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Selection index population_genetics

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Jinseob Kim
Jinseob Kim

The document summarizes Wright's F-statistics and Cockerham's ¦È-statistics, which are methods used to calculate genetic differentiation between populations. It then discusses methods to detect signatures of positive selection, including Extended Haplotype Homozygosity (EHH), integrated Haplotype Score (iHS), and cross population Extended Haplotype Homozygosity (xp-EHH). EHH detects when a haplotype is over-represented in a population due to recent positive selection. iHS and xp-EHH are derived from EHH to identify specific genomic regions under selection. The document uses examples and figures to illustrate key concepts.

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FST & Some Selection Index ??, ???? ???? ?? 2014 ??? GSPH, SNU October 29, 2014 ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 1 / 65
Fst Contents 1 Fst Wright¡¯s F-statistics Cockerham¡¯s ¦È-statistics 2 Selection Index EHH iHS xp-EHH 3 Practice ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 2 / 65
Fst Wright¡¯s F-statistics 3 types of Heterozygosity[4] Individual, Subpopulation, Total Population 1 HI = 1 n n i=1 ?Hi 2 HS = 1 n n i=1 2pi qi 3 HT = 2?p?q ( ?Hi : observed heterozygosity in ith subpopulation, 2pi qi : average heterozygosity in ith subpopulation, 2?p?q: average heterozygosity of total population) Locus ?? ? ???. ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 3 / 65
Fst Wright¡¯s F-statistics Wright¡¯s F-statistics[4] 1 FIS = HS ?HI HS 2 FST = HT ?HS HT 3 FIT = HT ?HI HT Example FST = 0 ¡ú Subpopulation? e?ect??!! ?? ??. FST = 1 ¡ú Subpopulation?? ??? ??. Simple relation 1 ? FIT = (1 ? FIS )(1 ? FST ) ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 4 / 65
Fst Wright¡¯s F-statistics http://academic.reed.edu/biology/professors/srenn/pages/ research/2011_students/sean/SM_thesis.html ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 5 / 65
Fst Wright¡¯s F-statistics http://www.johnderbyshire.com/Miscellaneous/Other/Fst.jpg ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 6 / 65
Fst Wright¡¯s F-statistics FST inference[5] Convenient measure of genetic di?erentiation. Most widely used descriptive statistics in population and evolutionary genetics. Natural selection in particular subpopulation. ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 7 / 65
Fst Wright¡¯s F-statistics Problem in estimation HT = 2?p?q 1 Subpopulation?? sample?? ????? 2 Ex: SASIA 1000?, Oceania 100?.. 3 ??? ? ?p ??? ??. ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 8 / 65
Fst Cockerham¡¯s ¦È-statistics ANOVA approach[1, 5] ¦È = ¦ÒP ¦ÒT (¦ÒP: variance due to population, ¦ÒT : total variance) ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 9 / 65
Fst Cockerham¡¯s ¦È-statistics Wright¡¯s FST = Cockerham¡¯s ¦È ?? ??? ??? ¦È ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 10 / 65
Fst Cockerham¡¯s ¦È-statistics ¦È inference Population > 2 ??? ?? population? ??!! ?? population??? ? ????. Pairwise FST 2 population? ??? ??. ???? ??. ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 11 / 65
