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Significance of variation

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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Significance of variation

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  1. Significance of variation McDonald and Kreitman 1991

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. Genome duplication associated with diversification of the angiosperms De Bodt et al. 2005 • Appear suddenly in the fossil record

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 2x Many species posses a ploidy series 4x 6x 8x 10x Chrysanthemum

  14. 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

  15. Do higher ploidy levels possess greater potential for evolutionary change?

  16. Do ploidy levels differ in their geographic distributions? Solidago altissima Late goldenrod

  17. Do alleles differ in their geographic distribution? • Cline in alcohol dehydrogenase locus of Drosophila melanogaster • Repeated on three continents Futuyma 1998

  18. 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

  19. 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

  20. 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?

  21. To what extent does natural selection operate at the molecular level? Some history…

  22. 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)

  23. “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

  24. 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

  25. 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

  26. 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

  27. 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

  28. 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

  29. 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?

  30. 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 = >

  31. 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

  32. 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

  33. 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

  34. Survey of rate of adaptive evolution at molecular level Eyre-Walker 2006

  35. 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

  36. 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)

  37. Evolution is the interplay between two tangled banks Natural turbulence Genetic turbulence

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