The document summarizes a study that analyzed genetic differences between human populations to understand patterns of human adaptation. The study found that: 1) Most genetic differences between populations can be explained by neutral processes like genetic drift rather than strong positive selection. 2) There are very few examples of alleles reaching near fixation between populations due to strong selection. 3) Population bottlenecks and weak selective pressures along with drift likely explain more of the genetic differences observed between human populations than strong positive selection alone.

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

2. Background: By: Rebeca Campos Sanchez

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

7. Estimate allele frequencies is basically count SNP alleles = A1 A2 Subpopulation 1 N= 100 (200 chromosomes) A1= 140 = 70% A2= 60 = 30% Subpopulation 2 N= 100 (200 chromosomes) A1= 60 = 30% A2= 140 = 70%

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

13. “ What are High F ST SNPS??” “ Genic SNPs vs. Nongenic SNPs” “ Genetic hitchhiking” http://www.australiaonlinetravel.com/Australian-Customs.html

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

17. -> 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 F ST SNPs are candidates for strong selections (E.g. Skin pigmentation, Lactase etc) TO SUMMARIZE……

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

19. Garam (Celine) Han Geographic Distribution of SNPs & Selective Sweeps

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

24. Selective sweep is a rapid change of allele frequency in a population Fixation - when a mutation has achieved a high frequency of 100% in a natural population AA aa Aa 25% 50% 25% AA aa Aa 90% 9% 1% Selective sweep

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

29. 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 F st SNPs.

30. Derived allele frequency comparison of HapMap Data By: Bongsoo Park

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

34. YRI - CEU CEU-ASN 10% - 90% + 90% + 10% - 10% - 90% + 90% + 10% - 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

40. How adaptations have occurred in different populations? By: Oscar Bedoya Reina

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

44. [http://blog.commodityweather.com] It is likely that environmental pressures vary smoothly with geographical distance

45. [http://igcministries.org/images/WorldMap.gif] Allele distribution may be explained by ancestral intermediate frequencies and population changes 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

51. 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.

52. 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.

54. Drift of neutral alleles Coop et al. 2009

55. Sharing of partial sweep signals among geographic regions . Coop et al. 2009

56. Drift and Weak Selection Weak selection – selection of alleles with smaller fitness advantage Coop et al. 2009

57. Derived frequency seen at SNPs with > 90% frequency difference Real Data Simulated Data Coop et al. 2009

58. Selection in African Population New selection pressures Polygenic response

59. Summary By: Tyler Malys

60. Does human adaptation result from strong selection? http://graphicleftovers.com/images/member/2336/three_women_thumb_watermark.png

61. Look at genetic differences between populations. SNPs HGDP HapMap Yoruba French Han Chinese

62. Detecting signals for selection Target for selection Coop et al. 2009

63. Genetic differences increase with geographic distance. Coop et al. 2009

64. Genetic differences can be divided into three groups Coop et al. 2009

65. Differences between groups are predicted by models for neutral selection. Coop et al. 2009

66. Few SNPs have high allele frequency differences between groups. Coop et al. 2009

67. Few alleles reach fixation because of strong selection. Coop et al. 2009

68. Selective pressures must be strong and maintainable. Coop et al. 2009

69. Population bottlenecks can aid weak selection in allele fixation. Coop et al. 2009

70. Differences between populations is due to weak or neutral selection. History of the Population Migration Genetic Drift