Fst Cockerham¡¯s ¦È-statistics ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 12 / 65
Fst Cockerham¡¯s ¦È-statistics Figure: FST calculated for each SNP between Tibetan and Han populations[6] ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 13 / 65
Fst Cockerham¡¯s ¦È-statistics Figure: Inter-population pairwise comparisons of FST statistics http://academic.reed.edu/biology/professors/srenn/pages/ research/2011_students/sean/SM_thesis.html ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 14 / 65
Selection Index Contents 1 Fst Wright¡¯s F-statistics Cockerham¡¯s ¦È-statistics 2 Selection Index EHH iHS xp-EHH 3 Practice ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 15 / 65
Selection Index ?? ????? ?? haplotype? ???? Example: Erik Corona¡¯s slide - Next slide ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 16 / 65
Selection Index Population?Genetics Glucose HAPLOTYPES GATTACAGATTACA 22% AATTACAGATTAAA 3% GACTACAGATTACC 19% GATTACCTATTAAC 24% AACTACAGATTACC 16% GATTACAGACTACA 7% AATTACAGATTACA 9% Lactase?+?H2O ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 17 / 65
Selection Index Population?Genetics Lactase?+?H2O Glucose HAPLOTYPES GATTACAGATTACA 22% AATTACAGATTAAA 3% GACTACAGATTACC 19% GATTACCTATTAAC 24% AACTACAGATTACC 16% GATTACAGACTACA 7% AATTACAGATTACA 9% ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 18 / 65
Selection Index Population?Genetics Lactase?+?H2O Glucose HAPLOTYPES GATTACAGATTACA 22% AATTACAGATTAAA 3% GACTACAGATTACC 19% GATTACCTATTAAC 24% AACTACAGATTACC 16% GATTACAGACTACA 7% AATTACAGATTACA 9% AATTGCAGATTACA <1% ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 19 / 65
Selection Index Population?Genetics Lactase?+?H2O Glucose HAPLOTYPES GATTACAGATTACA 22% AATTACAGATTAAA 3% GACTACAGATTACC 19% GATTACCTATTAAC 24% AACTACAGATTACC 16% GATTACAGACTACA 7% AATTACAGATTACA 9% AATTGCAGATTACA <1% ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 20 / 65
Selection Index Population?Genetics Lactase?+?H2O Glucose HAPLOTYPES GATTACAGATTACA 21% -1% AATTACAGATTAAA 3% GACTACAGATTACC 19% GATTACCTATTAAC 24% AACTACAGATTACC 16% GATTACAGACTACA 7% AATTACAGATTACA 8% -1% AATTGCAGATTACA 2% +2% ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 21 / 65
Selection Index Population?Genetics Lactase?+?H2O Glucose HAPLOTYPES GATTACAGATTACA 21% -1% AATTACAGATTAAA 3% GACTACAGATTACC 19% GATTACCTATTAAC 23% -1% AACTACAGATTACC 15% -1% GATTACAGACTACA 7% AATTACAGATTACA 7% -2% AATTGCAGATTACA 5% +5% ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 22 / 65
Selection Index Population?Genetics Lactase?+?H2O Glucose HAPLOTYPES GATTACAGATTACA 20% -2% AATTACAGATTAAA 3% GACTACAGATTACC 19% GATTACCTATTAAC 23% -1% AACTACAGATTACC 15% -1% GATTACAGACTACA 6% -1% AATTACAGATTACA 5% -4% AATTGCAGATTACA 9% +9% ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 23 / 65
Selection Index EHH EHH: Sabeti, Reich et al. (2002)[7] Extended Haplotype Homozygosity Random?? 2? haplotype ??? ? ??? ?? ????? 0 ¡ú haplotype? ? ???. 1 ¡ú haplotype? ?? ??. ???? haplotype? Core? ??. EHHt = s i=1 eti 2 ct 2 (t: core haplotype, c: the number of samples of a particular core haplotype, e: the number of samples of a particular extended haplotype, s: the number of unique extended haplotype) ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 24 / 65
