dominant alleles, and are not exposed to selection. If q = 50%, 50% then 50% of all recessive alleles are in heterozygous state. If q = 10%, 10% then 98% of all recessive alleles are in heterozygous state. If q = 1%, 1% then 99. 98% of all recessive alleles are in heterozygous state. 57

Selection against dominant lethal alleles Dr. George Sumner Huntington 1850 -1916 Protein: huntingtin Gene: 180 Kb (chromosome 4) Exons: 67 Amino acids: 3, 141 Mode: autosomal dominant 58

Selection against dominant lethal alleles 59

It should be easy to rid a population of dominant alleles, because all of them are exposed to selection at all frequencies. So why are there dominant lethal diseases? 60

1. 2. 3. 4. Recurrent mutations. Late age of onset. Variable expressivity. Incomplete penetrance. 61

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Overdominance Genotype A 1 A 1 Fitness w 11 w 12 > w 11, w 22 Frequency p 2 A 1 A 2 2 pq A 2 A 2 q 2 63

Underdominance Genotype A 1 A 1 Fitness w 11 w 12 < w 11, w 22 Frequency p 2 A 1 A 2 2 pq A 2 A 2 q 2 64

The change in the frequency of A 2 from generation to generation is: 65

At equilibrium, i. e. , when ∆q = 0. 66

overdominance s = 0. 04 and t = 0. 02 underdominance 67 s = - 0. 02 and t = - 0. 01

Overdominant selection is inherently inefficient, even if the two homozygotes are not viable. RIP Powderpuff Chinese Crested 68

The peculiar case of sickle-cell anemia 69

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Glutamic acid Valine 71

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mvhltpveksavtalwgkvn vdevggealgrllvvypwtq rffesfgdlstpdavmgnpk vkahgkkvlgafsdglahld nlkgtfatlselhcdklhvd penfrllgnvlvcvlahhfg keftppvqaayqkvvagvan alahkyh 147 aa 73

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Intuitive Model normal fitness somewhat reduced fitness 79

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In theory, the end result should have been directional selection — a S drastic reduction in H allele frequency in the population. 81

Worldwide distribution of sickle-cell anemia 82

In practice, the frequency of the S H allele may reach enormous values in some populations. >20% 83

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Plasmodium falciparum 85

An evolutionary “experiment”: Slave trade 86

West Africa Frequency= >20% Curaçau no malaria HS frequency = 5% Surinam endemic malaria HS frequency = 20% 300 years = 10 -15 generations 87

• With malaria in the background, heterozygotes have a huge advantage over the wild type homozygotes. • In the absence of malaria, the heterozygotes have a slight disadvantage in comparison to wild type homozygotes. • The fitness of the Hs. Hs homozygotes is not affected by the presence or absence of malaria. 88

Modiano D, Luoni G, Sirima BS, Simpore J, Verra F, Konate A, Rastrelli E, Olivieri A, Calissano C, Paganotti GM, D'Urbano L, Sanou I, Sawadogo A, Modiano G, Coluzzi M. 2001. Haemoglobin C protects against clinical Plasmodium falciparum malaria. Nature 414: 305 -308. 89

Hemoglobin C E to V = HS E to K = HC codon position 6! Glutamic acid Lysine 90

“…in the long term and in the absence of malaria control, Hb. C would replace Hb. S in central West Africa. ” 91

The peculiar case of Rh-blood groups 92

Underdominant selection? Why does Rh– still exist? 93

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A summary: Selection may lead to changes in allele frequencies over time. A mere change in allele frequencies from generation to generation does not necessarily indicate that selection is at work. A lack of change in allele frequencies does not necessarily indicate that selection is absent. 97

Selection is a very important evolutionary force. At least, in principle… 98