Human Comparative Genomics

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Human Comparative Genomics

• April 6th 2005
• Bio5488

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• What is the sequence of the normal Human Genome?
• What accounts for the genetic differences
  between individuals?

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Finding Segmental Duplications in the Human Genome
Bailey et al (2002) Science 2971003-07
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Segmental Duplications in the Human Genome
Bailey et al (2002) Science 2971003-07
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Polymorphism in Segmental Duplications
Iafrate et al (2004) Nat Genet 36949-51
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Polymorphism in Segmental Duplications

• CGH studies find many copy number polymorphisms
  in segmental duplications (12 per individual)
• Rare and common polymorphisms
• Many overlap coding regions
• Critical for the interpretation of amplifications
  in cancers
• Responsible for phenotypic differences between
  people?

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SNPs/Hap Map

• http//www.hapmap.org/
• 1 SNP/1000 bp

The International HapMap Project is a
multi-country effort to identify and catalog
genetic similarities and differences in human
beings. Using the information in the HapMap,
researchers will be able to find genes that
affect health, disease, and individual responses
to medications and environmental factors. The
Project is a collaboration among scientists and
funding agencies from Japan, the United Kingdom,
Canada, China, Nigeria, and the United States.
All of the information generated by the Project
will be released into the public domain
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Clustering human populations by genotype

• K-means clustering of gene expression data
• Pick a number (k) of cluster centers
• Assign every gene to its nearest cluster center
• Move each cluster center to the mean of its
  assigned genes
• Repeat 2-3 until convergence

• EM-based clustering of genotype data
• Pick a number (k) of sub-populations
• Assign every individual to a sub-population based
  on the allele frequencies in the sub-population
• Recalculate the allele frequencies in each sub
  population
• Repeat 2-3 until convergence

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An Example
I1 (A1,B1,C2) I2 (A1,B1,C2) I3 (A1,B2,C2) I4
(A2,B2,C1) I5 (A1,B1,C1) I6 (A1,B1,C2) I7
(A1,B1,C2) I8 (A2,B2,C2) I9 (A1,B2,C1) I10
(A2,B1,C2) I11 (A2,B2,C2) I12 (A2,B2,C2)
12 individuals genotyped at three different
independent biallelic loci
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k1
k3
k2
I1 (A1,B1,C2) I2 (A1,B1,C2) I3 (A1,B2,C2) I4
(A2,B2,C1)
I5 (A1,B1,C1) I6 (A1,B1,C2) I7 (A1,B1,C2) I8
(A2,B2,C2)
I9 (A1,B2,C1) I10 (A2,B1,C2) I11
(A2,B2,C2) I12 (A2,B2,C2)
F(A1)k10.75 F(B1)k10.5 F(C1)k10.25
F(A1)k20.75 F(B1)k20.75 F(C1)k20.25
F(A1)k30.25 F(B1)k30.25 F(C1)k30.25
Consider individual I1 (A1,B1,C2) P(I1 in k1)
(.75)(.5)(.75) 0.28 P(I1 in k2)
(.75)(.75)(.75) 0.42 P(I1 in k3)
(.25)(.25)(.75) 0.046 Therefore reassign I1 to
k2
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Questions

• How many sub-populations (k) best partition the
  data?
• How strong is the evidence for the clusters?
• Do the inferred clusters correspond to our
  notions of race, ethnicity, ancestry, or
  geography?
• Given the inferred clusters can we accurately can
  we classify new individuals?
• Can we identify population admixture or migration
  events?

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Attempts to group humans by genotype
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? and Fst

• ?, average nucleotide diversity (1
  in 1000 bp)
• Fst, proportion of genetic variation that can be
  ascribed to differences between populations
  (10)

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Summary of Findings

• ? and Fst are small
• Diversity within African populations is highest
• Unsupervised clustering tends to support either 3
  or 4 sub-populations depending on number and type
  of markers and individuals included in the study,
  but the composition of the groups are often
  different in different studies

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An exampleBamshad et al (2003) Am. J. Hum.
Genet. 72578-89
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ButBamshad et al (2003) Am. J. Hum. Genet.
72578-89
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A contradiction?

• Although they differed on the extent and
  composition of sub-populations, so far all
  studies have found evidence of significant
  sub-structure in human populations
• And yet, all studies agree that Fst is small
  (between 3-15)

See review by Jorde and Wooding (2004) Nature
Genet. 36 S28-S33
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Small Fst does not imply lack of structure
E2
C2
C1
C1
A1
A2
E2
A1
B1
A1
E1
C2
A1
A2
D1
D1
E1
E2
C2
A2
B1
B2
A1
C1
D1
D2
E1
A1
D2
A2
D1
A1
B1
A1
E2
E1
D2
A1
B2
E2
B2
C2
A1
A1
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Pharmacogenomics

• Many drugs never reach the market because of side
  effects in a small minority of patients
• Many drugs on the market are efficacious in only
  a small fraction of the population
• This variation is (in part) due to genetic
  determinants
• Orissa?EGF mutations
• Codeine?cytochrome P450 alleles

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Question Is race, ancestry, ethnicity, geography
or genetic substructure a reasonable proxy for
genotype at alleles relevant for drug metabolism?
Answer So farNo. Still looks as if we will
have to genotype the relevant loci before making
any guesses
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Population genetic structure of variable drug
response.Wilson et al (2001) Nat Genet. 29
265-269
A
B
C
CYP1A2
A African B European C Asian
GSTM1
CYP2C19
DIA4
NAT2
CYP2D6
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Evidence for Archaic Asian Ancestry on the Human
X ChromosomeGarrigan et al. (2005) Mol. Biol.
And Evol. 22189-192

• Pseudogene on the X-chromosome
• 18 substitutions between human-chimp
• 15 substitutions between two human alleles
• Assuming a molecular clock the split between the
  two human alleles is about 2 million years
• Both alleles found in southern Asia, only one
  allele found in Africa
• Only human gene tree to root in Asia

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Garrigan et al. (2005) Mol. Biol. And Evol.
22189-192
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Human evolution in a nutshell
5-6 mya
H. ergaster
1 mya
0.5 mya
H. erectus
0.2 mya
H. neanderthalis
chimps
H. sapien
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Garrigan et al. (2005) Mol. Biol. And Evol.
22189-192
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So what happened?

• Strong selection for the Asian allele in southern
  Asia
• -not likely since this is a pseudogene locus
• -fails Tajimas D test
• Gene flow between H. sapien and H.erectus in
  southern Asia
• -branch lengths are about right for 2 million
  years of divergence
• -H. erectus was in southern Asia until 18,000
  years ago (Morwood et al. and Brown et al. in
  Nature (2004) vol 431.)
• -supporting evidence from genetic analysis of
  lice and other human parasites (Reed et al (2004)
  PLoS 21972-83)

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Human evolution in a nutshell
5-6 mya
H. ergaster
1 mya
0.5 mya
H. erectus
H. neanderthalis
0.2 mya
?
chimps
H. sapien