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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