colloquium presentation 2009 fall bongsoo
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Presented by: Rebeca Campos SanchezSri Krishna SundaresanGaram (Celine ) HanBongsoo ParkOscar Bedoya ReinaShriya KumarTyler Malys
1
Published in PLOSGenetics 2009
Background:
By: Rebeca Campos Sanchez
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Humans have adapted “recently” to their environment
DietClimate
Animals
Diseases
http://nadge.org/?p=1993
The process underlying adaptation is positive natural selection
SLC24A5*SLC45A2KITLG
http://anthro.palomar.edu/adapt/images/map_of_skin_color_distribution.gif4
Candidate genes show biological evidence of positive selection and genetic evidence by…
1. Unusual haplotype patterns
2. Homozygosity
3. Extreme Fst
5
The most common variation in the genome are the SNPs
SNP alleles = A/G
http://science.marshall.edu/murraye/341/snps/Human%20Genetics%20MTHFR%20SNP%20Page.html6
Estimate allele frequencies is basically count
SNP alleles = A1 A2
Subpopulation 1N= 100 (200 chromosomes)A1= 140 = 70%A2= 60 = 30%
Subpopulation 2N= 100 (200 chromosomes)A1= 60 = 30%A2= 140 = 70%
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Fst: a measure of population differentiation
Subpopulation 1N= 100A1= 70%
Subpopulation 2N= 100A1= 30%
Fst = HT – HS = HT
Close to 0 means SIMILAR
Close to 1 means DIFFERENT
Fst = 0.16
8
The input data are genome-wide SNPs
Human Genome Diversity Panel CEPH (HGDP)
640,000 SNPs938 individuals53 human populations
http://scienceblogs.com/geneticfuture/2008/11/diy_searching_for_evolutions_signa.php9
The input data are genome-wide SNPs
Phase II HapMap
3 million SNPs270 individuals:> Yoruban, Nigeria (YRI)> Descendents of NW Europe (CEU)> Beijing and Tokyo (ASN)
http://www.sanger.ac.uk/Info/Press/2004/041213.shtml?;decor=printable10
The main hypothesis…
Positive selection
Geographic distribution
High frequencies of new alleles
Particular populations or groups closely related
“How effective has selection been at driving allele frequency differentiation between continental groups?” (Coop et al. 2009)
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High FST SNPS as candidates for selection
By: Sri Krishna Sundaresan
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“ What are High FST SNPS??”
“Genic SNPs vs. Nongenic SNPs”
“Genetic hitchhiking”
http://www.australiaonlinetravel.com/Australian-Customs.html 13
E. Asian Yoruba, Nigeria
X axis : Signed difference (δ) in allele frequencies
Fraction of SNPs in the bin that are genic (nongenic)Y axis : Fold enrichment:
Fraction of all SNPs that are genic (nongenic)
Genic SNPs get enriched between population pairs
Coop G, Pickrell JK, Novembre J, Kudaravalli S, Li J, et al. (2009) The Role of Geography in Human Adaptation14
Yoruba, Nigeria European
E. Asian
Coop G, Pickrell JK, Novembre J, Kudaravalli S, Li J, et al. (2009) The Role of Geography in Human Adaptation
Similar enrichment of genic SNPs between other population pairs
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Mean FST can correspond to geographical distance between population pairs
Y axis: Maximum autosomal allele frequency difference between each population pair
Geographically/Genetically
closer
Geographically/Genetically
distantCoop G, Pickrell JK, Novembre J, Kudaravalli S, Li J, et al. (2009) The Role of Geography in Human Adaptation
Han- ChineseYor- Yoruba
Fra- FrancePal – Palestinian
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→ There is similar enrichment for SNPs in genic regions (especially non synonymous variants, Barreiro et al) for all population pairs and they’re therefore used as signals for detection
→ Local adaptation is not a strong force as it was thought to be
→ Extreme FST SNPs are candidates for strong selections (E.g. Skin pigmentation, Lactase etc)
TO SUMMARIZE……
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Extreme FST SNPs between 3 population pairs chosen to study geographic distribution
Coop G, Pickrell JK, Novembre J, Kudaravalli S, Li J, et al. (2009) The Role of Geography in Human Adaptation18
Garam (Celine) Han
Geographic Distribution of SNPs
& Selective Sweeps
19
Top 50 SNPs
Geographic Distribution?
The goal is to study the geographic distribution of the top extreme 50 SNPs
20Coop et al. 2009
A / G
SNP of interest
Global allele frequency distribution of a specific SNP of interest was examined
A : ancestral (major) - BlueG : derived (minor) - Red
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Major allele
Minor allele
Example of global allele frequency distribution
22Coop et al. 2009
These global allele frequency distributions can show different sweep patterns
Non-African sweep (KITLG)
West Eurasian sweep (SLC24A5)
East Asian sweep (MC1R)
Major
Minor
23Coop et al. 2009
Selective sweep is a rapid change of allele frequency in a population
AA aaAa25% 50% 25%
AA aaAa90% 9% 1%
Selective sweep
• Fixation - when a mutation has achieved a high frequency of 100% in a natural population
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SLC24A5 (Solute Carrier Family 24, Member 5): a gene involved in skin pigmentation variation between black African and white European
A skin pigmentation variation gene, SLC24A5, shows a unique global allele frequency distribution
25Coop et al. 2009
Haplotype
SNP of interest (SLC24A5)
SNP 2(A/G)
SNP 1 SNP 3 SNP 4 SNP 5 SNP 6(G/T) (A/G)(A/G) (G/T) (G/A)
Haplotype is a set of SNPs on a single chromatid that are transmitted together
26
Haplotype patterns show that SLC24A5 gene is a signal of positive selection
27Coop et al. 2009
KITLG (Non-African sweep)
Various signals of positive selection may show distinctively different haplotype patterns
SLC24A5 (West Eurasian)
MC1R (East Asian)
28Coop et al. 2009
Summary (of Figure 3 &4)
• Geographic distribution of top SNPs agree with population clusters identified using haplotypes.
