Is heterozygosity common or rare? Sewell Wright Theodosius Dobzhansky.

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 (fo, 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. 1968. Nature 217: 624-6.

Endorsement of the Neutral Theory

Science (1969) 164: 788-798

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 commonancestor of A and B

A B

Time (millions of years)

Rate = number of genetic differences twice the divergence time of A and B

geneticdifferences

Single calibration point - a no-noin modern rate analyses

Fossil calibrations of turtle phylogeny

Hominid slowdown

Males in the fast lane

• 56• 57• 91-205

• 27• 28• 33

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 FemalesSpecies

Number of germ line divisions

MiceMice RatsRats HumansHumans

M:F Ratio

2.12.1 2.02.0 3-63-6

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 altitudehummingbirds

Low altitudehummingbirds

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 02 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, 17741-17746

Fig. 1. Substitution rates in Plantago are highly elevated and variable in mt genes compared with chloroplast (cp) and nuclear (nc) genes

Phe 12s rRNAVal

16s rRNA

LeuIle

Gln

Met

Trp

Ala

Asn

Cys

Tyr

COI

SerAspCOII

LysATP8

ATP6COIII

GlyNADH3

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

Controversy Old divergence time New divergence time

5 million years ago 5 million years ago

200,000 years ago200,000 years ago

1.2 billion years 1.2 billion years agoago

110 million years 110 million years agoago

Nearly Neutral Theory(Tomoko Ohta)

• Recognizes that mutations in which 2Ns << 1 behave as if they are neutral, even if deleterious or advantageous.

Small population large population

Fixation probability of nearly neutral mutations

Fixation probability

Comparison of neutral and nearly neutral world views

Distribution of fitness effects of spontaneous mutations

Distribution of fitness effects of spontaneous mutations

Speciation and the rate of molecular evolution

Neutral theory: E = M x F: Surprisingly, bottlenecks have noinfluence 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

Rat

e of

mol

ecul

ar

evol

utio

n

Tests of nearly neutral theory using island birds

Synonymous Non-synonymous