1. Comparative genomics Why humans have big heads and language

2. Genome Projects etc Genome browser: http://genome.cse.ucsc.edu/ http://genome.cse.ucsc.edu/ Homologene: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=homologene http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=homologene Nature Chimp Genome: http://www.nature.com/nature/focus/chimpgenome/index.html http://www.nature.com/nature/focus/chimpgenome/index.html Genomic biology: http://www.ncbi.nlm.nih.gov/Genomes/

3. 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 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) K a /K s is ratio of non-synonymous mutations per non-synonymous site, to synonymous mutations per synonymous site Whats expected for K a /K s under different types of selection: = 1 implies neutral (no selective effect) < 1 implies negative or purifying selection > 1 implies positive selection

4. Codon and mutantsAmino-acid Synonymous siteNon-synonymous site GCTA ACTT+ CCTP+ TCTS+ GATD+ GGTG+ GTTV+ GCAA+ GCCA+ GCGA+ 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

5. 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)

7. K a /K s in primate lineages

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

9. 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.

10. 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

12. FOXP2 evolution Enard W et al, Nature (2002) 418: 869-872 Zhang J et al, Genetics (2002) 162: 1825- 1835 Didnt use K a /K s, but looked at probabilities of observed mutations in human and other lineages

13. From Zhang et al Acceleration index takes into account evolutionary timescale of human-chimp and primate-rodent divergence

15. From Enard et al

16. 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

17. 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

18. 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

19. 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

21. 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

23. 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

25. K a /K s varies along the microcephalin gene

26. 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

27. Global distribution of microcephalin D-haplogroup

28. …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

29. 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