Detection of positive selection in humane

genome

Introduction

IntroductionBefore 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 populationsThought 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 400-4000 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.

DiscussionWhy have many earlier results fared poorly in

genome-wide studies?

Discussion

1.- False positives and negatives2.- Ascertainment bias of data

3.- Demographic events 4.- Bias DNA repair

Bibliography