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Transcript
Molecular Evolution Nothing in biology makes sense except in the light of evolution Dobzhansky, 1973 1 Study evolution to make sense of biology What kind of changes occur at the DNA level during evolution? How does the environment influence our genes? What can our genes tell us about the past environment? Can we “read” the evolutionary patterns of our genes to understand their functions? The molecule : DNA actgaatg |||||||| tgacttac gene MALVK protein genome Population …. Speciation 2 Advantages: Highly divergent organisms can be compared quantitatively without relying on morphological characters Changes at the DNA level not presenting phenotypic effects can be also used as additional information to compare sequences from different species Molecular data • Protein: biochemical properties • Protein: sequence • DNA: sequence – Coding (makes protein) – Non-coding 3 • DNA is both the raw material and the marker of evolution – Genes determine inherited differences, which is what evolution acts on – Genes change and can be used to measure evolution A genome (complete DNA of an organism) is a historical record of evolution. By analysing and comparing the DNA of related organisms, can learn about their evolutionary history. … We can also start to classify their relationships (phylogenetics) 4 Complete Genomes Evolution 5 Functional constraint Abraham Wald B-29 Bomber Molecular Evolution Part 1: Understand patterns and processes of mutation Part 2: Examine cases where patterns of divergence differ from patterns of mutation 6 Molecular Variation • • • • Nucleotide substitution Insertions or deletions (indels) Recombination Gene duplication and loss Molecular Variation Single Nucleotide Polymorphisms (SNPs) – One bp difference between “alleles” – Human genome • Coding DNA – 1 SNP per 1-3 kb (kb = 1000bp) • Non-coding DNA – 1 SNP per 0.5-1 kb DNA sequencing …ACGTGACTGAGGACCGTG CGACTGAGACTGACTGGGT CTAGCTAGACTACGTTTTA TATATATATACGTCGTCGT ACTGATGACTAGATTACAG ACTGATTTAGATACCTGAC TGATTTTAAAAAAATATT… 7 Evolution • interested in genetic variation - understand generation and maintenance • initially (until 1960s) only possible to study indirectly - phenotype • paucity of data led to controversy on the extent of genetic variation Classic school - very little genetic variation due to cost associated with natural selection Muller Balance school - lots of genetic variation maintained by natural selection Dobzhansky • debate settled with advent of molecular approaches (direct) to the study of genetic variation - electrophoresis, sequencing • Zuckerkandel & Pauling – 1960s • Electrophoretic gel separation of proteins • Proteins travel at different speeds according biochemical properties or molecular weight • 15-50% of genes have 2 or more electrophoretic alleles 8 • Too much polymorphism to be explained by mutation and positive selection alone (NeoDarwinian model) • Why so much? The Neutral Theory of Molecular Evolution How can we explain the large amounts of variation that exist in populations? • Most mutations are selectively neutral (not advantageous or disadvantageous) … generate new neutral alleles • These will be fixed (= present at 100% frequency) in the population by Genetic Drift 9 Random Genetic Drift Selection 100 Allele frequency advantageous disadvantageous 0 time time The Neutral Theory of Molecular Evolution • The rate of neutral evolution is equal to the rate of neutral mutation Kimura reasoned that the majority of both polymorphism (allelic frequencies within populations) and substitution (fixed differences between populations) result from fixation of selectively neutral variants by random genetic drift - the main role of natural selection is elimination of deleterious variants (maintenance of the status quo) - molecular evolution is conservative - adaptively favorable mutations fixed by natural selection are a small minority of all nucleotide substitutions Huge debate between selectionists (variation is a product of natural selection) and neutralists (variation is