Download Mendelian Genetics in Populations II

Mendelian Genetics in Populations II
Migration, Genetic Drift, and
Nonrandom Mating
1
Chance events can alter allele and genotype
frequencies (Fig. 6.10a)
In the “sampling”
of egg and sperm
to make zygotes,
there were 14 A1
and 6 A2 alleles.
So the allele
frequencies
changed to 0.7 for
A1 and 0.3 for A2
Note: these
alleles are not
affected by
natural selection
= neutral alleles
2
Range of possible outcomes when 20 gametes are sampled from a
population with allele frequencies of p = 0.6 and q = 0.4 (Fig. 6.11)
3
Genetic drift is evolution that happens by
chance
The figure on the previous slide demonstrates
that:
1) Allele frequencies are more likely to change
than stay the same across generations
2) Small per generation changes in allele
frequency are more likely than large changes
3) If the “initial” frequency of an allele is > 0.5,
it is more likely to increase in frequency that
decrease in the next generation
4
Computer simulations of random genetic drift
• Random sample of 20 gametes from a population
with p(A1) = 0.6 and q(A2) = 0.4
• Using Populus 5.3
– http://www.cbs.umn.edu/populus/Download/download.html
5
Evolutionary effects of genetic drift – 1
• Genetic drift results in the eventual fixation of one allele,
and the loss of all other alleles (provided no other “forces”
are acting = neutral alleles)
• As one allele drifts toward fixation, the heterozygosity of
the population declines
• The probability of eventual fixation of a neutral allele is
equal to its current frequency in the population (Note: in a
diploid population of size N, a new mutation will have a
frequency of 1/2N)
• Larger populations require more time for fixation
• Drift also operates on alleles that are affected by selection
(more on that later)
6
Genetic drift and heterozygosity (Fig. 6.15)
7
Genetic drift in experimental lab populations
107 populations of size N = 16, initial allele frequencies 0.5, incomplete
dominance
8
Loss of heterozygosity in a laboratory population
•
Heterozygosity
•
•
•
Dashed line is the
theoretical prediction
for population size N
= 16
Solid gray line is
theoretical prediction
for N = 9
The effective
population size was
smaller than the actual
population size
See previous slide for
additional
experimental details
Generation
9
Population size and genetic diversity in natural
populations (Fig. 6.19a,b)
Polymorphism =
proportion of loci for
which the frequency
of the most common
allele is < 0.99
Allelic richness =
average number of
alleles per locus
10
Genetic variation in Ozark glade populations of
collared lizard (Fig.
•
•
•
The colors in the pie chart at left represent 7
different multilocus genotypes based on:
malate dehydrogenase (MDH) genotypes,
mtDNA haplotypes, and ribosomal DNA
(rDNA) genotypes.
Populations in different glades are represented
by colored circles on the maps
A solid-color circle indicates that only one
multilocus genotype is present in that
population.
11
Founder effects and bottlenecks are special cases of
genetic drift
• Founder effects occur when a new population is
started with a small number of migrants from
another (usually larger) population
• Bottlenecks occur when a large population is
reduced to a small size
• In both cases drift is strong because of small
population size, which may persist for a number of
generations
12
How founder effects and bottlenecks change
the genetic composition of populations
• Reduce genetic variation through loss of low
frequency alleles
• Increase the frequency of some very rare
(probably harmful) alleles that happen to be
present in founders or survivors of bottlenecks
• Lead to inbreeding, which increases the chance
that recessive mutations will be homozygous
13
The founder effect in an island-hopping bird
the silvereye, Zosterops lateralis (Fig. 6.13)
•
Progressive founder events reduce genetic diversity as measured by the average number
of alleles at six microsatellite loci
14
A founder effect in a human population: achromatopsia in the
Pingelapese people of the Eastern Caroline Islands
• The current population of about 3,000 people on the
Pingelap Atoll are descended from 20 survivors of a
typhoon in about 1775
• The frequency of achromatopsia (complete colorblindness,
extreme sensitivity to light, and poor visual accuity), a
homozygous recessive disorder, is about 1 in 20 (compared
to less than 1 in 20,000 in most populations)
• At least one of the survivors of the typhoon carried at least
one copy of the defective allele, which means that among
the survivors the frequency of the defective allele was at
least 2.5%
• The frequency of the defective allele has since increased to
> 20% under the influence of drift
15
Migration and genetic drift
• Migration of individuals (movement from one
population to another) retards the rate of drift
within each population
• If migration among populations is high enough,
the several populations become, in effect, one
larger population in which drift is slower
• In general, 2 or more migrants into a population
per generation is enough gene flow to make
several populations behave like one larger
population
16
Selection and genetic drift – 1
• Genetic drift also affects the frequencies of alleles that are under
selection
• Suppose the fitnesses (relative survivorships) of genotypes at a locus
are as follows:
A1A1
A1A2
A2A2
1
1+s
1 + 2s
• According to what we have learned, if A2 is a new mutation,
directional selection should result in the fixation of allele A2 because
A2A2 homozygotes have the highest survivorship: that is, the Pr(fix A2)
≈ 1.0
• However in a finite population of size N, it’s not so simple
• If the quantity 4Ns is greater than about 2, then Pr(fix A2) ≈ 2s, which
will be much less than 1.0 for realistic selection coefficients
• If the quantity 4Ns is less than about 1, then Pr(fix A2) ≈ 1/2N, which
is the probability of fixation of a new neutral mutation by drift, and
will also be less than 1.0
• Either way, most beneficial mutations are lost from populations
because of random genetic drift! And it’s even worse if A2 is
17
recessive!
