Presented by: Rebeca  Campos Sanchez Sri  Krishna  Sundaresan Garam  (Celine ) Han Bongsoo  Park Oscar  Bedoya Reina Shriy...
Background: By: Rebeca Campos Sanchez
Humans have adapted “recently” to their environment Diet Climate Animals Diseases http://nadge.org/?p=199
The process underlying adaptation is positive natural selection SLC24A5* SLC45A2 KITLG http://anthro.palomar.edu/adapt/ima...
Candidate genes show biological evidence of positive selection and genetic evidence by… 1.  Unusual haplotype patterns 2. ...
The most common variation in the genome are the SNPs  SNP alleles = A/G   http://science.marshall.edu/murraye/341/snps/Hum...
Estimate allele frequencies is basically count SNP alleles =  A1 A2   Subpopulation 1 N= 100  (200 chromosomes) A1= 140 = ...
F st : a measure of population differentiation Subpopulation 1 N= 100 A1= 70% Subpopulation 2 N= 100 A1= 30% F st   =  H T...
The input data are genome-wide SNPs  H uman  G enome  D iversity  P anel CEPH ( HGDP ) 640,000 SNPs 938 individuals 53 hum...
The input data are genome-wide SNPs  Phase II HapMap 3 million SNPs 270 individuals: > Yoruban, Nigeria (YRI) > Descendent...
The main hypothesis… Positive selection Geographic distribution High frequencies of new alleles Particular populations or ...
High F ST  SNPS as candidates for selection By: Sri Krishna Sundaresan
<ul><li>“  What are High F ST  SNPS??” </li></ul><ul><li>“ Genic SNPs vs. Nongenic SNPs” </li></ul><ul><li>“ Genetic hitch...
E. Asian  Yoruba, Nigeria X axis : Signed difference ( δ ) in allele frequencies   Fraction of SNPs in the bin that are ge...
Yoruba, Nigeria European E. Asian Coop G, Pickrell JK, Novembre J, Kudaravalli S, Li J, et al. (2009) The Role of Geograph...
Mean F ST  can correspond to geographical distance between population pairs   Y axis: Maximum autosomal allele frequency d...
<ul><li>->  There is similar enrichment for SNPs in genic regions (especially non synonymous variants, Barreiro et al) for...
Extreme F ST  SNPs between 3 population pairs chosen to study geographic distribution Coop G, Pickrell JK, Novembre J, Kud...
Garam (Celine) Han Geographic Distribution of SNPs  & Selective Sweeps
Top 50 SNPs The goal is to study the geographic distribution of the top extreme 50 SNPs Coop et al. 2009 Geographic Distri...
A  /  G SNP of interest Global allele frequency distribution of a specific SNP of interest was examined  A : ancestral (ma...
Example of global allele frequency distribution  Coop et al. 2009 Major allele Minor allele
These global allele frequency distributions can show different sweep patterns Coop et al. 2009 Non-African  sweep (KITLG) ...
Selective sweep is a rapid change of allele frequency in a population <ul><li>Fixation - when a mutation has achieved a hi...
SLC24A5   ( S o l ute  C arrier Family  24 , Member  5 ) : a gene involved in  skin pigmentation variation  between black ...
SNP of interest (SLC24A5) SNP 2 (A/G) Haplotype is a set of SNPs on a single chromatid that are transmitted together Haplo...
Haplotype patterns show that SLC24A5 gene is a signal of positive selection Coop et al. 2009
KITLG (Non-African sweep) Various signals of positive selection may show distinctively different haplotype patterns SLC24A...
Summary  (of Figure 3 &4) <ul><li>Geographic distribution of top SNPs agree with population clusters identified using hapl...
Derived allele frequency  comparison of HapMap Data By: Bongsoo Park
HGDP HapMap Higher SNPs Density HapMap Phase II  3.1million SNPs Transition of database
What does it mean ‘Higher Density’ of SNPs? PHASE I PHASE II The International HapMap Consortium, A second generation huma...
10% -  90% +  90% + 10% - YRI - ASN Number of SNPs YRI-ASN, derived allele frequency comparison Coop et al. 2009
YRI - CEU CEU-ASN 10% -  90% +  90% + 10% - 10% -  90% +  90% + 10% - Coop et al. 2009
First, More than 80% of the high- F ST  SNPs occur  in the Yoruba–east Asia comparison. 229 39 Coop et al. 2009
Second, The derived allele is almost always at higher  Frequency in Europeans or east Asians than in Yoruba SNPs 10% -  90...
