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Ancient and recent adaptive evolution of primate non-homologous end joining genes.

Demogines A, East AM, Lee JH, Grossman SR, Sabeti PC, Paull TT, Sawyer SL - PLoS Genet. (2010)

Bottom Line: 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.In order to characterize the molecular evolution of the human NHEJ pathway, we generated large simian primate sequence datasets for NHEJ genes.

View Article: PubMed Central - PubMed

Affiliation: Section of Molecular Genetics and Microbiology, and Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas, USA.

ABSTRACT
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.

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Sliding window analysis identifies five candidate NHEJ genes evolving under positive selection.A) A schematic of the mammalian non-homologous end joining pathway is shown, illustrating the roles of all proteins included in this study. B) A cladogram shows the relationship of the primate species used in the sliding window analysis. Branch colors correspond to the sliding window comparisons graphed in panel C. C) Sliding window analysis of dN/dS along the length of KU70 and XRCC4. In each case, three pairwise sequence alignments were analyzed (human - orangutan comparison in pink, human - rhesus comparison in green, and rhesus - marmoset comparison in orange). D) The table summarizes the maximum dN/dS peak height found along the length of each pairwise sliding window comparison made. Asterisks indicate statistically significant peaks (p<0.05). In gray highlight are the five genes with significant peaks in at least two out of three comparisons.
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pgen-1001169-g001: Sliding window analysis identifies five candidate NHEJ genes evolving under positive selection.A) A schematic of the mammalian non-homologous end joining pathway is shown, illustrating the roles of all proteins included in this study. B) A cladogram shows the relationship of the primate species used in the sliding window analysis. Branch colors correspond to the sliding window comparisons graphed in panel C. C) Sliding window analysis of dN/dS along the length of KU70 and XRCC4. In each case, three pairwise sequence alignments were analyzed (human - orangutan comparison in pink, human - rhesus comparison in green, and rhesus - marmoset comparison in orange). D) The table summarizes the maximum dN/dS peak height found along the length of each pairwise sliding window comparison made. Asterisks indicate statistically significant peaks (p<0.05). In gray highlight are the five genes with significant peaks in at least two out of three comparisons.

Mentions: We utilized primate sequence datasets to study the evolutionary history of human NHEJ genes. With human population genetic data, evolutionary pressures can usually only be summarized for chromosomal regions larger than a single gene. However, with inter-species divergence data, resolution of evolutionary signatures can be increased to the level of a single gene, and it is sometimes possible to see the serial fixation of mutations in particular gene regions or even codons. The limitation in these studies is the number of available primate sequences. We first performed a preliminary survey of the selective pressures that have shaped all of the major genes of the NHEJ pathway (Figure 1A), so that we could generate appropriate primate datasets for candidate genes containing signatures suggestive of positive selection.


Ancient and recent adaptive evolution of primate non-homologous end joining genes.

Demogines A, East AM, Lee JH, Grossman SR, Sabeti PC, Paull TT, Sawyer SL - PLoS Genet. (2010)

Sliding window analysis identifies five candidate NHEJ genes evolving under positive selection.A) A schematic of the mammalian non-homologous end joining pathway is shown, illustrating the roles of all proteins included in this study. B) A cladogram shows the relationship of the primate species used in the sliding window analysis. Branch colors correspond to the sliding window comparisons graphed in panel C. C) Sliding window analysis of dN/dS along the length of KU70 and XRCC4. In each case, three pairwise sequence alignments were analyzed (human - orangutan comparison in pink, human - rhesus comparison in green, and rhesus - marmoset comparison in orange). D) The table summarizes the maximum dN/dS peak height found along the length of each pairwise sliding window comparison made. Asterisks indicate statistically significant peaks (p<0.05). In gray highlight are the five genes with significant peaks in at least two out of three comparisons.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2958818&req=5

pgen-1001169-g001: Sliding window analysis identifies five candidate NHEJ genes evolving under positive selection.A) A schematic of the mammalian non-homologous end joining pathway is shown, illustrating the roles of all proteins included in this study. B) A cladogram shows the relationship of the primate species used in the sliding window analysis. Branch colors correspond to the sliding window comparisons graphed in panel C. C) Sliding window analysis of dN/dS along the length of KU70 and XRCC4. In each case, three pairwise sequence alignments were analyzed (human - orangutan comparison in pink, human - rhesus comparison in green, and rhesus - marmoset comparison in orange). D) The table summarizes the maximum dN/dS peak height found along the length of each pairwise sliding window comparison made. Asterisks indicate statistically significant peaks (p<0.05). In gray highlight are the five genes with significant peaks in at least two out of three comparisons.
Mentions: We utilized primate sequence datasets to study the evolutionary history of human NHEJ genes. With human population genetic data, evolutionary pressures can usually only be summarized for chromosomal regions larger than a single gene. However, with inter-species divergence data, resolution of evolutionary signatures can be increased to the level of a single gene, and it is sometimes possible to see the serial fixation of mutations in particular gene regions or even codons. The limitation in these studies is the number of available primate sequences. We first performed a preliminary survey of the selective pressures that have shaped all of the major genes of the NHEJ pathway (Figure 1A), so that we could generate appropriate primate datasets for candidate genes containing signatures suggestive of positive selection.

Bottom Line: 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.In order to characterize the molecular evolution of the human NHEJ pathway, we generated large simian primate sequence datasets for NHEJ genes.

View Article: PubMed Central - PubMed

Affiliation: Section of Molecular Genetics and Microbiology, and Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus