Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA.
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02114, USA.
Am J Hum Genet. 2021 Apr 1;108(4):597-607. doi: 10.1016/j.ajhg.2021.02.012. Epub 2021 Mar 5.
Each human genome includes de novo mutations that arose during gametogenesis. While these germline mutations represent a fundamental source of new genetic diversity, they can also create deleterious alleles that impact fitness. Whereas the rate and patterns of point mutations in the human germline are now well understood, far less is known about the frequency and features that impact de novo structural variants (dnSVs). We report a family-based study of germline mutations among 9,599 human genomes from 33 multigenerational CEPH-Utah families and 2,384 families from the Simons Foundation Autism Research Initiative. We find that de novo structural mutations detected by alignment-based, short-read WGS occur at an overall rate of at least 0.160 events per genome in unaffected individuals, and we observe a significantly higher rate (0.206 per genome) in ASD-affected individuals. In both probands and unaffected samples, nearly 73% of de novo structural mutations arose in paternal gametes, and we predict most de novo structural mutations to be caused by mutational mechanisms that do not require sequence homology. After multiple testing correction, we did not observe a statistically significant correlation between parental age and the rate of de novo structural variation in offspring. These results highlight that a spectrum of mutational mechanisms contribute to germline structural mutations and that these mechanisms most likely have markedly different rates and selective pressures than those leading to point mutations.
每个人类基因组都包含在配子发生过程中产生的新生突变。虽然这些生殖系突变代表了新遗传多样性的基本来源，但它们也可能产生影响适应性的有害等位基因。虽然人类生殖系中点突变的速率和模式现在已经很好理解，但对于影响新生结构变体 (dnSV) 的频率和特征知之甚少。我们报告了一项基于家族的研究，该研究涉及来自 33 个多代 CEPH-Utah 家族和 2384 个 Simons 基金会自闭症研究倡议家族的 9599 个人类基因组中的生殖系突变。我们发现，通过基于比对的短读长 WGS 检测到的新生结构突变，在未受影响的个体中，每个基因组的总体发生率至少为 0.160 个事件，而在 ASD 受影响的个体中，这一速率明显更高 (0.206 个事件/基因组)。在先证者和未受影响的样本中，近 73%的新生结构突变发生在父配子中，我们预测大多数新生结构突变是由不需要序列同源性的突变机制引起的。在多重测试校正后，我们没有观察到父母年龄与后代新生结构变异率之间存在统计学显著相关性。这些结果表明，一系列突变机制导致生殖系结构突变，这些机制的速率和选择压力很可能与导致点突变的机制明显不同。
