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An Analysis of Human/ Chimp/ Macaque
Orthologs
Heather Lawson
“Origin of man now proved…he
who understand baboon would do
more toward metaphysics than
Locke…”
Charles Darwin, Notebooks
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Theories of human
evolution often
give priority to the
head
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Early skull material
challenged longheld
presuppositions
Morphological
differences provide
phylogenetic
information
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Sequencing of primate
whole-genomes adds
explicitness to
statements about
genes related to
primate evolution
“Batch” approaches
focusing in on a ‘prime
mover’ capable of
explaining the whole
of human evolution
Evolution Is Not So Simple!
Evolution Is Not So Simple!
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Traits have unique evolutionary histories
Many traits of interest are continuous
Many traits of interest are present in
both humans and other primates
Many of the changes associated with
anatomically modern humans occurred
before the origin of the genus Homo
Genotype  Phenotype
Pan
Homo
Macaca
≈5-6mya
Old World Monkeys
Hominoids
≈21-25mya
Human
Annotation
File
Human /
Chimp
Whole
Genome
File
Human /
Macaque
Whole
Genome
File
Gene Extraction
Engine
##maf version=1 scoring=multiz.v8
a score=93185.000000
s hg17.chr22
14430000 1039 + 49554710
GATCTGATAAGTCCCAGGACTTCAGAAGagctgtgagaccttggcca
agtcacttcctccttcagGAACATTGCAGTGGGCCTAAGTGCCTCCTC
TCGGGACTGGTATGGGGACGGTCATGCAATCTGGACAACATT
CACCTTTAAAAGTTTATTGATCTTTTGTGACATGCACGTGGGT
TCCCAGTAGCAAGAAACTAAAGGGTCGCAGGCCGGTTTCTGCT
AATTTCTTTAATTCCAAGACAGTCTCAAATATTTTCTTATTAAC
TTCCTGGAGGGAGGCTTATCATTCTCTCTTTTGGATGATTCTA
AGTACCAGCTAAAATACAGCTATCATTCATTTTCCTTGATTTG
GGAGCCTAATTTCTTTAATTTAGTATGCAAGAAAACCAATTTG
GAAATATCAACTGTTTTGGAAACCTTAGACCTAGGTCATCCTT
AGTAAGATcttcccatttatataaatacttgcaagtagtagtgccataattacca
aacataaagccaactgagatgcccaaagggggccactctccttgcttttcctccttt
ttagaggatttatttcccatttttcttaaaaaggaagaacaaactgtgccctagggtt
tactgtgtcagaacagagtgtgccgattgtggtcaggactccatagcatttcacca
ttgagttatttccgcccccttacgtgtctctcttcagcggtctattatctccaagaggg
cataaaacactgagtaaacagctcttttatatgtgtttcctggatgagccttcttttaa
ttaattttgttaagggatttcctctagggccactgcacgtcatggggagtcaccccc
agacactcccaattggccccttgtcacccaggggcacatttcagctAtttgtaaaa
cctgaaatcactagaaaggaatgtctagtgacttgtgggggccaaggcccttgtt
atggggatgaaggctcttaggtggtagccctccaagagaatagatggtgaatgtc
tcttttcagacattaaaggtgtcagactctcag
s panTro1.chrUn_random 24771498 1037 + 240967748
GATCTGATAAGTCCCAGGACTTCAGAAGAGCTGTGCGACCTTG
GCCAAGTCCCTTCCTCCTTCAGGAACATTGCAGTGGGCCTAAG
TGCCTCCTCTCGGGACTGGTATGGGGACAGTCATGCAATCTG
GACAACATTCACCTTTAAATGTTTATTGATCTTTTGTGACATG
CACGTGGGTTCCCAGTAGCAAGAAACTCAAGGGTCGCAGGCC
GGTTTCTGCTAATTTCTTGAATTCCAAGACAGTCTCCAATATT
TTCTTATTAACTTCCTGGAGGGAGGCTTATCATTCTCTCTTTT
GGATGATTCTAGGTACCAGCTAAAACACAGCTGTCATTCATTT
TCCTTGATTTGGGAGCCTAATTTCTTTAATTTAGTAAGCAAGA
AAACCAATTTGGAAATATCAACCATTTTGGAAACTTTAGACCT
AGGTCATCCTTAGTAAGATcttcccatttatataaatacttgcaagtagtag
tgccataattaccaaacataaagccaactgagatgctcaaagggggccactctcc
ttgcttttcctcctttttagaggatttatttcccattttttttaaaaaggaagaacaaac
tgtgccctagggtttagtgtgtcagaacagagtgtgccgattgtggtcaggactcc
atagcatttcaccattgagttatttccaccctcttacgtgtctctcttcagagatctatt
atctccaagagggcataaaacactgagtaaacagctc-ttatatgtgtttcctggatgagccttcttttaattaattttgttatgggatttcgtctagg
gtcactgcacatcatggggagtcaccctcagacactcccaattggccccttgtcac
ccaggggcacATttcagctatttgtaaaacctgaaatcactagaaaggaatgtct
agtaacttgtgggggtcaaggcccttgttatggggatgaaggctcttaggtggta
gccctccaagagaatagatggtgaatgtctcttttcagactttaaaggtgtcagact
ctcag
>Human
ATGGAGCCCGCGATGGAGCCGGAGACTCTGGAGGCGCGAATCAATA
GAGCCACGAACCCCCTGAACAAGGAGCTCGACTGGGCCAGCATCAA
