random fixation and loss of heterozygosity frequency of heterozygotes decreases over time, as...

Random fixation and loss of heterozygosityFrequency 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.

Random fixation and loss of heterozygosityFrequency 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 the next generation

amount of heterozygosity in this generation

Random fixation and loss of heterozygosityThe frequency of heterozygotes should fall in every generation


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





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)





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 will decrease by 1% per generation.

NO MATTER WHAT YOU DO.

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


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


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


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)

Genetic bottlenecks & the founder effectA bottleneck is a dramatic reduction in the number of surviving individuals in a population

A “founder effect” is a special form of bottleneck that occurs when a new population is founded by a small number of individuals, who come from a larger, ancestral population

Both are special cases of genetic drift, when a random sample of alleles is effectively taken from the large starting population, either by the survivors of a die-off, or founders of a new population

Genetic bottlenecks & the founder effectBoth are special cases of genetic drift, when a random sample of alleles is effectively taken from the large starting population, either by the survivors of a die-off, or founders of a new population

When a new population is started by a few survivors or initial colonizers, their genetic make-up will largely determine the allele frequencies as the young population grows

2 signatures of a bottleneck or founder event:

reduced genetic diversity: a small group of founders won’t carry all the alleles present in the population they came from

shift in allele frequencies: if founders happened to carry rare alleles, those will be over-represented in the new population (relative to the original, large population they came from)

2 signatures of a founder event: reduced genetic diversity: a small group of founders won’t carry all the alleles present in the population they came from - California now has ~ 125,000 Northern elephant seals

- seals were hunted down to ~30 individuals in the 1800s, then grew to 350 by 1922, when they were protected

- sequencing one region of mitochondrial DNA revealed only 2 variable (polymorphic) positions out of 300 base pairs of DNA

- in contrast, the southern elephant seal (never hunted under 1000 animals) has 23 variable positions in the same region

Genetic bottleneck

Founder effect2 signatures of a founder event: reduced genetic diversity: a small group of founders won’t carry all the alleles present in the population they came from shift in allele frequencies: if founders happened to carry rare alleles, those will be over-represented in the new population (relative to the original, large population they came from) 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

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

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Genetic drift and Elephant tusks

98% of 174 female elephants in the Addo National Park lack tusks

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- 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?

Drift vs. Selectionn = 10 individuals n = 100 n = 1,000 n = 10,000

100

50

0

% of helpfulallele

- introduce a helpful allele that gives you a 5% fitness boost

- initially, allele is present at a frequency of 5%

What happens to the frequency of that good allele over time?

in small populations, good alleles are often lost due to drift

in large populations, selection is stronger than drift, so good alleles rise in frequency until they fix

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 so much variation at the molecular level?

Why hasn’t the most advantageous allele become fixed in a population


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)


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

“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

“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

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

Neutral or Selectionist?

Polymorphic sites 1: DNA changes

Some positions are polymorphic (different nucleotides are found) between some of the species

- a single nucleotide is fixed within each species

Other positions are polymorphic within one species, but are otherwise fixed among species

E. papillosa a GGTGCAGTAAACTTTATTACTACTATTTTTAATATACGGTCACCTGGTATAAGAATGGAACGTTTAAGATTATTTGTTTGATCAGTTTTA E. papillosa b .....G.................................................................................... E. patina 06Jam11 .....G..........................C..G.....T.....G..G.C...............T...........G......C.C E. patina 07Dom05 .....G..........................C..G.....T.....G..G.C.........C.....T...........G......C.C E. zuleicae 04Ber03 .....G...........C..A...........C..G..C..T.....A..G.C...............T..................C.. E. zuleicae 04SSal11 .....G..............A.G.........C..G..C..T.....A..G.C...............T........C.........C..

