Detection of positive selection in humane genome

Introduction

Before and after genome sequencing

Detection Methods

1.- High proportion of function-altering mutations Sperm proteamine P1: Protamines are small, arginine-rich, nuclear proteins that replace histones late in the haploid phase of spermatogenesis and are believed essential for sperm head condensation and DNA stabilization

2.- Reduction in genetic diversity Region with low diversity and excess of rare alleles

3.- High-frequency derived alleles African populations Thought to be the result of selection for resistance to P.vivax malaria.

4.- Differences between populations

5.- Long haplotype

Results Candidate region characteristics: Mean length : 815kb Max length: 3.5Mb Often contain multiple genes. Mean: 4 Max: 15 A typical region harbour common SNP (frec >5%) ¾ SNP database ½ Genotyped HapMap2 ¿Which are the true signatures of positive selection?

They performed a similar analysis on all the 22 candidate regions. –9166 SNPs associated with the long-haplotype signal (Long haplotype) –480 satisfied the two other criteria (Population differences and Derived allele) –41 (0’2% of all SNPs genotyped in the regions) possibly functional on the basis of newly compiled database 41 SNPs: –8 encode non-synonymous changes. SLC24A5 (well kwon) · EDAR PCDH15 · ADAT1 KARS · HERC1 SLC30A9 · BLFZ1 –The remaining 33 potentially functional SNPs lie within Conserved transcriptional factors motifs Introns UTRs Other non-coding regions Results SLC24A5: –600KB region –914 genotyped SNPs –Filter application: 857 SNPs associated with long-haplotype signal 233 of 867 are high-frequency derived alleles 12 of which are highly differentiated between populations 5 of which are common in Europe and rare in Asia and Africa 1 of these 5 is only one implicated as functional by current knowledge –Strongest signal of positive selection –Encodes A111T polymorphism associated with pigment differences in humans. LCT: –2.4Mb –24 SNPs fulfill first two criteria –Confer adult persistence of lactase. –Only was identified as functional after extensive study of the LCT gene.

Some specific cases PS on copy number –Expression differences exist between populations and can confer different fitness advantage and thus be positively selected. –Therefore, positive selection can potentially act on copy number and on non-coding regions. –AMY1: copy number is positively correlated with salivary amylase protein expression. Mean AMY1 copy was higher in the high-starch population PS on Noncoding Genomic Regions

Red triangles: previous candidates for selection (81) Gray diamonds: newly available genome-wide empirical data set. Discussion Why have many earlier results fared poorly in genome-wide studies?

Discussion 1.- False positives and negatives 2.- Ascertainment bias of data 3.- Demographic events 4.- Bias DNA repair

Bibliography