Significance of variation McDonald and Kreitman 1991.
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Transcript of Significance of variation McDonald and Kreitman 1991.
Significance of variation
McDonald and Kreitman 1991
Mutations are the raw material of evolution
• Source of new alleles• Source of new genes• Produce heritable variation that is transmitted across
generations
1. Small-scale mutations2. Macromutations
• Polyploidy• Doubling of whole genomic DNA
Genome and gene duplications create evolutionary novelty
Sanetra et al.Frontiers in Zoology 2005 2:15
• Vertebrate evolution punctuated by three widespread gene or genome duplications
• Associated with:• Increases in
morphological complexity
• Adaptive radiations in body design
• Is genome duplication the explanation?
Secretory calcium binding phosphoprotein (SCPP) gene family
Tunicate Ray-finned fish Lobe-finned fish
In mammals, formation of
tooth, bone and milk depends
upon SCPP
Genome duplications = evolutionary novelty • If this is true, what pattern would you expect to see
on a phylogenetic tree after genome duplication event in terms of species diversity?
• Burst of diversification• Not supported
Extant lineages
Extinct lineages
Number of families per
clade
Donoghue and Purnell 2005
Clades
Evolution of jawed fish
• If this is true, what pattern would you expect to see on a phylogenetic tree after genome duplication event?
• Burst of diversification• Not supported
Extant lineages
Extinct lineages
Fossil evidence
Donoghue and Purnell 2005
Evolution of ray-finned fishes
Genome duplications = evolutionary novelty
Crow and Wagner 2005. Mol. Bio. Evol. 23:887-892
Genome duplications provide robustness
Extant lineages
Extinct lineages
• Focus on the high rate of extinction before duplication
• Provides robustness against extinction
Genome duplication associated with diversification of the angiosperms
De Bodt et al. 2005
• Appear suddenly in the fossil record
Darwin referred to the rapid rise and early diversification of the angiosperms
as an “abominable mystery”
• Tried to identify a single causal factor
• Described his efforts “wretchedly poor”
Letter to J.D. Hooker dated July 22 1897
Genome duplication associated with diversification of the angiosperms
De Bodt et al. 2005
• Appear suddenly in the fossil record
• Polyploidy created developmental and regulatory gene families found in angiosperms
Are genome-wide and single-gene duplications equally valuable from an evolutionary perspective?• Genes involved in signal transduction
transcriptional regulation and are preferentially retained following polyploidy
Maere et al. 2005. PNAS.102, 5454–5459Blanc & Wolfe. 2004.Plant Cell 16, 1679–1691Seoighe & Gehring. 2004. Trends Genet. 20, 461–464
Are genome-wide and single-gene duplications equally valuable from an evolutionary perspective?• Genes involved in signal transduction
transcriptional regulation and are preferentially retained following polyploidy
• Developmental genes also retained at higher frequency
• Fewer of these genes survive single gene duplications
• Transcription factors and genes involved in signal transduction show high dosage effects
• Protein components must be present in stoichiometric qualities
Meiotic Nonreduction
Fertilization
Polyploidy in plants is an ancient and ongoing process
X
Tetraploid
Diploid
• 70-80% of plants have polyploidy origins
• Speciation via polyploidy has been observed in modern times
2x
4x
6x
8x
10x
Chrysanthemum
Many species posses a ploidy series
2x
4x
6x
8x
10x
Do higher ploidy levels possess greater potential for evolutionary change?
More gene products
Greater genetic
diversity
Opportunity for
duplicated genes to
diverge in function
More gene
interactions
Artificial selection on
timing of flowering
Will polyploids evolve faster?
G0
G1
G2
G3
G4
Days to flower
control
Days to flower
control
Tetraploid
Chromosome count = 36
Diploid
Chromosome count = 18
Figure 1. Countable chromosome images from the ploidy levels included in this artificial selection experiment
Tetraploid
Chromosome count = 36
Diploid
Chromosome count = 18
Figure 1. Countable chromosome images from the ploidy levels included in this artificial selection experiment
Do higher ploidy levels possess greater potential for evolutionary change?
