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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 Small-scale mutations Macromutations Polyploidy Doubling of whole genomic DNA.

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slide1

Significance of variation

McDonald and Kreitman 1991

slide2

Mutations are the raw material of evolution

  • Source of new alleles
  • Source of new genes
  • Produce heritable variation that is transmitted across generations
    • Small-scale mutations
    • Macromutations
      • Polyploidy
        • Doubling of whole genomic DNA
slide3

Genome and gene duplications create evolutionary novelty

Secretory calcium binding phosphoprotein (SCPP) gene family

  • 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?

In mammals, formation of tooth, bone and milk depends upon SCPP

Tunicate

Ray-finned fish

Lobe-finned fish

Sanetra et al.Frontiers in Zoology 2005 2:15

slide4

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

Number of families per clade

Clades

Extant lineages

Extinct lineages

Evolution of jawed fish

Donoghue and Purnell 2005

slide5

Genome duplications = evolutionary novelty

  • If this is true, what pattern would you expect to see on a phylogenetic tree after genome duplication event?
  • Burst of diversification
  • Not supported

Fossil evidence

Extant lineages

Extinct lineages

Evolution of ray-finned fishes

Donoghue and Purnell 2005

slide6

Genome duplications provide robustness

  • Focus on the high rate of extinction before duplication
  • Provides robustness against extinction

Extant lineages

Extinct lineages

Crow and Wagner 2005. Mol. Bio. Evol. 23:887-892

slide7

Genome duplication associated with diversification of the angiosperms

De Bodt et al. 2005

  • Appear suddenly in the fossil record
slide8

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

slide9

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
slide10

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, 5454–5459

Blanc & Wolfe. 2004.Plant Cell 16, 1679–1691

Seoighe & Gehring. 2004. Trends Genet. 20, 461–464

slide11

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
polyploidy in plants is an ancient and ongoing process

Diploid

X

Tetraploid

Polyploidy in plants is an ancient and ongoing process

Meiotic Nonreduction

  • 70-80% of plants have polyploidy origins
  • Speciation via polyploidy has been observed in modern times

Fertilization

slide13

2x

Many species posses a ploidy series

4x

6x

8x

10x

Chrysanthemum

slide14

Do higher ploidy levels possess greater potential for evolutionary change?

2x

4x

  • More gene products
  • Greater genetic diversity
  • Opportunity for duplicated genes to diverge in function
  • More gene interactions

6x

8x

10x

slide18

Do alleles differ in their geographic distribution?

  • Cline in alcohol dehydrogenase locus of Drosophila melanogaster
  • Repeated on three continents

Futuyma 1998

slide19

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

slide20

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

slide21

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?
slide23

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)
slide24

“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

slide25

The central tenants of the neutral theory

  • 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
slide26

Neutral theory seemed to work!

  • Estimates of overall heterozygosity
      • Nei 1983. Genetic polymorphism and role of mutation in evolution. In The evolution of genes and proteins p. 165-190
  • Distribution of single locus heterozygosity
      • Nei et al. 1976 Testing the neutral mutation hypothesis by distribution of single locus heterozygosity. Nature 262:491-493
  • Variance in heterozygosity
      • Gojobori 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 locus
      • Chakaraborty 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
slide27

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
slide28

A few clear cases showed accelerated protein evolution

Can you make this into a general test?

  • 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
slide29

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
slide31

Does selection act at the molecular level?

  • 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):
      • Synonymous (no change in amino acid sequence or regulatory sequences)
      • Nonsynonymous (change in amino acid sequence or regulatory sequence)

If neutral - expect more syn or nonsyn?

Divergence

Ds and Dn

Polymorphism

Ps and Pn

If neutral - expect more syn or nonsyn?

slide32

The verbal argument…

  • 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?

Divergence

Ds and Dn

Dn Pn

Ds Ps

Polymorphism

Ps and Pn

=

>

slide33

The mathmatical argument…

Time it takes a new mutation to become fixed if that is its destiny from Kimura’s equations

  • Ne = effective population size
  • = nucleotide mutation rate

Ls = number of synonymous sites

k = constant

number sequences sampled

sampling strategy

demography

Ln = number of nonsynonymous

sites

f = proportion of amino acid

mutations that are neutral

t = time since divergence of two

species

 = proportion of nonsynonymous

mutations that are adaptive

Ps = 4NeLsk

Pn = 4NeLnfk

Ds = 2Lst

Dn = 2Lntf

1 - 

Dn = Pn

Ds Ps

  • = 1 – DsPn

DnPs

slide34

Dn = Pn

Ds Ps

MK test for adaptive evolution

115 genes in two species of Drosophila

Divergence Polymorphism

3648

439

Non-synonymous

Synonymous

7365

1741

0.25

0.49

  • = 1 – (7365)(439)

(3648)(1741)

= 0.49

  • = 1 – DsPn

DnPs

slide35

Inferring the strength of adaptive evolution

  • 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
slide37

Is the pattern uniform across species?

  • 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
slide38

What do all these substitutions do?

  • 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)
slide39

Evolution is the interplay between two tangled banks

Natural turbulence

Genetic turbulence