使用双链测序测量的人类精子突变频率和谱与基于三联体的从头突变分析相关-动脉网

Frequency and spectrum of mutations in human sperm measured using duplex sequencing correlate with trio-based de novo mutation analyses

Nature 等信源发布 2024-10-08 19:42



可切换为仅中文







AbstractDe novo mutations (DNMs) are drivers of genetic disorders. However, the study of DNMs is hampered by technological limitations preventing accurate quantification of ultra-rare mutations. Duplex Sequencing (DS) theoretically has < 1 error/billion base-pairs (bp). To determine the DS utility to quantify and characterize DNMs, we analyzed DNA from blood and spermatozoa from six healthy, 18-year-old Swedish men using the TwinStrand DS mutagenesis panel (48 kb spanning 20 genic and intergenic loci).

摘要从头突变（DNM）是遗传疾病的驱动因素。然而，DNM的研究受到技术限制的阻碍，无法准确定量超罕见突变。理论上，双链测序（DS）具有<1个错误/十亿个碱基对（bp）。为了确定DS用于量化和表征DNM的效用，我们使用TwinStrand DS诱变小组（跨越20个基因和基因间位点的48 kb）分析了来自6名健康的18岁瑞典男性的血液和精子中的DNA。

The mean single nucleotide variant mutation frequency (MF) was 1.2 × 10− 7 per bp in blood and 2.5 × 10− 8 per bp in sperm, with the most common base substitution being C > T. Blood MF and substitution spectrum were similar to those reported in blood cells with an orthogonal method. The sperm MF was in the same order of magnitude and had a strikingly similar spectrum to DNMs from publicly available whole genome sequencing data from human pedigrees (1.2 × 10− 8 per bp).

平均单核苷酸变异突变频率（MF）在血液中为每bp 1.2×10-7，在精子中为每bp 2.5×10-8，最常见的碱基取代是C＞T。血液MF和取代谱与正交法在血细胞中报道的相似。。

DS revealed much larger numbers of insertions and deletions in sperm over blood, driven by an abundance of putative extra-chromosomal circular DNAs. The study indicates the strong potential of DS to characterize human DNMs to inform factors that contribute to disease susceptibility and heritable genetic risks..

DS揭示了精子在血液中的大量插入和缺失，这是由大量假定的染色体外环状DNA驱动的。这项研究表明，DS具有强大的潜力来表征人类DNM，以告知导致疾病易感性和遗传风险的因素。。

IntroductionDe novo mutations (DNMs) are a major cause of heritable genetic disorders including malformations, epilepsy, autism, cancer predisposition syndromes, and infertility1. Globally, DNMs contribute to approximately 400,000 cases per year of developmental disorders2. Indeed, a large part (30–70%) of genetic disorders have been attributed to DNMs3,4,5, accounting for a majority of inpatient pediatric admissions6,7.

引言从头突变（DNM）是遗传性遗传疾病的主要原因，包括畸形，癫痫，自闭症，癌症易感综合征和不育1。在全球范围内，DNM每年约导致40万例发育障碍2。事实上，遗传性疾病的很大一部分（30-70%）归因于DNMs3,4,5，占住院儿科住院人数的大多数6,7。

Despite the clear importance of DNMs for individual and population health, there remain major gaps in our understanding of the endogenous and exogenous variables that mediate the rate, spectrum, and distribution of these mutations in the human genome.Human pedigree studies have demonstrated that approximately 80% of DNMs have a paternal origin1,8,9.

尽管DNM对个人和人群健康具有明显的重要性，但我们对介导人类基因组中这些突变的速率，频谱和分布的内源性和外源性变量的理解仍存在重大差距。人类谱系研究表明，大约80%的DNM具有父系起源1,8,9。

Thus, male germ cells are the main source of mutations transmitted to children. There is very strong evidence that environmental factors significantly impact male germ cell mutation and DNM frequency in animal models10. However, aside from ageing, the existence of human germ cell mutagens has yet to be convincingly demonstrated11.

因此，男性生殖细胞是传播给儿童的突变的主要来源。有非常有力的证据表明，环境因素显着影响动物模型中的雄性生殖细胞突变和DNM频率10。然而，除了衰老之外，人类生殖细胞诱变剂的存在尚未得到令人信服的证明11。

Nonetheless, recent studies applying whole genome sequencing to human families provide intriguing support that certain pharmaceuticals and lifestyle factors cause DNMs in offspring via paternal germ cells10,12,13.The major challenge to the study of spontaneous and induced mutagenesis is the lack of sufficiently accurate methodologies to measure the extremely low mutation frequencies occurring in the germ line (e.g., 1 × 10− 8 per nucleotide in sperm14).

尽管如此，最近将全基因组测序应用于人类家庭的研究提供了有趣的支持，即某些药物和生活方式因素通过父系生殖细胞在后代中引起DNM[10,12,13]。自发和诱导诱变研究的主要挑战是缺乏足够准确的方法来测量生殖系中发生的极低突变频率（例如，精子中每个核苷酸1×10-8个14）。

The measurement of such low frequencies is hindered by the use of conventional next-generation sequencing (NGS) technologies that introduce errors in ~ 1 of every 103 nucleotides sequenced15. Nonetheless, deep NGS has been applied t.

传统的下一代测序（NGS）技术的使用阻碍了这种低频率的测量，这种技术在每103个核苷酸测序中约有1个引入错误15。。

Data availability

数据可用性

Data on DNA sequences can be found at NIH, National Library of Medicine through BioProject Accession: PRJNA928759 (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA928759).

有关DNA序列的数据可以通过生物项目登录号在美国国立卫生研究院国家医学图书馆找到：PRJNA928759(https://www.ncbi.nlm.nih.gov/bioproject/PRJNA928759)。

ReferencesAcuna-Hidalgo, R., Veltman, J. A. & Hoischen, A. New insights into the generation and role of de novo mutations in health and disease. Genome Biol.17, 241. https://doi.org/10.1186/s13059-016-1110-1 (2016).Article

参考文献Acuna-Hidalgo，R.，Veltman，J.A。＆Hoischen，A。对从头突变在健康和疾病中的产生和作用的新见解。基因组生物学17241。https://doi.org/10.1186/s13059-016-1110-1（2016年）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Deciphering, D. & Disorders, S. Prevalence and architecture of de novo mutations in developmental disorders. Nature. 542, 433–438. https://doi.org/10.1038/nature21062 (2017).Article

Deciphering，D。＆Disorders，S。发育障碍中从头突变的流行和结构。自然。542433-438。https://doi.org/10.1038/nature21062（2017年）。文章

