Recombination activating gene 1 also known as RAG-1 is a protein that in humans is encoded by the RAG1gene.[5]
The RAG1 and RAG2 genes are largely conserved in humans. 55.99% and 55.98% of the encoded amino acids contain no reported variants, respectively.[6]
Function
The protein encoded by this gene is involved in antibody and T-cell receptorV(D)J recombination. RAG-1 is involved in recognition of the DNA substrate, but stable binding and cleavage activity also requires RAG-2. The RAG-1/2 complex recognizes recombination signal sequences (RSSs) that flank the V, D and J regions in the genes that encode the heavy and light chains of antibodies and components of T-cell receptors. The complex binds to the RSSs and nicks the DNA. This leads to the removal of the intervening DNA and the eventual ligation of the V, D and J sequences.[7] Defects in this gene can cause several different diseases.[5]
Clinical significance
Because of these effects, Rag1 deletion is used in mouse models of disease to impair T cell and B cell development, and functionally deletes mature T and B cells from the immune system.[8]
In humans, RAG deficiency was first recognised as a form of immune dysregulation known as Omenn syndrome. RAG deficiency is considered an autosomal recessive disease. The disorder is generally identified in infants. Complete loss-of-function in RAG1/2, the main components responsible for V(D)J recombination activity, produces severe immunodeficiency in humans. Hypomorphic RAG variants can retain partial recombination activity[9] and result in a distinct phenotype of combined immunodeficiency with granuloma and/or autoimmunity (CID-G/A),[10][11][12] as well as other milder forms, such as antibody deficiency,[13] Idiopathic CD4+ T lymphopenia [14] or vasculitis.[15] RAG deficiency can be measured by in vitro quantification of recombination activity.[16][17][18] 71 RAG1 and 39 RAG2 variants have been functionally assayed to date (2019) (less than 10% of the potential point mutations that may cause disease). However, top candidate variants have been ranked by their predicted clinical relevance.[6]
Use in phylogenetics
RAG1 is frequently used as a marker in phylogenetic studies. That is, RAG1 sequences are often used to construct phylogenetic trees in order to investigate the relationships between species or higher taxa. Although the selection of RAG1 was somewhat arbitrary, it is one of several universal nuclear protein-coding loci (NPCL) that are applicable across diverse taxa and show good phylogenetic discrimination. For instance, RAG1 has been successfully used to make phylogenetic inferences within all major groups of fish and reptiles.[19][20] In many cases, RAG1 is used together with mitochondrial sequences as these evolve much faster and thus provide information about more closely related taxa.[21] A combination of nuclear and mitochondrial DNA is usually recommended due to fact that they may yield discrepant phylogenetic relationshis, a phenomenon called mito-nuclear discordance.[22]
