Hilton Hugo G, Blokhuis Jeroen H, Guethlein Lisbeth A, Norman Paul J, Parham Peter
Department of Structural Biology, School of Medicine, Stanford University, Stanford, CA 94305; and
Department of Microbiology and Immunology, School of Medicine, Stanford University, Stanford, CA 94305
J Immunol. 2017 Mar 1;198(5):1961-1973. doi: 10.4049/jimmunol.1601835. Epub 2017 Jan 25.
is an inactive member of the human family, which includes all HLA-C-specific receptor genes. The lethal, and only, defect in is a nucleotide deletion in codon 88. Fixed in modern humans, the deletion is also in archaic human genomes. is polymorphic, with dimorphism at specificity-determining position 44. By repairing the deletion, we resurrected 11 alleles of , the functional antecedent of We demonstrate how K44-KIR2DP1 with lysine 44 recognized C1HLA-C, whereas T44-KIR2DP1 recognized C2HLA-C. Dimorphisms at 12 other KIR2DP1 residues modulate receptor avidity or signaling. KIR2DP1 and KIR2DL1 are neighbors in the centromeric region and are in tight linkage disequilibrium. Like , contributed to and haplotype differences. Encoded on , C1-specific K44-KIR2DP1 were stronger receptors than the attenuated C2-specific T44-KIR2DP1 encoded on The last common ancestor of humans and chimpanzees had diverse that passed on to chimpanzees but not to humans. Early humans inherited activating and an inhibitory , likely encoding a C1-specific receptor. The latter spawned the modern family of HLA-C receptors. KIR2DP1 has properties consistent with having been the founder gene. The first alleles encoded K44-C1 receptors; subsequently alleles encoding T44-C2 receptors evolved. The emergence of dedicated and genes encoding C1 and C2 receptors, respectively, could have led to obsolescence of Alternatively, pathogen subversion caused its demise. Preservation of functional polymorphism was a side effect of fixation of the deletion in by micro gene conversion.
是人类家族中的一个无活性成员，该家族包括所有HLA - C特异性受体基因。其致命且唯一的缺陷是密码子88处的核苷酸缺失。该缺失在现代人类中固定下来，在古代人类基因组中也存在。具有多态性，在特异性决定位置44处存在二态性。通过修复缺失，我们复活了11个等位基因，其是功能前身。我们展示了赖氨酸44的K44 - KIR2DP1如何识别C1 HLA - C，而苏氨酸44的T44 - KIR2DP1识别C2 HLA - C。KIR2DP1其他12个残基处的二态性调节受体亲和力或信号传导。KIR2DP1和KIR2DL1是着丝粒区域的相邻基因，处于紧密连锁不平衡状态。与一样，对单倍型差异有贡献。在编码的C1特异性K44 - KIR2DP1比在编码的减弱的C2特异性T44 - KIR2DP1是更强的受体。人类和黑猩猩的最后一个共同祖先有多样的，传递给了黑猩猩但没有传递给人类。早期人类继承了激活型和抑制型，可能编码一种C1特异性受体。后者产生了现代的HLA - C受体家族。KIR2DP1具有与作为奠基基因一致的特性。最初的等位基因编码K44 - C1受体；随后编码T44 - C2受体的等位基因进化而来。分别编码C1和C2受体的专用和基因的出现可能导致过时。或者，病原体的颠覆导致了它的消亡。通过微基因转换在中固定缺失的一个副作用是保留了功能多态性。
