Download 20.Human.Neanderthal.Selection

Rates of recombination around genes
Most traits in organisms
Show continuous variation
How do we find the genes
That affect these
“quantitative” traits
Scan the genome for
Nucleotide sites that
Co-vary with the
phenotype
Marker association studies
Mutation “causing”
variation in height
Tall
Tall
Tall
Tall
Short
Short
Short
Short
A
A
A
A
G
G
G
G
Adjacent SNPs are linked
Distant sites show no genotype-phenotype association
Problem: how do we find the causal SNPs? Needle in a haystack
Genotype and Haplotype
Single locus genotype: Mom Dad
Aa
Bb
Cc
dD
A
b
C
d
Multiple locus genotype:
a
b
c
D
AabbCcDd
Haplotypes:
AbCd
A
b
C
d
a
b
c
D
abcD
Association tests
with fixed markers
A/T
1
G/A
2
G/C
3
T/C
4
G/C
5
A/C
6
Tests of association:
SNP 1
SNP 3
A
A
T
T
G
G
A
A
high r2
G
C
G
C
T
C
C
C
high r2
G
C
G
C
A
C
C
C
SNPs actually tested:
SNP 1
SNP 3
SNP 2
SNP 5
Origins of modern humans
• African replacement model
– African origin of H. sapiens
– Second wave of migration
– Hs eliminates resident H.
erectus or Neanderthals
• Hybridization model
– Like repacement model
– involves hybridization
between Hs and others
• Multiregional model
– Parallel origin of Hs in
different regions
– Requires gene flow
http://www.linfield.edu/~mrobert/originsfigure5.html
H. erectus
H. sapiens
http://emuseum.mnsu.edu/biology/humanevolution/fosrec.html
Figure 3. The migration of modern Homo sapiens.
The scheme outlined above begins with a radiation from East Africa to the rest of
Africa about 100 kya and is followed by an expansion from the same area to Asia,
probably by two routes, southern and northern between 60 and 40 kya. Oceania,
Europe and America were settled from Asia in that order.
The common variant G6PD-202A
confers partial protection against
malaria, with a case-control study
estimating a reduction in disease
risk of about 50%
The CD40 ligand gene (TNFSF5)
encodes a proteinwith a critical role
in immune response to infectious
agents. TNFSF5-726C, is
associated with a similar degree of
protection against malaria.
Extended haplotype homozygosity
Sabeti et al. 2002: We measured LD at a distance x from the core region by
calculating the extended haplotype homozygosity (EHH).EHHis defined as the
probability that two randomly chosen chromosomes carrying the core haplotype
of interest are identical by descent (as assayed by homozygosity at all SNPs8)
for the entire interval from the core region to the point x. EHH thus detects the
transmission of an extended haplotype without recombination. Our test for
positive selection involves finding a core haplotype with a combination of high
frequency and high EHH
Core haplotypes and EHH
Data:
800,000 polymorphic SNPs
309 unrelated individuals:
• 89 Japanese and Han Chinese from Tokyo and
Beijing denoted as East Asian (ASN)
• 60 northern and western Europeans (CEU)
• 60 Yoruba (YRI) from Ibadan, Nigeria.
In plots of EHH versus distance, the area under the EHH curve
will usually be much greater for a selected allele than for a
neutral allele.
We compute the integral of the observed decay of EHH away
from a specified core allele until EHH reaches 0.05.
This integrated EHH (iHH) denoted iHHA or iHHD, depending on
whether it is computed with respect to the ancestral or derived
core allele.
In neutral models, low frequency alleles are younger and are associated with
longer haplotypes than higher frequency alleles
We adjust the unstandardized iHS to obtain our final statistic which has mean 0
and variance 1 regardless of allele frequency at the core SNP:
Discovering the patterns of human migration from haplotypes
Hominid fossil ranges
See also: http://www.handprint.com/LS/ANC/stones.html
H. Sapiens
Cro Magnon
H. heidelbergensis
http://www.handprint.com/LS/ANC/evol.html#chart
H. neanderthalensis
H. erectus
H. ergaster
http://www.sciencemag.org/content/vol328/issue5979/images/me
dium/328_680_F1.gif
http://www.visionmagazine.com/archives/0712/images/culture_b
elief.jpg
Porgaigas
New Guinea
Still practice cannibalis
G/wi Hunter gatherers
Kalahari, Africa
Amerind
Caucasian (from Caucasus Mts
Northern European
Asian
Human geographic races
•
•
•
•
•
•
•
•
•
Are races legacies of ancient H.
erectus lineages?
Did races originate after the rise
of modern H. sapiens?
Age of alleles
Geographic origin of alleles
Age of neutral alleles
4Ne generations from origin to
fixation (± large error)
4 * 10,000 * 20 = 800,000 years
H.erectus left Africa about
1,000,000 years ago
Molecular methods can identify
recent origin, but are at the limit
of resolution for “proving” an
older origin of races
Gene genealogies
Most recent
common
ancestor
old medium young old
Ages of alleles
Time
Fig. 1 Samples and sites from which DNA was retrieved
R. E. Green et al., Science 328, 710-722 (2010)
Published by AAAS
Neandertal
mtDNA
Tree and
Pairwise
Divergence
Green et al.
2008
Challenges for nuclear sequences:
Ancestral polymorphism
Most regions may be identical
Contamination – 95%!
Deamination: C->T
Fig. 2 Nucleotide substitutions inferred to have occurred on the evolutionary lineages leading to the
Neandertals, the human, and the chimpanzee genomes
R. E. Green et al., Science 328, 710-722 (2010)
Published by AAAS
Fig. 4 Selective sweep screen
R. E. Green et al., Science 328, 710-722 (2010)
Published by AAAS
Fig. 6 Four possible scenarios of genetic mixture involving Neandertals
R. E. Green et al., Science 328, 710-722 (2010)
Published by AAAS