Models of Molecular Evolution I

1. Models of Molecular Evolution I Level 3 Molecular Evolution and Bioinformatics Jim Provan Page and Holmes: Sections 7.1 – 7.2

2. 1.00 600 500 Shark 0.75 Carp Fossil divergence time 400 Frog Dayhoff distance (to humans) Myr ago 0.50 300 Alligator Molecular divergence time Chicken 200 0.25 Quoll 100 Cow Baboon The a-globin molecular clock

3. The a-globin molecular clock • As relationships between species diverge, number of amino acid differences appear to increase proportionally • Assuming the divergence time of one of the points is known (humans and cows diverged 80 Myr ago), other divergence times can be calculated: • 17 of 149 amino acids (Dayhoff distance 0.131) differ between humans and cows • 47 differences (Dayhoff distance 0.445) between humans and alligators • Suggests that humans and alligators diverged 3.4 times as long ago as humans and cows (~270 Myr ago) • Fossil record suggests that humans and alligators diverged ~300 Myr ago: a-haemoglobin is behaving like a molecular clock

4. Processes of molecular evolution • Why should such a clock exist and how accurate is it? • Answer to this question will give insights into how nucleotide and amino acid sequences evolve • Since the 1960s there have been two conflicting models of how molecular evolution takes place: • One (neutralist) is dominated by the genetic drift of neutral mutations • The other (selectionist) states that natural selection of advantageous mutations is more important • Knowing which model best explains molecular evolution will ultimately lead to development of more realistic models of DNA substitution and thus allow the construction of more accurate phylogenies

5. The classical and balance schools of population genetics • Foundation of the neutralist-selectionist debate was laid in the 1950s in the debate between the classical and balance schools of population genetics: • The classical school believed that natural selection was predominantly a purifying force, removing deleterious alleles, and that there would be little genetic variation in populations • The balance school claimed that levels of genetic variation were so high that most loci were polymorphic and that individuals were heterozygous at a large number of loci – this scenario was maintained by balancing (overdominant) selection • Both schools were agreed that natural selection was the driving force in evolution but there was no evidence for the divisive issue: how much genetic variation existed within and between species?

6. 0.5 Drosophila 0.4 Invertebrates exc. insects All invertebrates Insects exc. Drosophila 0.3 European humans Amphibians Plants Proportion of polymorphic loci Reptiles 0.2 All vertebrates Fish Mammals Birds 0.1 0.0 0.00 0.05 0.10 0.15 Heterozygosity Levels of variation in allozymes

7. The cost of natural selection and the rise of the neutral theory • Technical advances had revealed that the balance school was correct concerning levels of variation • These results posed a problem: • If natural selection had produced all this diversity, would it not also be true that individuals with inferior alleles would be selectively removed from the population? • The population could go extinct with all this “selective death” - this is known as the cost of natural selection • Cost of natural selection is part of the overall genetic load – the loss of overall fitness due to deleterious alleles: • Reason why classical school through there was low variation • This would be appropriate for substitutional load

8. Segregational load • Occurs when a polymorphism is maintained due to overdominant selection • Classic example is human sickle-cell anaemia: • Individuals homozygous for HbA haemoglobin allele produce normal haemoglobin • Individuals homozygous for HbS haemoglobin allele produce mutant haemoglobin (sickle cell-anaemia: 80% fatal) but are much less susceptible to malaria • Heterozygous individuals do not suffer from sickle-cell anaemia and are much more resistant to malaria • Laws of Mendelian segregation show that individuals who are susceptible to malaria (HbA /HbA) or to sickle-anaemia (HbS /HbS) will still be produced

9. The neutral theory of molecular evolution • High levels of genetic variation could be maintained in populations without excessive selective death if natural selection was not the driving force in molecular evolution • Neutral mutations could be lost (usually) or fixed (very occasionally) by genetic drift: • The neutral theory of molecular evolution suggests that mutation and drift predominate • The selectionist school believed that selection was the dominant force • Both agree that selection removes deleterious alleles • Central dogma of chance vs. necessity

10. Neutralist Selectionist Deleterious Neutral Advantageous Neutralist and selectionist models of molecular evolution

11. The neutralist-selectionist debate • Neutralist theory is not anti-Darwinist: • Claims that fixation through selection – the main process of morphological evolution – occurs at low frequency • Effectively believes that most genes and proteins are already almost-optimally adapted through selection • Current debate centres around four major predictions of the neutral theory: • There is an inverse correlation between substitution rate and degree of functional constraint acting on a gene • Patterns of base composition and codon usage reflect mutational rather than selective processes • There is a constant rate (molecular clock) of sequence evolution • Level of within species variation is a product of only population size and mutation rate

12. Functional constraint and amino acid substitution • Rates of amino acid substitution are extremely variable: • Fibrinopeptides evolve 900 times faster than histones • To neutralists, this difference is explainable by differences in selective constraint, rather than positive selection • The more functionally constrained a gene is, the higher the chance that a mutation will be deleterious • Correlation between functional constraint and substitution rate is proposed as evidence for the neutral theory

13. Functionally constrained gene Less functionally constrained gene Non-coding DNA Deleterious Neutral Functional constraint and amino acid substitution

14. Functional genes Gene Mouse ya3 Human ya1 Rabbit yb2 Goat ybx and yz Average Pseudogene 5.0 5.1 4.1 4.4 4.7 Position 1 0.75 0.75 0.94 0.94 0.85 Position 2 0.68 0.68 0.71 0.71 0.70 Position 3 2.65 2.65 2.02 2.02 2.34 Rates of nucleotide substitution per site, per year x 10-9 Functional constraint at the nucleotide level