Haplotype allelic classes in the lactase persistence locus

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1 Haplotype allelic classes in the lactase persistence locus Robert Cedergren Colloquium november 3 rd 28 Julie Hussin 1,2, Philippe Nadeau 1,2, Jean-François Lefebvre 2 and Damian Labuda Bioinformatics Program, Université de Montréal, 2 CHU Sainte-Justine, 3 Département de Pédiatrie, Université de Montréal, PQ, Canada

2 To begin with

3 Context Phenotypical variability results from environmental exposure, chance and genetic variants. 9 sequences 6 haplotypes mutated allele ancestral allele SNP

4 Context Phenotypical variability results from environmental exposure, chance and genetic variants. One way to find functionally important variants : identify loci under natural selection Positive selection occurs when a new mutation confers a fitness advantage to the individuals carrying it.

5 Context Hitchiking effect : leaves a distinct mark on the pattern of genetic variation. This process causes a selective sweep Source : Neilsen et al. 27

6 Existing methods Weir and Cockerham Clark et al. Tajima F. McDonald and Kreitman Fu and Li Fay and Wu Kim and Stephan Kayser et al. Akey et al. Carlson et al. Zeng et al. Payseur et al. Storz et al. Nielsen et al. Voight et al. Akey et al. Ohashi et al. Wang et al. Sabeti et al. Hanchard et al.

7 Existing methods High false positive rate Weir and Counfouded Clark et al. by Tajima demographic F. McDonald events Fu and Cockerham and Kreitman Li Time consuming methods Linkage disequilibrium 2 Fay and Wu Cannot be applied to data with ascertainement Carlson et al. bias (e.g. HapMap data) Kim and Stephan Kayser et al. Akey et al. Payseur et al. Zeng et al. Storz et al. Nielsen et al. Voight et al. Akey et al. Ohashi et al. Wang et al. Sabeti et al. Hanchard et al.

8 Haplotype Allelic Classes

9 Reference Haplotype Definition The Reference Haplotype R is the haplotype composed of all the major alleles. R

10 Haplotype allelic classes Definition The Haplotype Allelic Class (HAC) C k represents the haplotypes in the sample having k differences from the Reference Haplotype. R Proportion of haplotypes,6,4, Haplotype allelic classes C k

11 Haplotype allelic classes Proportion of haplotypes Proportion of haplotypes,5,6,5,4,3,2,1,6,5,4,3,2,1 Bottleneck Growth Recombination Neutrality Incomplete selective sweep Complete selective sweep Neutrality Under various demographic scenarios, HAC distributions differ slightly. A selective sweep drastically distort the neutral distribution The most pronounced deviation is caused by an incomplete selective sweep Haplotype allelic classes C k

12 Haplotype allelic classes Proportion of haplotypes Proportion of haplotypes,5,6,5,4,3,2,1,6,5,4,3,2,1 Bottleneck Growth Recombination Neutrality Idea : to develop a summary statistic based on HAC to detect an incomplete selective sweep Incomplete selective sweep Complete selective sweep Neutrality Under various demographic scenarios, HAC distributions differ slightly. A selective sweep drastically distort the neutral distribution The most pronounced deviation is caused by an incomplete selective sweep Haplotype allelic classes C k

14 Introducing Svd Neutral SNP Under neutrality, the two distributions have similar variances R Proportion of haplotypes,6,4, ,6 HAC R HAC r,4, Haplotype allelic classes C k R,6,6 Selected SNP Because of the sweep, the HAC R variance is lower than the HAC r variance Proportion of haplotypes,4, HAC R HAC r,4, Haplotype allelic classes C k

15 Introducing Svd 1, 2, i-1, i, s Svd i = ( Var(HAC R,i ) Var(HAC r,i ) ) x f mut,i

16 Introducing Svd Neutral SNP Under neutrality Svd is close to R Proportion of haplotypes,6,4, ,6 HAC R HAC r,4, Haplotype allelic classes C k R,6,6 Selected SNP Under selection Svd is highly positive Proportion of haplotypes,4, HAC R HAC r,4, Haplotype allelic classes C k

17 Power Detection Power and False Positive : At a false positive rate.5, the detection power is around 8%. Length of haplotypes (in number of SNPs) : The detection power of the method increases with the length of the haplotypes. Recombination rate : The detection power of the method decreases as the recombination rate becomes higher. with the presence of recombination hotspots.

18 Validating Svd on genomic data (HapMap data)

19 Lactase Persistence Locus One of the strongest signal of recent positive selection yet documented in the human genome - Bersaglieri et al. 24

Lactase persitence in Europeans as been demonstrated to have a genetic basis.

20 Lactase Persistence Locus Ability to digest lactose depends upon the action of the lactase enzyme In most mammals, activity declines after weaning phase Lactase persitence in Europeans as been demonstrated to have a genetic basis. C " T variant at position (w/r to LCT gene) within intron 13 of the MCM6 gene

