Mutation as an evolutionary force

1. Mutation as an evolutionary force Alleles may be kept in a population through a balance between mutation (creating deleterious alleles) and selection (removing them) - in mutation-selection balance, the frequency with which new alleles are created by mutation equals the rate at which they are eliminated by selection When the frequency of a harmful allele (say, cystic fibrosis) is higher in a population than you’d expect from the mutation rate of that gene, then you have reason to suspect some other force (i.e., selection) may be keeping that allele around

2. Mutation as an evolutionary force Why does the F508 allele, which causes cystic fibrosis, occur at a high frequency (0.02) in populations of European descent? - selection against homozygotes is strong - mutation rate is too low to explain high allele frequency - protects against infection by typhoid fever bacterium?

3. Mutation as an evolutionary force More importantly, mutation promotes evolutionary change by genetic innovation - once a rare beneficial allele is created by mutation, it can rapidly become fixed in the population through selective sweeps bacteria evolved in a series of jumps: new mutations that resulted in larger cell size appeared, rapidly spread through the population

4. Migration Migration is the movement of alleles between populations Migration can rapidly change allele frequencies, especially for small populations - individuals leaving a continent make little difference to the allele frequencies on that continent 

5. Migration Example: banded vs unbanded water snakes

6. Migration Example: banded vs unbanded water snakes - one gene w/ 2 alleles determines banded, unbanded or intermediate morph - natural selection favors banded snakes on mainland, where they are cryptic (hidden from predators) - selection favors unbanded snakes on islands, where bands stand out when snakes sun themselves on rocks to warm up

7. distribution of banded vs unbanded snakes proportion of unbanded snakes increases as you move further out into middle of lake there’s always some banded snakes present on every island, though

8. Migration Why doesn’t selection fix the unbanded allele on islands? (drive it to a frequency of 100%) - migrants from mainland continually introduce banded allele into island population - about 13 snakes per year move to islands, which have ~1300 snakes (roughly 1% migration per year) Migration acts as a homogenizing force: - equalizes allele frequencies among populations; makes them more similar than they would otherwise be 

9. Genetic Drift A sampling process (flipping a coin, drawing beans from a bag) may produce results different from theoretical expectations - flip a coin four times, and you may get 4 heads When the actual results differ from theory, this is sampling error Sampling error depends largely on the number of samples drawn - flip a coin 40 times, and you are very unlikely to get 40 heads - will probably get ~20 heads, give or take a few 

10. Genetic Drift Sampling error in production of offspring in a population is genetic drift Initial frequencies are always heavily skewed during random sampling - ie, drawing alleles one at a time from a big “batch” (= gene pool)

11. Genetic Drift Sampling error is very sensitive to population size - as population increases, effects of genetic drift diminish - odds of getting the expected allele frequencies when you make 10 zygotes by drawing alleles at random

12. Random fixation of alleles pop. size = 4 Given enough time, any allele will eventually become fixed or disappear if genetic drift is the only mechanism at work - when one allele is fixed, all others have a frequency of zero - the odds that any given allele will be the one that goes to fixation is the initial frequency of that allele  40 400

13. Genetic Drift (1) Every population follows a unique evolutionary trajectory, because sampling error affects allele frequencies at random - if selection were at work, different populations would evolve along similar trajectories (2) drift works faster and stronger in small populations - allele frequencies change more dramatically if population size is small (3) even in large populations, drift can cause substantial evolution over long times - geographic isolation results in differentiated populations eventually, different species

14. Random fixation and loss of heterozygosity Frequency of heterozygotes decreases over time, as alleles drift towards fixation or extinction - all else being equal (no selection, etc), the frequency of heterozygotes should fall in every generation We can talk about “heterozygosity” as an average across all genes, and across all individuals in a population - at what % of loci are you heterozygous? - what is the average % for individuals in your population? More genetic diversity (polymorphism) usually means more heterozygosity... usually.