CAS

中科院

Google Scholar

谷歌学者

Rosell, A. M. et al. Not the end of the odyssey: parental perceptions of whole exome sequencing (WES) in pediatric undiagnosed disorders. J. Genet. Couns.25, 1019–1031. https://doi.org/10.1007/s10897-016-9933-1 (2016).Article

Rosell，A.M.等人，《奥德赛尚未结束：父母对儿科未诊断疾病中全外显子组测序（WES）的看法》。J、基因。国家251019-1031。https://doi.org/10.1007/s10897-016-9933-1（2016年）。文章

PubMed

Google Scholar

谷歌学者

Stranneheim, H. et al. Integration of whole genome sequencing into a healthcare setting: high diagnostic rates across multiple clinical entities in 3219 rare disease patients. Genome Med.13, 40. https://doi.org/10.1186/s13073-021-00855-5 (2021).Article

Straneheim，H。等人。将全基因组测序整合到医疗保健环境中：3219名罕见病患者的多个临床实体的高诊断率。基因组医学13,40。https://doi.org/10.1186/s13073-021-00855-5。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Yang, Y. et al. Molecular findings among patients referred for clinical whole-exome sequencing. JAMA. 312, 1870–1879. https://doi.org/10.1001/jama.2014.14601 (2014).Article

Yang，Y.等人。临床全外显子组测序患者的分子发现。杰玛。3121870年至1879年。https://doi.org/10.1001/jama.2014.14601（2014年）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

McCandless, S. E., Brunger, J. W. & Cassidy, S. B. The burden of genetic disease on inpatient care in a children’s hospital. Am. J. Hum. Genet.74, 121–127. https://doi.org/10.1086/381053 (2004).Article

McCandless，S.E.，Brunger，J.W。和Cassidy，S.B。遗传病对儿童医院住院治疗的负担。《美国J·哼·基因》74121-127。https://doi.org/10.1086/381053（2004年）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Moya, A., Hernandez, M. & Mellado, C. Prevalence of genetic diseases in admissions to a tertiary care hospital pediatric service. Rev. Med. Chil.144, 188–193. https://doi.org/10.4067/S0034-98872016000200007 (2016).Article

Moya，A.，Hernandez，M。＆Mellado，C。三级保健医院儿科服务入院时遗传疾病的患病率。医学杂志144188-193。https://doi.org/10.4067/S0034-98872016000200007（2016年）。文章

PubMed

Google Scholar

谷歌学者

Sasani, T. A. et al. Large, three-generation human families reveal post-zygotic mosaicism and variability in germline mutation accumulation. Elife. 8https://doi.org/10.7554/eLife.46922 (2019).Jonsson, H. et al. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.

Sasani，T.A。等人。大型三代人类家族揭示了合子后镶嵌和种系突变积累的变异性。埃利夫。8https://doi.org/10.7554/eLife.46922（2019年）。。

Nature. 549, 519–522. https://doi.org/10.1038/nature24018 (2017).Article .

自然。549519-522。https://doi.org/10.1038/nature24018（2017年）。文章。

ADS

CAS

中科院

PubMed

Google Scholar

谷歌学者

Marchetti, F., Douglas, G. R. & Yauk, C. L. A return to the origin of the EMGS: rejuvenating the quest for human germ cell mutagens and determining the risk to future generations. Environ. Mol. Mutagen.61, 42–54. https://doi.org/10.1002/em.22327 (2020).Article

Marchetti，F.，Douglas，G.R。＆Yauk，C.L。回归肌电图的起源：重新寻找人类生殖细胞诱变剂并确定对后代的风险。环境。分子诱变剂61，42-54。https://doi.org/10.1002/em.22327（2020年）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Bline, A. P. et al. Heritable hazards of smoking: applying the clean sheet framework to further science and policy. Environ. Mol. Mutagen.61, 910–921. https://doi.org/10.1002/em.22412 (2020).Article

Bline，A.P.等人，《吸烟的遗传危害：将不吸烟清单框架应用于进一步的科学和政策》。环境。分子诱变剂61910-921。https://doi.org/10.1002/em.22412（2020年）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Kaplanis, J. et al. Genetic and chemotherapeutic influences on germline hypermutation. Nature. 605, 503–508. https://doi.org/10.1038/s41586-022-04712-2 (2022).Article

Kaplanis，J.等人。遗传和化学治疗对种系超突变的影响。自然。605503–508。https://doi.org/10.1038/s41586-022-04712-2（2022年）。文章

ADS

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Wang, C. et al. Association of assisted reproductive technology, germline de novo mutations and congenital heart defects in a prospective birth cohort study. Cell. Res.31, 919–928. https://doi.org/10.1038/s41422-021-00521-w (2021).Article

Wang，C.等人。前瞻性出生队列研究中辅助生殖技术，种系从头突变和先天性心脏缺陷的关联。细胞。第31919-928号决议。https://doi.org/10.1038/s41422-021-00521-w。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Abascal, F. et al. Somatic mutation landscapes at single-molecule resolution. Nature. 593, 405–410. https://doi.org/10.1038/s41586-021-03477-4 (2021).Article

Abascal，F。等人。单分子分辨率的体细胞突变景观。自然。593405-410。https://doi.org/10.1038/s41586-021-03477-4。文章

ADS

CAS

中科院

PubMed

Google Scholar

谷歌学者

Salk, J. J., Kennedy, S. R. & Next-Generation Genotoxicology Using modern sequencing technologies to assess somatic mutagenesis and cancer risk. Environ. Mol. Mutagen.61, 135–151. https://doi.org/10.1002/em.22342 (2020).Article

Salk，J.J.，Kennedy，S.R。&使用现代测序技术评估体细胞突变和癌症风险的下一代基因毒理学。环境。。https://doi.org/10.1002/em.22342（2020年）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Breuss, M. W. et al. Unbiased mosaic variant assessment in sperm: a cohort study to test predictability of transmission. Elife. 11https://doi.org/10.7554/eLife.78459 (2022).Wang, J., Fan, H. C., Behr, B. & Quake, S. R. Genome-wide single-cell analysis of recombination activity and de novo mutation rates in human sperm.

Breuss，M.W.等人，《精子无偏镶嵌变异评估：一项队列研究，以测试传播的可预测性》。埃利夫。11https://doi.org/10.7554/eLife.78459（2022年）。Wang，J.，Fan，H.C.，Behr，B。＆Quake，S.R。人类精子重组活性和从头突变率的全基因组单细胞分析。

Cell. 150, 402–412. https://doi.org/10.1016/j.cell.2012.06.030 (2012).Article .

