1. Presented by: Rebeca Campos Sanchez Sri Krishna Sundaresan Garam (Celine ) Han Bongsoo Park Oscar Bedoya Reina Shriya Kumar Tyler Malys Published in PLOSGenetics 2009
3. Humans have adapted “recently” to their environment Diet Climate Animals Diseases http://nadge.org/?p=199
4. The process underlying adaptation is positive natural selection SLC24A5* SLC45A2 KITLG http://anthro.palomar.edu/adapt/images/map_of_skin_color_distribution.gif
5. Candidate genes show biological evidence of positive selection and genetic evidence by… 1. Unusual haplotype patterns 2. Homozygosity 3. Extreme F st
6. 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.html
8. F st : a measure of population differentiation Subpopulation 1 N= 100 A1= 70% Subpopulation 2 N= 100 A1= 30% F st = H T – H S = H T Close to 0 means SIMILAR Close to 1 means DIFFERENT F st = 0.16
9. The input data are genome-wide SNPs H uman G enome D iversity P anel CEPH ( HGDP ) 640,000 SNPs 938 individuals 53 human populations http://scienceblogs.com/geneticfuture/2008/11/diy_searching_for_evolutions_signa.php
10. The input data are genome-wide SNPs Phase II HapMap 3 million SNPs 270 individuals: > Yoruban, Nigeria (YRI) > Descendents of NW Europe (CEU) > Beijing and Tokyo (ASN) http://www.sanger.ac.uk/Info/Press/2004/041213.shtml?;decor=printable
11. 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)
12. High F ST SNPS as candidates for selection By: Sri Krishna Sundaresan
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14. 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 Adaptation
15. 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
16. Mean F ST can correspond to geographical distance between population pairs Y axis: Maximum autosomal allele frequency difference between each population pair Geographically/Genetically closer Geographically/Genetically distant Coop G, Pickrell JK, Novembre J, Kudaravalli S, Li J, et al. (2009) The Role of Geography in Human Adaptation Han- Chinese Yor- Yoruba Fra- France Pal – Palestinian
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18. Extreme F ST 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 Adaptation
20. Top 50 SNPs The goal is to study the geographic distribution of the top extreme 50 SNPs Coop et al. 2009 Geographic Distribution?
21. A / G SNP of interest Global allele frequency distribution of a specific SNP of interest was examined A : ancestral (major) - Blue G : derived (minor) - Red
22. Example of global allele frequency distribution Coop et al. 2009 Major allele Minor allele
23. These global allele frequency distributions can show different sweep patterns Coop et al. 2009 Non-African sweep (KITLG) West Eurasian sweep (SLC24A5) East Asian sweep (MC1R) Major Minor
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25. SLC24A5 ( S o l ute C arrier 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 Coop et al. 2009
26. SNP of interest (SLC24A5) SNP 2 (A/G) Haplotype is a set of SNPs on a single chromatid that are transmitted together Haplotype SNP 1 SNP 3 SNP 4 SNP 5 SNP 6 (G/T) (A/G) (A/G) (G/T) (G/A)
27. Haplotype patterns show that SLC24A5 gene is a signal of positive selection Coop et al. 2009
28. KITLG (Non-African sweep) Various signals of positive selection may show distinctively different haplotype patterns SLC24A5 (West Eurasian) MC1R (East Asian) Coop et al. 2009
31. HGDP HapMap Higher SNPs Density HapMap Phase II 3.1million SNPs Transition of database
32. 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
33. 10% - 90% + 90% + 10% - YRI - ASN Number of SNPs YRI-ASN, derived allele frequency comparison Coop et al. 2009
35. First, More than 80% of the high- F ST SNPs occur in the Yoruba–east Asia comparison. 229 39 Coop et al. 2009
36. Second, The derived allele is almost always at higher Frequency in Europeans or east Asians than in Yoruba SNPs 10% - 90%+ YRI - ASN Coop et al. 2009
37. Third, alleles that are at low frequency in YRI and at high frequency in ASN are intermediate frequency in Europeans SNPs 10% - 90%+ YRI - ASN Coop et al. 2009
38. 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 Coop et al. 2009
39. 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
41. Data analyses provide conflicting evidence on recent adaptation in humans [Barreiro et al. 2008] SNPs in genic regions are more likely to have high F st Neutral processes have a high influence on their distribution
42. 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
43. Even the highest F st 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 Coop et al. 2009
47. SNPs with the highest F st 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 Coop et al. 2009
48. 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 Coop et al. 2009
49. 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 Coop et al. 2009
50. SNPs with High F ST between Continental groups By: Shriya Kumar
http://anthro.palomar.edu/adapt/images/map_of_skin_color_distribution.gif Mention positive and negative selection The influence of each gene and the geographic distribution according to environment
There are selection signals in and around genes
Remind concept of SNP http://science.marshall.edu/murraye/341/snps/Human%20Genetics%20MTHFR%20SNP%20Page.html
Explain the formula Concept of allele frequency Modified from http://johnhawks.net/weblog/reviews/evolution/mathematical/fst_frisbee_2007.html Heterozygosity or gene diversity Nei 1987: H=n(1-∑x i 2 )/n-1
Focus of this paper: studying the nature and prevalence of positive selection in human (rather than focusing on identifying genes and phenotypes involved in selection) Previous studies: suggest that selection in humans might be a strong force that allows for local adaptation via large allele frequency shifts at individual loci.
Fixation - Describes the situation in which a mutation has achieved a frequency of 100% in a natural population. The process by which new favorable mutations become fixed so quickly that physically linked alleles also become either fixed or lost depending on the phase of the linkage…. Hitch-hiking… fixation. Genetic Hitchhiking - increase of mutation frequency due to linkage with a positively selected mutation
- Why these candidate genes were chosen: much biological studies have been done showing that this gene was under selection. Also strong evidence for selection from unusual haplotype patterns, homozygosity or extreme values of Fst.
REDUCE TEXT!!! Overall distribution of selected alleles is strongly determined by historical relationships among populations. Therefore, local selection pressures have not given rise to very high- Fst SNPs. (What does this mean??) Next: Confirm result with HapMap data, which have higher SNP density, to further investigate these candidate sweeps.