Polymorphic sites 2: amino acid changes

E. papillosa a VYPPLSGPIGHGGASVDLAIFSLHLAGMSSILGAVNFITTIFNMRSPGMSMERLSLFVWSVLVTAVLLLLSLPVLAGAITMLLTDRNFNTSF E. papillosa b .................................................S...............V.......................... E. patina 06Jam11 .................................................T...............F.......................... E. patina 07Dom05 .................................................T...............F.......................... E. zuleicae 04Ber04 .................................................T...............F.......................... E. zuleicae 04Ber06 .................................................T...............F.......................... E. zuleicae 04Boc102 .................................................T...............F.......................... E. zuleicae 06Jam07 .................................................T...............F...................G...... E. zuleicae 07LSS02 .................................................T...............F.......................... E. zuleicae 04SSal03 .................................................T...............F.......................... E. zuleicae 04Boc101 .................................................T...............F.......................... E. zuleicae 07SSal01 .................................................T...............F.......................... E. zuleicae 06Jam03 .................................................T...............F.......................... E. zuleicae 04SSal11 .......................................S.........T...............F.......................... E. zuleicae 04Bocas103 .................................................T...............F.......................... E. zuleicae 04SSal06 .................................................T...............F.......................... E. zuleicae 09Cur105 .................................................T...............F.......................... E. zuleicae 09Cur09 .......S.........................................T...............F.......................... E. zuleicae 07Cur12 .................................................T...............F.......................... E. zuleicae 09Cur13 .................................................T...............F.......................... E. zuleicae 09Cur14 .................................................T...............F..........................

S or T V or F

different amino acids can be fixed between species

different amino acids can occur at a site within one species

Normally, most substitutions that survive to be detected are silent

When non-synonymous changes pile up faster than silent changes (given that codons differ in whether one mutation can change the amino acid), it indicates positive selection is acting to quickly fix mutations before they get lost to drift

E. papillosa a GGTGCAGTAAACTTTATTACTACTATTTTTAATATACGGTCACCTGGTATAAGAATGGAACGTTTAAGATTATTTGTTTGATCAGTTTTA E. papillosa b .....G.................................................................................... E. patina 06Jam11 .....G..........................C..G.....T.....G..G.C...............T...........G......C.C E. patina 07Dom05 .....G..........................C..G.....T.....G..G.C.........C.....T...........G......C.C E. zuleicae 04Ber03 .....G...........C..A...........C..G..C..T.....A..G.C...............T..................C.. E. zuleicae 04SSal11 .....G..............A.G.........C..G..C..T.....A..G.C...............T........C.........C..

1. DNA – 17 polymorphic sites

2. amino acid – 4 polymorphic sites (= non-synonymous changes)E. papillosa a VYPPLSGPIGHGGASVDLAIFSLHLAGMSSILGAVNFITTIFNMRSPGMSMERLSLFVWSVLVTAVLLLLSLPVLAGAITMLLTDRNFNTSF E. papillosa b .................................................S...............V.......................... E. patina 06Jam11 .................................................T...............F.......................... E. patina 07Dom05 .................................................T...............F.......................... E. zuleicae 06Jam07 .................................................T...............F...................G...... E. zuleicae 04SSal11 .......................................S.........T...............F..........................

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


Begun et al. (2007) found amount of polymorphism was correlated with recombination rate across Drosophila simulans 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?...


Selection favoring one allele will also tend to drag alleles at nearby or linked loci to high frequency

A B C D E F

a b c d e f

...it will also tend to favor “B” and “D” alleles, if they happen to be linked to “C” on a chromosome


if selection strongly favors “big C” allele of the C gene...

Selection favoring one allele will also tend to drag alleles at nearby or linked loci to high frequency

A B C D E F

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

in regions of high recombination, linked loci can escape the effects of selection on nearby genes

crossing over “breaks up the team”

A B C D E F

a b c d e f

Even if selection strongly favors C allele... alleles of other genes can cross over onto C chromosomes

In regions of high recombination, many alleles at linked loci can “hitchhike” onto chromosomes with favorable alleles, and thus survive selection greater overall polymorphism

a b C d e f


Begun et al. (2007) found amount of polymorphism was correlated with recombination rate across Drosophila simulans genome

in regions of low recombination, linked loci can’t escape the effects of selection on nearby genes

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

random fixation and loss of heterozygosity frequency of heterozygotes decreases over time, as...

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