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Valecha, M. & Posada, D. Somatic variant calling from single-cell DNA sequencing data. Comput. Struct. Biotechnol. J.20, 2978–2985. https://doi.org/10.1016/j.csbj.2022.06.013 (2022).Article

Valecha，M。＆Posada，D。从单细胞DNA测序数据进行体细胞变异调用。计算机。结构。。J、 202978-2985。https://doi.org/10.1016/j.csbj.2022.06.013（2022年）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Salk, J. J., Schmitt, M. W. & Loeb, L. A. Enhancing the accuracy of next-generation sequencing for detecting rare and subclonal mutations. Nat. Rev. Genet.19, 269–285. https://doi.org/10.1038/nrg.2017.117 (2018).Article

Salk，J.J.，Schmitt，M.W。＆Loeb，L.A。提高了用于检测罕见和亚克隆突变的下一代测序的准确性。《自然修订版Genet.19269-285》。https://doi.org/10.1038/nrg.2017.117（2018年）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Schmitt, M. W. et al. Detection of ultra-rare mutations by next-generation sequencing. Proc. Natl. Acad. Sci. USA. 109, 14508–14513. https://doi.org/10.1073/pnas.1208715109 (2012).Article

Schmitt，M.W.等人。通过下一代测序检测超罕见突变。程序。纳特尔。阿卡德。科学。美国10914508–14513。https://doi.org/10.1073/pnas.1208715109（2012年）。文章

ADS

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Short, N. J. et al. Ultra-accurate duplex sequencing for the assessment of pretreatment ABL1 kinase domain mutations in Ph + ALL. Blood Cancer J.10, 61. https://doi.org/10.1038/s41408-020-0329-y (2020).Article

Short，N.J.等人。超精确双链测序，用于评估Ph + ALL中的预处理ABL1激酶结构域突变。血癌J.10，61。https://doi.org/10.1038/s41408-020-0329-y（2020年）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Valentine, C. C. III et al. Direct quantification of in vivo mutagenesis and carcinogenesis using duplex sequencing. Proc. Natl. Acad. Sci. USA. 117, 33414–33425. https://doi.org/10.1073/pnas.2013724117 (2020).Article

Valentine，C.C.III等人。使用双链测序直接定量体内诱变和致癌作用。程序。纳特尔。阿卡德。科学。美国。11733414–33425。https://doi.org/10.1073/pnas.2013724117（2020年）。文章

ADS

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

LeBlanc, D. P. M. et al. Duplex sequencing identifies genomic features that determine susceptibility to benzo(a)pyrene-induced in vivo mutations. BMC Genom.23, 542. https://doi.org/10.1186/s12864-022-08752-w (2022).Article

LeBlanc，D.P.M.等人的双重测序鉴定了决定对苯并（a）芘诱导的体内突变易感性的基因组特征。BMC基因组23542。https://doi.org/10.1186/s12864-022-08752-w（2022年）。文章

CAS

中科院

Google Scholar

谷歌学者

Ohno, M. Spontaneous de novo germline mutations in humans and mice: rates, spectra, causes and consequences. Genes Genet. Syst.94, 13–22. https://doi.org/10.1266/ggs.18-00015 (2019).Article

Ohno，M。人类和小鼠的自发性从头种系突变：速率，光谱，原因和后果。基因Genet。系统94，13-22。https://doi.org/10.1266/ggs.18-00015（2019年）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Salazar, R. et al. Discovery of an unusually high number of de novo mutations in sperm of older men using duplex sequencing. Genome Res.32, 499–511. https://doi.org/10.1101/gr.275695.121 (2022).Article

Salazar，R。等人使用双链测序发现老年男性精子中异常高数量的从头突变。基因组研究32499-511。https://doi.org/10.1101/gr.275695.121（2022年）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Wang, Y. et al. Genetic toxicity testing using human in vitro organotypic airway cultures: assessing DNA damage with the CometChip and mutagenesis by duplex sequencing. Environ. Mol. Mutagen.62, 306–318. https://doi.org/10.1002/em.22444 (2021).Article

Wang，Y.等人。使用人体体外器官型气道培养物进行遗传毒性测试：使用ComeChip评估DNA损伤，并通过双链测序进行诱变。环境。分子诱变剂62306-318。https://doi.org/10.1002/em.22444。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Axelsson, J., Rylander, L., Rignell-Hydbom, A. & Giwercman, A. No secular trend over the last decade in sperm counts among Swedish men from the general population. Hum. Reprod.26, 1012–1016. https://doi.org/10.1093/humrep/der045 (2011).Article

Axelsson，J.，Rylander，L.，Rignell-Hydbom，A。＆Giwercman，A。在过去十年中，瑞典普通男性的精子数量没有长期趋势。哼。报告261012-1016。https://doi.org/10.1093/humrep/der045（2011年）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

World Health, O. WHO Laboratory Manual for the Examination of Human Semen and semen-cervical Mucus Interaction (Cambridge University Press on behalf of the World Health Organization, 1999).Wu, H., de Gannes, M. K., Luchetti, G. & Pilsner, J. R. Rapid method for the isolation of mammalian sperm DNA.

世界卫生组织，《世卫组织人类精液和精液-宫颈粘液相互作用检测实验室手册》（剑桥大学出版社，代表世界卫生组织，1999年）。Wu，H.，de Gannes，M.K.，Luchetti，G。＆Pilsner，J.R。用于分离哺乳动物精子DNA的快速方法。

Biotechniques. 58, 293–300. https://doi.org/10.2144/000114280 (2015).Article .

生物技术。58, 293–300.https://doi.org/10.2144/000114280(2015).第条。

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Dodge, A. E. et al. Duplex sequencing provides detailed characterization of mutation frequencies and spectra in the bone marrow of MutaMouse males exposed to procarbazine hydrochloride. Arch. Toxicol.97, 2245–2259. https://doi.org/10.1007/s00204-023-03527-y (2023).Article

Dodge，A.E.等人的双重测序提供了暴露于盐酸丙卡巴嗪的MutaMouse雄性骨髓中突变频率和光谱的详细表征。。毒理学972245-2259。https://doi.org/10.1007/s00204-023-03527-y（2023年）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Seo, J. E. et al. Evaluating the mutagenicity of N-nitrosodimethylamine in 2D and 3D HepaRG cell cultures using error-corrected next generation sequencing. Arch. Toxicol.98, 1919–1935. https://doi.org/10.1007/s00204-024-03731-4 (2024).Article

Seo，J.E.等人。使用错误校正的下一代测序评估N-亚硝基二甲胺在2D和3D HepaRG细胞培养物中的致突变性。。Toxicol.981919-1935。https://doi.org/10.1007/s00204-024-03731-4（2024年）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Besenbacher, S. et al. Novel variation and de novo mutation rates in population-wide de novo assembled Danish trios. Nat. Commun.6, 5969. https://doi.org/10.1038/ncomms6969 (2015).Article

