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Distinct landscapes of deleterious variants in DNA damage repair system in ethnic human populations.

ABSTRACT: Deleterious variants in DNA damage repair (DDR) system can cause genome instability and increase cancer risk. In this study, we analyzed the deleterious variants in DDR system in 16 ethnic human populations. From the genetic variants in 169 DDR genes involved in nine DDR pathways collected from 158,612 individuals of different ethnic background, we identified 1,781 deleterious variants in 81 DDR genes in eight DDR pathways (https://genemutation.fhs.um.edu.mo/dbddr-global/). Our analysis showed although the quantity of deleterious variants was loaded at a similar level, the landscape of the variants differed substantially among different populations that two-third of the variants were present in single ethnic populations, and the rest was mostly shared between the populations with closer geographic and genetic relationship. The highly ethnic-specific DDR deleterious variation suggests its potential relationship with different disease susceptibility in ethnic human populations.

SUBMITTER: Qin Z

PROVIDER: S-EPMC9122833 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Distinct landscapes of deleterious variants in DNA damage repair system in ethnic human populations.

Qin Zixin Z Huang Teng T Guo Maoni M Wang San Ming SM

Life science alliance 20220520 9

Deleterious variants in DNA damage repair (DDR) system can cause genome instability and increase cancer risk. In this study, we analyzed the deleterious variants in DDR system in 16 ethnic human populations. From the genetic variants in 169 DDR genes involved in nine DDR pathways collected from 158,612 individuals of different ethnic background, we identified 1,781 deleterious variants in 81 DDR genes in eight DDR pathways (https://genemutation.fhs.um.edu.mo/dbddr-global/). Our analysis showed a ...[more]

PMID: 35595529

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Project description:BackgroundDNA damage repair (DDR) system is vital in maintaining genome stability and survival. DDR consists of over 160 genes in 7 different pathways to repair specific type of DNA damage caused by external and internal damaging factors. The functional importance of DDR system implies that evolution could play important roles in maintaining its functional intactness to perform its function. Indeed, it has been observed that positive selection is present in BRCA1 and BRCA2 (BRCA), which are key genes in homologous recombination pathway of DDR system, in the humans and its close relatives of chimpanzee and bonobos. Efforts have been made to investigate whether the same selection could exist for BRCA in other mammals but found no evidence so far. However, as most of the studies in non-human mammals analyzed only a single or few individuals in the studied species, the observation may not reflect the true status in the given species. Furthermore, few studies have studied evolution selection in other DDR genes except BRCA. In current study, we used laboratory mouse C57BL/6 J as a model to address evolution selection on DDR genes in non-primate mammals by dynamically monitoring genetic variation across 30 generations in C57BL/6 J.ResultsUsing exome sequencing, we collected coding sequences of 169 DDR genes from 44 C57BL/6 J individual genomes in 2018. We compared the coding sequences with the mouse reference genome sequences derived from 1998 C57BL/6 J DNA, and with the mouse Eve6B reference genome sequences derived from 2003 C57BL/6 J DNA, covering 30 generations of C57BL/6 J from 1998 to 2018. We didn't identify meaningful coding variation in either Brca1 or Brca2, or in 167 other DDR genes across the 30 generations. In the meantime, we did identify 812 coding variants in 116 non-DNA damage repair genes during the same period, which served as a quality control to validate the reliability of our analytic pipeline and the negative results in DDR genes.ConclusionsDDR genes in laboratory mouse strain C57BL/6 J were not under positive selection across its 30-generation period, highlighting the possibility that DDR system in rodents could be evolutionarily stable.

Project description:BackgroundGenome stability is maintained by the DNA damage repair (DDR) system composed of multiple DNA repair pathways of hundreds of genes. Germline pathogenic variation (PV) in DDR genes damages function of the affected DDR genes, leading to genome instability and high risk of diseases, in particular, cancer. Knowing evolutionary origin of the PVs in human DDR genes is essential to understand the etiology of human diseases. However, answer to the issue remains largely elusive. In this study, we analyzed evolutionary origin for the PVs in human DDR genes.MethodsWe identified 169 DDR genes by referring to various databases and identified PVs in the DDR genes of modern humans from ClinVar database. We performed a phylogenetic analysis to analyze the conservation of human DDR PVs in 100 vertebrates through cross-species genomic data comparison using the phyloFit program of the PHAST package and visualized the results using the GraphPad Prism software and the ggplot module. We identified DDR PVs from over 5000 ancient humans developed a database to host the DDR PVs ( https://genemutation.fhs.um.edu.mo/dbDDR-AncientHumans ). Using the PV data, we performed a molecular archeological analysis to compare the DDR PVs between modern humans and ancient humans. We analyzed evolution selection of DDR genes across 20 vertebrates using the CodeML in PAML for phylogenetic analysis.ResultsOur phylogenic analysis ruled out cross-species conservation as the origin of human DDR PVs. Our archeological approach identified rich DDR PVs shared between modern and ancient humans, which were mostly dated within the last 5000 years. We also observed similar pattern of quantitative PV distribution between modern and ancient humans. We further detected a set of ATM, BRCA2 and CHEK2 PVs shared between human and Neanderthals.ConclusionsOur study reveals that human DDR PVs mostly arose in recent human history. We propose that human high cancer risk caused by DDR PVs can be a by-product of human evolution.

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Distinct landscapes of deleterious variants in DNA damage repair system in ethnic human populations.

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Distinct landscapes of deleterious variants in DNA damage repair system in ethnic human populations.

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