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RATES OF NUCLEOTIDE SUBSTITUTION

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  1. RATES OF NUCLEOTIDE SUBSTITUTION rate = # substitutions per site per unit time (year or generation) Ancestral sequence Sequence 2 Sequence 1 If r = rate K = # sub between 2 homologous sequences T = time of divergence r = K / 2T Then Why is there 2T in the denominator of equation?

  2. In the literature, K or d (rather than r) is often used for rate, (eg. Table 4.17, p.163) …so be sure to check context and units in figures Within coding sequences, can separate the rates into: KA = amino acid-altering substitution rate # non-synonymous sub. / non-syn. site / year KS = synonymous substitution rate # synonymous sub. / syn. site / year dN/dS term often used when comparing rates of non-syn sub vs. syn sub What are rates of nt substitutions between wheat and maize nuclear genes (i) at synonymous sites and (ii) at non-synonymous sites? p. 159-160

  3. Rates of nt substitution in different parts of genes Fig. 4.3

  4. 1. Non-degenerate sites under greatest functional constraint - any change will alter protein 2. Sequences that are “selectively neutral” evolve rapidly eg pseudogenes, 4-fold degenerate, introns… - can be useful in “molecular clock” studies 3. Flanking (5’) & untranslated regions somewhat constrained - because contain gene regulatory signals

  5. Similarity profile for 2 aligned DNA sequences Fig. 4.4

  6. Table legend: “Rates are in units of substitutions per site per 109 years” Non-synonymous rates vary greatly among genes (~100-fold range), but synonymous rates are relatively similar KS usually much higher than KA

  7. Ribosomal proteins - fundamental role in protein synthesis - interact with rRNA and/or other rib. proteins Histones - fundamental role in DNA packing - basic, compact proteins that interact with DNA and/or other histones Immunoglobulins - antibody diversity important for immune response & recognition of foreign antigens Fig. 4.6 For non-synonymous sites, the stronger the functional constraint on aa sequence, the slower the rate of evolution

  8. Convert Table 4.1 information into Figure format On log scale, plot values of KS and KA for: S14 ribosomal protein insulin a-globin growth hormone Ig k interferon b 1 10 102 103 104 105 Need to choose appropriate range for scale (and units)…

  9. Non-synonymous substitutions rates within genes Various functional (or structural) domains can be subject to different constraints and evolve at different rates Fig. 4.5

  10. Rate of nt substitution depends on: 1. Functional constraints - usually strong selective pressure against changes that alter the protein, but … cases of positive selection 2. Mutational rate - certain regions of genome may evolve at different rates Y chromosome sequences evolve ~ 4 - 6 fold faster than homologues on other chromosomes Number of germ cell divisions for egg vs. sperm production males ~ 200 females ~ 33 DNA replication errors, lack of recombinational repair…

  11. Number of germ cell divisions for egg vs. sperm production Oogenesis Zfx, Zfy – zinc finger genes on chr X & Y DAX – sex-determination “anti-testis” genes on chr3 & Y Spermatogenesis Female ~ 24 Male ~ 35 + 23(age in years -15) If average reproductive age is 20, then ~ 195 divisions Note: errors not repaired during DNA replication are also not removed by homologous recombination during meiosis (since Y chromosome is effectively unpaired, unlike autosomes) Strachan & Read, Fig. 10.4

  12. Positive selection (Adaptive evolution) - rate of nonsynonymous substitution exceeds rate of synonymous substitution KA >KS Examples: - some immunoglobulin genes (antibody diversity) - surface antigen genes of parasites and viruses (evade host) • some sex-related genes (for speciation, reproductive barriers • to restrict gene flow?) abalone sperm cell protein: KA / KS = 5.15 !! But may be difficult to detect if - number of substitutions is low - only one part of protein under positive selection

  13. Parallelism or molecular convergence • independent occurrence of identical substitutions • at homologous sites in different evolutionary lineages • resulting in same phenotypic outcome Example – lysozymes in certain mammals (cow, langur) and birds (hoatzin) adapted for activity at low pH in posterior chamber of stomach Fig. 4.8

  14. Is ability of crocodile to stay underwater for long times related to hemoglobin structure evolution? Comparison of crocodile (NC), alligator (MA), caiman (SC) and human (HS) globin sequences Komiyama et al. Nature 373:244, 1995

  15. By genetic engineering, changed several specific codons in human globin gene, so amino acids identical to crocodilian ones - then measured O2 affinity of modified Hb (a) (b) Oxygen-binding curves of crocodile Hb (circles) and human Hb (squares) determined in the absence (empty symbols) and presence (filled symbols) of 5% CO2. (a) Wild-type Hb proteins (b) Human beta-chain modified at positions 29, 31, 38, 39, & 41 Komiyama et al. Nature 373:244, 1995

  16. “These results indicate that an entirely new function which enables species to adapt to a new environment could evolve in a protein by a relatively small number of amino acid substitutions in key positions, rather than by gradual accumulation of minor mutations.” Komiyama et al. Nature 373:244, 1995

  17. Possible reasons for variation in Ks among genes? - if functional constraint at levels other than amino acid sequence? 1. due to RNA folding? or cis-elements important for RNA processing … ? 2. codon usage bias? If all codons specifying a particular amino acid are functionally equivalent (selectively neutral), expect similar frequencies but … observe non-random distribution, with different patterns among organisms

  18. Fig. 4.13

  19. Correlation between codon usage pattern and: 1. tRNA availability in cell (E. coli and yeast) translational efficiency? 2. bias against certain dinucleotides (mutational hotspots) eg CpG in animal DNA 3. GC content of tightly-packed genomes eg organellar, bacterial

  20. Non-random mutation at CpG sites in animal DNA - deamination of C to U can be repaired by uracil-DNA glycolyase - but in animal DNA cytosine of CpG is often methylated and 5-methyl C to T mutation escapes repair … so shift from C to T base pair G A Griffiths Fig. 7.16 Comparison of human and chimpanzee DNA sequences (over ~ 1.9 Mbp) to assess behaviour of CpG sites of changes EbersbergerAm. J. Hum. Genet. 70:1490 (2002)

  21. Fig. 8.29