KIR3DL3 gene diversity in worldwide populations and evolutionary aspects

Killer-cell Immunoglobulin-like Receptors (KIRs) are transmembrane receptors expressed in Natural Killer cells and cytotoxic T cells. These receptors recognize molecules from the immune system, mainly molecules from the major class I histocompatibility complex on somatic cells' surface. KIR genes are highly polymorphic regarding the number of copies of each locus and their sequence content. KIR3DL3 is a framework KIR gene present in every individual. Here we addressed KIR3DL3 genetic diversity and evolutionary aspects in worldwide human populations, using a bioinformatics pipeline created for this study, minimizing mapping bias and genotyping errors. The samples included 2504 individuals from 26 populations (1000 Genomes Project consortium), and 216 Brazilians samples sequenced using second-generation sequencing. Ancestry informative markers were used in the Brazilian population to access the contribution of the different ancestry profiles of each individual and to obtain an average of the whole population. KIR3DL3 genetic variability is far more significant than we currently acknowledge, especially when considering intronic segments and regulatory sequences. KIR3DL3 protein diversity is strongly influenced by the ancestry background, with different frequencies of protein versions and amino acid residues among Africans, Europeans, and other populations. In this matter, populations from East Asia present an unusual pattern considering protein frequencies, regulatory sequences diversity, and how natural selection has shaped KIR3DL3 diversity and haplotype frequencies. Because of that, any association study involving KIR3DL3 should be performed concerning for population stratification. Some KIR3DL3 segments are highly conserved, such as the exons encoding the leader peptide and the extracellular domain D2, important for HLA interaction, while other segments, such as the promoter region and exon 6 (the transmembrane domain) are highly variable. We found evidence of balancing selection in the promoter region, probably maintaining sequences with different promotion capabilities, and it is evident among Europeans and East Asians. We also find evidence of balancing selection in some large intronic segments, and they must be considered as possibly carrying regulatory elements. (AU)