UV-exposure, endogenous DNA damage, and DNA replication errors shape the spectra of genome changes in human skin.
UV-exposure, endogenous DNA damage, and DNA replication errors shape the spectra of genome changes in human skin.
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DOI：
10.1371/journal.pgen.1009302
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发表时间：
2021-01
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;Giacobone CK;Klimczak LJ;Papas BN;Burkholder AB;Li JL;Fargo DC;Bai R;Gerrish K;Innes CL;Schurman SH;Gordenin DA
人类皮肤持续暴露于环境DNA损伤，导致个体一生中体细胞突变的积累。人皮肤细胞中的突变也可以由内源性DNA损伤和DNA复制错误引起。这些过程对健康人皮肤中体细胞突变负荷的贡献迄今尚未得到准确评估，因为来自当前测序方法的低数目的突变排除了测序错误和真正的体细胞基因组变化之间的区别。在这项工作中，我们对从一个大的健康个体群体的初级皮肤细胞中获得的单细胞来源的克隆谱系的基因组进行了测序。我们在这里报告的突变负荷的范围和各种体细胞基因组的变化，积累在皮肤细胞的综合看法。我们证明，紫外线诱导的碱基替换，插入和缺失是突出的，即使在防晒皮肤。此外，我们还检测到由于甲基化胞嘧啶的自发脱氨基以及这些细胞中DNA复制错误的插入和缺失特征引起的突变积累。内源诱导的体细胞突变和插入缺失也表现出随年龄的线性增加，而紫外线诱导的突变负荷是年龄无关的。最后，我们表明，DNA复制停滞在常见的脆性位点是人类细胞中总染色体重排的潜在来源。因此，健康个体皮肤中的体细胞突变反映了环境和内源性因素在促进基因组不稳定性和致癌作用中的相互作用。皮肤是抵御各种环境毒素和DNA破坏剂的第一道屏障。此外，皮肤细胞的DNA在复制过程中遭受内源性损伤和错误。总而言之，这些病变引起各种基因组变化，导致包括癌症在内的疾病。然而，由于先前研究的技术或生物学限制，健康皮肤中基因组变化的范围和完整谱的准确测量缺失。我们在这里提出了我们在21名年龄从25岁到79岁的供体的皮肤成纤维细胞和黑素细胞中发现的各种类型的体细胞基因组变化的准确测量，这使得能够区分年龄相关的与年龄无关的变化。我们的队列包含白色和非裔美国人供体，允许估计肤色对诱变的影响。因此，我们揭示了完整的谱，并确定了健康人皮肤成纤维细胞和黑素细胞的体细胞基因组变化及其病因的范围，并强调了这些变化的分子机制。因此，我们的研究为定义皮肤基因组不稳定性的疾病水平引入了一条基线。
Human skin is continuously exposed to environmental DNA damage leading to the accumulation of somatic mutations over the lifetime of an individual. Mutagenesis in human skin cells can be also caused by endogenous DNA damage and by DNA replication errors. The contributions of these processes to the somatic mutation load in the skin of healthy humans has so far not been accurately assessed because the low numbers of mutations from current sequencing methodologies preclude the distinction between sequencing errors and true somatic genome changes. In this work, we sequenced genomes of single cell-derived clonal lineages obtained from primary skin cells of a large cohort of healthy individuals across a wide range of ages. We report here the range of mutation load and a comprehensive view of the various somatic genome changes that accumulate in skin cells. We demonstrate that UV-induced base substitutions, insertions and deletions are prominent even in sun-shielded skin. In addition, we detect accumulation of mutations due to spontaneous deamination of methylated cytosines as well as insertions and deletions characteristic of DNA replication errors in these cells. The endogenously induced somatic mutations and indels also demonstrate a linear increase with age, while UV-induced mutation load is age-independent. Finally, we show that DNA replication stalling at common fragile sites are potent sources of gross chromosomal rearrangements in human cells. Thus, somatic mutations in skin of healthy individuals reflect the interplay of environmental and endogenous factors in facilitating genome instability and carcinogenesis. Skin forms the first barrier against a variety of environmental toxins and DNA damaging agents. Additionally, DNA of skin cells suffer from endogenous damage and errors during replication. Altogether, these lesions cause a variety of genome changes resulting in disease including cancer. However, the accurate measurement of the range and complete spectrum of genome changes in healthy skin was missing due to technical or biological limitations of prior studies. We present here accurate measurements of the various types of somatic genome changes that we found in skin fibroblasts and melanocytes from 21 donors ranging in ages from 25 to 79 years, which allowed to distinguish age related from age independent changes. Our cohort contains both White and African American donors, allowing an estimation of the impacts of skin color on mutagenesis. As a result, we revealed the complete spectrum and determined the range of somatic genome changes and their etiologies in healthy human skin fibroblasts and melanocytes and highlighted molecular mechanisms underlying these changes. Therefore, our study introduces a base line for defining disease levels of genome instability in skin.
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影响因子：
12.3
作者：
Blokzijl F;Janssen R;van Boxtel R;Cuppen E
通讯作者：
Cuppen E
影响因子：
4.3
作者：
Delacote, Fabien;Lopez, Bernard S.
通讯作者：
Lopez, Bernard S.
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：
30.8
作者：
Chan K;Roberts SA;Klimczak LJ;Sterling JF;Saini N;Malc EP;Kim J;Kwiatkowski DJ;Fargo DC;Mieczkowski PA;Getz G;Gordenin DA
通讯作者：
Gordenin DA
DOI：
10.1073/pnas.0605247103
发表时间：
2006-11-28
影响因子：
11.1
作者：
Dumstorf, Chad A.;Clark, Alan B.;Kunkel, Thomas A.
通讯作者：
Kunkel, Thomas A.