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Molecular clocks 1 Molecular clock? • The molecular clock hypothesis was put forward by Zuckerkandl and Pauling in 1962. • They noted that rates of amino acid replacements in animal hemoglobins were proportional to time of divergence—as judged from the fossil record. 2 3 4 5 Molecular clocks? • Zuckerkandl and Pauling, therefore, proposed that for any given protein, the rate of molecular evolution is approximately constant over time in all lineages. 6 7 The molecular clock hypothesis If proteins evolve at constant rates, then the number of substitutions between two sequences may be used to estimate divergence times. This is analogous to the dating of geological times by radioactive decay. 8 Example: The rate of nonsynonymous substitution for a-globin is 0.56 10–9 nonsynonymous substitutions per nonsynonymous site per year. Rat and human a-globins differ by 0.093 nonsynonymous substitutions per nonsynonymous site. If the universal molecular-clock hypothesis is correct, then human and rat diverged from a common ancestor 0.093/2 0.56 10 –9 = 83 million years ago. 9 Allan C. Wilson Morris Goodman 10 The “sacrament” of the straight line 11 Q: How to draw a straight line? A1: Have no more than two observation points. 12 Q: How to draw a straight line? A2: With more than two observation points, use a very thick line. 13 Q: How to draw a straight line? A3: With more than two observation points, deny the accuracy of the measurements on one or both axes. 14 15 Relative Rate Tests 16 Sarich & Wilson’s Test 17 KAB = KOA + KOB KAC = KOA + KOC KBC = KOB + KOC 18 KOA = (KAC + KAB – KBC)/2 KOB = (KAB + KBC – KAC)/2 KOC = (KAC + KBC – KAB)/2 19 If the molecular clock hypothesis is correct, then 20 KAC – KBC = 0 Not significantly different from 0 21 22 No such difference is seen at nonsynonymous sites, indicating that mutational differences, rather than selectional differences, are involved. 23 24 25 The results of the relative rate test depend on knowledge of true tree. 26 Tests involving duplicated genes 27 KA B 1 1 KAA KOA KOB KBB 1 1 28 KA B 2 2 KAA KOA KOB KBB 2 2 29 If A1 evolves at the same rate as A2, and B1 evolves at the same rate as B2, then KA B KA B 0 1 1 2 2 30 31 32 33 34 A = adult; E = embryonic; F = fetal Relative rate tests have shown that there is no universal molecular clock. However, sufficiently accurate local clocks may exist. 35 slow fast 36 Mutation rate per site per year versus genome size (Gago S, Elena SF, Flores R, Sanjuán R. Extremely high mutation rate of a hammerhead viroid. 2009. Science 323:1308.) 37 The ranking of organisms started with the Aristotelian Scala Naturae… 38 39 … and was used by Linnaeus in his Systema Naturae. Primates (humans and monkeys) Secundates (mammals) Tertiates (all others) 40 In the literature one often encounters the adjective “primitive” attached to the name of an organism. For example, sponges are defined as “primitive.” 41 Humans, on the other hand, are always referred to as “advanced.” 42 43 Advanced Primitive 44 Causes of variation in substitution rates among evolutionary lineages The factors most commonly invoked to explain the differences in the rate of substitution among lineages are: (1) replication-dependent factors, i.e., mutation. (2) replication-independent factors, i.e., selection. 45 46 Generation Time 47 Rates of evolution tend to correlate with generation times. 48 Metabolic rate = amounts of O2 consumed per weight unit per time unit. 49 metabolic-rate effect mice newts whales sharks 50 51 Rates of evolution tend to correlate with metabolic rates. 52 Generation times tend to correlate with metabolic rates. The big ones are the slow ones. 53 Organelles: Mutation Rates Animals nucleus mitochondria LOW HIGH Plants mitochondria LOW chloroplast nucleus HIGH 54 Evolution of RNA viruses: RNA VIRUSES evolve at rates that are about 106 times faster than those of DNA organisms. Therefore, significant numbers of nucleotide substitutions accumulate over short time periods, and differences in nucleotide sequences between strains isolated at relatively short time intervals are detectable. This property allows for a novel approach to estimating evolutionary rates. 55 Model tree for RNA viruses: l1 and l2 = numbers of substitutions on the branches leading to isolates 1 and 2, respectively. Sequence 1, which was isolated at t1, was collected t years earlier than sequence 2, which was isolated at t2. r = rate of substitution per site per year 56 l2 – l1 = rt2 – rt1 = rt l2 – l1 = d23 – d13 d d 23 13 r t 57 58 Example: Two strains of the HIV1 virus, denoted as 1 and 2 were isolated from a two-year-old child on 3 October 1984 and 15 January 1985, respectively. The child was presumed to have been infected once perinatally by her mother by a single strain of HIV1. 59 03 Dec. 1984 15 Jan. 1985 Reference t = 3.4 months (0.28 year) d13 = 0.0655 d23 = 0.0675 a = 7.1 10–3 substitutions/site/year 60 61 Tempo of Evolution: 62 63 Punctuated equilibrium (Punk eek) Niles Eldredge & Steven J. Gould (1972). Punctuated equilibrium: An alternative to phyletic gradualism. pp. 82-115. In: T. J. M. Schopf (ed.) Models in Paleobiology, Freeman, Cooper & Co., San Francisco. 64 “... it is probable that the periods, during which each [species] underwent modification, though many and long as measured by years, have been short in comparison with the periods during which each remained in an unchanged condition.” Charles Darwin, from the final 6th edition (1872) of On the Origin of Species 65 time Phyletic gradualism change 66 time Punctuated equilibria associated with speciation events speciation stasis change revolution 67 time Punctuated equilibria disassociated from speciation events change 68 69 During most mammalian evolution, growth-hormones evolved quite slowly (~0.3 10–9 replacements per site per A There phylogenetic tree two year). are, however, forincreases: the growth-hormone rate a 40-fold increase prior to primate gene in mammals divergence, and a 20-fold increase prior to ruminant divergence. 70 Possible explanations for the increased rates in ruminants and primates: (1) an increase in mutation rate (2) positive selection (3) relaxation of purifying selection 71 Rates of amino-acid replacement ( 109 standard error) and the ratio of nonsynonymous (KA) to synonymous (KS) substitution in growth-hormone genes during mammalian evolution _________________________________________________________ Rate of amino-acid Phase replacement KA/KS _________________________________________________________ Slow phase Ruminant rapid phase Primate rapid phase 0.3 0.1 5.6 1.4 10.8 1.3 0.03 0.30 0.49 _________________________________________________________ 72 Mindell, Sykes & Graur Test 73 74 75 IS THERE A RELATIONSHIP BETWEEN MOLECULAR RATES OF EVOLUTION & MORPHOLOGICAL RATES OF EVOLUTION? 76 A living fossil: Limulus polyphemus (Atlantic horseshoe crab) fossil (500 mya) extant 77 Living fossils Blue shark (Prionace glauca) Alligator (Alligator mississippiensis) Molecularly fast-evolving lineages 78 Living fossils Yellow mud turtle (Kinosternon flavescens) Molecularly slow-evolving lineages 79 IS THERE A RELATIONSHIP BETWEEN MOLECULAR RATES OF EVOLUTION & MORPHOLOGICAL RATES OF EVOLUTION? NO! 80 Some scientists have even suggested that the lack of relationship between the two levels of description is so total as to deserve to be called: “The Big Divorce” 81