Understanding V(D)J recombination initiator RAG1 gene using molecular phylogenetic and genetic variant analyses and upgrading missense and non-coding variants of clinical importance.

The recombination-activating genes (RAGs) encode for V(D)J recombinases responsible for rearrangements of antigen-receptor genes during T and B cell development, and RAG expression is known to correlate strictly with the process of rearrangement. There have been several studies of RAG1 illustrating biochemical, physiological and immunological properties. Hitherto, there are limited studies on RAG1 focusing molecular phylogenetic analyses, evolutionary traits, and genetic variants in human populations. Hence, there is a need of a comprehensive study on this topic. In the current report, we have shed light into insights of evolutionary traits and genetic variants of human RAG1 gene using 1092 genomes from human populations. Syntenic analyses revealed that two RAG genes are physically linked and conserved on the same locus in head-to-head orientation from sea urchin to human for about 550 MY. Spliceosomal introns have been in invaded in fishes and sea urchin, whereas gene structures of RAG1 gene from tetrapods remained single exon architecture. We compiled 751 genetic variants in human RAG1 gene using 1092 human genomes; where major stockholders of variant classes are 79% single nucleotide polymorphisms (SNPs), 12.2% somatic single nucleotide variants (somatic SNVs) and 6.8% deletion. Out of 267 missense variants, 140 are deleterious mutations. We identified 284 non-coding variants with 94% regulatory in nature.