Transcript neutral theory, inbreeding - Cal State LA

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
Non-random mating: Inbreeding
Violates one of the assumptions of Hardy-Weinberg
Can affect genotype frequencies without affecting allele frequencies
Selfing (not the same as cloning)
- many plants and some animals can self-fertilize
- homozygotes always give rise to homozygotes
- heterozygotes produce 1/2 homozygotes and 1/2 heterozygotes
Aa
AA
1
Aa
:
2
aa
:
1
Non-random mating: Inbreeding
Result:
in every generation of selfing, the # of heterozygotes is halved
- however, the allele frequencies are unchanged
thus, inbreeding also causes loss of heterozygosity,
and has a strong evolutionary impact
-
Inbreeding and loss of heterozygosity
Case study: malaria parasite
- most people in New Guinea are infected by only one mosquito
- most reproduction occurs between brother and sister offspring
when another mosquito bites an infected person (inbreeding)
prediction: there should be an excess of homozygotes at loci
that are polymorphic
- in other words, even when there are a lot of alleles out there,
selfing should result in few heterozygotes
Inbreeding and loss of heterozygosity
very polymorphic loci
Coefficient of inbreeding
Inbreeding among more distant relatives has the same effect,
but less drastic
Degree of relatedness is reflected in a measure called the
coefficient of inbreeding, F
F is the probability that the two alleles in an individual are related
by descent from a common ancestor
F = 0.5 for selfing: there’s a 50/50 chance selfing will produce an
offspring with both alleles derived from the same parental allele
Coefficient of inbreeding
F is the probability that the two alleles in an individual are
related by decent from a common ancestor
Coefficient of inbreeding
Ordinary genotype frequencies predicted by Hardy-Weinberg:
AA
Aa
aa
p2
2pq
q2
In an inbred population, genotype frequencies are given by:
AA
p2(1-F) + pF
Aa
2pq(1-F)
aa
q2(1-F) + qF
-- why? odds of getting a homozygote = sum of 2 possible ways
way #1 - p x (odds of an unrelated p), which is p x p(1-F)
way #2 - p x (odds of a related p), which is pF
Coefficient of inbreeding
In an inbred population, genotype frequencies are given by:
AA
p2(1-F) + pF
Aa
2pq(1-F)
aa
q2(1-F) + qF
test: insert the value F = 0
- this is true for unrelated gametes
- gives you the Hardy-Weinberg genotype odds
Inbreeding depression
Although inbreeding doesn’t change allele frequencies, it creates an
excess of homozygotes
This exposes loss-of-function alleles, which are normally masked
in heterozygotes
- creates lower fitness among offspring of relatives
Inbreeding depression
inbreeding coefficient
population size
Keller et al. (1994) followed a population of sparrows (small birds)
on a Canadian island for 15 years
Two population crashes, in 1980
(27 survivors) and 1989 (11 survivors)
Inbreeding coefficient of survivors
(those still alive in the crash year) was
much lower than the average value in
the year before the crash
ones who survived the terrible
winters were the least inbred;
inbreeding lowers survival chances
when environment goes bad