Detection of the footprint of natural selection in the genome Josefa Domenech Cabrera

Methods to detect natural selection

Methods to detect natural selection

SOLUTION: Cross-Population Extended Haplotype Homozygosity (XP-EHH) Analysis of HapMap An allele under positive selection may rise to high frequency rapidly enough that long-range association with nerby polimorphisms will not have time to be eliminated by recombination Long-Range Haplotype (LRH) Integrated Haplotype Score (iHS) DISADGVANTAGE: Only local variation is taken into account to calculate recombination rates SOLUTION: Cross-Population Extended Haplotype Homozygosity (XP-EHH)

Analysis of HapMap More than 300 candidate regions to have been positive selected where found applying the LRH, iHS and XP-EHH methods A simulation was done in order to see the neutral evolution of a 10 Gb sequence 22 of the 300 events were not found in the simulated neutral evolution CHALLENGE: sift through genetic variation in those 22 candidate regions to identify the variants which were targets of selection

They looked for alleles common in populations under selection Analysis of HapMap CRITERIA APPLIED: They focused on newly arisen alleles identified by comparison to primate outgroups They looked for alleles common in populations under selection They focused on non-synonymous coding SNPs and SNPs in evolutionary conserved sequences

Analysis of HapMap Non-synonymous coding SNPs with highly differentiated high-frequency alleles: European sample: genes involved in skin pigment differences among humans Gene SLC24A5: SLC24A5AIIIT polymorphism selected in Europe Gene SLC45A2: L375F polymorphism selected in Europe

Analysis of HapMap African sample: genes with biologicals links to the Lassa fever virus Gene LARGE: glycosylase that modifies post-transcriptionally α-dystroglycan Gene DMD: cytosolic adaptor protein that binds to α-dystroglycan

Analysis of HapMap Asian sample: genes involved in the ectodysplasin (EDA) pathway Gene EDAR: encodes the receptor for the ligand EDA A1 Polymorphism V370A is near fixation in Asia Gene EDA2R: encodes the receptor for the ligand EDA A2 Polymorphism R57K is fixed in Asia

Bibliography Detecting Natural Selection in Genomic Data. Joseph J. Vitti, Sharon R. Grossman, and Pardis C. Sabeti. Genome-wide detection and characterization of positive selection in human populations. Pardis C. Sabeti, Patrick Varilly, Ben Fry, Jason Lohmueller, Elizabeth Hostetter, Chris Cotsapas, Xiaohui Xie, Elizabeth H. Byrne, Steven A. McCarroll, Rachelle Gaudet, Stephen F. Schaffner, Eric S. Lander and The International HapMap Consortium National Human Genome Research Institute - International HapMap Project. (www.genome.gov) SNPedia (www.snpedia.com) Centers for Disease Control and Prevention (www.cdc.gov)