colloquium presentation 2009 fall bongsoo

Presented by: Rebeca Campos SanchezSri Krishna SundaresanGaram (Celine ) HanBongsoo ParkOscar Bedoya ReinaShriya KumarTyler Malys

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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

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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

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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

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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

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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

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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

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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

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Coop et al. 2009

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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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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

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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