Trends in Genetics
Volume 29, Issue 10, October 2013, Pages 575-584
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Review
Feature Review
Properties and rates of germline mutations in humans

https://doi.org/10.1016/j.tig.2013.04.005Get rights and content

Highlights

  • We describe insights into mutation rate from high-throughput genome sequencing of families.

  • A paternal bias and agebeffect in mutation has been quantified at the genome-wide level.

  • Copy number variants arise less frequently than do point mutations, but affect more bases.

  • Future research will yield insights into the mutation rate of other forms of variation.

All genetic variation arises via new mutations; therefore, determining the rate and biases for different classes of mutation is essential for understanding the genetics of human disease and evolution. Decades of mutation rate analyses have focused on a relatively small number of loci because of technical limitations. However, advances in sequencing technology have allowed for empirical assessments of genome-wide rates of mutation. Recent studies have shown that 76% of new mutations originate in the paternal lineage and provide unequivocal evidence for an increase in mutation with paternal age. Although most analyses have focused on single nucleotide variants (SNVs), studies have begun to provide insight into the mutation rate for other classes of variation, including copy number variants (CNVs), microsatellites, and mobile element insertions (MEIs). Here, we review the genome-wide analyses for the mutation rate of several types of variants and suggest areas for future research.

Section snippets

The fundamental process in genetics

The replication of the genome before cell division is a remarkably precise process. Nevertheless, there are some errors during DNA replication that lead to new mutations. If these errors occur in the germ cell lineage (i.e., the sperm and egg), then these mutations can be transmitted to offspring. Some of these new genetic variants will be deleterious to the organism, and a select few will be advantageous and serve as substrates for selection. Therefore, knowledge about the rate at which new

SNV mutation rate

It is now feasible to perform whole-genome sequencing on all individuals from a nuclear family; from these data, one can identify de novo mutations that ‘disobey’ Mendelian inheritance (Box 1, Figure I). The first two papers to apply this approach were limited in scope to three families 4, 5, thus restricting the total number of de novo SNVs observed. Even with this limitation, these two analyses reported similar overall mutation rates of approximately 1 × 10−8 SNV mutation per base pair per

CNV mutation rate

In addition to SNVs, there has been considerable effort in estimating the rates of formation of CNVs. Although CNVs are operationally defined as deletions and duplications of 50 bp or more [17], most studies have assessed de novo events only in the multi-kilobase pair range. As with SNVs, initial studies in this area focused on only a few loci. These analyses found that the locus mutation rate was higher for CNVs (2.5 × 10−6–1 × 10−4 mutations per locus per generation) compared with SNVs and that

Other classes of genetic variation

In addition to CNVs and SNVs, there are many other forms of genetic variation that arise by completely different mutational processes and, consequently, have distinct biases. The largest, of course, are aneuploidies (the duplication or deletion of an entire chromosome). Due to the severity of these mutations (the most well-studied aneuploidy is Down syndrome), most aneuploidies are lethal in utero. Studies of spontaneous abortions and embryos created with in vitro fertilization suggest that

Nonrandom distribution of new mutations

Given the tendency for certain types of loci to mutate, it is not surprising that new SNV and CNV mutations are not random. Several reported and predicted properties of new SNVs have been confirmed in recent genome-wide analyses. First, transitions outnumber transversions by twofold for de novo SNVs 4, 5, 30. The rate of mutation at CpG dinucleotides has been observed to be ten- to 18-fold the rate of non-CpG dinucleotides 3, 6, 7, 30. CpG dinucleotides are predicted to be more mutagenic

Parental bias and paternal age effects

It has long been hypothesized and observed that more mutations arise on the paternal germline 2, 88, and this difference is thought to be due to the larger number and continuous nature of cell divisions in spermatogenesis. Female eggs arise from a finite number of 22–33 cell divisions, whereas male sperm monotonically increase every 15–16 days as a result of mitotic maintenance of the spermatogonial pool (reviewed in [89]). The dependence of SNV mutation on replication dictates an increase in

New mutations, selection, and human disease

There has been much recent interest in identifying de novo mutations that play a role in the development of human disease; knowledge of the patterns of human mutation is critical to the interpretation of these studies. Some broad themes are beginning to emerge. First, it is clear that deleterious de novo mutations contribute significantly to human disease and probably have played a more important role in all diseases than previously anticipated as a result of the super exponential increase in

Inferring dates of human evolution

The increasing number of direct analyses in human families has led to discussion aimed at resolving these new rate estimates with our knowledge of important dates in human evolution. This stems from the fact that the mutation rates calculated directly in human families are approximately half of that calculated based on sequence divergence and fossil record 107, 108. As a result of these updated mutation rates, generation times in the great ape lineages may be longer than previously thought [107]

Concluding remarks

Over the past few years, genomic technologies have made it possible to obtain direct knowledge concerning rates of human mutation. Recent studies are converging on similar SNV mutation rates, quantifying the male mutation bias and its relation with paternal age. The current rate estimate for SNVs likely represents a lower boundary because of biases in next-generation sequencing technology 31, 62 and the stringent filtering required to remove false positive calls. In addition, we have gained new

Acknowledgments

We thank Santhosh Girirajan and Bradley Coe for sharing data and figures. We are grateful to Andrew Wilkie, Anne Goriely, and Peter Sudmant for helpful discussions and to Tonia Brown for assistance with manuscript preparation. We would like to thank Jacob Michaelson and Jonathan Sebat for sharing a prepublication version of their manuscript. C.D.C. was supported by a Ruth L. Kirschstein National Research Service Award (NRSA; F32HG006070). E.E.E. is an Investigator of the Howard Hughes Medical

Glossary

Autozygosity
large regions of homozygous sequence inherited from a recent ancestor; also referred to as homozygosity by recent descent.
De novo mutation
a mutation observed in a child but not in his or her parents. Such mutations are assumed to have occurred in one of the parental germlines.
Haplotype phase
determination of which alleles segregate on the same physical chromosomes. For example, which alleles of nearby variants in a child occur on the chromosome inherited from his or her father.

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