Selection Index EHH How?can?we?detect?Pos.?Sel.? AATTACAGATTACA 50 people have this GATTACAGATTACA 50 people have this ---- 50 KB ---- ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 25 / 65
Selection Index EHH 50 KB + 20 KB = 70 KB__ AATTACAGATTACA AACACGC 10 AATTACAGATTACA ATGATAG 8 AATTACAGATTACA AACCCAG 7 AATTACAGATTACA CTGACAG 5 AATTACAGATTACA CAGACAG 3 AATTACAGATTACA AACACAG 6 AATTACAGATTACA CACACAG 4 AATTACAGATTACA CACCCAG 7 GATTACAGATTACA CACATAG 24 GATTACAGATTACA CACACAG 26 How?can?we?detect?Pos.?Sel.? ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 26 / 65
Selection Index EHH Extended?Haplotype?Homozygosity (EHH) AATTACAGATTACA AACACGC 10 AATTACAGATTACA ATGATAG 8 AATTACAGATTACA AACCCAG 7 AATTACAGATTACA CTGACAG 5 AATTACAGATTACA CAGACAG 3 AATTACAGATTACA AACACAG 6 AATTACAGATTACA CACACAG 4 AATTACAGATTACA CACCCAG 7 GATTACAGATTACA CACATAG 24 GATTACAGATTACA CACACAG 26 ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 27 / 65
Selection Index EHH ( (3 2 5 2 7 2 8 2)+ Extended?Haplotype?Homozygosity (EHH) AATTACAGATTACA AACACGC 10 AATTACAGATTACA ATGATAG 8 AATTACAGATTACA AACCCAG 7 AATTACAGATTACA CTGACAG 5 AATTACAGATTACA CAGACAG 3 AATTACAGATTACA AACACAG 6 AATTACAGATTACA CACACAG 4 AATTACAGATTACA CACCCAG 7 GATTACAGATTACA CACATAG 24 GATTACAGATTACA CACACAG 26 10 2)+( )+( )+ )+( )+6 2( )+4 2( )7 2 )50 2( ( ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 28 / 65
Selection Index EHH )+ Extended?Haplotype?Homozygosity (EHH) AATTACAGATTACA AACACGC 10 AATTACAGATTACA ATGATAG 8 AATTACAGATTACA AACCCAG 7 AATTACAGATTACA CTGACAG 5 AATTACAGATTACA CAGACAG 3 AATTACAGATTACA AACACAG 6 AATTACAGATTACA CACACAG 4 AATTACAGATTACA CACCCAG 7 GATTACAGATTACA CACATAG 24 GATTACAGATTACA CACACAG 26 10 2( )+ 8 2( )+7 2( )+5 2( )+3 2( )+6 2( )+4 2( )7 2( )50 2( 0.121 ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 29 / 65
Selection Index EHH EHH?Drops?Over?Genetic?Distance EHH?drops?off?quickly?over? genetic?distance Starts?with?1 Ends?at?0 Every?hap?block?will? eventually?be?unique ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 30 / 65
Selection Index EHH AATTACAGATTACA AACACGC 10 AATTACAGATTACA ATGATAG 8 AATTACAGATTACA AACCCAG 7 AATTACAGATTACA CTGACAG 5 AATTACAGATTACA CAGACAG 3 AATTACAGATTACA AACACAG 6 AATTACAGATTACA CACACAG 4 AATTACAGATTACA CACCCAG 7 GATTACAGATTACA CACATAG 24 GATTACAGATTACA CACACAG 26 EHH?What?It?Is?&?What?It?Isn¡¯t Detects?over©\representation?of?a?haplotype This?will?raise?the?p(two?haps?are?homozygous) Does?NOT detect?if?a?haplotype?spread?quickly Low?recombination?!=?spread?quickly AATTACAGATTACA AACACGC 22 AATTACAGATTACA ATGATAG 28 GATTACAGATTACA CACATAG 24 GATTACAGATTACA CACACAG 26 ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 31 / 65
Selection Index EHH Compare?EHH Scores AATTACAGATTACA AACACGC 10 AATTACAGATTACA ATGATAG 8 AATTACAGATTACA AACCCAG 7 AATTACAGATTACA CTGACAG 5 AATTACAGATTACA CAGACAG 3 AATTACAGATTACA AACACAG 6 AATTACAGATTACA CACACAG 4 AATTACAGATTACA CACCCAG 7 GATTACAGATTACA CACATAG 24 GATTACAGATTACA CACACAG 26 )+24 2( )26 2( )50 2( 0.121 0.490 Low Recombination Over Represented ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 32 / 65