Besenbacher，S.等人。丹麦人群从头组装的三重奏中的新变异和从头突变率。国家通讯65969。https://doi.org/10.1038/ncomms6969（2015年）。文章

ADS

CAS

中科院

PubMed

Google Scholar

谷歌学者

Chen, W. & Zhang, L. The pattern of DNA cleavage intensity around indels. Sci. Rep.5, 8333. https://doi.org/10.1038/srep08333 (2015).Article

Chen，W。＆Zhang，L。插入缺失周围DNA切割强度的模式。科学。代表58333。https://doi.org/10.1038/srep08333（2015年）。文章

ADS

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Kosugi, S. & Terao, C. Comparative evaluation of SNVs, indels, and structural variations detected with short- and long-read sequencing data. Hum. Genome Variation. 11, 18. https://doi.org/10.1038/s41439-024-00276-x (2024).Article

Kosugi，S。和Terao，C。用短读和长读测序数据检测到的SNV，插入缺失和结构变异的比较评估。嗯。基因组变异。11、18。https://doi.org/10.1038/s41439-024-00276-x（2024年）。文章

CAS

中科院

Google Scholar

谷歌学者

Piegorsch, W. W. & Bailer, A. J. Statistical approaches for analyzing mutational spectra: some recommendations for categorical data. Genetics. 136, 403–416. https://doi.org/10.1093/genetics/136.1.403 (1994).Article

Piegorsch，W。W。和Bailer，A。J。分析突变谱的统计方法：对分类数据的一些建议。遗传学。136403-416。https://doi.org/10.1093/genetics/136.1.403（1994年）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Alexandrov, L. B., Nik-Zainal, S., Wedge, D. C., Campbell, P. J. & Stratton, M. R. Deciphering signatures of mutational processes operative in human cancer. Cell. Rep.3, 246–259. https://doi.org/10.1016/j.celrep.2012.12.008 (2013).Article

Alexandrov，L.B.，Nik Zainal，S.，Wedge，D.C.，Campbell，P.J。＆Stratton，M.R。解密在人类癌症中起作用的突变过程的特征。细胞。代表3246-259。https://doi.org/10.1016/j.celrep.2012.12.008（2013年）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Bergstrom, E. N. et al. SigProfilerMatrixGenerator: a tool for visualizing and exploring patterns of small mutational events. BMC Genom.20, 685. https://doi.org/10.1186/s12864-019-6041-2 (2019).Article

Bergstrom，E.N.等人，《SigProfilerMatrixGenerator：可视化和探索小突变事件模式的工具》。BMC基因组20685。https://doi.org/10.1186/s12864-019-6041-2（2019年）。文章

Google Scholar

谷歌学者

Savvateeva, M. et al. Somatic mutation profiling in head and neck paragangliomas. J. Clin. Endocrinol. Metab.107, 1833–1842. https://doi.org/10.1210/clinem/dgac250 (2022).Article

Savvateeva，M.等人。头颈部副神经节瘤的体细胞突变分析。J、临床。内分泌。Metab.1071833-1842。https://doi.org/10.1210/clinem/dgac250（2022年）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Islam, S. M. A. et al. Uncovering novel mutational signatures by de novo extraction with SigProfilerExtractor. Cell. Genomics. 100179. https://doi.org/10.1016/j.xgen.2022.100179 (2022).Herrera-Pariente, C. et al. Identification of new genes involved in germline predisposition to early-onset gastric cancer.

Islam，S.M.A.等人通过SigProfileXtractor从头提取揭示了新的突变特征。细胞。基因组学。100179https://doi.org/10.1016/j.xgen.2022.100179（2022年）。Herrera Pariente，C.等人。鉴定与早发性胃癌种系易感性有关的新基因。

Int. J. Mol. Sci.22https://doi.org/10.3390/ijms22031310 (2021).Ueda, S. et al. A quantification method of somatic mutations in normal tissues and their accumulation in pediatric patients with chemotherapy. Proc. Natl. Acad. Sci. USA. 119, e2123241119. https://doi.org/10.1073/pnas.2123241119 (2022).Article .

国际分子科学杂志22https://doi.org/10.3390/ijms22031310。Ueda，S.等人。正常组织中体细胞突变及其在儿科化疗患者中积累的定量方法。程序。纳特尔。阿卡德。科学。美国119，e2123241119。https://doi.org/10.1073/pnas.2123241119（2022年）。文章。

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Wilfert, A. B. et al. Recent ultra-rare inherited variants implicate new autism candidate risk genes. Nat. Genet.53, 1125–1134. https://doi.org/10.1038/s41588-021-00899-8 (2021).Article

Wilfert，A.B.等人最近的超罕见遗传变异暗示了新的自闭症候选风险基因。《自然遗传学》531125-1134。https://doi.org/10.1038/s41588-021-00899-8。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Goldmann, J. M. et al. Germline de novo mutation clusters arise during oocyte aging in genomic regions with high double-strand-break incidence. Nat. Genet.50, 487–492. https://doi.org/10.1038/s41588-018-0071-6 (2018).Article

Goldmann，J.M。等人。生殖系从头突变簇在卵母细胞衰老过程中出现在双链断裂发生率高的基因组区域。《自然遗传学》50487-492。https://doi.org/10.1038/s41588-018-0071-6（2018年）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Goldmann, J. M. et al. Parent-of-origin-specific signatures of de novo mutations. Nat. Genet.48, 935–939. https://doi.org/10.1038/ng.3597 (2016).Article

Goldmann，J.M.等人。从头突变的起源特异性亲本特征。《自然遗传学》48935-939。https://doi.org/10.1038/ng.3597（2016年）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Halldorsson, B. V. et al. Characterizing mutagenic effects of recombination through a sequence-level genetic map. Science. 363https://doi.org/10.1126/science.aau1043 (2019).Kessler, M. D. et al. De novo mutations across 1,465 diverse genomes reveal mutational insights and reductions in the amish founder population.

Halldorsson，B.V.等人。通过序列水平遗传图谱表征重组的诱变效应。科学。363https://doi.org/10.1126/science.aau1043（2019年）。Kessler，M.D。等人，跨越1465个不同基因组的从头突变揭示了阿米什人创始人群体的突变见解和减少。

Proc. Natl. Acad. Sci. USA. 117, 2560–2569. https://doi.org/10.1073/pnas.1902766117 (2020).Article .