21 Lactase Persistence Locus Standardized Svd Standardized Svd -32, , , , , , , , , , , , , , , , , ,774-42, , , ,866-4, , , , , , , ,1974-2, , , , , , , , , , , ,462-16, , , , , , , , , , , , , , , , , , , , ,3761-4, , , , , , , , , , , , , , , , , ,732 93, , , , , , , , , , , ,7593-4, , , ,577-2, , , , ,732 -, , , , , , , ,1989 -, , , , , , , , , , , , , , , ,587217, , , , , , , , , ,283884, , , , , , , , , , , , , , , , , , , , , ,15371, ,933396, , , , , ,51355, , , , , ,279955, ,283283, ,97221, , , , , , ,16659, ,11746, , , , , , , , , , ,51355, , , , ,97221, , , ,7211 2,5315 1,7173 2,532 1,7147 2,5324 1,7111 2,5324 1,768 2,523 1,788 2,516 1,715 2,5126 1,742 2,587 1,76 2,5141 1,736 2,514 1,751 2,5194 1,767 2,5288 1,744 2,5197 1,764 2,522 1,6989 2,5224 1,6954 2,5253 1,6957 2,5159 1,6961 2,5164 1,6976 2,576 1,7211 2,5195 1,6998 2,5133 1,7173 2,5278 2,5137 1,7147 2,5353 1,7111 2,5361 1,768 2,5373 1,788 2,5386 1,715 2,535 1,742 2,5312 1,76 2,5313 1,736 2,5245 1,751 2,5244 1,767 2,5252 1,744 2,5268 1,764 2,5351 1,6989 2,5357 1,6954 2,5444 1,6957 2,5378 1,6961 2,5378 1,6976 2,5461 1,7211 1,6998 2,5544 1,7173 2,5551 1,7147 1,7111 1,768 1,788 1,715 1,742 1,76 1,736 1,751 1,767 1,744 1,764 1,6989 1,6954 1,6957 1,6961 1,6976 1,6998 -,552 -,9996 -,51-1,16 -,5139 -,998 -,5145 -,9974 -,5273 -,9972 -,5283 -,998 -,5288 -,9995 -,534-1,12 -,539 -,9889 -,5298 -,9882 -,5311 -,9894 -,535 -,9897 -,538-1,85 -,5318-1,111 -,5325-1,121 -,533-1,114 -,5329-1,112 -,5329-1,123 -,5342-1,139 -, ,7957 -,5379-1,159 -,51-1,7983-1,124 -,5139-1,7967 -,5145-1,7976 -,5273-1,7983 -,5283-1,828 -,5288-1,7982 -,534-1,796 -,539-1,7892 -,5298-1,784 -,5311-1,7776 -,535-1,7818 -,538-1,7811 -,5318-1,783 -,5325-1,7845 -,533-1,787 -,5329-1,7882 -,5329-1,7814 -,5342-1,7841 -, ,5379-1,7867 -,51-1,7845 -,5139 -,5145 -,5273 -,5283 -,5288 -,534 -,539 -,5298 -,5311 -,535 -,538 -,5318 -,5325 -,533 -,5329 -,5329 -, ,5379 2,43 3,2366 2,356 3,2389 2,45 3,236 2,421 3,2354 2,498 3,2267 2,525 3,229 2,545 3,2191 2,52 3,217 2,473 3,219 2,49 3,212 2,516 3,2163 2,525 3,2252 2,58 3,2338 2,535 3,2383 2,472 3,2396 2,444 3,2415 2,446 3,2328 2,45 3,2342 2,476 3,2276 2,43 3,872 2,529 3,2345 2,356 3,8819 3,2319 2,45 3,8874 2,421 3,8888 2,498 3,895 2,525 3,8956 2,545 3,8843 2,52 3,883 2,473 3,8771 2,49 3,8663 2,516 3,866 2,525 3,8651 2,58 3,8659 2,535 3,8728 2,472 3,8771 2,444 3,8872 2,446 3,8822 2,45 3,8763 2,476 3,8862 2,43 2,529 3,896 2,356 3,8947 2,45 2,421 2,498 2,525 2,545 2,52 2,473 2,49 2,516 2,525 2,58 2,535 2,472 2,444 2,446 2,45 2,476 2,529 European-derived US population 1,116 1,281 1,118 1,2846 1,1418 1,2375 1, , , , ,281 1, ,2846 1, , , ,2375 1, ,2587 1, , ,47 1, , , ,4353 1, ,4524 1, , , ,5933 1, ,5178 1, ,5416 1,47 1, , ,8312 1, , ,118 1,838 1, ,1418 1, , ,49 1, ,51 1,281 1,9772 1,2846 1,98 1, , ,2375 1, ,2587 1, , , , ,167 1, ,1639 1, ,1177 1, , , ,113 1, , , , ,47 1, , , , ,118 1, ,1418 1, , ,281 1,2846 1, ,2375 1,2587 1, , , , , , , , , , Chromosome 2 position (Mb) Chinese and Japenese population Nigerian population Chromosome 2 position (Mb) Chromosome 2 position (Mb)

22 Lactase Persistence Locus C " T variant

23 Lactase Persistence Locus Unstandardized Svd rs rs38279 rs rs37695 rs rs rs rs rs rs rs rs rs3918 rs rs rs rs rs rs rs39176 rs rs SNP id rs rs rs rs % 5%

24 Take home message New intuitive approach, quite simple to understand Demonstrate a good detection power with low false positive rate in simulations. Not sensitive to demographic scenarios Low computational complexity Can be applied to data with ascertainement bias (e.g. Hap Map data)

25 Haplotype allelic classes Definition R The Haplotype Allelic Class (HAC) C k represents the haplotypes in the sample having k differences from the Reference Haplotype. 1,4 This new way of looking at the data is promising and we would benefit from a deeper study of the HAC,2 in population genetics Proportion of haplotypes, Haplotype allelic classes C k

26 Thank you # Damian Labuda And all the lab members, especially : # Jean-François Lefebvre # Philippe Nadeau # Claude Bherer # Véronique Ladret

Supplementary Figure 1: Attenuation of association signals after conditioning for the lead SNP. a) attenuation of association signal at the 9p22.

Supplementary Figure 1: Attenuation of association signals after conditioning for the lead SNP. a) attenuation of association signal at the 9p22.32 PCOS locus after conditioning for the lead SNP rs10993397;