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  • Review Article
  • Published:

Understanding what determines the frequency and pattern of human germline mutations

Nature Reviews Genetics volume 10, pages 478–488 (2009)Cite this article

Key Points

  • Recent technological advances have made it possible to directly measure the frequency of rare nucleotide substitution mutations in human germline DNA. Semen is an ideal source of genetic material as a single sample can contain over 108 sperm.

  • Some human nucleotides have mutation frequencies that are orders of magnitude greater than the genome average and, at least in some disease-causing examples, there is evidence that this increased frequency is not due to more frequent mutation. Rather, a selective advantage conferred on the male germline cells by the mutation has been suggested; other diseases may also achieve high frequencies in the population owing to germline selection.

  • The indirect method of studying nucleotide substitution mutations by comparing aligned sequences in different species has found that the mutation rate varies across the genome. Many genomic factors such as coding versus non-coding sequence, base identity, GC content, recombination rate, and proximity to insertions or deletions are correlated with this rate, although it is likely that no single factor can explain all the variation.

  • Both interspecific sequence comparisons and analysis of parental origins of human disease mutations in families suggest that nucleotide substitutions occur more frequently in males than females. Recent studies have shown that mutations at CpG sites are significantly more male-biased if the CpG sites are in CpG islands.

  • Human disease mutations increase in frequency with the father's age; this has long been thought to result from the life-long divisions of the male germ cells. In some cases, new evidence suggests that selection of germ cells carrying the new mutation can explain the age-dependent increase.

Abstract

Surprising findings about human germline mutation have come from applying new technologies to detect rare mutations in germline DNA, from analysing DNA sequence divergence between humans and closely related species, and from investigating human polymorphic variation. In this Review we discuss how these approaches affect our current understanding of the roles of sex, age, mutation hot spots, germline selection and genomic factors in determining human nucleotide substitution mutation patterns and frequencies. To enhance our understanding of mutation and disease, more extensive molecular data on the human germ line with regard to mutation origin, DNA repair, epigenetic status and the effect of newly arisen mutations on gamete development are needed.

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Figure 1: Human testis and epididymis.
Figure 2: Distribution of mutations at a single nucleotide site in the testis.
Figure 3: Mutation hot spot and selection models of germline cell divisions.

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Acknowledgements

This work was supported in part by grants from the National Institute of General Medical Sciences (N.A. and P.C.) and the Ellison Medical Research Foundation (N.A.).

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  1. Molecular and Computational Biology Program, University of Southern California, 1050 Childs Way, Los Angeles, 90089–2910, California, USA

    Norman Arnheim & Peter Calabrese

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DATABASES

OMIM

achondroplasia

Apert syndrome

DMD

Down syndrome

fragile X syndrome

haemophilia A

MEN2B

Rett syndrome

FURTHER INFORMATION

Norman Arnheim's homepage

Peter Calabrese's homepage

Glossary

Ligase chain reaction

Amplification of a small DNA fragment by successive rounds of DNA ligation using one pair of adjacent primers for each of the two complementary target DNA strands.

Effective population size

The number of breeding individuals in an idealized population that would show similar characteristics to the population under consideration. For a number of reasons, the effective population size is typically smaller than the actual number of individuals in the population.

Achondroplasia

A common form of dwarfism, inherited in an autosomal dominant fashion.

Apert syndrome

An autosomal dominant disorder characterized by premature closing of cranial sutures and fused fingers and toes.

Spermatogonia

Premeiotic diploid cells of the mature male germ line.

Transversion mutation

A point mutation in which a purine base is substituted for a pyrimidine base and vice versa; for example, an A˙T to C˙G transversion.

Multiple endocrine neoplasia type 2B

Mutation in the proto-oncogene RET. The mutation is inherited in an autosomal dominant fashion and leads to early childhood thyroid cancer.

Transition mutation

A point mutation in which a purine base (adenine or guanine) is substituted for a different purine base, and a pyrimidine base (cytosine or thymidine) is substituted for a different pyrimidine base; for example, an A˙T to G˙C transition.

Rett syndrome

AnXlinked neurodevelopmental disorder that is associated with mental retardation. It is found sporadically and almost exclusively in females who inherit a new mutation in the methyl-CpG-binding protein 2 gene (MECP2) from their father.

Transcription-coupled repair

A form of DNA repair that removes DNA lesions that inhibit the progression of RNA polymerase during transcription. The repair process specifically targets lesions on the template strand.

Biased gene conversion

A non-reciprocal copy and paste of one allele onto the other one at heterozygous loci during meiotic recombination. Some authors have proposed that this process is biased such that at a site heterozygous for a G˙C or C˙G allele and an A˙T or T˙A allele there will be more G˙C or C˙G gametes produced.

Recombination fraction

Estimate of the proportion of all gametes that were derived from meiotic crossing-over events in a chosen interval.

Epigenomics

Analysis of epigenetic marks (DNA and protein modifications) on a genome-wide scale.

Duchenne muscular dystrophy

A disorder caused by mutations in the X-linked dystrophin gene and characterized by rapidly worsening muscle weakness.

Haemophilia A

A blood clotting disease resulting from mutations in the X-linked factor VIII gene.

CpG island

A region at least several hundred base pairs in length that is characterized by a high GC content and a large number of unmethylated CpG dinucleotides. CpG islands are found to overlap a large fraction of human gene promoters.

Bisulphite sequencing

Chemical treatment of genomic DNA before sequencing that allows identification of those cytosines that were methylated in the DNA from a particular tissue source. Unmethylated cytosines are converted to uracils, whereas methylated cytosines remain unmodified.

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Arnheim, N., Calabrese, P. Understanding what determines the frequency and pattern of human germline mutations. Nat Rev Genet 10, 478–488 (2009). https://doi.org/10.1038/nrg2529

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