Questions

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?

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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.
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Structure Sequence
Stepping through structure and sequence
space the FGF / IL-1 beta-trefoil story
Sequence
J Mol Biol. 2000 Oct 6302(5)1041-7.
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beta-trefoils
J.Mol.Biol. 302, 1041-1047
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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
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Conservation and Selection over Time
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Do all tissues organs evolve at the same rate?
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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
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• 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 lt maxTS 0.2
• (3) 0.2 lt maxTS 0.3
• (4) 0.3 lt maxTS 0.4
• (5) maxTS gt 0.4

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All
Non-secreted
Protein secretion accounts for much of the
elevation in KA /KS for Tissue-Specific genes.
Secreted
Non-disease
Eitan Winter
Disease
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Thymus
Liver
Brain
Blood
Kidney
Slow
Fast
Evolutionary Rates
(KA/KS0.13)
(KA/KS0.04)
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Trachaea
Liver
Brain
Blood
Testis
Kidney
Low
High
Protein Secretion ()
50
(12.2)
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All
Non-secreted
Housekeeping genes are under-represented among
disease genes
Secreted
Eitan Winter
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Trachaea
Liver
Brain
Blood
Testis
Kidney
Low
High
Human Disease ()
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(5.0)
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Tissue-specific genes Ks
Winter et al. Genome Research 1454-61, 2004
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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.

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Human-Mouse Orthologues Expression Profile
Correlations
Eitan Winter
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Pan troglodytes genome

• 4X coverage
• average nucleotide divergence of just 1.2

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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 27640282-7)

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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

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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 lt 0.001
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Loss of Olfactory Receptor Genes Coincides with
the Acquisition of Full Trichromatic Vision in
Primates.PLoS Biol. 2004 Jan2(1)E5. Epub 2004
Jan 20 Gilad et al.
Figure 2. The Proportion of OR Pseudogenes in 20
Species
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Clark et al. Inferring Nonneutral Evolution from
Human-Chimp-Mouse Orthologous Gene Trios
Science (2003) 302 1960-1963
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• 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.

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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.

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Near Future
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Genome Sequencing Capacity (NHGRI)
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Sampling the placental mammalphylogeny
(Murphy et al. Science 2001 294 2348-51 )


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• 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

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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