Interleukin-37 gene variants segregated anciently coexist during hominid evolution

IL37 is a member of IL-1 cytokine family but conveys anti-inflammatory functions. The biological characteristic and genetic heterogeneity of IL37 are not fully understood yet. Here using the whole-genome sequencing data from 1000 Genomes Project, we performed population and evolutionary genetic analysis of human IL37 gene. First, 2184 IL37 gene sequences from different human populations were retrieved. The IL37 protein sequences were inferred from the coding DNA sequences and multiple species alignment was made. Then, the phylogenetic tree of IL37 was built and dN/dS ratios were calculated for each evolutionary branch, the classic McDonald and Kreitman test was also performed. Next, we conducted intraspecific evolutionary genetic analysis and built the genealogy network of 116 unique IL37 haplotypes through median-joining network analysis. Finally, we compared IL37 sequences between the modern and archaic humans. Our results for the first time provide solid evidence that common IL37 variants other than NCBI reference sequence are present worldwide. Our data also supports that IL37 variants are shaped and maintained by selection instead of neutral evolution. We further identified that human IL37 variants consist of two major haplogroups and their presence in archaic humans corroborates its ancient origin in hominid evolution. In conclusion, these data indicate that common IL37 variants are maintained among human populations by selective force, suggesting their potential involvements in immune regulation and human diseases. In addition, the ancient history of IL37 variants reveals interesting insight into the complicated human evolutionary history.