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? 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 (), 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. Stepping through structure and sequence space: the FGF / IL-1 beta-trefoil story Structure & Sequence Sequence J Mol Biol. 2000 Oct 6;302(5):1041-7. FGFs, interleukin-1s beta-trefoils
EXTRACELLULAR (CELL-CELL SIGNALLING): FGF IL-1 VERT., INVERT. VERT. INTRACELLULAR (ACTIN-BINDING PROTEINS): Fascin Hisactophilin VERT., INVERT., FUNGI Dictyostelium. J.Mol.Biol. 302, 1041-1047 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 Conservation and Selection over Time C o n s e r v a tio n ( % id e n tity ) 1 0 0 .0 0 % 9 0 .0 0 % 50% a 8 0 .0 0 % b 7 0 .0 0 % c
d 6 0 .0 0 % 5 0 .0 0 % e f g h i M o u s e -ra t H u m a n -m o u s e H u m a n -fu g u 0 j 150 300 T im e o f D iv e rg e n c e (M y r)
450 % o f o rth o lo g s fo u n d in fu g u 100% Percentage of sequences Do all tissues & organs evolve at the same rate? 100% 80% Cytoplasmic domains Nuclear domains Secreted domains 60% 40% 20% 0% 0.00 0.10
0.20 KA /KS 0.30 0.40 Need to investigate expression of tissue-specific genes. PNAS | April 2, 2002 | vol. 99 | no. 7 | 4465-4470 Genetics Large-scale analysis of the human and mouse transcriptomes Andrew I. Su et al. http://expression.gnf.org 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 All Protein secretion accounts for much of the elevation in KA /KS for Tissue-Specific genes. Non-secreted Secreted Non-disease Eitan Winter Disease Thymus Blood
Low (12.2%) Protein Secretion (%) High 50% All Housekeeping genes are under-represented among disease genes Non-secreted Secreted Non-disease Eitan Winter Disease Trachaea
Blood Brain Liver Testis Kidney Low (5.0%) Human Disease (%) High 39% Tissue-specific genes Ks 0.8 Median Ks-value 0.7 0.6
0.5 0.4 0.3 0.2 0.1 0 Winter et al. Genome Research 14:54-61, 2004 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. 18 Human-Mouse Orthologues Expression Profile Correlations
0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 Pan troglodytes genome 4X coverage average nucleotide divergence of just 1.2% 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) 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 Alzheimers disease pathology incomplete 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. P < 0.001 Grey bars indicate amino acid changes. 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 20 Gilad et al. Figure 2. The Proportion of OR Pseudogenes in 20 Species Table 1. Biological processes showing the strongest evidence for positive selection. The top panel includes the categories showing the greatest acceleration in human lineage, and the bottom panel includes categories with the greatest acceleration in the chimp lineage.
Clark et al. Inferring Nonneutral Evolution from Human-Chimp-Mouse Orthologous Gene Trios Science (2003) 302: 1960-1963 Biological process Number of PMW (human/Model PMW (chimp/Model genes* 2)* 2)* Categories showing the greatest acceleration in human lineage Olfaction Sensory perception Cell surface receptormediated signal transduction Chemosensory perception Nuclear transport G proteinmediated signaling Signal transduction Cell adhesion Ion transport Intracellular protein traffic
0.0276 (0.0092) 0.3718 0.8025 0.8099 0.7199 0.1324 0.0075 0.8486 0.2322 0.9634 Categories with the greatest acceleration in the chimp lineage Signal transduction Amino acid metabolism Amino acid transport Cell proliferation and differentiation Cell structure Oncogenesis Cell structure and motility Purine metabolism Skeletal development Mesoderm development Other oncogenesis DNA repair *
0.9363 0.0276 (0.0092) 0.0075 0.0102 0.0182 0.0233 0.0267 0.0299 0.0423 0.0438 0.0439 0.0469 0.0477 The number of genes and the PMW values excluding olfactory receptor genes are shown in Table 2. Molecular functions showing the strongest evidence for positive selection. The table includes only human-accelerated categories, because the only categories accelerated in the chimp lineage are chaperones (P = 0.0124), cell adhesion molecules (P = 0.0220), and extracellular matrix (P = 0.0333). Molecular function Number of genes*
G protein coupled receptor G protein modulator Receptor Ion channel Extracellular matrix Other G protein modulator Extracellular matrix glycoprotein 199 (153) 62 448 134 97 (95) 32 44 (42) 0 (0.2533) 0.0008 0.0030 0.0043 0.0120 (0.0178) 0.0149 0.0178 (0.0269)
0.8689 (0.6776) 0.3776 0.9798 0.8993 0.1482 (0.1593) 0.4441 0.1579 (0.1765) Voltage-gated ion channel Other hydrolase Oxygenase Protein kinase receptor Transporter Ligand-gated ion channel Microtubule binding motor protein Microtubule family cytoskeletal protein 62 95 46 37 214 45
PMW (human/Model PMW (chimp/Model 2)* 2)* The number of genes and the PMW values excluding olfactory receptor genes are shown in parentheses. 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. 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 Lons lecture? How can gene function contribute to behaviour? Seen in rodents, but not yet in primates. Near Future Genome Sequencing Capacity (NHGRI) YEAR 7X genome (3 Gb) 1X
You can create any number of collections to meet the scale requirements of your applications. Each capacity unit includes a quota of collections, if you reach the collection quota for your account you can purchase additional capacity units.
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