The Impact of Environmental and Endogenous Damage on Somatic Mutation Load in Human Skin Fibroblasts.
The Impact of Environmental and Endogenous Damage on Somatic Mutation Load in Human Skin Fibroblasts.
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DOI：
10.1371/journal.pgen.1006385
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发表时间：
2016-10
期刊：
影响因子：
4.5
通讯作者：
Gordenin DA
中科院分区：
文献类型：
--
作者：
Saini N;Roberts SA;Klimczak LJ;Chan K;Grimm SA;Dai S;Fargo DC;Boyer JC;Kaufmann WK;Taylor JA;Lee E;Cortes-Ciriano I;Park PJ;Schurman SH;Malc EP;Mieczkowski PA;Gordenin DA
由于环境和内源性病变，人体基因组中的体细胞变化的积累与衰老和癌症有关。了解这些过程对诱变的影响对于了解病因学，改善癌症和其他遗传疾病的预后和预防至关重要。以前的方法依赖于诱导多能干细胞的产生或单细胞基因组的测序，这本身就容易出错，并且不允许对突变进行独立验证。在当前的研究中，我们通过对单细胞衍生的克隆成纤维细胞谱系进行高覆盖率基因组测序来消除这些潜在的错误来源，所述克隆成纤维细胞谱系在培养中最小繁殖后获得，从两个健康成年人的皮肤活检制备。我们在这里报告的准确测量全基因组的大小和光谱的突变累积在皮肤成纤维细胞的健康成年人。我们发现，每个细胞至少包含一个染色体重排和600- 13，000个碱基替换。碱基置换与表观基因组特征的光谱和相关性类似于许多癌症。此外，由于活组织检查是从阳光照射不同的身体部位进行的，我们可以描绘出环境和内源性因素对同一个体内遗传变化的准确贡献。我们在这里表明，紫外线诱导的和内源性DNA损伤可以有一个相当的影响皮肤成纤维细胞的体细胞突变负荷。ClinicalTrials.gov NCT 01087307体细胞基因组不断积累由内源性病变、DNA复制和修复错误以及环境损伤引起的变化。尽管体细胞基因组不稳定性在衰老和与年龄相关的病理学（包括癌症）中的重要性，但健康细胞中突变负荷的准确测量仍然缺失。在这项研究中，我们开发了一种实验方法来准确地确定健康人一生中细胞谱系中累积的体细胞基因组变化。我们发现皮肤细胞中突变的数量和类型与许多癌症相似，从而表明导致致癌的机制在健康细胞中也起作用。此外，暴露在阳光下的皮肤细胞由于紫外线辐射（UV）而具有更高的突变负荷，这与受衣服保护的臀部细胞不同。我们的工作提供了人类皮肤单细胞突变负荷的精确测量。此外，我们的数据允许定义同一个体内环境和内源性过程的致突变影响，并得出结论，这些过程对体细胞突变负荷具有相当的影响。
Accumulation of somatic changes, due to environmental and endogenous lesions, in the human genome is associated with aging and cancer. Understanding the impacts of these processes on mutagenesis is fundamental to understanding the etiology, and improving the prognosis and prevention of cancers and other genetic diseases. Previous methods relying on either the generation of induced pluripotent stem cells, or sequencing of single-cell genomes were inherently error-prone and did not allow independent validation of the mutations. In the current study we eliminated these potential sources of error by high coverage genome sequencing of single-cell derived clonal fibroblast lineages, obtained after minimal propagation in culture, prepared from skin biopsies of two healthy adult humans. We report here accurate measurement of genome-wide magnitude and spectra of mutations accrued in skin fibroblasts of healthy adult humans. We found that every cell contains at least one chromosomal rearrangement and 600–13,000 base substitutions. The spectra and correlation of base substitutions with epigenomic features resemble many cancers. Moreover, because biopsies were taken from body parts differing by sun exposure, we can delineate the precise contributions of environmental and endogenous factors to the accrual of genetic changes within the same individual. We show here that UV-induced and endogenous DNA damage can have a comparable impact on the somatic mutation loads in skin fibroblasts. ClinicalTrials.gov NCT01087307 Somatic genomes are constantly accumulating changes caused by endogenous lesions, errors in DNA replication and repair, as well as environmental insults. Despite the importance of somatic genome instability in aging and age-related pathologies, including cancers, accurate measurements of mutation loads in healthy cells is still missing. In this study, we developed an experimental approach to accurately determine the somatic genome changes accrued in cell lineages over the lifetime of healthy humans. We show that the amounts and types of mutations in skin cells resemble many cancers, thus indicating that the mechanisms that lead to carcinogenesis are also functional in healthy cells. Moreover, sun-exposed skin cells have a higher mutation load attributable to ultraviolet radiation (UV) unlike cells from hips that were protected by clothing. Our work provides precise measurements of the mutation loads in single cells in human skin. Furthermore our data allowed defining the mutagenic impacts of environmental and endogenous processes within the same individual and led to conclusion that these processes have a comparable impact on the somatic mutation load.
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正常细胞的基因组测序揭示了发育谱系和突变过程。
影响因子：
64.8
作者：
Behjati, Sam;Huch, Meritxell;van Boxtel, Ruben;Karthaus, Wouter;Wedge, David C.;Tamuri, Asif U.;Martincorena, Inigo;Petljak, Mia;Alexandrov, Ludmil B.;Gundem, Gunes;Tarpey, Patrick S.;Roerink, Sophie;Blokker, Joyce;Maddison, Mark;Mudie, Laura;Robinson, Ben;Nik-Zainal, Serena;Campbell, Peter;Goldman, Nick;van de Wetering, Marc;Cuppen, Edwin;Clevers, Hans;Stratton, Michael R.
通讯作者：
Stratton, Michael R.
DOI：
10.1093/bioinformatics/btt017
发表时间：
2013-03-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Douville C;Carter H;Kim R;Niknafs N;Diekhans M;Stenson PD;Cooper DN;Ryan M;Karchin R
通讯作者：
Karchin R
影响因子：
8.8
作者：
Cai X;Evrony GD;Lehmann HS;Elhosary PC;Mehta BK;Poduri A;Walsh CA
通讯作者：
Walsh CA
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
14.9
作者：
Ding Z;Mangino M;Aviv A;Spector T;Durbin R;UK10K Consortium
通讯作者：
UK10K Consortium