This is a response to a letter by Ding et al. (1).
We found a HLA class II peptide receptor that is formed by mixing class II proteins from DRα and DPβ isotypes. We showed that there are four families of receptors carrying DPβ chains with either K/GGPM, E/GGPM, K/DEAV, or E/DEAV at amino acids 69/84–86, respectively. Only DPβ with K/GGPM is capable of forming a matched receptor with DRα. This motif could influence selection of HLA-DP functional variation.
The K/GGPM sequence was identified in the HLA-DPB1*0401 allele, and an almost identical sequence was found in the Neanderthal genome. This allele however is rare in sub-Saharan Africa. We are attempting to explain why the HLA-DPB1*0401 is a major allotype in Europe but rare in Africa. Although HLA-DPB1*0402 also contains the K/GGPM sequence it differs from the Neanderthal HLA-DP as it carries DE at amino acids 55 and 56, whereas DPB1*0401 is AA (Ala-Ala) at amino acids 55 and 56 as is the Neanderthal sequence.
We agree that phylogenetic trees are most consistent with early coalescence of HLA-DPB1*0401 and -*0402. However, given the unique features of HLA recombination, allele conversion, gene conversion, and selection, it seems premature to rule out the possibility of multiple gene flow events in ancient populations (2, 3). In our paper we wanted to point out that the association of K/GGPM HLA-DP proteins with HLA-DRα as well as HLA-DPα, which we documented biochemically, as a novel receptor, could have consequences for selection. We noted that one allele with these properties, closest to the Neanderthal sequence, expanded out of Africa toward Asia, hence the suggestion of a possible relationship with Neanderthals. We did not want to rule out other scenarios. We thank Drs. Ding, Hu, and Jin for their most valuable comments.
References
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