Comparative genomics

Why humans have big heads and language

Genome Projects etc

• Genome browser: http://genome.cse.ucsc.edu/

• Homologene: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=homologene

• Nature Chimp Genome: http://www.nature.com/nature/focus/chimpgenome/index.html

• Genomic biology:

http://www.ncbi.nlm.nih.gov/Genomes/

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?db=homologene&cmd=search&term=foxp2

• 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

• What’s expected for Ka/Ks under different types of selection: = 1 implies neutral (no selective effect)< 1 implies negative or purifying selection> 1 implies positive selection

Codon and mutants Amino-acid Synonymous site Non-synonymous site

GCT A

ACT T +

CCT P +

TCT S +

GAT D +

GGT G +

GTT V +

GCA A +

GCC A +

GCG A +

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

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)

Ka/Ks

in primate lineages

Language disorder• Rare, autosomal

dominant language disorder in the “KE” family – developmental verbal dyspraxia (problems with control of orofacial movements), language processing and grammar

Review article: Bishop DVM, Trends in Genetics (2002) 18: 57-59

Affected members of the KE familyhave a striking and specific impairmentin one aspect of grammar, the abilityto use grammatical features, such asinflections for marking tense andagreement. For instance, they havemajor problems with a task where anartificial verb stem had to be convertedinto 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 difficultiesin producing or imitating intelligiblespeech, and in producing non-speechoral movements (although they had noproblems with limb movements), inaddition to measurable but less severedifficulties in tests of picture naming,word recognition and grammaticalcomprehension.

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

FOXP2 evolution

• Enard W et al, Nature (2002) 418: 869-872

• Zhang J et al, Genetics (2002) 162: 1825-1835

• Didn’t use Ka/Ks, but looked at probabilities of observed mutations in human and other lineages

From Zhang et al

Acceleration index takes intoaccount evolutionary timescale of human-chimp and primate-rodent divergence

From Enard et al

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

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

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

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

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 >> 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

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

Ka/Ks varies along the microcephalin gene

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 it’s under positive selection• Nature of selection unknown

Global distribution of microcephalin D-haplogroup

…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 >2000 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

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