a product of random fixation of neutral variants) 10 Molecular Clock • MOLECULAR CLOCK # differences • Rate of substitution = rate of mutation time • Number of changes is proportional to time • Use number of changes to estimate relative divergence of species or genes • Neutral Theory makes explicit quantitative predictions about levels of genetic variation - null hypothesis of molecular evolution • functionally important parts of a molecule will change slower than non-functional parts (Molecular Clock does not always hold) 11 Evolution of protein coding sequences Rates and patterns of nucleotide substitution in protein-coding seqs • Controlled by three things – Functional constraint (negative selection) – Positive selection – Mutation rate 12 Standard Genetic Code Phe Leu Leu Ile UUU Ser UCU Tyr UAU Cys UCC UUA UCA ter UAA ter UGA UUG UCG ter UAG Trp UGG CCU His CAU Arg CGU CUU Pro CUC CCC CUA CCA CUG CCG AUU Thr ACU AUC ACC AUA ACA Met AUG ACG Val GUU Ala GCU GUC GCC GUA GCA GUG GCG UAC UGU UUC Gln Asn UGC CAC CGC CAA CGA CAG CGG AAU Ser AAC Lys AAA AGC Arg AAG Asp Glu GAU AGU AGA AGG Gly GGU GAC GGC GAA GGA GAG GGG synonymous subs - do not change encoded amino acid nonsynoymous subs - do change encoded amino acid GAT AAC ATC CAA GGA ATA ACT GCA ATC GAC AAC ATC CAA GGT ATC ACG GCT ATC Asp Asn Ile Gln Gly Ile Thr Ala Ile • in virtually every gene ever studied synonymous sites change at a higher rate than nonsynonymous sites 13 Evolution of protein-coding sequences • The Genetic Code is redundant • Some nucleotide changes do not change the amino acid coded for – 3rd codon position often synonymous – 2nd position never – 1st position sometimes Synonymous Consensus Seq1 Seq2 Seq3 Consensus: AAT GGC TCT TTT GAA AAA ... N Seq4 Seq5 Seq6 G F F N K . Seq2: AAC GGA TGT TTC GAG AAA... N Seq7 Seq8 Seq9 Seq10 Seq11 G C F E K . Non-synonymous Number of individuals Positive selection Neutrally fixed Purifying selection E Number of mutations AAT GGC TGT TTT GAA AAA ... N G C F N K . 14 rates • In general, the rates of nucleotide substitution are lowest at nondegenerate sites (0.78 x 10-9 per site per year) • Intermediate at two-fold degenerate sites (2.24 x 10-9) • Highest at fourfold degenerate sites (3.71 x 10-9) Effect of amino acid substitutions • Deleterious • Neutral • Advantgageous 86% 14% 0.0% ? (very low) • In protein coding sequences, selection is often acting to remove changes • Less common outcome is drift of neutral changes • Rarely see positive selection for advantageous changes 15 Functional constraint Abraham Wald B-29 Bomber Functional Constraint • Proteins often have some functional constraint • This may involve • a few amino acids in a critical site – Haeme pocket of Haemoglobin is constrained – The rest just needs to be hydrophillic • Or almost the whole protein – Histone 4 – Almost all in contact with DNA or other proteins • Or hardly be present at all – Fibrinopeptide amino acid sequence is not important • The stronger the functional constraint, the slower the rate of evolution 16 Rates and Patterns • Patterns of change can be informative of the function of a protein • Different genes evolve at different rates • Amino acids that are always conserved are likely to be critical to the function synonymous substitutions - little or no effect on the fitness of the organism. non-synonymous substitutions always change the protein. Since most changes are deleterious, we expect these changes to be removed by selection. rate of evolution at synonymous sites is greater than at non-synonymous sites. 17 • The differences in the rates of evolution are usually due to functional constraints • mutations that remove or reduce the function of a gene are removed by negative selection • very important genes tend to evolve slowly • proteins (gene products) that interact with other proteins etc. also evolve slowly at interacting interfaces – mutations may disturb the interaction and be consequently deleterious • if there is low or no functional constraint, then the proteins will fix new mutations by random drift and so evolve faster 18