ADS

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Rahbari, R. et al. Timing, rates and spectra of human germline mutation. Nat. Genet.48, 126–133. https://doi.org/10.1038/ng.3469 (2016).Article

Rahbari，R。等人。人类种系突变的时间，速率和光谱。《自然遗传学》48126-133。https://doi.org/10.1038/ng.3469（2016年）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Gori, K. & Baez-Ortega, A. Sigfit: flexible bayesian inference of mutational signatures. bioRxiv. 372896https://doi.org/10.1101/372896 (2020).Shibata, Y. et al. Extrachromosomal microDNAs and chromosomal microdeletions in normal tissues. Science. 336, 82–86. https://doi.org/10.1126/science.1213307 (2012).Article .

Gori，K。＆Baez-Ortega，A。Sigfit：突变特征的灵活贝叶斯推断。生物十四。372896https://doi.org/10.1101/372896（2020年）。Shibata，Y.等人。正常组织中的染色体外微DNA和染色体微缺失。科学。336，82-86。https://doi.org/10.1126/science.1213307（2012年）。文章。

ADS

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Dillon, L. W. et al. Production of extrachromosomal microDNAs is linked to mismatch repair pathways and transcriptional activity. Cell. Rep.11, 1749–1759. https://doi.org/10.1016/j.celrep.2015.05.020 (2015).Article

Dillon，L.W。等人。染色体外microDNA的产生与错配修复途径和转录活性有关。细胞。代表111749-1759。https://doi.org/10.1016/j.celrep.2015.05.020（2015年）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Mehanna, P. et al. Characterization of the microDNA through the response to chemotherapeutics in lymphoblastoid cell lines. PLoS ONE. 12, e0184365. https://doi.org/10.1371/journal.pone.0184365 (2017).Article

Mehanna，P。等人。通过对淋巴母细胞样细胞系中化疗药物的反应来表征microDNA。PLoS ONE。12，e0184365。https://doi.org/10.1371/journal.pone.0184365（2017年）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Paulsen, T., Shibata, Y., Kumar, P., Dillon, L. & Dutta, A. Small extrachromosomal circular DNAs, microDNA, produce short regulatory RNAs that suppress gene expression independent of canonical promoters. Nucleic Acids Res.47, 4586–4596. https://doi.org/10.1093/nar/gkz155 (2019).Article .

Paulsen，T.，Shibata，Y.，Kumar，P.，Dillon，L。＆Dutta，A。小的染色体外环状DNA，microDNA产生短的调节RNA，其抑制独立于经典启动子的基因表达。。https://doi.org/10.1093/nar/gkz155（2019年）。文章。

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Wang, Y. et al. eccDNAs are apoptotic products with high innate immunostimulatory activity. Nature. 599, 308–314. https://doi.org/10.1038/s41586-021-04009-w (2021).Article

Wang，Y。等人。eccDNA是具有高先天免疫刺激活性的凋亡产物。自然。599308-314。https://doi.org/10.1038/s41586-021-04009-w。文章

ADS

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Meier, M. J. et al. In utero exposure to benzo[a]pyrene increases mutation burden in the soma and sperm of adult mice. Environ. Health Perspect.125, 82–88. https://doi.org/10.1289/EHP211 (2017).Article

Meier，M.J.等人在子宫内暴露于苯并[a]芘会增加成年小鼠体细胞和精子的突变负担。环境。健康展望125,82-88。https://doi.org/10.1289/EHP211（2017年）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Marchetti, F. et al. Error-corrected next generation sequencing - promises and challenges for genotoxicity and cancer risk assessment. Mutat. Res. Rev. Mutat. Res.792, 108466. https://doi.org/10.1016/j.mrrev.2023.108466 (2023).Article

Marchetti，F.等人，《纠正错误的下一代测序-遗传毒性和癌症风险评估的前景和挑战》。突变。Res.修订版Mutat。第792108466号决议。https://doi.org/10.1016/j.mrrev.2023.108466（2023年）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Alexandrov, L. B. et al. The repertoire of mutational signatures in human cancer. Nature. 578, 94–101. https://doi.org/10.1038/s41586-020-1943-3 (2020).Article

Alexandrov，L.B.等人，《人类癌症突变特征库》。自然。578、94-101。https://doi.org/10.1038/s41586-020-1943-3（2020年）。文章

ADS

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Moore, L. et al. The mutational landscape of human somatic and germline cells. Nature. 597, 381–386. https://doi.org/10.1038/s41586-021-03822-7 (2021).Article

Moore，L.等人，《人类体细胞和种系细胞的突变景观》。自然。。https://doi.org/10.1038/s41586-021-03822-7。文章

ADS

CAS

中科院

PubMed

Google Scholar

谷歌学者

Blokzijl, F. et al. Tissue-specific mutation accumulation in human adult stem cells during life. Nature. 538, 260–264. https://doi.org/10.1038/nature19768 (2016).Article

。自然。538260-264。https://doi.org/10.1038/nature19768（2016年）。文章

ADS

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Bae, J. H. et al. Single duplex DNA sequencing with CODEC detects mutations with high sensitivity. Nat. Genet.55, 871–879. https://doi.org/10.1038/s41588-023-01376-0 (2023).Article

Bae，J.H.等人。使用编解码器的单双链DNA测序以高灵敏度检测突变。《自然遗传学》55871-879。https://doi.org/10.1038/s41588-023-01376-0（2023年）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Kohailan, M. et al. Patterns and distribution of de novo mutations in multiplex Middle Eastern families. J. Hum. Genet.67, 579–588. https://doi.org/10.1038/s10038-022-01054-9 (2022).Article

Kohailan，M.等人。多重中东家庭中从头突变的模式和分布。J、嗯。基因67579-588。https://doi.org/10.1038/s10038-022-01054-9（2022年）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Noyes, M. D. et al. Familial long-read sequencing increases yield of de novo mutations. Am. J. Hum. Genet.109, 631–646. https://doi.org/10.1016/j.ajhg.2022.02.014 (2022).Article

Noyes，M.D。等人。家族性长读测序增加了从头突变的产量。《美国J.哼哼》Genet.109631-646。https://doi.org/10.1016/j.ajhg.2022.02.014（2022年）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Robinson, P. S. et al. Increased somatic mutation burdens in normal human cells due to defective DNA polymerases. Nat. Genet.53, 1434–1442. https://doi.org/10.1038/s41588-021-00930-y (2021).Article

Robinson，P.S.等人，由于DNA聚合酶缺陷，增加了正常人类细胞的体细胞突变负担。《自然遗传学》531434-1442。https://doi.org/10.1038/s41588-021-00930-y。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Samur, M. K. et al. Genome-wide somatic alterations in multiple myeloma reveal a Superior Outcome Group. J. Clin. Oncol.38, 3107–3118. https://doi.org/10.1200/JCO.20.00461 (2020).Article