Ploidy Level
Tetraploid Diploid
% o
f Sel
ectio
n lin
es th
at a
re
sign
fican
tly d
iffer
ent t
han
the
cont
rols
0
20
40
60
80
100
Chi-square = 9.9; P = 0.002
Diploid
Chromosome count = 18
experiment
Tetraploid
Chromosome count = 36
Chromosome count = 18
Do ploidy levels differ in their geographic distributions?
2x4x>4x
2x4x>4x
Cytotypes
Diploid Triploid Tetraploid Higher
Gen
ome
size
(pg
DN
A)
3.0
3.5
4.0
4.5
5.0
5.5
6.0
6.5
F3,768 = 2591 P < 0.0001
Cytotypes
Diploid Triploid Tetraploid Higher
Gen
ome
size
(pg
DN
A)
3.0
3.5
4.0
4.5
5.0
5.5
6.0
6.5
F3,768 = 2591 P < 0.0001
Figure 1. Genome size for Solidago altissima plants with different cytotypes which are putatively diploid, triploid, tetraploid, and a mix of pentaploids and hexaploids. Calclations based on an internal standard with a known genome size (chicken red blood cells)
Solidago altissimaLate goldenrod
Futuyma 1998
Do alleles differ in their geographic distribution?
• Cline in alcohol dehydrogenase locus of Drosophila melanogaster
• Repeated on three continents
Are different alleles being favored over time?
Anderson et al. 2005. The latitudinal cline in the In(3R)Payne inversion polymorphism has shifted in the last 20 years in Australian Drosophila
melanogaster populations. Molecular Ecology 14: 851–858
Selectionist mission
Link biochemical differences to fitness in nature
Few well-known examples where natural selection is clearly involved in the maintenance of enzyme polymorphism
http://anthro.palomar.edu/synthetic/images/map_of_sickle_cell_frequencies.gif
Significance of variation
• Chimps and humans differ in 1% of our genes
• ~3,400,000 nucleotides• ~60,000 amino acid differences
• What proportion of these differences have been fixed because they were beneficial and allowed us to adapt to our environments?
• How many of these differences were simply fixed by random genetic drift?
To what extent does natural selection operate at the molecular level?
Some history…
Significance of variation
• Study of variation at the molecular level began with proteins (allozymes).
Hubby and Lewontin. 1966. A molecular approach to the study of genic heterozygosity in natural populations. The number of alleles at differ loci in Drosophila pseudoobscura. Genetis 54:577-94.Harris 1966. Enzyme polymorphism in man. Proc. Roy. Soc. B. 164:298-310.
• Discovered astonishing level of polymorphism• Challenged our fundamental understanding of how
adaptive evolution occurs• Most variation must be neutral – Kimura’s neutral theory
of evolution (1970)
“The maintenance of abundant polymorphism and heterozygosity in populations demands, however, an explanation… The easiest way to cut the Gordian knot is, of course, to assume that a great majority of the polymorphisms observed involve gene variants that are selectively neutral, that is, have no appreciable effects on the fitness of their carriers” Dobzhansky 1970
The beginning of neutralist-selectionist debate
• Kimura (1968)• Most mutations are deleterious and are rapidly
eliminated• A very small number of mutations are favorable and
are rapidly fixed• Most of the variation that we observe within species
is selectively neutral and is governed by the interplay of mutation and drift
• Most differences between species are simply due to the random fixation of mutations
The central tenants of the neutral theory
• Estimates of overall heterozygosityNei 1983. Genetic polymorphism and role of mutation in evolution. In The evolution of genes and proteins p. 165-190
• Distribution of single locus heterozygosityNei et al. 1976 Testing the neutral mutation hypothesis by distribution of single locus heterozygosity. Nature 262:491-493
• Variance in heterozygosityGojobori 1982 Means and variances of heterozygosity and protein function. In Molecular Evoluton, Protein Polymorphism and the Neutral Theory pp 137-150
• Number of alleles per locusChakaraborty et al. 1980. Statistical studies on protein polymorphism in natural populations. III. Distribution of allele frequencies and the number of alleles per locus. Genetics 94:1039-1063
• The correlation of single-locus heterozygosity between related species
Braverman et al. 1995. The hitchhiking effect on the site frequency spectrum of DNA polymorphism Genetics 140:783-795
Neutral theory seemed to work!
