Searching for signals of evolutionary selection in 168 genes related to immune function

Abstract

Pathogens have played a substantial role in human evolution, with past infections shaping genetic variation at loci influencing immune function. We selected 168 genes known to be involved in the immune response, genotyped common single nucleotide polymorphisms across each gene in three population samples (CEPH Europeans from Utah, Han Chinese from Guangxi, and Yoruba Nigerians from Southwest Nigeria) and searched for evidence of selection based on four tests for non-neutral evolution: minor allele frequency (MAF), derived allele frequency (DAF), Fst versus heterozygosity and extended haplotype homozygosity (EHH). Six of the 168 genes show some evidence for non-neutral evolution in this initial screen, with two showing similar signals in independent data from the International HapMap Project. These analyses identify two loci involved in immune function that are candidates for having been subject to evolutionary selection, and highlight a number of analytical challenges in searching for selection in genome-wide polymorphism data.

Genetic variation at the CYP2C locus and its association with torsemide biotransformation

“…32 The LD block including CYP2C9 identified by the software program Sweep spanned 16 polymorphisms and revealed eight haplotypes. Although only three of the polymorphisms were identical to those analysed in our sample, this data set revealed the haplotypes H7 to H10 having comparable frequencies (23,17,15 and 6%) as with our polymorphism set. The remaining four haplotypes amount to 40% and were subhaplotypes of H6.…”

“…As CYP2C9 metabolizes organic anions, it is striking that in a search for signals of evolutionary selection in 168 genes related to immune function the haplotype with the most outstanding haplotype length in Caucasians was the most frequent allele of the multispecific organic anion transporter gene ABCC1. 17 Well-established in vivo phenotyping probes for CYP2C9 activity are warfarin and tolbutamide. 4,26,[36][37][38] Tolbutamide will probably not be available as a registered drug in the next years in many countries and warfarin requires more sophisticated enantiospecific analysis to be optimal.…”

“…The EHH method has the potential to differentiate between variants, which were evolutionarily selected due to their functional benefits for the organism from those variants, which have merely been selected due to linkage to a primarily selected variant. 17,18 Torsemide is a loop diuretic drug quite specifically metabolized by CYP2C9. 19,20 Methyl-and phenyl-hydroxylation form metabolites termed M1 and M3.…”

Using human demographic history to infer natural selection reveals contrasting patterns on different families of immune genes

“…we used the middle base rather than the middle exonic base), along with all associated GO codes. In addition, we also downloaded a list of 168 genes from a previous paper examining selection on immune genes [28], along with their locations. This list was used as a supplementary test of the association between selection and immune genes.…”

Major histocompatibility complex and its importance towards controlling infection

“…This is understandable in the light of the evolutionary pressure so that we are equipped to face the multitude of infectious challenges. Infectious diseases are a major selective pressure; [15][16][17][18] and genes involved in the immune response are the most numerous and diverse in the human genome; 19 reflecting the evolutionary advantages of a diverse immunological response to a wide range of infectious pathogens. 20 …”