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Our mt genome can easily be aligned with those of other primates. At most nucleotide positions (“sites”), everyone has the same nucleotide state. But some sites are variable. At these variable sites, some patterns are more common than others. Here are the first 180 bp of the ~16.5 bp alignment for some famous hominoids. Molecular Evolution Alan R. Rogers January 15, 2016 modern Neander. chimp gorilla GTTTATGTAGCTTACCTCCTCAAAGCAATACACTGAAAATGTTTAGACGGGCTCACATCA GTTTATGTAGCTTACCTCCTCAAAGCAATACACTGAAAATGTTTAGACGGGCTCACATCA GTTTATGTAGCTTACCCCCTCAAAGCAATACACTGAAAATGTTTCGACGGGTTTACATCA GTTTATGTAGCTTACCTCCCCAAAGCAATACACTGAAAATGTTTCGACGGGCTCACATCA **************** ** ************************ ****** * ****** modern Neander. chimp gorilla CCCCATAAACAAATAGGTTTGGTCCTAGCCTTTCTATTAGCTCTTAGTAAGATTACACAT CCCCATAAACAAATAGGTTTGGTCCTAGCCTTTCTATTAGCTCTTAGTAAGATTACACAT CCCCATAAACAAACAGGTTTGGTCCTAGCCTTTCTATTAGCTCTTAGTAAGATTACACAT CCCCATAAACAAATAGGTTTGGTCCTAGCCTTTCTATTAACTCTTAGTAGGATTACACAT ************* ************************* ********* ********** modern Neander. chimp gorilla GCAAGCATCCCCGTTCCAGTGAGTTCACCCTCTAAATCACCACGATCAAAAGGAACAAGC GCAAGCATCCCCATTCCAGTGAGTTCACCCTCTAAATCACCACGATCAAAAGGGACAAGC GCAAGCATCCCCGCCCC-GTGAGT-CACCCTCTAAATCGCCATGATCAAAAGGAACAAGT GCAAGCATCCCCGCCCCAGTGAGT-CACCCTCTAAATCACCACGATCAAAAGGAACAAGC ************ ** ****** ************* *** ********** ***** 1/1 Molecular differences accumulate linearly 2/1 Different proteins evolve at different rates Amino Acid Substitutions per 100 Sites Cyt C Why linear? ● Fibrinopeptides Globins 80 60 Why do the slopes differ? 40 ● 20 ● ● ● ● ● ● 100 200 300 400 500 Divergence Time (my) 600 3/1 4/1 The neutral theory of molecular evolution ADH in D. melanogaster Codon (above) specifies an amino acid (below). Superscripts: variant nucleotides. Pos. 578: lysine → threonine. I Most mutations are deleterious and are removed by selection. I Some are selectively neutral and may drift to fixation (i.e. until they are 100% of the population) I Very rarely, advantageous mutations arise. The neutral theory holds that case 2 predominates. Implications Why so many 3rd-position changes? I Selection acts as a brake on molecular evolution. I Rate of molecular evolution approximately constant. Why so few amino acid differences? 5/1 6/1 Why neutral evolution is linear We expect evolution to be fast where selective constraint is weak. In a population of size N and mutation rate u, there are 2Nu new mutations each generation. A fraction 1/2N of these drifts to fixation. Resulting rate: 2Nu × 1 2N Where is constraint weak? = u. Where is it strong? Constant mutation rate ⇒ const rate of molecular evolution. 7/1 8/1 The genetic code (DNA version) First Position A G T C A Phe Phe Leu Leu Leu Leu Leu Leu Ile Ile Ile Met Val Val Val Val Second Position G T C Ser Tyr Cys Ser Tyr Cys Ser Stop Stop Ser Stop Trp Pro His Arg Pro His Arg Pro Gln Arg Pro Gln Arg Thr Asn Ser Thr Asn Ser Thr Lys Arg Thr Lys Arg Ala Asp Gly Ala Asp Gly Ala Glu Gly Ala Glu Gly ADH in D. melanogaster Third Position A G T C A G T C A G T C A G T C Codon (above) specifies an amino acid (below). (adenine) (guanine) (thymine) (cytosine) Superscripts: variant nucleotides. Few 1st-position changes are synonymous. Pos. 578: lysine → threonine. Weaker constraint in 2nd position. 3rd position varies most. Weakest in 3rd-position. Supports neutral theory. 10 / 1 9/1 Pig and human insulin genes ADH sequence in 2 species Line 1: DNA sequence in D. melanogaster Line 2: Nucleotides that differ in D. erectus Line 3: Amino acids that differ in D. erectus 24 synonymous differences; 10 amino acid differences I Left portion (exon) is functional—codes for protein I Right portion (intron) isn’t. I Vertical lines show idential nucleotides in human and pig. I There are more differences in intron than in exon. I Nonfunctional DNA evolves faster. Most species differences are neutral. 11 / 1 12 / 1 Pseudogenes evolve faster than functional genes Synonymous versus nonsynonymous clocks Within each protein, synonymous (S) sites evolve faster than non-synonymous (N) sites. 14 / 1 13 / 1 Morphological evolution doesn’t predict molecular evolution Molecular (transversion) differences in mtDNA Frogs and opossums have changed little in many millions of years. Yet their proteins and DNA evolve as fast as those of other animals. Bovid Gibbon Orang. Goril. Chimp. Human “The serological differences in albumins found among frogs are far larger than morphological analysis would lead us to expect. Frogs that are anatomically, and presumably physiologically, similar enough to merit taxonomic distinction only at the species level often exhibit differences in their albumins larger than those usually seen between mammals placed in distinct families or suborders. By contrast, the clock hypothesis appears to predict rather well.” Mouse Bovid Gibbon Orang. Goril. Chimp. 91 83 69 90 65 18 85 71 19 15 86 71 18 16 5 89 70 19 15 4 3 (Hasegawa, Kishino, & Yano 1985) (Wallace, Maxson, and Wilson, 1971) 16 / 1 15 / 1 The molecular clock: a numerical example Other topics I Human-Orang difference is 15 nucleotides in (say) 14 my, a rate of r = 1.07 per my. I Human-Chimp difference is 4 nucleotides. I Estimating dates from molecular data. I Solve rt = 4 to get t = 3.7 my, an estimate of the chimp-human separation time. I Caveats: saturation, purifying selection, metabolic rate, generation time, calibration This estimate is too low, because we failed to correct for multiple mutations per nucleotide site in the orang-human comparison. Nonetheless, it illustrates the logic. 17 / 1 18 / 1 Summary 1. Molecular differences accumulate at roughly constant rate. 2. Evolution is fastest where selective constraint is weak. 3. Supports idea that most molecular evolution is neutral. 4. Does not imply that neutral evolution at level of organism. 19 / 1