15. Random fixation and loss of heterozygosity Frequency of heterozygotes decreases over time, as alleles drift towards fixation or extinction - all else being equal (no selection, etc), the frequency of heterozygotes should fall in every generation - given by the relationship Hg+1 = Hg 1 - 1 where N = population size 2N amount of heterozygosity in this generation amount of heterozygosity in the next generation

16. Random fixation and loss of heterozygosity The frequency of heterozygotes should fall in every generation - given by the relationship Hg+1 = Hg 1 - 1 where N is population size 2N You are trying to maintain a group of 50 endangered llamas. How much will heterozygosity decrease in one generation? Hg+1 = Hg 1 – 1 =Hg 1 – 1 2(50) 100

17. Random fixation and loss of heterozygosity The frequency of heterozygotes should fall in every generation - given by the relationship Hg+1 = Hg 1 - 1 where N is population size 2N You are trying to maintain a group of 50 endangered llamas. How much will heterozygosity decrease in one generation? Hg+1 = Hg 1 – 1 =Hg 1 – 1 =Hg (99/100) = Hg (0.99) 2(50) 100 Heterozygosity in the next generation (Hg+1) will be 99% of heterozygosity now (Hg)

18. Random fixation and loss of heterozygosity The frequency of heterozygotes should fall in every generation - given by the relationship Hg+1 = Hg 1 - 1 where N is population size 2N You are trying to maintain a group of 50 endangered llamas. How much will heterozygosity decrease in one generation? Hg+1 = Hg 1 – 1 =Hg 1 – 1 =Hg (99/100) = Hg (0.99) 2(50) 100 thus, despite your efforts to arrange random matings, heterozygosity willdecrease by 1% per generation. NO MATTER WHAT YOU DO.

19. Random fixation and loss of heterozygosity Heterozygosity decreases in every generation, but more slowly in large populations - the faster an allele disappears due to drift, the more quickly you lose heterozygosity

20. Random fixation and loss of heterozygosity tested experimentally by Buri with fruit flies - started 107 replicate populations each with 8 boy + 8 girl flies - all flies were initially heterozygotes for a brown eye color allele (bw/bw-75) - each generation, out of all offspring, 16 were chosen to start the next generation - monitored for 19 generations

21. Random fixation and loss of heterozygosity Expected result: - no selective advantage, so bw-75 allele should drift to fixation 50% of the time and be lost 50% of the time - heterozygosity should decrease over time Results after 19 generations: - in 30 populations, bw-75 allele was lost - in 28, it was fixed

22. Random fixation and loss of heterozygosity Heterozygosity could also be directly scored by eye color - decreased every generation, as predicted by theory - actually decreased faster than expected, as though N = 9 flies (not 16)

23. Founder Effect When a population is founded by a few initial colonizers, their genetic make-up will largely determine the allele frequencies as the young population grows A small group of founders will not carry all the alleles present in the larger population they came from (reduced genetic diversity) - if founders carry rare alleles, these alleles will be over- represented in the new population relative to the original large population example: Pennsylvania Amish carry allele for a rare form of dwarfism, at a frequency of 7% - only present at 0.1% in most populations - one of original 200 founders had the recessive allele - consequence: way more Amish dwarves than you’d expect

24. Genetic drift and Elephant tusks 98% of 174 female elephants in the Addo National Park lack tusks - population was reduced to 11 individuals by hunting, until protected in 1931 - at that point, 50% of females lacked tusks - near loss of female tusks is likely a result of genetic drift, following population bottleneck proportion of females w/ tusks population size

25. Genetic drift and Elephant tusks 98% of 174 female elephants in the Addo National Park lack tusks - Alternative hypothesis: ivory hunters imposed strong selection against tusks - if tusklessness were a recessive trait, what would you expect to happen to the frequency of tusklessness since the population was protected? Why? proportion of females w/ tusks population size

26. Variation in natural populations When scientists started measuring protein variation in natural populations, they were surprised by how much polymorphism there was – about 25% of loci have multiple alleles visible by gel electrophoresis, in a wide range of species Why is there somuch variation at the molecular level? Why hasn’t the most advantageous allele become fixed in a population

27. Variation in natural populations Why is there so much allelic variation in natural populations? 2 opposing theories: Neutral theory: most allelic differences don’t make a difference to fitness; they neither hurt nor help the organism - most mutations are bad (make the protein worse) so they are rapidly removed by selection (we never see them) - mutations that survive are neutral (make no difference) - may become fixed by genetic drift (chance, not selection) 

