De Novo Mutations Reflect Development and Aging of the Human Germline

Abstract

Human germline de novo mutations (DNMs) are both a driver of evolution and an important cause of genetic diseases. In the past few years, whole-genome sequencing (WGS) of parentoffspring trios has facilitated the large-scale detection and study of human DNMs, which has led to exciting discoveries. The overarching theme of all of these studies is that the DNMs of an individual are a complex mixture of mutations that arise through different biological processes acting at different times during human development and life. De novo mutationsHuman de novo mutations (DNMs, see Glossary) are germline mutations that newly occurred within one generation. While the vast majority of the genome has been inherited from earlier generations, DNMs provide new genetic variation. The consequences of the new genetic mutation can vary widely. While neutral or advantageous mutations might become established in the genome of our species and thereby contribute to human evolution, changes to crucial genetic sequences can also result in misfunctioning of biological systems, resulting in severe disease. One of the earliest known examples of this was Down syndrome, which is caused by a de novo trisomy of chromosome 21 [1][2][3]. In recent years DNMs have been found to be a prominent cause of neurodevelopmental diseases, including intellectual disability, autism, and schizophrenia [4,5]. The unbiased study of de novo point mutations in humans was for many years hampered by the lack of techniques to scan the entire genome in a cost-effective way. The introduction of next-generation sequencing (NGS) technologies has spurred investigations of DNMs in humans [6]. DNMs can refer to a variety of different mutation types, such as single-nucleotide substitutions, insertions, deletions, and copy-number variants (CNVs). In this review we focus on single-nucleotide mutations and review the progress made in this field since the introduction of WGS, exploring their biology and possible underlying mechanisms (Figure 1, Key Figure ), but not the potential pathological consequences.

A comparison of humans and baboons suggests germline mutation rates do not track cell divisions

“…In particular, a recent review argued that germline mutations are replicative in origin and hence track cell divisions but that the rate of SSC divisions is much lower than previously believed [45]. Although plausible [45,46], this explanation alone would not explain our findings: If mutations were due to replication errors and if rates of SSC divisions were very low, then without making further assumptions, we would expect human and baboon paternal mutation rates per generation to be highly similar, when they are not. In turn, the approximately 2-fold lower mutation rate observed in baboon compared with human females could be explained if there are fewer rounds of DNA replication in baboons than humans (or greater replication fidelity).…”

The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting

“…Human germline de novo mutations are both a driver of evolution and an important cause of genetic disease (Goldmann et al 2019 ; Veltman and Brunner 2012 ; Acuna-Hidalgo et al 2016 ). Indeed, whole-genome studies have suggested that de novo mutations may be responsible for a considerable proportion of congenital or early-onset neurodevelopmental disorders, including autism spectrum disorder, epilepsy and intellectual disability/developmental delay (Neale et al 2012 ; Iossifov et al 2014 ; Hamdan et al 2017 ).…”

A novel de novo dominant mutation of NOTCH1 gene in an Iranian family with non‐syndromic congenital heart disease

“…24 De novo variants are an important reason of early-onset genetic disease such as CHD, hearing loss. 37 The identified NOTCH1 variant was found to be novel de novo which not reported on 1000…”