Comparative genomics

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Comparative genomics

• Why humans have big heads and language

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Genome Projects etc

• Genome browser http//genome.cse.ucsc.edu/
• Homologene http//www.ncbi.nlm.nih.gov/entrez/que
  ry.fcgi?dbhomologene
• Nature Chimp Genome http//www.nature.com/nature/
  focus/chimpgenome/index.html
• Genomic biology
• http//www.ncbi.nlm.nih.gov/Genomes/

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Evolutionary concepts

• Homologues are structures (genes, proteins, body
  parts) with a common evolutionary origin
• Homologous genes and proteins are identified by
  database searching (BLAST)
• Example from HomoloGene database
  http//www.ncbi.nlm.nih.gov/entrez/query.fcgi?dbh
  omologenecmdsearchtermfoxp2
• Mutations can be synonymous (no change in
  aminoacid) or non-synonymous (changes aminoacid)
• Ka/Ks is ratio of non-synonymous mutations per
  non-synonymous site, to synonymous mutations per
  synonymous site
• Whats expected for Ka/Ks under different types
  of selection
• 1 implies neutral (no selective effect)
• lt 1 implies negative or purifying selection
• gt 1 implies positive selection

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Compare all codons along the alignment of 2 (or
more) genes count numbers of synonymous and
non-synonymous changes divide by number of
synonymous or non-synonymous sites
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Rapidly-evolving genes

• Dorus S et al, Cell (2004) 119 1027-1040
• Do nervous system genes evolve faster in
  primates?
• Compare humans with macaque monkeys (primates),
  and rats with mice (rodents)
• Define groups of genes nervous system (brain
  expression, role in brain diseases) and
  housekeeping (basic biochemical functions in all
  tissue and cell types)

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Ka/Ks in primate lineages
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Language disorder

• Rare, autosomal dominant language disorder in the
  KE family developmental verbal dyspraxia
  (problems with control of orofacial movements),
  language processing and grammar

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Review article Bishop DVM, Trends in Genetics
(2002) 18 57-59
Affected members of the KE family have a striking
and specific impairment in one aspect of grammar,
the ability to use grammatical features, such
as inflections for marking tense and agreement.
For instance, they have major problems with a
task where an artificial verb stem had to be
converted into a past tense (e.g. every day I
plam yesterday I(plammed). They have
difficulty judging that the boys played football
yesterday is grammatical whereas the boys play
football yesterday is not.
The phenotypic impairments extend well beyond
grammatical features. The affected members had
severe difficulties in producing or imitating
intelligible speech, and in producing
non-speech oral movements (although they had
no problems with limb movements), in addition to
measurable but less severe difficulties in tests
of picture naming, word recognition and
grammatical comprehension.
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FOXP2 gene mutated in KE family

• Positional cloning led to the FOXP2 gene (Lai CS
  et al, Nature (2001) 413 519-523)
• Protein contains a forkhead/winged helix (FOX)
  domain, found also in a family of transcription
  factors
• Expressed in regions of CNS during development

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FOXP2 evolution

• Enard W et al, Nature (2002) 418 869-872
• Zhang J et al, Genetics (2002) 162 1825-1835
• Didnt use Ka/Ks, but looked at probabilities of
  observed mutations in human and other lineages

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From Zhang et al
Acceleration index l takes into account
evolutionary timescale of human-chimp and
primate-rodent divergence
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From Enard et al
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FOXP2 in Neanderthals

• Neanderthals lived alongside our ancestors until
  30000 years ago common ancestor 300000 years
  ago
• Krause et al sequenced Neanderthal DNA and found
  FOXP2 has same changes as modern humans
• Selection for this version of gene began before
  our ancestors split from Neanderthals
• Coop et al were sceptical and proposed other
  explanations

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Microcephaly

• Congenital defect causing severe reduction in
  head size and brain development, without other
  gross abnormalities
• At least 6 autosomal recessive loci are known, of
  which 2 have causal genes identified
• Evans PD et al, Human Molec. Genet. (2004) 13
  1139-1145 and 489-494

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The smaller brain of a 13-year-old with
microcephaly (left) and the normal brain of an
11-year-old (right). From www.sciencenews.org
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ASPM

• Abnormal spindle-like microcephaly associated
• Expressed mainly in regions of brain neurogenesis
  such as cerebral cortex, also in many other
  tissues
• Drosophila homologue is a microtubule-binding
  protein required for mitotic spindle organisation
  in neurodevelopment
• Human version is also associated with spindles in
  mitosis

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Another test for positive selection

• Compare non-synonymous/synonymous ratio within
  species to ns/s ratio between species
  (McDonald-Kreitman test)
• If ratio between species is gtgt than within
  species, suggests positive selection is acting
• To investigate, sequenced ASPM from 40 people
  from across the world compared differences
  within human species to those between humans and
  other species

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Microcephalin

• 14 exons, 2.5kb of coding sequence, 3 BRCT
  domains (as found in BRCA1 and implicated in
  protein-protein and protein-DNA interactions)
• Function unknown
• Expressed in many tissues, especially in areas of
  active neurogenesis

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Ka/Ks varies along the microcephalin gene
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Microcephalin still evolving

• Evans, Gilbert, et al 2005
• Haplogroup of the gene defined by G to C mutation
  in exon 8, changing Asp to His
• Arose 37000 years ago, has spread too quickly
  than would be explained by genetic drift
• Suggests its under positive selection
• Nature of selection unknown

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Global distribution of microcephalin D-haplogroup
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but not because it makes you any smarter!

• Mekel-Bobrov et al (2007) studied microcephalin
  and ASPM adaptive alleles in relation to measures
  of IQ in gt2000 subjects
• Found no overall association
• Found association in Dutch children with
  microcephalin D-haplogroup, but it was the other
  way round in Dutch adults, and not replicated in
  other samples

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General conclusions

• Having genome sequences of many organisms allows
  large-scale comparisons, potentially automated
• Can test hypotheses about genes whose rapid
  evolution may be related to special features of a
  particular species
• In humans, this includes several genes with roles
  in brain development
• The most uniquely human feature of all, language,
  also seems to depend on rapidly-evolving genes
• May be lots more information in non-coding
  regions of genes e.g. promoters