CGGCTTCTGCGAGCAGCTCAACGAGGACTTTGAGGGGCCTCCACTC
GCCACCCGGCTGCTGGCCCACAAGATCCAGTCCCCACAGGAGTGGG
AGGCGATCCAGGCCTTGACGGTGAGAAGGGGAGAGGCCACCATCCG
TCCCCCGCCATGTGACGACACCAAGGGAGGCCAAGACTGA
>Chimp
ATGGAGCCCGCGATGGAGCCGGAGACTCTGGAGGCGCGAATCAATA
GAGCCACGAACCCCCTGAACAAGGAGCTCGACTGGGCCAGCATCAA
CGGCTTTTGCGAGCAGCTCAACGAGGACTTTGAGGGGCCTCCACTC
GCCACCCGGCTGCTGGCCCACAAGATCCAGTCCCCACAGGAGTGGG
AGGCGATCCAGGCCTTGACGGTGAGAAGGGGAGAGGCCACCATCCA
TCCCCCGCCATGTGACGACACCAAGGGAGGCCAAGACTGA
>Macaque
ATGGAGCCCGCGATGGAGCCGGAGACTCTGGAGGCGCGAATCAATA
GAGCCACGAATCCCCTGAACAAGGAGCTTGACTGGGCCAGCATCAA
CGGCTTCTGCGAGCAGCTCAACGAGGACTTTGAGGGGCCTCCACTC
GCCACCCGACTGCTGGCCCACAAGATCCAGTCCCCGCAGGAGTGGG
AGGCGATCCAGGCCTTGACGGTGAGAAGGGGAGAGACCACCATCCG
TCCCCGGCCATGTGATGACACCAAGGGAGGCCAAGACTGA
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KA and KS values for a gene in a given
comparison between species can be
informative about the way that gene has
evolved
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KA / K S < 1
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KA / K S =1
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Purifying selection
Neutral evolution
KA / KS > 1
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Positive selection
Generate
Protein
Sequences
Read Data
Re-align
Multiple
Sequences
Check
Alignment
Format
Estimate
Ka/Ks
Result!!!
Results
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Extraction
6,831 putatively orthologous coding trios
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PAML
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211 genes suggestive of positive selection in the
human lineage
255 genes suggestive of positive selection in the
chimp lineage
70 genes suggestive of positive selection in the
human / chimpanzee common ancestral lineage
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Distribution of genes in specific ontological
categories can stimulate hypotheses about
evolutionary change
Over-representation of genes involved in
olfaction and nuclear transport (Clark et
al., 2003)
Over-representation of genes involved in
tumor suppression, apoptosis and
spermatogenesis (Nielsen et al., 2005)
Results: GO Distribution in Human
Lineage
Gene Ontology
# of Genes
p-value
Receptor binding
62
1.95e-12
Response to external
biotic stimulus
53
1.95e-12
Cytokine activity
28
6.07e-10
Response to pest,
pathogen or parasite
47
6.07e-10
Results: GO Distribution in Chimp
Lineage
Gene Ontology
# of Genes
p-value
Receptor binding
56
1.79e-10
Response to extermal
biotic stimulus
42
2.65e-06
Response to pest,
pathogen or parasite
39
6.81e-06
Extracellular space
26
1.48e-05
Issues
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Errors in sequence
(chimp / macaque)
Orthology???
Rates and patterns of
amino acid substitution
are affected by various
genomic properties
Overall amino acid
changes among these
three species is low, thus
signal may be weak
Issues
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The three functional
categories are not
mutually exclusive
Rationale and
reasoning underlying
classifications can be
unclear
Future Analyses: Regulation and
Expression
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How does what we know about expression
in the brain (timing, intensity etc.)
correlate with what we know about
craniofacial development?
Compare rates of sequence divergence in
certain classes of intergenic DNA.
Between species differences in gene
regulatory networks?
Future Analyses: Between Species
Differences in Product Interactions
Many Thanks…
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Charles Addo-Quaye
Anne Buchanan
Webb Miller
Anton Nekrutenko
Joan Richtsmeier
Alan Walker
Ken Weiss