Selection Index EHH Can?EHH?Detect?Pos.?Sel.? ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 33 / 65
Selection Index EHH Relative?EHH Detects?over©\representation?of?a?haplotype Low?recombination This?will?raise?the?p(two?haps?are?homozygous) Does?detect?if?a?haplotype?spread?quickly Other?haplotype?blocks?are?controls! Recombination?cold©\spot?/?hot©\spot?agnostic Low?score?if?both?alleles?are?assoc.?w/?high?or? low?recombination AATTACAGATTACA AACACGC 22 AATTACAGATTACA ATGATAG 28 GATTACAGATTACA CACATAG 24 GATTACAGATTACA CACACAG 26 ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 34 / 65
Selection Index EHH Extended?Haplotype?Homozygosity (EHH) AATTACAGATTACA AACACGC 10 AATTACAGATTACA ATGATAG 8 AATTACAGATTACA AACCCAG 7 AATTACAGATTACA CTGACAG 5 AATTACAGATTACA CAGACAG 3 AATTACAGATTACA AACACAG 6 AATTACAGATTACA CACACAG 4 AATTACAGATTACA CACCCAG 7 GATTACAGATTACA CACATAG 24 GATTACAGATTACA CACACAG 26 0.121 0.490 0.490 0.121 = 4.05REHH = ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 35 / 65
Selection Index EHH REHH:?Problem?#1 We?get?a?different?REHH?value?at?different?genetic? distance?cutoffs AATTACAGATTACA 50 GATTACAGATTACA 50 ---- 50 KB ---- REHH = 1.0 AATTACAGATTACA AACACGC 10 AATTACAGATTACA ATGATAG 8 AATTACAGATTACA AACCCAG 7 AATTACAGATTACA CTGACAG 5 AATTACAGATTACA CAGACAG 3 AATTACAGATTACA AACACAG 6 AATTACAGATTACA CACACAG 4 AATTACAGATTACA CACCCAG 7 GATTACAGATTACA CACATAG 24 GATTACAGATTACA CACACAG 26 ---------- 70 KB --------- REHH = 4.05 ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 36 / 65
Selection Index EHH Which?REHH?value?to?use? Extend?to?the?right AGTTACAGATTACAAACACGC AAATACAGATTACAATGATAG AATTACAGATTACAAACCCAG AATTTCAGATTACACTGACAG AATTAAAGATTACACAGACAG AATTACCGATTACAAACACAG AATTACAAATTACACACACAG AATTACAGGTTACACACCCAG GATTACAGATTACACACATAG GATTACAGATTACACACACAG ---------- 70 KB --------- REHH = 4.05 ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 37 / 65
Selection Index EHH ¡­ACAGATTACAGTTACAGATTACAAACACGC¡­ ¡­ACAGATTACAAATACAGATTACAATGATAG¡­ ¡­ACAGATTACAATTACAGATTACAAACCCAG¡­ ¡­ACAGATTACAATTTCAGATTACACTGACAG¡­ ¡­ACAGATTACAATTAAAGATTACACAGACAG¡­ ¡­ACAGATTACAATTACCGATTACAAACACAG¡­ ¡­ACAGATTACAATTACAAATTACACACACAG¡­ ¡­ACAGATTACAATTACAGTTACACACCCAG¡­ ¡­TACAGATTAGATTACAGATTACACACATAG ¡­TACAGATTAGATTACAGATTACACACACAG ---------- 70 KB --------- REHH = 4.05 Which?REHH?value?to?use? Extend?to?the?right ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 38 / 65
Selection Index EHH Which?REHH?value?to?use? Extend?to?the?right ¡­ACAGATTACAGTTACAGATTACAAACACGC¡­ ¡­ACAGATTACAAATACAGATTACAATGATAG¡­ ¡­ACAGATTACAATTACAGATTACAAACCCAG¡­ ¡­ACAGATTACAATTTCAGATTACACTGACAG¡­ ¡­ACAGATTACAATTAAAGATTACACAGACAG¡­ ¡­ACAGATTACAATTACCGATTACAAACACAG¡­ ¡­ACAGATTACAATTACAAATTACACACACAG¡­ ¡­ACAGATTACAATTACAGTTACACACCCAG¡­ ¡­TACAGATTAGATTACAGATTACACACATAG ¡­TACAGATTAGATTACAGATTACACACACAG ---------- 70 KB --------- REHH = 4.05 ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 39 / 65
