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Questions

Questions. Are we ‘just’ E. coli, except more so? Where do new genes come from? Do all genes evolve at the same rate? Do all tissues & organs evolve at the same rate? Where do we fit in the tree of life? What specifies the differences between us and rodents, or us and chimps?

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Questions

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  1. Questions • Are we ‘just’ E. coli, except more so? • Where do new genes come from? • Do all genes evolve at the same rate? • Do all tissues & organs evolve at the same rate? • Where do we fit in the tree of life? • What specifies the differences between us and rodents, or us and chimps? • What specifies the elevated complexity of us versus other animals? • Can we understand sequence variation among humans? • How can gene function contribute to behaviour?

  2. Where do new genes come from? ‘New Domains’ 23 of 94 InterPro families: Defense and Immunity e.g. IL-1, interferons, defensins 17 of 94 InterPro families: Peripheral nervous system e.g.Leptin, prion, ependymin 4 of 94 InterPro families: Bone and cartilage GLA, LINK, Calcitonin, osteopontin 3 of 94 InterPro families: Lactation Caseins (a, b, k), somatotropin 2 of 94 InterPro families: Vascular homeostasis Natriuretic peptide, endothelin 5 of 94 InterPro families: Dietary homeostasis Glucagon, bombesin, colipase, gastrin, IlGF-BP 18 of 94 InterPro families: Other plasma factors Uteroglobin, FN2, RNase A, GM-CSF etc.

  3. Structure & Sequence Stepping through structure and sequence space: the FGF / IL-1 beta-trefoil story Sequence J Mol Biol. 2000 Oct 6;302(5):1041-7.

  4. FGFs, interleukin-1s EXTRACELLULAR (CELL-CELL SIGNALLING): IL-1a FGF VERT., INVERT. VERT. INTRACELLULAR (ACTIN-BINDING PROTEINS): Fascin Hisactophilin VERT., INVERT., FUNGI Dictyostelium. beta-trefoils J.Mol.Biol. 302, 1041-1047

  5. Gene Genesis • Positive selection often leads to the erosion of sequence similarity • If this erosion is extensive, homology cannot be inferred from database search strategies. • If, concomitantly, there is positive selection for duplication of these genes, this gives the appearance of a new gene/domain family that lacks antecedents. Copley, Goodstadt, Ponting Current Opinion in Genetics & Development Volume 13, December 2003, Pages 623-628

  6. Conservation and Selection over Time

  7. Do all tissues & organs evolve at the same rate?

  8. Need to investigate expression of tissue-specific genes. PNAS | April 2, 2002 | vol. 99 | no. 7 | 4465-4470 GeneticsLarge-scale analysis of the human and mouse transcriptomes Andrew I. Su et al. http://expression.gnf.org

  9. Tissue Specificity of a Gene: TS • A gene's fractional expression in a tissue relative to the sum of its expression in all tissues • max TS : an indicator of Tissue Specificity. • Divide data into 5 sets: • (1) maxTS≤ 0.1; • (2) 0.1 < maxTS ≤0.2; • (3) 0.2 < maxTS≤ 0.3; • (4) 0.3 < maxTS ≤ 0.4; • (5) maxTS > 0.4

  10. All Non-secreted Protein secretion accounts for much of the elevation in KA /KS for Tissue-Specific genes. Secreted Non-disease Eitan Winter Disease

  11. Thymus Liver Blood Brain Kidney Slow Fast Evolutionary Rates (KA/KS=0.13) (KA/KS=0.04)

  12. Trachaea Liver Blood Brain Testis Kidney Low High Protein Secretion (%) 50% (12.2%)

  13. Non-disease Disease All Non-secreted Housekeeping genes are under-represented among disease genes Secreted Eitan Winter

  14. Trachaea Liver Blood Brain Testis Kidney Low High Human Disease (%) 39% (5.0%)

  15. Tissue-specific genes’ Ks Winter et al. Genome Research 14:54-61, 2004

  16. Tissue/Organ Evolution • Mammalian tissues & organs are evolving at different rates, according to the genes that are specifically expressed in them. • Perhaps this is not too surprising since there are mammalian-specific tissues & organs! • Tissue-specific genes are ‘mutating’ at different rates, possibly due to transcription-coupled repair in the germline. • Mendelian disease acts non-uniformly among genes and tissues.

