Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden.
J Med Genet. 2013 Apr;50(4):203-11. doi: 10.1136/jmedgenet-2013-101519. Epub 2013 Feb 9.
Human germline mutations arise anew during meiosis in every generation. Such spontaneously occurring genetic variants are termed de novo mutations. Although the introduction of microarray based approaches led to the discovery of numerous de novo copy number variants underlying a range of human genetic conditions, de novo single nucleotide variants (SNVs) remained refractory to analysis at the whole genome level until the advent of next generation sequencing technologies such as whole genome sequencing and whole exome sequencing. These approaches have recently allowed the estimation of the mutation rate of de novo SNVs and greatly increased our understanding of their contribution to human genetic disease. Indeed, de novo SNVs have been found to underlie various common human neurodevelopmental conditions such as schizophrenia, autism and intellectual disability, as well as sporadic cases of rare Mendelian disorders. In many cases, however, confirmation of the pathogenicity of identified de novo SNVs remains a major challenge.
人类种系突变在每一代的减数分裂中都会重新出现。这种自发发生的遗传变异被称为新生突变。尽管基于微阵列的方法的引入导致了许多新生拷贝数变异的发现，这些变异是一系列人类遗传疾病的基础，但直到新一代测序技术（如全基因组测序和全外显子组测序）的出现，新生单核苷酸变异（SNVs）的全基因组水平分析仍然难以进行。这些方法最近允许估计新生 SNVs 的突变率，并大大提高了我们对它们在人类遗传疾病中的贡献的理解。事实上，新生 SNVs 已被发现是各种常见的人类神经发育疾病（如精神分裂症、自闭症和智力障碍）以及罕见孟德尔疾病的散发病例的基础。然而，在许多情况下，确定新生 SNVs 的致病性仍然是一个主要挑战。