Selection and genetic drift – 2
• Let’s look at some numbers:
• Suppose N = 200, and s = 0.01 (i.e., a 1% selective advantage to A2
when heterozygous)
• Then 4Ns = 8, which is “large”, and the probability of eventual
fixation of A2 if it is a new mutation ≈ 2s = 0.02
• On the other hand:
• Suppose N = 5, and s = 0.01
• Then 4Ns = 0.2, which is “small”, and the probability of eventual
fixation of A2 is ≈ 1/2N = 0.1
• In this particular example, then, our new favorable mutation, A2, is
more likely to become fixed in a small population, where its initial
frequency is higher, than in a large population, where its initial
frequency is lower.
18
The Neutral Theory of Molecular Evolution – 1
• It is important to distinguish between evolution of proteins
(i.e., amino acid sequences) and evolution of nucleotide
sequences
• It is reasonable to assume that much nucleotide sequence
evolution is selectively neutral or nearly so: pseudogenes,
introns and other non-translated regions; synonymous
substitutions
• On the other hand, we might expect many amino acid
substitutions to be under selection
• The long-standing argument between neutralists and
selectionists is really about whether most protein evolution
(= amino acid substitutions = non-synonymous nucleotide
substitutions) is neutral, or is adaptive and driven by
natural selection
19
The Neutral Theory of Molecular Evolution – 2
• Neutralists do not claim that most mutations are neutral
• However, they do argue that most of the protein variation
that we see within populations has no fitness consequences
(i.e. alleles are neutral), and that most of the evolutionary
change in proteins that we see between related taxa is due
to drift acting on selectively neutral alleles. According to
neutralists, positive selection (= adaptation) plays little or
no role in evolution at the molecular level
• For neutralists, as well as selectionists, most mutations are
harmful and are removed from populations by the action of
natural selection
20
Neutral theory predicts a molecular clock
• Let the neutral mutation rate be µ(= proportion of new
mutant copies of a gene per generation, e.g., 1 in a million)
• In a diploid population of size N, there will be 2Nµ new
mutations at a gene per generation
• Since these mutations are neutral, the probability of
eventual fixation of any one mutation is 1/2N, and its
probability of loss is 1 - (1/2N) which will be very close to
1.0 for reasonably large populations
• Most new neutral mutations will be lost by drift within a
few generations, but occasionally a new mutation will
increase infrequency under drift and replace previously
existing alleles – this is known as an allelic substitution
21
Mutation and allelic substitution over time (Fig. 6.20)
22
The average rate of allelic substitution, which
is the rate of neutral evolution, is equal to the
neutral mutation rate
• The average number of allelic fixations per
generation is equal to the number of new
mutations per generation x the probability that any
one mutation eventually becomes fixed = 2Nµ x
1/2N = µ
• So, the predicted average amount of time between
allelic substitutions is 1/µ generations: this is the
molecular clock
23
Molecular divergence among three related taxa
C
B
A
2t
Neutral theory predicts:
1. The amount of molecular difference between A and C will
be the same as the amount of difference between B and C,
since the amount of evolutionary time is the same in both
comparisons
2. The amount of molecular difference between A and C (or B
and C) will be twice the amount of difference between A
and B, since the common ancestor of A and B lived half as
long ago as the common ancestor of A and C (or B and C)
Time since most recent common ancestor
t
24
Synonymous and non-synonymous base
substitutions (Fig. 6.21)
25
Molecular
evolution in
influenza
viruses is
consistent
with neural
theory (Fig.
