P061Allele-level genotyping of KIR2DL4 in large european population samples reveals highly significant heterozygote excess for 9A/10A allelic variants

Abstract

Aim KIR2DL4 is an evolutionarily conserved framework member of the human killer-cell immunoglobulin-like receptor (KIR) gene family. It is unique amongst KIR genes in that it may elicit both activation and inhibition signals. Moreover, KIR2DL4 alleles are polymorphic for a frameshift mutation in the transmembrane domain that leads to a truncated cytoplasmatic tail. Alleles with a 10A homopolymer in exon 7 encode receptors that are expressed on the cell surface of NK cells. In contrast, alleles with a 9A frameshift mutation have been shown to produce soluble secreted KIR2DL4 receptors. Here, we investigate allele and genotype frequencies of 9A and 10A alleles in large European population samples. Methods In 2016, DKMS Life Science Lab has established an exon-based NGS workflow for KIR genotyping. Between 09/2017 and 03/2018, we have performed successful allelic-resolution genotyping for KIR2DL4 for approximately 380,000 potential bone-marrow donor samples originating from Germany (DE), Great Britain (GB), and Poland (PL). These samples where checked for presence of the 9A frameshift mutation. Results Overall, the defective 9A variant was slightly underrepresented in DE (AF9A = 0.496, n = 242,983) and GB (AF9A = 0.475, n = 31,100) but overrepresented in the Polish sample (AF9A = 0.537, n = 101,998). The fraction of homozygous individuals (10A/10A or 9A/9A) ranges from 44.4% (DE) to 44.9% (PL). Comparing expected and observed genotype frequencies indicates a highly significant deviation from Hardy–Weinberg Equilibrium (P Conclusions The high frequency of 10A alleles in all three populations indicates no negative selection against a lack of cell surface expression of KIR2DL4. Rather, the strong signature of heterozygote excess across populations may best be explained as a result of overdominant selection (i.e., “heterozygous advantage”). This suggests that the presence of both, cell-surface-expressed KIR2DL4 receptors and soluble secreted KIR2DL4 receptors confers a selective advantage to humans.