Selection Index EHH Which?REHH?value?to?use? Extend?to?the?right ¡­ACAGATTACAGTTACAGATTACAAACACGC¡­ ¡­ACAGATTACAAATACAGATTACAATGATAG¡­ ¡­ACAGATTACAATTACAGATTACAAACCCAG¡­ ¡­ACAGATTACAATTTCAGATTACACTGACAG¡­ ¡­ACAGATTACAATTAAAGATTACACAGACAG¡­ ¡­ACAGATTACAATTACCGATTACAAACACAG¡­ ¡­ACAGATTACAATTACAAATTACACACACAG¡­ ¡­ACAGATTACAATTACAGTTACACACCCAG¡­ ¡­TACAGATTAGATTACAGATTACACACATAG ¡­TACAGATTAGATTACAGATTACACACACAG ---------- 70 KB --------- REHH = 4.05 ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 40 / 65
Selection Index EHH Which?REHH?value?to?use? Extend?to?the?right ¡­ACAGATTACAGTTACAGATTACAAACACGC¡­ ¡­ACAGATTACAAATACAGATTACAATGATAG¡­ ¡­ACAGATTACAATTACAGATTACAAACCCAG¡­ ¡­ACAGATTACAATTTCAGATTACACTGACAG¡­ ¡­ACAGATTACAATTAAAGATTACACAGACAG¡­ ¡­ACAGATTACAATTACCGATTACAAACACAG¡­ ¡­ACAGATTACAATTACAAATTACACACACAG¡­ ¡­ACAGATTACAATTACAGTTACACACCCAG¡­ ¡­TACAGATTAGATTACAGATTACACACATAG ¡­TACAGATTAGATTACAGATTACACACACAG ---------- 70 KB --------- REHH = 4.05 ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 41 / 65
Selection Index EHH Which?REHH?value?to?use? Extend?to?the?right ¡­ACAGATTACAGTTACAGATTACAAACACGC¡­ ¡­ACAGATTACAAATACAGATTACAATGATAG¡­ ¡­ACAGATTACAATTACAGATTACAAACCCAG¡­ ¡­ACAGATTACAATTTCAGATTACACTGACAG¡­ ¡­ACAGATTACAATTAAAGATTACACAGACAG¡­ ¡­ACAGATTACAATTACCGATTACAAACACAG¡­ ¡­ACAGATTACAATTACAAATTACACACACAG¡­ ¡­ACAGATTACAATTACAGTTACACACCCAG¡­ ¡­TACAGATTAGATTACAGATTACACACATAG ¡­TACAGATTAGATTACAGATTACACACACAG ---------- 70 KB --------- REHH = 4.05 ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 42 / 65
Selection Index EHH Which?REHH?value?to?use? Extend?to?the?left ¡­ACAGATTACAGTTACAGATTACAAACACGC¡­ ¡­ACAGATTACAAATACAGATTACAATGATAG¡­ ¡­ACAGATTACAATTACAGATTACAAACCCAG¡­ ¡­ACAGATTACAATTTCAGATTACACTGACAG¡­ ¡­ACAGATTACAATTAAAGATTACACAGACAG¡­ ¡­ACAGATTACAATTACCGATTACAAACACAG¡­ ¡­ACAGATTACAATTACAAATTACACACACAG¡­ ¡­ACAGATTACAATTACAGTTACACACCCAG¡­ ¡­TACAGATTAGATTACAGATTACACACATAG ¡­TACAGATTAGATTACAGATTACACACACAG ---------- 70 KB --------- REHH = 4.05 ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 43 / 65
Selection Index EHH Which?REHH?value?to?use? Extend?to?the?left ¡­ACAGATTACAGTTACAGATTACAAACACGC¡­ ¡­ACAGATTACAAATACAGATTACAATGATAG¡­ ¡­ACAGATTACAATTACAGATTACAAACCCAG¡­ ¡­ACAGATTACAATTTCAGATTACACTGACAG¡­ ¡­ACAGATTACAATTAAAGATTACACAGACAG¡­ ¡­ACAGATTACAATTACCGATTACAAACACAG¡­ ¡­ACAGATTACAATTACAAATTACACACACAG¡­ ¡­ACAGATTACAATTACAGTTACACACCCAG¡­ ¡­TACAGATTAGATTACAGATTACACACATAG ¡­TACAGATTAGATTACAGATTACACACACAG ---------- 70 KB --------- REHH = 4.05 ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 44 / 65
Selection Index EHH Which?REHH?value?to?use? Extend?to?the?left ¡­ACAGATTACAGTTACAGATTACAAACACGC¡­ ¡­ACAGATTACAAATACAGATTACAATGATAG¡­ ¡­ACAGATTACAATTACAGATTACAAACCCAG¡­ ¡­ACAGATTACAATTTCAGATTACACTGACAG¡­ ¡­ACAGATTACAATTAAAGATTACACAGACAG¡­ ¡­ACAGATTACAATTACCGATTACAAACACAG¡­ ¡­ACAGATTACAATTACAAATTACACACACAG¡­ ¡­ACAGATTACAATTACAGTTACACACCCAG¡­ ¡­TACAGATTAGATTACAGATTACACACATAG ¡­TACAGATTAGATTACAGATTACACACACAG ---------- 70 KB --------- REHH = 4.05 ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 45 / 65
Selection Index EHH REHH:?Problem?#2 REHH?score?is?heavily? biased?by?allele? frequencies Must?normalize P(REHH?|?Allele?Freq.) ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 46 / 65
Selection Index EHH REHH:?Problem?#3 Not?possible?to?detect? selection?in?high? frequency?alleles Solution?requires?a?X©\ population?approach? (discussed?later) ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 47 / 65