6.21c)
26
A paradox and an inconsistency
• The paradox is that under neutral theory, in which
allelic substitutions are due only to drift (rather
than directional selection) the rate of evolution
does not depend upon population size but only the
mutation rate to neutral alleles
• The inconsistency is that the theory predicts a
clock that “ticks” in generation time, yet much of
the evidence for a molecular clock is based on
“clock” time
27
Nearly neutral theory – 1
• Neutralists have addressed the problem of time
scale with what is known as nearly neutral theory
• The idea is that many slightly deleterious
mutations will be effectively neutral, depending on
population size
• In general, as we saw above, drift will govern the
fate of alleles if the quantity 4Ns is “small”, where
N is effective population size and s is the
coefficient that describes the action of natural
selection on the heterozygote
28
Nearly neutral theory – 2
• Imagine a species in which effective population size, N, is
500. If the selection coefficient, s, against a mutant
heterozygote is 0.0005, then 4Ns = 1.0, which qualifies as
“small”, and the mutation is effectively neutral
• On the other hand, the same selection coefficient in a
population of 5,000 would mean that 4Ns = 10.0, which
would be “large” and would mean that natual selection
would act against the mutation (that is, the mutation is
harmful – not neutral)
• If species with long generation times tend to have small
population sizes, then the mutation rate to effectively
neutral mutations will be greater in species with longer
generations, and this higher mutation rate per generation
will compensate for the longer generation time
• The net result is that the molecular clock will tend to tick 29
at the same speed in clock time for all species
Population size, generation time, and nearly neutral
mutations (Fig. 22)
30
Synonymous and non-synonymous
substitutions and the molecular clock – 1
• Evolution of synonymous nucleotide substitutions
generally supports a molecular clock (this is not
controversial)
• In some cases, non-synonymous substitutions also
appear to be clock-like (e.g., the influenza virus
data in Fig. 6.21)
31
Synonymous and non-synonymous
substitutions and the molecular clock – 2
• Data from many genes indicates that the rate of
evolution of synonymous substitutions is higher
(often much higher) than the rate of evolution of
non-synonymous substitutions (see Table 6.1 in
your text)
– This observation is consistent with the expectation that
most amino acid changes will be deleterious and,
therefore, that the neutral mutation rate will be lower
for non-synonymous substitutions (as would be
predicted by both neutralists and selectionists)
32
Molecular
evolution in
influenza
viruses is
consistent
with neural
theory (Fig.
6.21c)
33
Evidence for molecular evolution by
“positive” selection
• Neutral theory states that if we compare protein coding
sequences (exons) between species, there will be more
nucleotide substitutions at synonymous than nonsynonymous sites (because the neutral mutation rate is
lower at non-synonymous sites) : dN/dS < 1.0
• On the other hand, if much evolution involves positive
selection on alleles that increase fitness, then evolution at
non-synonymous sites may be faster than at synonymous
sites (because positive selection will substitute alleles
faster than drift): dN/dS > 1.0
34
Positive
selection on
the BRCA1
gene in
humans and
chimpanzees
(Fig. 6.23)
Ratio of
replacement to
silent mutations that
is greater than 1.0
on branches leading
to humans and
chimps is evidence
for positive
selection
35
Molecular evolution – summary
• Neutral theory appears describe much evolution at
the nucleotide level in untranslated parts of the
genome and at synonymous sites
• However, for many, but not all proteins, there is
evidence that evolution has been driven by
positive selection on non-synonymous
substitutions:
– recently duplicated genes that have attained new
functions, disease-resistance loci (e.g., genes that code
for antibody proteins), genes involved in interactions
between egg and sperm at fertilization, genes that code
for certain enzymes (e.g., alcohol dehydrogenase)
36
Nonrandom mating
• Most commonly, nonrandom mating takes the form of
inbreeding, or mating with relatives
• Inbreeding can be “systematic”, such as by selffertilization in hermaphroditic plants and animals (this is
the most extreme form of inbreeding)
• Inbreeding can be “accidental”, as when mating occurs
between related individuals in finite, especially small,
populations
• In either case, the genetic effect of inbreeding is to reduce
heterozygosity below Hardy-Weinberg expectation (2pq),
and to increase homozygosity
• One way of defining the inbreeding coefficient:
F = (HH-W - Hobserved) / HH-W
37
Inbreeding increases homozygosity – the
example of selfing (Fig. 6.25a)
38
Inbreeding increases homozygosity – the
example of selfing (Fig. 6.25b)
39
The effects of inbreeding
• Because inbreeding increases homozygosity, it
makes it more likely that deleterious recessive
alleles in a population will be expressed
• This increases the effectiveness of selection
against harmful recessives
• However, in species that do not normally inbreed,
it also leads to inbreeding depression
40
Inbreeding depression in humans (Fig. 6.28)
Children of first
cousins have
higher mortality
rates than children
of unrelated
parents (by about
4 percentage
points)
41
Inbreeding depression in great tits (Fig. 6.30)
F = 1/4 is the
inbreeding
coefficient of
children of
brother-sister
matings
F= 1/16 is the
inbreeding
coefficient of
children of 1st
cousins
42
Synergism between small population size, drift and
inbreeding – 1
• Drift is especially strong in small populations
• Drift reduces genetic variation (= increased
homozygosity)
• It is possible for deleterious alleles to increase in
frequency under drift (think about bottlenecks and
achromatopsia in Pingelapese islanders)
• In small populations, inbreeding (mating between
relatives) is unavoidable (remember the Pingelapese who are
all descended from 20 survivors of a typhoon) This is true even
if the population is mating at random
43
Synergism between small population size, drift and
inbreeding – 2
• So, small population size results in loss of genetic
variation, chance increases in the frequency of
harmful alleles, and inbreeding
• Inbreeding results in inbreeding depression, which
further reduces population size, which further
enhances the effect of drift, and also results in
more inbreeding, which results in more inbreeding
depression, which results in further reductions in
population size, etc., etc., etc.
• This has been referred to as the “extinction
vortex”
44