  17. Human-Mouse Orthologues’ Expression Profile Correlations Eitan Winter

  18. Pan troglodytes genome • 4X coverage • average nucleotide divergence of just 1.2%

  19. How do the 2 gene complements differ? • Gene duplications observed in the human genome. • Lack of N-glycolylneuraminic acid (Neu5Gc) in humans due to mutation in CMP-sialic acid hydroxylase (Chou et al. PNAS 95(20):11751-6.) • Mutation in a Siglec (sialic acid receptor) (Angata et al. JBC 276:40282-7)

  20. How do the Great Apes differ from us? • Rare HIV progression to AIDS • Resistant to malarial infection • Menopause rare • Coronary atherosclerosis rare • Epithelial cancers rare • Alzheimer’s disease pathology incomplete

  21. FOXP2 • A point mutation in FOXP2 co-segregates with a disorder in a family in which half of the members have impaired linguistic and grammatical abilities • Human FOXP2 contains missense mutations and a pattern of nucleotide polymorphism, which strongly suggest that this gene has been the target of selection during recent human evolution. Enard et al. Nature 418, 869 - 872 Figure 2 Silent and replacement nucleotide substitutions mapped on a phylogeny of primates. Bars represent nucleotide changes. Grey bars indicate amino acid changes. P < 0.001

  22. Loss of Olfactory Receptor Genes Coincides with the Acquisition of Full Trichromatic Vision in Primates.PLoS Biol. 2004 Jan;2(1):E5. Epub 2004 Jan 20Gilad et al. Figure 2. The Proportion of OR Pseudogenes in 20 Species

  23. Clark et al. Inferring Nonneutral Evolution from Human-Chimp-Mouse Orthologous Gene Trios Science (2003) 302: 1960-1963

  24. “Smell, Hearing Genes Differ between Chimps and Humans” Genome News Network January 9 2004 • “The 2.5Gb mouse genome sequence reveals about 30,000 genes, with 99% having direct counterparts in humans.” Nature editorial 5 December 2002.

  25. Questions • Are we ‘just’ E. coli, except more so? Not at all. • Where do new genes come from? Old genes! • Do all genes evolve at the same rate? No. • Do all tissues & organs evolve at the same rate? No. • Where do we fit in the tree of life? Primates! • What specifies the differences between us and rodents, or us and chimps? Jury is out. Duplicates? • What specifies the elevated complexity of us versus other animals? Jury is out. • Can we understand sequence variation among humans? Not yet – Lon’s lecture? • How can gene function contribute to behaviour? Seen in rodents, but not yet in primates.

  26. Near Future

  27. Genome Sequencing Capacity (NHGRI)

  28. Sampling the placental mammalphylogeny(Murphy et al. Science 2001 294: 2348-51 ) * *

  29. MRC Functional Genetics Unit, Oxford Leo Goodstadt Richard Emes Eitan Winter Steve Rice Scott Beatson Nick Dickens Caleb Webber Michael Elkaim Jose Duarte Zoe Birtle Tania Oh Ensembl (Ewan Briney, Michele Clamp, Abel Ureta-Vidal); Richard Copley (WTCHG, Oxford); Ziheng Yang (UCL); The Human, Mouse and Rat Genome Sequencing Consortia; UCSC

  30. Bibliography Human Genome Papers: Lander et al. Nature (2001) 409, 860-921 Venter et al. Science (2001) 291, 1304-1351. Mouse Genome Paper: Waterston et al. Nature (2002) 420, 520-62. Rat Genome Paper: submitted. Comparative genomics & evolutionary rates: Hardison et al. Genome Res. (2003) 13, 13-26. Adaptive evolution of genomes: Emes et al. Hum Mol Genet. (2003) 12, 701-9 Wolfe & Li Nat Genet. (2003) 33 Suppl: 255-65

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