Selection Index EHH Leaves?a?lot?to?be?desired Picking?the?maximum?is?arbitrary Why?not?the?mean?REHH?score? Biased?by?allele?frequency ln(REHH?|?allele?freq)?~?norm?dist. Still?widely?used?and?published?with REHH?Overview ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 48 / 65
Selection Index EHH Site-speci?c EHH[9] ? allele? EHH?? ???? ??(weight: squared allele frequencies) Focal SNP? ???? EHH?? ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 49 / 65
Selection Index iHS iHS: sabeti(2007)[8] ?? ??? ?? ??!!!!?? ?? ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 50 / 65
Selection Index iHS Integrated?Haplotype?Score?(iHS) Unstandardized iHS =? EHH y? x y?=?bwd distance x?=?fwd?distance EHHD =?derived?allele EHHA =?ancestral?allele ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 51 / 65
Selection Index iHS ¡­ACAGATTACAGTTACAGATTACAAACACGC¡­ ¡­ACAGATTACAAATACAGATTACAATGATAG¡­ ¡­ACAGATTACAATTACAGATTACAAACCCAG¡­ ¡­ACAGATTACAATTTCAGATTACACTGACAG¡­ ¡­ACAGATTACAATTAAAGATTACACAGACAG¡­ ¡­ACAGATTACAATTACCGATTACAAACACAG¡­ ¡­ACAGATTACAATTACAAATTACACACACAG¡­ ¡­ACAGATTACAATTACAGTTACAACACCCAG¡­ ¡­TACAGATTAGATTACAGATTACACACATAG ¡­TACAGATTAGATTACAGATTACACACACAG + 0.5 = 1.20.7 4.0 + 4.4 = 8.4 Unstandardized iHS ln(8.4/3.2)??=??0.419? Integrated?Haplotype?Score?(iHS) ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 52 / 65
Selection Index iHS iHS Characteristics As?both?alleles?have?the?same?AUC,?iHS zero Large?negative?values?indicate?selection?of?allele?in?the? denominator Large?positive?values?indicate?selection?of?allele?in?the? numerator Still?heavily?biased?by?allele?frequency! Z©\score?normalization ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 53 / 65
Selection Index iHS Unstandardized iHS ©\ E(iHS |?Allele?Frequency)? SD(iHS |?Allele?Frequency)? E(iHS |?Allele?Freq.):???Estimated?from?empirical?distribution SD(iHS |?Allele?Freq.):?Estimated?from?empirical?distribution Integrated?Haplotype?Score?(iHS) =?iHS ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 54 / 65
Selection Index iHS iHS Overview iHS and?REHH?are?EHH?based?methods?to?detect? positive?selection iHS outperforms?REHH?in?specific?allele?frequencies They?don¡¯t?completely?outperform?each?other ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 55 / 65
Selection Index iHS iHS:?Problem?#1 Still?can¡¯t?detect?selection?in?high?frequency?(old)? alleles Relatively?High?EHH?values? are?not?present?high? frequency?(old)?alleles! Use?a?reference?population If?pos.?sel.?didn¡¯t?take?place? in?ref.?population,?EHH?is? high ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 56 / 65
Selection Index xp-EHH xp-EHH: sabeti(2007)[8] Population ?, ?? allele? integreted EHH? ??!! ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 57 / 65
Selection Index xp-EHH Cross?Population?EHH?(XP©\EHH) AATTACAGATTACA AACACGC 10 AATTACAGATTACA ATGATAG 8 AATTACAGATTACA AACCCAG 7 AATTACAGATTACA CTGACAG 5 AATTACAGATTACA CAGACAG 3 AATTACAGATTACA AACACAG 6 AATTACAGATTACA CACACAG 4 AATTACAGATTACA CACCCAG 7 Same allele but diff population AATTACAGATTACA CACATAG 20 AATTACAGATTACA CACACAG 30 0.5 XP©\EHH?=?ln(3.3/0.5)?=?1.89? Z©\score?Norn Integrate?EHH?over?distance?from?allele Calculated?for?fwd/rev?sides?independently Integrate?until?EHH?=?0.04?in?e.a.?population 3.3 ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 58 / 65
