Ancient and recent adaptive evolution of primate non-homologous end joining genes.
In human cells, DNA double-strand breaks are repaired primarily by the non-homologous end joining (NHEJ) pathway. Given their critical nature, we expected NHEJ proteins to be evolutionarily conserved, with relatively little sequence change over time. Here, we report that while critical domains of these proteins are conserved as expected, the sequence of NHEJ proteins has also been shaped by recurrent positive selection, leading to rapid sequence evolution in other protein domains. In order to characterize the molecular evolution of the human NHEJ pathway, we generated large simian primate sequence datasets for NHEJ genes. Codon-based models of gene evolution yielded statistical support for the recurrent positive selection of five NHEJ genes during primate evolution: XRCC4, NBS1, Artemis, POLλ, and CtIP. Analysis of human polymorphism data using the composite of multiple signals (CMS) test revealed that XRCC4 has also been subjected to positive selection in modern humans. Crystal structures are available for XRCC4, Nbs1, and Polλ; and residues under positive selection fall exclusively on the surfaces of these proteins. Despite the positive selection of such residues, biochemical experiments with variants of one positively selected site in Nbs1 confirm that functions necessary for DNA repair and checkpoint signaling have been conserved. However, many viruses interact with the proteins of the NHEJ pathway as part of their infectious lifecycle. We propose that an ongoing evolutionary arms race between viruses and NHEJ genes may be driving the surprisingly rapid evolution of these critical genes.
Demogines
Ann
A
Section of Molecular Genetics and Microbiology, and Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas, USA.
East
Alysia M
AM
Lee
Ji-Hoon
JH
Grossman
Sharon R
SR
Sabeti
Pardis C
PC
Paull
Tanya T
TT
Sawyer
Sara L
SL
D000222:Adaptation, Physiological / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D019951:DNA Polymerase beta / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004706:Endodeoxyribonucleases; D004720:Endonucleases; D019143:Evolution, Molecular; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010802:Phylogeny; D011323:Primates / Q000145:classification / Q000235:genetics*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011995:Recombination, Genetic / Q000235:genetics*; D012641:Selection, Genetic; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C112156:NBN protein, human; D009687:Nuclear Proteins; C101467:XRCC4 protein, human; C415367:DNA polymerase beta2; D019951:DNA Polymerase beta; C426344:DCLRE1C protein, human; D004706:Endodeoxyribonucleases; D004720:Endonucleases; C410741:RBBP8 protein, human