• Distribution of alleles in population is strongly determined by historical relationship (i.e. migration).
• Therefore, local selection pressures did not give rise to high Fst SNPs.
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Derived allele frequency comparison ofHapMap Data
By: Bongsoo Park
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HGDP HapMap
Higher SNPs DensityHapMap Phase II 3.1million SNPs
Transition of database
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What does it mean ‘Higher Density’ of SNPs?
PHASE I
PHASE II
The International HapMap Consortium, A second generation
human haplotype map of over 3.1 million SNPs, Nature (449):851-861
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10% - 90% +
90% + 10% -
YRI - ASN
Number of SNPs
YRI-ASN, derived allele frequency comparison
33Coop et al. 2009
YRI - CEU CEU-ASN10% - 90% +
90% + 10% -
10% - 90% +
90% + 10% - 34Coop et al. 2009
First, More than 80% of the high- FST SNPs occur in the Yoruba–east Asia comparison.
229 39
35Coop et al. 2009
Second, The derived allele is almost always at higher Frequency in Europeans or east Asians than in Yoruba
SNPs10% - 90%+
YRI - ASN
36Coop et al. 2009
Third, alleles that are at low frequency in YRI and at highfrequency in ASN are intermediate frequency in Europeans
SNPs10% - 90%+
YRI - ASN
37Coop et al. 2009
Finally, there are few SNPs in the genome have extreme allele frequency differences between populations
There are only 13 nonsynonymous SNPs with a frequency Difference > 90% between YRI, ASN
risk of developing insulin resistance, type II diabetes
38
Coop et al. 2009
Summary
1. More than 80% of the high- FST SNPs occur in the Yoruba–east Asia comparison
2. The derived allele is almost always at higher frequency in Europeans or east Asians than in Yoruba
3. Essentially all of these alleles are at intermediate frequency in Europeans
4. There s few SNPs in the genome have extreme allele frequency differences between populations
39
How adaptations have occurred in different
populations?
By: Oscar Bedoya Reina
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Data analyses provide conflicting evidence on recent adaptation in humans
[Barreiro et al. 2008]
SNPs in genic regions are more likely to have high Fst
Neutral processes have a high influence on their distribution
4141
Populations living on antagonistic environments are under antagonistic selective pressures
[Sabeti et al., 2007]
Species may adapt to local selection pressures by large frequency change at few loci
4242
Even the highest Fst SNPs follow patterns predictable by neutral variation
Geographical distribution of alleles with high Fst are predictable
Closely related populations do not have SNPs with very extreme allele frequency differences
4343Coop et al. 2009
[http://blog.commodityweather.com]
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It is likely that environmental pressures vary smoothly with geographical distance
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[http://igcministries.org/images/WorldMap.gif]
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Allele distribution may be explained by ancestral intermediate frequencies and population changes
45
Coop et al. 2009
46
SNPs with the highest Fst between continental populations show different histories
The total number of nearly fixed differences is low
But enrichment of genic SNPs with high Fst argues against a mostly neutral model
4747Coop et al. 2009
Results show contrasting results on gene flow from African to other populations
[http://igcministries.org/images/WorldMap.gif]
High rate of gene flow could prevent favored alleles from achieving high Fst
But selected alleles have not been able to spread freely between continents
4848Coop et al. 2009
Results suggest that is rare for strong selection to drive new mutations rapidly to near fixation
Genic regions around high Fst SNPs show a modest increase of homozygosity
Despising the separation times between populations, strong selection rarely fix variants
4949Coop et al. 2009
SNPs with High FST between Continental
groups
By: Shriya Kumar
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• Non – African populations may have experienced more novel selection pressures than Africans
• Bottlenecks inflated the number of weakly selected alleles in non-African populations
• Fluctuating environments and Polygenic Adaptation.
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Novel Selection pressures on Non- Africans
• High frequency high Fst SNPs – HapMap Europeans and Asians than Yoruba
• Plausible explanation – Novel Selection pressure in new habitats and cooler conditions
• Selective pressure for novel phenotype Eg. Skin pigmentation gene.
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53
Drift of neutral alleles
54Coop et al. 2009
Sharing of partial sweep signals among geographic regions.
55Coop et al. 2009
Drift and Weak Selection
• Weak selection – selection of alleles with smaller fitness advantage
56Coop et al. 2009
Real DataSimulated Data
Derived frequency seen at SNPs with > 90% frequency difference
57Coop et al. 2009
Selection in African Population
• New selection pressures• Polygenic response
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Summary
By: Tyler Malys
59
Does human adaptation result from strong selection?
http://graphicleftovers.com/images/member/2336/three_women_thumb_watermark.png60
Look at genetic differences between populations.
SNPsHGDP
HapMap
Yoruba French
Han Chinese
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Detecting signals for selection
Target for selection
62Coop et al. 2009
Genetic differences increase with geographic distance.
63Coop et al. 2009
Genetic differences can be divided into three groups
64Coop et al. 2009
Differences between groups are predicted by models for neutral selection.
65Coop et al. 2009
Few SNPs have high allele frequency differences between groups.
66Coop et al. 2009
Few alleles reach fixation because of strong selection.
67Coop et al. 2009
Selective pressures must be strong and maintainable.
68Coop et al. 2009
Population bottlenecks can aid weak selection in allele fixation.
69Coop et al. 2009
Differences between populations is due to weak
or neutral selection.
History of the Population Migration
Genetic Drift70
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