Transcript lecture 06 - loss of Hg, founder events

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.
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
2N
where N = population size
amount of heterozygosity
in the next generation
amount of heterozygosity
in this generation
Random fixation and loss of heterozygosity
The frequency of heterozygotes should fall in every generation
- given by the relationship
Hg+1 = Hg
1-1
2N
where N is population size
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
Random fixation and loss of heterozygosity
The frequency of heterozygotes should fall in every generation
- given by the relationship
Hg+1 = Hg
1-1
2N
where N is population size
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)
Random fixation and loss of heterozygosity
The frequency of heterozygotes should fall in every generation
- given by the relationship
Hg+1 = Hg
1-1
2N
where N is population size
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 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
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
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
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)
Genetic bottlenecks & the founder effect
A 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 effect
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
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)
Genetic bottleneck
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
Founder effect
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
 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
population size
proportion of
females w/ 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
Genetic drift and Elephant tusks
population size
proportion of
females w/ 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?
Drift vs. Selection
n = 10 individuals
n = 100
n = 1,000
n = 10,000
100
% of
helpful
allele
50
0
- 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
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)

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
“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
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
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
E. papillosa a
E. papillosa b
GGTGCAGTAAACTTTATTACTACTATTTTTAATATACGGTCACCTGGTATAAGAATGGAACGTTTAAGATTATTTGTTTGATCAGTTTTA
.....G....................................................................................
E. patina 06Jam11
E. patina 07Dom05
.....G..........................C..G.....T.....G..G.C...............T...........G......C.C
.....G..........................C..G.....T.....G..G.C.........C.....T...........G......C.C
E. zuleicae 04Ber03
E. zuleicae 04SSal11
.....G...........C..A...........C..G..C..T.....A..G.C...............T..................C..
.....G..............A.G.........C..G..C..T.....A..G.C...............T........C.........C..
Other positions are polymorphic within one species, but
are otherwise fixed among species
Polymorphic sites 2: amino acid changes
S or T
V or F
E. papillosa a
E. papillosa b
VYPPLSGPIGHGGASVDLAIFSLHLAGMSSILGAVNFITTIFNMRSPGMSMERLSLFVWSVLVTAVLLLLSLPVLAGAITMLLTDRNFNTSF
.................................................S...............V..........................
E. patina 06Jam11
E. patina 07Dom05
.................................................T...............F..........................
.................................................T...............F..........................
E.
E.
E.
E.
E.
E.
E.
E.
E.
E.
E.
E.
E.
E.
E.
E.
E.
.................................................T...............F..........................
.................................................T...............F..........................
.................................................T...............F..........................
.................................................T...............F...................G......
.................................................T...............F..........................
.................................................T...............F..........................
.................................................T...............F..........................
.................................................T...............F..........................
.................................................T...............F..........................
.......................................S.........T...............F..........................
.................................................T...............F..........................
.................................................T...............F..........................
.................................................T...............F..........................
.......S.........................................T...............F..........................
.................................................T...............F..........................
.................................................T...............F..........................
.................................................T...............F..........................
zuleicae
zuleicae
zuleicae
zuleicae
zuleicae
zuleicae
zuleicae
zuleicae
zuleicae
zuleicae
zuleicae
zuleicae
zuleicae
zuleicae
zuleicae
zuleicae
zuleicae
04Ber04
04Ber06
04Boc102
06Jam07
07LSS02
04SSal03
04Boc101
07SSal01
06Jam03
04SSal11
04Bocas103
04SSal06
09Cur105
09Cur09
07Cur12
09Cur13
09Cur14
different amino acids
can occur at a site
within one species
different amino acids
can be fixed
between species
Normally, most substitutions that survive to be detected are silent
1. DNA – 17 polymorphic sites
E. papillosa a
E. papillosa b
GGTGCAGTAAACTTTATTACTACTATTTTTAATATACGGTCACCTGGTATAAGAATGGAACGTTTAAGATTATTTGTTTGATCAGTTTTA
.....G....................................................................................
E. patina 06Jam11
E. patina 07Dom05
.....G..........................C..G.....T.....G..G.C...............T...........G......C.C
.....G..........................C..G.....T.....G..G.C.........C.....T...........G......C.C
E. zuleicae 04Ber03
E. zuleicae 04SSal11
.....G...........C..A...........C..G..C..T.....A..G.C...............T..................C..
.....G..............A.G.........C..G..C..T.....A..G.C...............T........C.........C..
2. amino acid – 4 polymorphic sites (= non-synonymous changes)
E. papillosa a
E. papillosa b
VYPPLSGPIGHGGASVDLAIFSLHLAGMSSILGAVNFITTIFNMRSPGMSMERLSLFVWSVLVTAVLLLLSLPVLAGAITMLLTDRNFNTSF
.................................................S...............V..........................
E. patina 06Jam11
E. patina 07Dom05
.................................................T...............F..........................
.................................................T...............F..........................
E. zuleicae 06Jam07
E. zuleicae 04SSal11
.................................................T...............F...................G......
.......................................S.........T...............F..........................
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
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
Neutral or Selectionist?
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?...
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
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
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
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
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
a
b
c
d
e
f
a
b
C
d
e
In regions of high recombination, many alleles at linked loci can
“hitchhike” onto chromosomes with favorable alleles, and thus
survive selection  greater overall polymorphism
f
Neutral or Selectionist?
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
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