Transcript Honours core course - Comparative genomics (both lectures in 1 file)

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 nonsynonymous (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 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.
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: 18251835
• Didn’t use Ka/Ks, but looked at probabilities
of observed mutations in human and other
lineages
From Zhang et al
Acceleration index l takes into
account 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 proteinDNA 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