What is molecular evolution? BIOL2007 Molecular Evolution. Modes of molecular evolution. Modes of molecular evolution

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1 BIOL2007 Molecular Evolution What is molecular evolution? Evolution at the molecular level Kanchon Dasmahapatra Modes of molecular evolution INDELS: insertions and deletions Modes of molecular evolution Gene duplication Slippage in tandem repeats

2 Modes of molecular evolution Substitutions Single base pair changes, substitutions or point mutations Insertions or deletions, also known as indels Gene duplications - formation of multigene families and pseudogenes Slippage microsatellite length changes Chromosomal mutations GTT GTC GTA GTG Proline GCGACGGGGGAG GCGACAGGGGAG 64 triplet codons coding for 20 amino acids CGT CGC Histidine Twofold TGG TGC Tryptophan Cysteine Fourfold SYNONYMOUS SUBSTITUTION (silent substitution) NON- SYNONYMOUS SUBSTITUTION Classical vs. Balance schools Who is right? Classical school polymorphisms are rare because selection gets rid of less fit alleles Balance school polymorphisms are common because of balancing selection Data in the form of allozymes showed that lots of polymorphisms are present. But... causes the problem of genetic load 30,000 to 50,000 genes in humans If only 000 are homozygous If selective coefficient = 0.0 Fitness per locus = 0.99 Summed over 000 loci, fitness = (0.99) 000 =

3 The neutral theory Neutralists vs. selectionists Proposed by Kimura (968) and King & Jukes (969) Neutralists Selectionists Majority of mutations that spread through a population have no effect on fitness Therefore, genetic drift NOT natural selection drives molecular evolution Mutations fixed by genetic drift Deleterious Neutral Advantageous Mutations fixed by selection Kimura s calculations Predictions from neutral theory µ = mutation rate per gene per generation N = population size (effective) No. of alleles in population = 2N No. of new mutations per generation = 2Nµ Probability of fixation = 2N Molecular clock rate of substitution functional constraint on gene Rate of substitution = 2Nµ 2N = µ Time for neutral mutation to fix by drift = 4N 3

4 Molecular clock Molecular clock Genes evolve at a constant rate X Y Z t 2t Time Predict that d XZ = 2d XY Estimate evolutionary time from genetic divergence Testing the molecular clock Testing the molecular clock The relative rate test X Y Z The relative rate test Old World monkeys Human New World monkeys X Y Z Gene Synonymous : 9 genes No. of bases 3520 d XZ d YZ 2.3±0.6 * Φη-globin pseudogene 827.5±0.4 * Three introns ±0.5 check if d XZ = d YZ If d XZ = d YZ, then d XZ - d YZ = 0 Two flanking regions ±. * 4

5 Variation in the molecular clock Predictions from neutral theory Lineage effects Generation time hypothesis Humans vs monkeys Primates vs rodents Metabolic rate hypothesis DNA repair efficiency hypothesis Molecular clock rate of substitution functional constraint on gene Functional constraints Functional constraints BETWEEN GENES Less constrained BETWEEN NUCLEOTIDES Fibrinopeptides Growth hormone Haemoglobin a- chain Prolactin Cytochrome c Histone H2B Histone H Deleterious Neutral Functionally constrained Substitutions per nucleotide site, per 0 9 years Non Twofold Fourfold Introns Pseudogenes Amino acid substitutions per site, per 0 9 years Non-synonymous mutations Synonymous or silent mutations 5

6 Functional constraints Testing neutrality of mutations Sequence copies of the gene of interest from a variety of species. Construct a phylogeny of the species using the sequence or other data. Identify synonymous and non-synonymous mutations. Calculate the average synonymous rate of subsititution, d S, the average non-synonymous rate of substitution, d N, and the ratio, ω = d N /d S. Testing neutrality of mutations Evidence for positive selection Substitutions per nucleotide site, per 0 9 years Non- Twofold Fourfold Introns Pseudogenes Major histocompatibility complex For most genes, ω = dn/ds < If dn > ds, ω > indicative of positive selection 6

7 Evidence for positive selection Points to take away HIV surface envelope protein Sooty mangabeys Macaques Human African green monkey Human Evolution at the level of DNA Lots of polymorphism present at the gene level Development of the neutral theory The molecular clock Functional constraint and the rate of substitution Detection of positive selection Both natural selection and genetic drift determine substitution dynamics Reading Page, R. D. M. & E. C. Holmes Molecular Evolution: a phylogenetic approach. Blackwell Publishing. Ch. 7 Models of molecular evolution. Li, W So, what about the molecular clock hypothesis? Current Opinion in Genetics and Development 3:

8 Improving detection of positive selection ω = ω = 0.9 ω = Yang & Bielawski (2000) TREE: 5