Selection Index xp-EHH REHH?and?iHS are?more?or?less?complementary e.a.?is?better?at?detecting?pos.?sel.?at?diff?freqs. XP©\EHH Can?detect?pos.?sel.?in?high?freq.?alleles Susceptible?to?population?variation?in? recombination?rate Overview ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 59 / 65
Selection Index xp-EHH Final?Verdict:?REHH?vs iHS vs XP©\EHH REHH iHS test XP©\EHH ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 60 / 65
Selection Index xp-EHH Rsb[9] Population?? ???? ??? ??. Population??? ??. Locus?? ? allele? integrated EHH? average: iES Locus? ???? selection??? population?? ??. ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 61 / 65
Practice Contents 1 Fst Wright¡¯s F-statistics Cockerham¡¯s ¦È-statistics 2 Selection Index EHH iHS xp-EHH 3 Practice ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 62 / 65
Practice FST hierfstat[3] PER3 gene in HGDP(Human Genome Diversity Panel): 289 SNPs & 7 population EHH, iHS rehh[2] ??? ?? ?? ?? ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 63 / 65
Practice Reference I [1] Cockerham, C. C. (1969). Variance of gene frequencies. Evolution, pages 72¨C84. [2] Gautier, M. and Vitalis, R. (2012). rehh: an r package to detect footprints of selection in genome-wide snp data from haplotype structure. Bioinformatics, 28(8):1176¨C1177. [3] Goudet, J. (2005). Hierfstat, a package for r to compute and test hierarchical f-statistics. Molecular Ecology Notes, 5(1):184¨C186. [4] Hamilton, M. (2011). Population genetics. John Wiley & Sons. [5] Holsinger, K. E. and Weir, B. S. (2009). Genetics in geographically structured populations: de?ning, estimating and interpreting fst. Nature Reviews Genetics, 10(9):639¨C650. [6] Huerta-S?anchez, E., Jin, X., Bianba, Z., Peter, B. M., Vinckenbosch, N., Liang, Y., Yi, X., He, M., Somel, M., Ni, P., et al. (2014). Altitude adaptation in tibetans caused by introgression of denisovan-like dna. Nature, 512(7513):194¨C197. [7] Sabeti, P. C., Reich, D. E., Higgins, J. M., Levine, H. Z., Richter, D. J., Scha?ner, S. F., Gabriel, S. B., Platko, J. V., Patterson, N. J., McDonald, G. J., et al. (2002). Detecting recent positive selection in the human genome from haplotype structure. Nature, 419(6909):832¨C837. [8] Sabeti, P. C., Varilly, P., Fry, B., Lohmueller, J., Hostetter, E., Cotsapas, C., Xie, X., Byrne, E. H., McCarroll, S. A., Gaudet, R., et al. (2007). Genome-wide detection and characterization of positive selection in human populations. Nature, 449(7164):913¨C918. [9] Tang, K., Thornton, K. R., and Stoneking, M. (2007). A new approach for using genome scans to detect recent positive selection in the human genome. PLoS biology, 5(7):e171. ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 64 / 65
Practice END Email : secondmath85@gmail.com O?ce: (02)880-2743 H.P: 010-9192-5385 ??? (GSPH, SNU) FST & Some Selection Index October 29, 2014 65 / 65

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