28. Variation in natural populations Why is there so much allelic variation in natural populations? Selectionist theory: natural selection maintains genetic diversity, because most alleles are beneficial under some set of circumstances Selectionists argue, there’s no way you’d see so much variation unless it was important (even if only under rare circumstances) Mutations may be favorable when colonizing a new environment, or if conditions change a lot year-to-year

29. “Nearly Neutral” Theory Neutral theory had some problems - predicts that large populations should have more genetic diversity, but they don’t Ohta proposed her nearly neutral theory to better explain observed results from nature: - most mutations are slightly deleterious (a little bad for you) - in large populations, selection will eliminate alleles that confer lower fitness over time - in small populations, a bad allele may rise to a high frequency by genetic drift before it gets wiped out by selection

30. “Nearly Neutral” Theory Ohta proposed her nearly neutral theory to better explain observed results from nature In nearly-neutral model, the relative power of selection vs. drift on new mutations depends on population size - a better explanation of empirical results, but harder to test predictions because population size is tough to determine Basic argument of both Neutral and Nearly-Neutral models is that selection acts against most mutations that cause protein variants In contrast, selectionists argue that selection often favors certain mutations, which keeps them hanging around and promotes genetic diversity or variability

31. Neutral or Selectionist? One way to test these theories is to look at th number of silent vs. non-synonymous substitutions over a given region of DNA are silent point mutations in DNA (no effect on phenotype) more common or less common than non-synonymous changes? Negative selection: amino acid substitutions are less common than silent DNA substitutions (change is bad) Positive selection: non-synonymous amino acid substitutions are more common than silent substitutions

32. Neutral or Selectionist? Evidence for positive selection suggests selection is driving the rate at which mutations are fixed as proteins evolve Smith & Ayre-Walker (2002) compared ratio of non-synonymous (dN) to synonymous (dS) substitutions within 2 Drosophila species, and between the two species, over the whole genome - found many sites where there were more non-synonymous changes between the species than within either species - indicates that selection favored differences between species - they estimated 45% of amino acid differences between the 2 species had been fixed by positive selection

33. Neutral or Selectionist? Begun et al. (2007) found amount of polymorphism was correlated with recombination rateacross Drosophilasimulans genome Different regions of the genome can differ in how often crossing over occurs – some places have more, others less Some genes are more polymorphic than others (have more alleles) Neutral theory predicts no relationship between amount of genetic polymorphism (# of alleles) and how often crossing over happens  Why does selectionist theory predict a correlation?...

34. Neutral or Selectionist? Selection favoring one allele will also tend to drag alleles at nearby or linked loci to high frequency if selection strongly favors “big C” allele of the C gene... ...it will also tend to favor “B” and “D” alleles, if they happen to be linked to “C” on a chromosome A B C D E F a b c d e f

35. Neutral or Selectionist? Selection favoring one allele will also tend to drag alleles at nearby or linked loci to high frequency if selection strongly favors “big C” allele of the C gene... A B C D E F ...all these alleles will be lost, unless they can get onto the “winning team”  i.e., any chromosome with a C allele a b c d e f

36. Neutral or Selectionist? in regions of high recombination, linked loci can escape the effects of selection on nearby genes  crossing over “breaks up the team” Even if selection strongly favors C allele... alleles of other genes can cross over onto C chromosomes A B C D E F ab C d e f a b c d e f In regions of high recombination, many alleles at linked loci can “hitchhike” onto chromosomes with favorable alleles, and thus survive selection  greater overall polymorphism

37. Neutral or Selectionist? Begun et al. (2007) found amount of polymorphism was correlated with recombination rate across Drosophilasimulans genome in regions of low recombination, linked locican’t escape the effects of selection on nearby genes if selection strongly favors “big C” allele of the C gene... A B C D E F a b c d e f ...all these alleles get lost  The correlation is strong evidence that selection acts on alleles all the time, across the whole genome  Supports selectionist theory, not neutral theory