Is heterozygosity common or rare? Sewell Wright Theodosius Dobzhansky

Neutral Theory “The vast majority of substitutions in DNA and proteins, and polymorphism within species, are caused not by positive Darwinian selection, but by random drift of alleles that are selectively neutral or neearly so.”

Neutral Theory of Molecular Evolution 1)For each protein, the rate of evolution (amino acid substitution) is approximately constant per generation as long as the functional constraint (f o, fraction of neutral mutations) remains constant 2)Functionally less important molecules or parts thereof will have a higher substitution rate than functionally important ones 3)Those substitutions that disrupt proteins less will occur more frequently than those that disrupt more 4)Selective elimination of alleles and the random fixation of neutral alleles are more prevalent than alleles fixed by positive Darwinian selection 5)Polymorphism is a transient phase of molecular evolution (substitution), not an adaptive stable state. Constant input of mutations, not natural selection, is the cause of polymorphism.

Justification for neutral theory Kimura, M Nature 217:

Endorsement of the Neutral Theory Science (1969) 164:

Critiques of the Neutral Theory

Inconsistencies with the neutral theory Overdispersion of the protein clock Lack of a generation time effect in protein clock Heterozygosity is much lower, and more even among species, than predicted from population size.

Calibrating a molecular clock is like estimating the speed of a car 2 present-day species Fossil species suspected to be the common ancestor of A and B A B Time (millions of years) Rate = number of genetic differences twice the divergence time of A and B genetic differences

Single calibration point - a no-no in modern rate analyses

Fossil calibrations of turtle phylogeny

Hominid slowdown

Males in the fast lane The larger number of cell divisions undergone by sperm during gametogenesis predicts that the Y chromosome of mammals (or the Z chromosome of birds) should change faster than the X (or W) chromosome. Males Females Species Number of germ line divisions Mice Mice Rats Rats Humans Humans M:F Ratio

Body size and rate of molecular evolution

The link between metabolic rate and molecular change (Martin and Palumbi 1993; Bleiweiss 1998) Metabolic rate Oxidative damage Rate of mutation Large mammals Small mammals High altitude hummingbirds Low altitude hummingbirds

Who’s fastest among the birds and beasts? Rodents Primates Birds Fish Short generation times; high metabolic rates Longer generation times Higher body temperatures, good 0 2 scavengers Ectotherms; often cold environments Faster clock

Copyright ©2004 by the National Academy of Sciences Cho, Yangrae et al. (2004) Proc. Natl. Acad. Sci. USA 101, Fig. 1. Substitution rates in Plantago are highly elevated and variable in mt genes compared with chloroplast (cp) and nuclear (nc) genes

Phe 12s rRNA Val 16s rRNA Leu Ile Gln Met Trp Ala Asn Cys Tyr COI Ser Asp COII Lys ATP8 ATP6 COIII Gly NADH3 Arg NADH4L NADH4 His Ser Leu NADH5 Cyt b Thr Control Region Pro NADH6 Glu noncoding Fast rate of vertebrate mitochondrial DNA (~17,000 bp) rRNA genes tRNA genes ATP synthase genes Cytochrome bc1 complex Cytochrome Oxidase NADH:Ubiquinone Oxidoreductase NADH1 NADH2

Rate acceleration in FOXP2, a ‘speech’ gene in humans

Recent controversies involving molecular clocks Divergence time of humans and chimps Origin of modern humans Origin of animals and the Cambrian explosion Origin of birds and mammals 15 million years ago 1 million years ago 600 million years ago 60 million years ago ControversyOld divergence timeNew divergence time 5 million years ago 5 million years ago 200,000 years ago 200,000 years ago 1.2 billion years ago 1.2 billion years ago 110 million years ago 110 million years ago

Nearly Neutral Theory (Tomoko Ohta) Recognizes that mutations in which 2Ns << 1 behave as if they are neutral, even if deleterious or advantageous. Small populationlarge population

Fixation probability of nearly neutral mutations Fixation probability

Comparison of neutral and nearly neutral world views

Distribution of fitness effects of spontaneous mutations

Speciation and the rate of molecular evolution Neutral theory: E = M x F: Surprisingly, bottlenecks have no influence on the rate at which neutral variation is incorporated (fixed) into new species; only changes in mutation rate can ultimately change E. However, for non-neutral variation, bottlenecks can accelerate or retard change population bottlenecks neutral non-neutral Rate of molecular evolution

Tests of nearly neutral theory using island birds SynonymousNon-synonymous