Samur，M.K.等人。多发性骨髓瘤的全基因组体细胞改变揭示了一个优越的结果组。J、临床。Oncol.383107-3118。https://doi.org/10.1200/JCO.20.00461（2020年）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Lindahl, T. Instability and decay of the primary structure of DNA. Nature. 362, 709–715. https://doi.org/10.1038/362709a0 (1993).Article

Lindahl，T。DNA一级结构的不稳定性和衰变。自然。362709-715。https://doi.org/10.1038/362709a0（1993年）。文章

ADS

CAS

中科院

PubMed

Google Scholar

谷歌学者

Pfeifer, G. P. Mutagenesis at methylated CpG sequences. Curr. Top. Microbiol. Immunol.301, 259–281. https://doi.org/10.1007/3-540-31390-7_10 (2006).Article

Pfeifer，G.P。甲基化CpG序列的诱变。货币。。微生物。免疫l.301259-281。https://doi.org/10.1007/3-540-31390-7_10（2006年）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Cagan, A. et al. Somatic mutation rates scale with lifespan across mammals. Nature. 604, 517–524. https://doi.org/10.1038/s41586-022-04618-z (2022).Article

Cagan，A。等人。体细胞突变率随着哺乳动物的寿命而变化。自然。604517-524。https://doi.org/10.1038/s41586-022-04618-z（2022年）。文章

ADS

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Douglas, G. R., Gingerich, J. D., Gossen, J. A. & Bartlett, S. A. Sequence spectra of spontaneous lacZ gene mutations in transgenic mouse somatic and germline tissues. Mutagenesis. 9, 451–458. https://doi.org/10.1093/mutage/9.5.451 (1994).Article

。诱变。9451-458。https://doi.org/10.1093/mutage/9.5.451（1994年）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Gelova, S. P., Doherty, K. N., Alasmar, S. & Chan, K. Intrinsic base substitution patterns in diverse species reveal links to cancer and metabolism. Genetics. 222https://doi.org/10.1093/genetics/iyac144 (2022).Alexandrov, L. B. et al. Signatures of mutational processes in human cancer.

Gelova，S.P.，Doherty，K.N.，Alasmar，S。＆Chan，K。不同物种的内在碱基取代模式揭示了与癌症和代谢的联系。遗传学。222https://doi.org/10.1093/genetics/iyac144（2022年）。Alexandrov，L.B.等人。人类癌症突变过程的特征。

Nature. 500, 415–421. https://doi.org/10.1038/nature12477 (2013).Article .

自然。500415-421。https://doi.org/10.1038/nature12477（2013年）。文章。

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Crisafulli, G. et al. Temozolomide treatment alters mismatch repair and boosts mutational burden in tumor and blood of colorectal cancer patients. Cancer Discov. 12, 1656–1675. https://doi.org/10.1158/2159-8290.CD-21-1434 (2022).Article

Crisafulli，G。等人。替莫唑胺治疗改变了错配修复，并增加了结直肠癌患者肿瘤和血液中的突变负担。癌症发现。121656-1675年。https://doi.org/10.1158/2159-8290.CD-21-1434（2022年）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Kucab, J. E. et al. A compendium of mutational signatures of environmental agents. Cell177, 821–836.e816 https://doi.org/10.1016/j.cell.2019.03.001 (2019).Cao, X. et al. Extrachromosomal circular DNA: category, biogenesis, recognition, and functions. Front. Vet. Sci.8, 693641. https://doi.org/10.3389/fvets.2021.693641 (2021).Article .

Kucab，J.E.等人，《环境因子突变特征纲要》。细胞177821-836.e816https://doi.org/10.1016/j.cell.2019.03.001（2019年）。Cao，X。等。染色体外环状DNA：类别，生物发生，识别和功能。正面。兽医。科学8693641。https://doi.org/10.3389/fvets.2021.693641。文章。

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Noer, J. B., Horsdal, O. K., Xiang, X., Luo, Y. & Regenberg, B. Extrachromosomal circular DNA in cancer: history, current knowledge, and methods. Trends Genet.38, 766–781. https://doi.org/10.1016/j.tig.2022.02.007 (2022).Article

Noer，J.B.，Horsdal，O.K.，Xiang，X.，Luo，Y。＆Regenberg，B。癌症中的染色体外环状DNA：历史，当前知识和方法。趋势基因38766-781。https://doi.org/10.1016/j.tig.2022.02.007（2022年）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Zhao, Y., Yu, L., Zhang, S., Su, X. & Zhou, X. Extrachromosomal circular DNA: current status and future prospects. Elife. 11https://doi.org/10.7554/eLife.81412 (2022).Mouakkad-Montoya, L. et al. Quantitative assessment reveals the dominance of duplicated sequences in germline-derived extrachromosomal circular DNA.

Zhao，Y.，Yu，L.，Zhang，S.，Su，X。＆Zhou，X。染色体外环状DNA：现状和未来前景。埃利夫。11https://doi.org/10.7554/eLife.81412（2022年）。Mouakkad Montoya，L。等人。定量评估揭示了种系衍生的染色体外环状DNA中重复序列的优势。

Proc. Natl. Acad. Sci. USA. 118https://doi.org/10.1073/pnas.2102842118 (2021).Henriksen, R. A. et al. Circular DNA in the human germline and its association with recombination. Mol. Cell82, 209–217.e207 https://doi.org/10.1016/j.molcel.2021.11.027 (2022).Hu, J. et al. Microhomology-mediated circular DNA formation from oligonucleosomal fragments during spermatogenesis.

程序。纳特尔。阿卡德。科学。美国118https://doi.org/10.1073/pnas.2102842118。Henriksen，R.A.等人，《人类种系中的环状DNA及其与重组的关系》。分子细胞82209–217.e207https://doi.org/10.1016/j.molcel.2021.11.027（2022年）。Hu，J。等人。精子发生过程中寡核小体片段的微同源性介导的环状DNA形成。

bioRxiv, 2023.2002.2027.530352, https://doi.org/10.1101/2023.02.27.530352 (2023).Muratori, M. et al. Investigation on the origin of sperm DNA fragmentation: role of apoptosis, immaturity and oxidative stress. Mol. Med.21, 109–122. https://doi.org/10.2119/molmed.2014.00158 (2015).Article .

bioRxiv，2023.2002.2027.530352，https://doi.org/10.1101/2023.02.27.530352（2023年）。Muratori，M.等人。精子DNA片段化起源的研究：细胞凋亡，不成熟和氧化应激的作用。摩尔医学21109-122。https://doi.org/10.2119/molmed.2014.00158（2015年）。文章。