Third, alleles that are at low frequency in YRI and at high frequency in ASN are  intermediate frequency in Europeans SNPs...
Finally, there are few SNPs in the genome have extreme  allele frequency differences between populations There are only 13...
Summary  1. More than 80% of the high- FST SNPs occur  in the Yoruba–east Asia comparison 2. The derived allele is almost ...
How adaptations have occurred in different populations? By: Oscar Bedoya Reina
Data analyses provide conflicting evidence on recent adaptation in humans [Barreiro et al. 2008] SNPs in genic regions are...
Populations living on antagonistic environments are under antagonistic selective pressures [Sabeti et al., 2007] Species m...
Even the highest F st  SNPs follow patterns predictable by neutral variation Geographical distribution of alleles with hig...
[http://blog.commodityweather.com] It is likely that environmental pressures vary smoothly with geographical distance
[http://igcministries.org/images/WorldMap.gif] Allele distribution may be explained by ancestral intermediate frequencies ...
SNPs with the highest F st  between continental populations show different histories The total number of nearly fixed diff...
Results show contrasting results on gene flow from African to other populations [http://igcministries.org/images/WorldMap....
Results suggest that is rare for strong selection to drive new mutations rapidly to near fixation Genic regions around hig...
SNPs with High F ST  between Continental groups By: Shriya Kumar
<ul><li>Non – African populations may have experienced more novel selection pressures than Africans </li></ul><ul><li>Bott...
Novel Selection pressures on Non- Africans <ul><li>High frequency high Fst SNPs – HapMap Europeans and Asians than Yoruba ...
Drift of neutral alleles Coop et al. 2009
Sharing of partial sweep signals among geographic regions . Coop et al. 2009
Drift and Weak Selection <ul><li>Weak selection – selection of alleles with smaller fitness advantage </li></ul>Coop et al...
Derived frequency seen at SNPs with > 90%  frequency difference Real Data Simulated Data Coop et al. 2009
Selection in African Population <ul><li>New selection pressures </li></ul><ul><li>Polygenic response </li></ul>
Summary By:  Tyler Malys
Does human adaptation result from strong selection? http://graphicleftovers.com/images/member/2336/three_women_thumb_water...
Look at genetic differences between populations. SNPs HGDP HapMap Yoruba French Han Chinese
Detecting signals for selection Target for selection Coop et al. 2009
Genetic differences increase with geographic distance. Coop et al. 2009
Genetic differences can be divided into three groups Coop et al. 2009
Differences between groups are predicted by models for neutral selection. Coop et al. 2009
Few SNPs have high allele frequency differences between groups. Coop et al. 2009
Few alleles reach fixation because of strong selection. Coop et al. 2009
Selective pressures must be strong and maintainable. Coop et al. 2009
Population bottlenecks can aid weak selection in allele fixation. Coop et al. 2009
Differences between populations is due to weak or neutral selection. History of the  Population Migration Genetic Drift
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Colloquium Presentation 2009 Fall Bongsoo

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  • http://nadge.org/?p=199 Migrations http://reference.findtarget.com/search/Human%20migration/ Neutral forces: migration and admixture Evolutionary forces acting: migration, genetic drift, natural selection
  • 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
  • HGDP http://scienceblogs.com/geneticfuture/2008/11/diy_searching_for_evolutions_signa.php Hgdp selection browser @ Pritchard lab: http://hgdp.uchicago.edu/cgi-bin/gbrowse/HGDP/
  • http://www.sanger.ac.uk/Info/Press/2004/041213.shtml?;decor=printable
  • 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.