Duplicate genes• Faster rates of nonsynonymous replacement than of
synonymous replacement• High selective value of protein divergence
• Hemoglobins• Visual pigments• Adrenergic receptors in humans• Antigen recognition sites in humans and mouse• Immunoglobulins• Growth hormone genes in humans and bovines
A few clear cases showed accelerated protein evolution
Duplicate genes• Faster rates of nonsynonymous replacement than of
synonymous replacement• High selective value of protein divergence
• Hemoglobins• Visual pigments• Adrenergic receptors in humans• Antigen recognition sites in humans and mouse• Immunoglobulins• Growth hormone genes in humans and bovines
A few clear cases showed accelerated protein evolution Can you make this
into a general test?
What can we learn by comparing the rate of synonymous and nonsynonymous
replacements?
• New light recently shed on debate because of:• Increase in DNA sequence data• New methods of analysis
• McDonald-Kreitman test (MK)• Neutral theory predicts the amount of
variation there should be within and between species
• We can use sequence data to calculate the amount of variation within a species (polymorphism) to the amount of variation between species (divergence):1. Synonymous (no change in amino
acid sequence or regulatory sequences)
2. Nonsynonymous (change in amino acid sequence or regulatory sequence)
Does selection act at the molecular level?
PolymorphismPs and Pn
DivergenceDs and Dn
If neutral - expect more syn or nonsyn?
If neutral - expect more syn or nonsyn?
• McDonald-Kreitman test (MK)• Nonsynonymous mutations that are
adaptive () contribute to divergence (Dn) but not so much to polymorphism (Pn)
• Rapidly fixed by selection so they are not segregating within species
• Synonymous mutations will accumulate at the neutral rate (Ds and Ps)
• If most molecular evolution is neutral then:
• If under selection?
The verbal argument…
PolymorphismPs and Pn
DivergenceDs and Dn
Dn Pn
Ds Ps
=>
Ps = 4NeLsk
Pn = 4NeLnfk
Ds = 2Lst
Dn = 2Lntf 1 -
Ne = effective population size = nucleotide mutation rateLs = number of synonymous sitesk = constant
number sequences sampledsampling strategydemography
Ln = number of nonsynonymous sitesf = proportion of amino acid mutations that are neutral t = time since divergence of two species = proportion of nonsynonymous mutations that are adaptive
Time it takes a new mutation to become fixed if that is its destiny from Kimura’s equations
Dn = Pn
Ds Ps
The mathmatical argument…
= 1 – DsPn
DnPs
Dn = Pn
Ds Ps
Divergence Polymorphism
Non-synonymous Synonymous
3648 4397365 1741
0.49 0.25
= 1 – DsPn
DnPs
= 1 – (7365)(439) (3648)(1741) = 0.49
MK test for adaptive evolution
115 genes in two species of Drosophila
• From this and other studies, adaptive value evolution in Drosophila protein-coding sequences converging at ~50%
• Can extrapolate to the whole genome• If = 0.45, then Drosophila would have one substitution
every 45 years or 450 generations• 22,000 substitutions per million years
Inferring the strength of adaptive evolution
Eyre-Walker 2006
Survey of rate of adaptive evolution at molecular level
• No.• The proportion of nonsynonymous mutations that are
adaptive is particularly low in comparisons of humans and other organisms
• Ranges 0-35%• Bias in 35% estimate of Fay et. al 2001
• Used genes associated disease and other critical function
• Also little evidence of adaptive evolution in Arabidopsis.• High levels of adaptive evolution in viruses and bacteria
Is the pattern uniform across species?
• D. melanogaster and D. simulans differ by 110,000 adaptive amino acid differences
• Species are almost identical morphologically• Physiology• Ecology• Arms race between hosts and parasites
• “It might be that we just have no idea how complex the environment really is and how it is constantly changing in ways that challenge organisms to adapt.” (Eyre-Walker 2006)
What do all these substitutions do?
Evolution is the interplay between two tangled banks
Natural turbulence Genetic turbulence