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Bungum, M., Bungum, L. & Giwercman, A. Sperm chromatin structure assay (SCSA): a tool in diagnosis and treatment of infertility. Asian J. Androl.13, 69–75. https://doi.org/10.1038/aja.2010.73 (2011).Article

Bungum，M.，Bungum，L。＆Giwercman，A。精子染色质结构测定（SCSA）：诊断和治疗不孕症的工具。亚洲J.Androl.13，69-75。https://doi.org/10.1038/aja.2010.73（2011年）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Axelsson, J. et al. The impact of paternal and maternal smoking on semen quality of adolescent men. PLoS ONE. 8, e66766. https://doi.org/10.1371/journal.pone.0066766 (2013)..Article

Axelsson，J.等人。父母吸烟对青春期男性精液质量的影响。PLoS ONE。8，e66766。https://doi.org/10.1371/journal.pone.0066766（2013年）。。文章

ADS

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Paulsen, T. et al. MicroDNA levels are dependent on MMEJ, repressed by c-NHEJ pathway, and stimulated by DNA damage. Nucleic Acids Res.49, 11787–11799. https://doi.org/10.1093/nar/gkab984 (2021).Article

Paulsen，T。等人。MicroDNA水平依赖于MMEJ，受c-NHEJ途径抑制，并受DNA损伤刺激。核酸Res.4911787-11799。https://doi.org/10.1093/nar/gkab984。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Singh, N. P. et al. Abundant alkali-sensitive sites in DNA of human and mouse sperm. Exp. Cell. Res.184, 461–470. https://doi.org/10.1016/0014-4827(89)90344-3 (1989).Article

Singh，N.P.等人。人和小鼠精子DNA中丰富的碱敏感位点。扩展单元格。第184461-470号决议。https://doi.org/10.1016/0014-4827（89）90344-3（1989）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Menon, V. & Brash, D. E. Next-generation sequencing methodologies to detect low-frequency mutations: catch me if you can. Mutat. Res. Rev. Mutat. Res.792, 108471. https://doi.org/10.1016/j.mrrev.2023.108471 (2023).Article

Menon，V.＆Brash，D.E。检测低频突变的下一代测序方法：如果可以的话，请抓住我。突变。Res.修订版Mutat。第792108471号决议。https://doi.org/10.1016/j.mrrev.2023.108471（2023年）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Download referencesAcknowledgementsWe thank Professor Aleksander Giwercman for providing access to the herein used samples and research time to JA. We also thank all staff at the Reproductive Medicine Centre, Skåne University Hospital Malmö, Sweden, for help with recruitment of men, collection of samples and analysis of sperm chromatin integrity.

。我们还要感谢瑞典马尔默Skåne大学医院生殖医学中心的所有工作人员，感谢他们帮助招募男性，收集样本和分析精子染色质的完整性。

We thank the Swedish Society of Medicine, ARMEC Lindebergs stiftelse, Maggie Stephens stiftelse, and the Faculty of Medicine, Lund University, for providing funding to make the study possible. FM acknowledges funding support from the Health Canada’s Genomic Research and Development Initiative. CLY acknowledges that this research was undertaken, in part, thanks to funding from the Canada Research Chairs Program (CRC award number CRC-2020-00060).FundingOpen access funding provided by Lund University.Author informationAuthors and AffiliationsDepartment of Biology, University of Ottawa, Ottawa, ON, K1N 6N5, CanadaJonatan Axelsson & Carole YaukReproductive Medicine Centre, Skåne University Hospital, Malmö, SwedenJonatan AxelssonDepartment of Translational Medicine, Lund University, Malmö, SwedenJonatan AxelssonDepartment of Laboratory Medicine, Lund University, Lund, SwedenJonatan AxelssonEnvironmental Health Science and Research Bureau, Health Canada, Ottawa, CanadaDanielle LeBlanc, Habiballah Shojaeisaadi, Matthew J Meier, Andrew Williams & Francesco MarchettiTwinStrand Biosciences, Inc., Seattle, WA, USADevon M.

我们感谢瑞典医学会、ARMEC Lindebergs stiftelse、Maggie Stephens stiftelse和隆德大学医学院为这项研究提供资金。FM感谢加拿大卫生部基因组研究与发展倡议的资金支持。CLY承认，这项研究的进行部分归功于加拿大研究主席计划（CRC奖项编号CRC-2020-00060）的资助。资金隆德大学提供的开放获取资金。作者信息作者和附属机构渥太华大学生物学系，渥太华，ON，K1N 6N5，CanadaJonatan Axelsson＆Carole YaukReproductive Medicine Centre，Skåne大学医院，Malmö，SwedenJonatan Axelsson隆德大学转化医学系，隆德，SwedenJonatan Axelsson实验室医学系，加拿大卫生部，渥太华，CanadaDanielle LeBlanc，Habiballah Shojaeisaadi，Matthew J Meier，Andrew Williams＆Francison ESCO Marchettititwinstrand Biosciences，Inc.，华盛顿州西雅图，美国德文郡M。

Fitzgerald, Daniela Nachmanson, Jedidiah Carlson, Alexandra Golubeva, Jake Higgins, Thomas Smith, Fang Yin Lo & Jesse SalkDepartment of Obstetrics & Gynecology, Wayne State University, Detroit, MI, USARichard PilsnerAuthorsJonatan AxelssonView author publicationsYou can also search for this author in.

菲茨杰拉德（Fitzgerald）、丹妮拉·纳奇曼森（DanielaNachmanson）、杰迪迪亚·卡尔森（JedidiahCarlson）、亚历山德拉·戈卢贝娃（AlexandraGolubeva）、杰克·希金斯（JakeHiggins）、托马斯·史密斯（ThomasSmith）、方茵·罗（FangyinLo）和杰西·索尔克（JesseSalkdepartment of Obstics＆Gynomy）、韦恩州立大学（WayneState University）、密歇根州底特律。

PubMed Google ScholarDanielle LeBlancView author publicationsYou can also search for this author in

PubMed Google ScholarDanielle LeBlancView作者出版物您也可以在

PubMed Google ScholarHabiballah ShojaeisaadiView author publicationsYou can also search for this author in

PubMed Google ScholarMatthew J MeierView author publicationsYou can also search for this author in

PubMed Google ScholarMatthew J MeierView作者出版物您也可以在

PubMed Google ScholarDevon M. FitzgeraldView author publicationsYou can also search for this author in

PubMed Google ScholarDevon M.FitzgeraldView作者出版物您也可以在

PubMed Google ScholarDaniela NachmansonView author publicationsYou can also search for this author in

PubMed Google ScholarDaniela NachmansonView作者出版物您也可以在

PubMed Google ScholarJedidiah CarlsonView author publicationsYou can also search for this author in