  • Colloquium Presentation 2009 Fall Bongsoo

    1. 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. 2. Background: By: Rebeca Campos Sanchez
    3. 3. Humans have adapted “recently” to their environment Diet Climate Animals Diseases http://nadge.org/?p=199
    4. 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. 5. Candidate genes show biological evidence of positive selection and genetic evidence by… 1. Unusual haplotype patterns 2. Homozygosity 3. Extreme F st
    6. 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. 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. 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. 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. 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. 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. 12. High F ST SNPS as candidates for selection By: Sri Krishna Sundaresan
    13. 13. <ul><li>“ What are High F ST SNPS??” </li></ul><ul><li>“ Genic SNPs vs. Nongenic SNPs” </li></ul><ul><li>“ Genetic hitchhiking” </li></ul>http://www.australiaonlinetravel.com/Australian-Customs.html
    14. 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. 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. 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. 17. <ul><li>-> 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 </li></ul><ul><li>-> Local adaptation is not a strong force as it was thought to be </li></ul><ul><li>-> Extreme F ST SNPs are candidates for strong selections (E.g. Skin pigmentation, Lactase etc) </li></ul>TO SUMMARIZE……
    18. 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. 19. Garam (Celine) Han Geographic Distribution of SNPs & Selective Sweeps
    20. 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. 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. 22. Example of global allele frequency distribution Coop et al. 2009 Major allele Minor allele
    23. 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. 24. Selective sweep is a rapid change of allele frequency in a population <ul><li>Fixation - when a mutation has achieved a high frequency of 100% in a natural population </li></ul>AA aa Aa 25% 50% 25% AA aa Aa 90% 9% 1% Selective sweep
    25. 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. 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. 27. Haplotype patterns show that SLC24A5 gene is a signal of positive selection Coop et al. 2009
    28. 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. 29. Summary (of Figure 3 &4) <ul><li>Geographic distribution of top SNPs agree with population clusters identified using haplotypes. </li></ul><ul><li>Distribution of alleles in population is strongly determined by historical relationship (i.e. migration). </li></ul><ul><li>Therefore, local selection pressures did not give rise to high F st SNPs. </li></ul>
    30. 30. Derived allele frequency comparison of HapMap Data By: Bongsoo Park
    31. 31. HGDP HapMap Higher SNPs Density HapMap Phase II 3.1million SNPs Transition of database
    32. 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. 33. 10% - 90% + 90% + 10% - YRI - ASN Number of SNPs YRI-ASN, derived allele frequency comparison Coop et al. 2009
    34. 34. YRI - CEU CEU-ASN 10% - 90% + 90% + 10% - 10% - 90% + 90% + 10% - Coop et al. 2009
    35. 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. 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. 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. 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. 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. 40. How adaptations have occurred in different populations? By: Oscar Bedoya Reina
    41. 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. 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. 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. 44. [http://blog.commodityweather.com] It is likely that environmental pressures vary smoothly with geographical distance
    45. 45. [http://igcministries.org/images/WorldMap.gif] Allele distribution may be explained by ancestral intermediate frequencies and population changes Coop et al. 2009
    46. 46.
    47. 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. 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. 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. 50. SNPs with High F ST between Continental groups By: Shriya Kumar
    51. 51. <ul><li>Non – African populations may have experienced more novel selection pressures than Africans </li></ul><ul><li>Bottlenecks inflated the number of weakly selected alleles in non-African populations </li></ul><ul><li>Fluctuating environments and Polygenic Adaptation. </li></ul>
    52. 52. Novel Selection pressures on Non- Africans <ul><li>High frequency high Fst SNPs – HapMap Europeans and Asians than Yoruba </li></ul><ul><li>Plausible explanation – Novel Selection pressure in new habitats and cooler conditions </li></ul><ul><li>Selective pressure for novel phenotype </li></ul><ul><li>Eg. Skin pigmentation gene. </li></ul>
    53. 53.
    54. 54. Drift of neutral alleles Coop et al. 2009
    55. 55. Sharing of partial sweep signals among geographic regions . Coop et al. 2009
    56. 56. Drift and Weak Selection <ul><li>Weak selection – selection of alleles with smaller fitness advantage </li></ul>Coop et al. 2009
    57. 57. Derived frequency seen at SNPs with > 90% frequency difference Real Data Simulated Data Coop et al. 2009
    58. 58. Selection in African Population <ul><li>New selection pressures </li></ul><ul><li>Polygenic response </li></ul>
    59. 59. Summary By: Tyler Malys
    60. 60. Does human adaptation result from strong selection? http://graphicleftovers.com/images/member/2336/three_women_thumb_watermark.png
    61. 61. Look at genetic differences between populations. SNPs HGDP HapMap Yoruba French Han Chinese
    62. 62. Detecting signals for selection Target for selection Coop et al. 2009
    63. 63. Genetic differences increase with geographic distance. Coop et al. 2009
    64. 64. Genetic differences can be divided into three groups Coop et al. 2009
    65. 65. Differences between groups are predicted by models for neutral selection. Coop et al. 2009
    66. 66. Few SNPs have high allele frequency differences between groups. Coop et al. 2009
    67. 67. Few alleles reach fixation because of strong selection. Coop et al. 2009
    68. 68. Selective pressures must be strong and maintainable. Coop et al. 2009
    69. 69. Population bottlenecks can aid weak selection in allele fixation. Coop et al. 2009
    70. 70. Differences between populations is due to weak or neutral selection. History of the Population Migration Genetic Drift
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