PubMed Google ScholarJedidiah CarlsonView作者出版物您也可以在

PubMed Google ScholarAlexandra GolubevaView author publicationsYou can also search for this author in

PubMed Google ScholarAlexandra GolubevaView作者出版物您也可以在

PubMed Google ScholarJake HigginsView author publicationsYou can also search for this author in

PubMed Google ScholarJake HigginsView作者出版物您也可以在

PubMed Google ScholarThomas SmithView author publicationsYou can also search for this author in

PubMed Google ScholarThomas SmithView作者出版物您也可以在

PubMed Google ScholarFang Yin LoView author publicationsYou can also search for this author in

PubMed Google ScholarFang Yin LoView作者出版物您也可以在

PubMed Google ScholarRichard PilsnerView author publicationsYou can also search for this author in

PubMed Google ScholarRichard PilsnerView作者出版物您也可以在

PubMed Google ScholarAndrew WilliamsView author publicationsYou can also search for this author in

PubMed Google ScholarAndrew WilliamsView作者出版物您也可以在

PubMed Google ScholarJesse SalkView author publicationsYou can also search for this author in

PubMed Google ScholarJesse SalkView作者出版物您也可以在

PubMed Google ScholarFrancesco MarchettiView author publicationsYou can also search for this author in

PubMed Google ScholarFrancesco MarchettiView作者出版物您也可以在

PubMed Google ScholarCarole YaukView author publicationsYou can also search for this author in

PubMed Google ScholarCarole YaukView作者出版物您也可以在

PubMed Google ScholarContributionsJ.A.: Conceptualization, Resources, Data analysis, Writing - Original Draft, Funding Acquisition, Project administration; D.LB.: Formal analysis, Resources, Data Curation; H.S.: Formal analysis, Data Curation, Writing - Review & Editing; M.M.: Formal analysis, Data Curation, Writing - Review & Editing; D.M.F.: Data analysis, Data Curation, Data Interpretation, Writing - Review & Editing; M.M.: Formal analysis, Interpretation, Writing - Review & Editing; D.N.: Data Analysis, Data Curation Writing - Review & Editing; J.C.: Data Analysis; A.G.: Sample Processing, Data Curation; J.H.: Data analysis, Data interpretation, Writing - Review & Editing; T.S.: Data Analysis; F.Y.L.: Data Analysis; R.P.: Sperm sample processing, Writing - Review & Editing; A.W.: Statistical analysis; J.S.: Scientific advisor, Data interpretation; F.M.: Supervision, Data interpretation, Writing - Original Draft, Review & Editing, Funding Acquisition; C.Y: Supervision, Resources; Data interpretation, Writing - Original Draft Review & Editing, Funding Acquisition.

PubMed谷歌学术贡献。A、：概念化，资源，数据分析，写作-原稿，资金获取，项目管理；D、 LB.：形式分析，资源，数据管理；H、美国：正式分析，数据管理，写作-评论和编辑；M、 M.：正式分析，数据管理，写作-评论和编辑；D、 M.F.：数据分析，数据管理，数据解释，写作-评论和编辑；M、 M.：形式分析，解释，写作-评论和编辑；D、 N.：数据分析，数据策划写作-评论和编辑；J、 C.：数据分析；A、 G：样品处理，数据管理；J、 H.：数据分析，数据解释，写作-审查和编辑；T、 S.：数据分析；F、 Y.L.：数据分析；R、 P：精子样本处理，写作-评论和编辑；A、 W.：统计分析；J、 S.：科学顾问，数据解释；F、 M：监督，数据解释，写作-原稿，审查和编辑，资金获取；C、 Y：监督，资源；数据解释，写作-原稿审查和编辑，资金获取。

All authors reviewed and approved the final version of the manuscript.Corresponding authorCorrespondence to.

所有作者都审查并批准了手稿的最终版本。对应作者对应。

Jonatan Axelsson.Ethics declarations

乔纳坦·阿克塞尔森。道德宣言

Competing interests

相互竞争的利益

JA, CY, MM, AW, FM declare no competing interests. DF, JC, SG, JH, TS, DN, FYL and JJS are employees and equity holders at TwinStrand Biosciences, Inc., or were during their contributions to this manuscript.

JA，CY，MM，AW，FM声明没有利益冲突。DF，JC，SG，JH，TS，DN，FYL和JJS是TwinStrand Biosciences，Inc.的员工和股东，或者在他们为本手稿做出贡献期间。

Additional informationPublisher’s noteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Electronic supplementary materialBelow is the link to the electronic supplementary material.Supplementary Material 1Rights and permissions

Additional informationPublisher的noteSpringer Nature在已发布地图和机构隶属关系中的管辖权主张方面保持中立。电子补充材料流是指向电子补充材料的链接。补充材料1权利和许可

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.

开放获取本文是根据知识共享署名4.0国际许可证授权的，该许可证允许以任何媒体或格式使用，共享，改编，分发和复制，只要您对原始作者和来源给予适当的信任，提供知识共享许可证的链接，并指出是否进行了更改。

The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/..

要查看此许可证的副本，请访问http://creativecommons.org/licenses/by/4.0/..

Reprints and permissionsAbout this articleCite this articleAxelsson, J., LeBlanc, D., Shojaeisaadi, H. et al. Frequency and spectrum of mutations in human sperm measured using duplex sequencing correlate with trio-based de novo mutation analyses.

转载和许可本文引用本文Axelsson，J.，LeBlanc，D.，Shojaeisaadi，H。等人。使用双链测序测量的人类精子突变的频率和频谱与基于三重的从头突变分析相关。

Sci Rep 14, 23134 (2024). https://doi.org/10.1038/s41598-024-73587-2Download citationReceived: 26 March 2024Accepted: 18 September 2024Published: 08 October 2024DOI: https://doi.org/10.1038/s41598-024-73587-2Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

科学报告1423134（2024）。https://doi.org/10.1038/s41598-024-73587-2Downloadhttps://doi.org/10.1038/s41598-024-73587-2Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

Provided by the Springer Nature SharedIt content-sharing initiative

由Springer Nature SharedIt内容共享计划提供

KeywordsSperm DNA mutationsDe novo mutationsMutation frequencyMutational spectrumExtrachromosomal circular DNADuplex sequencing

关键词精子DNA突变从头突变突变频率突变谱染色体外循环DNA多重测序

CommentsBy submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

评论通过提交评论，您同意遵守我们的条款和社区指南。如果您发现有虐待行为或不符合我们的条款或准则，请将其标记为不合适。

全球产业链接平台

重庆市渝北区金星科技大厦A区5楼512室

联系电话：023-67139735（重庆）

关于我们

产品服务