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Understanding what determines the frequency and pattern of human germline mutations

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.

References

  1. Weatherall, D. J. The global problem of genetic disease. Ann. Hum. Biol. 32, 117–122 (2005).

    CAS  PubMed  Google Scholar 

  2. Hassold, T., Hall, H. & Hunt, P. The origin of human aneuploidy: where we have been, where we are going. Hum. Mol. Genet. 16, R203–R208 (2007).

    CAS  PubMed  Google Scholar 

  3. Pacchierotti, F., Adler, I. D., Eichenlaub-Ritter, U. & Mailhes, J. B. Gender effects on the incidence of aneuploidy in mammalian germ cells. Environ. Res. 104, 46–69 (2007).

    CAS  PubMed  Google Scholar 

  4. Rosenbusch, B. E. Mechanisms giving rise to triploid zygotes during assisted reproduction. Fertil. Steril. 90, 49–55 (2008).

    PubMed  Google Scholar 

  5. Ellegren, H. Microsatellites: simple sequences with complex evolution. Nature Rev. Genet. 5, 435–445 (2004).

    CAS  PubMed  Google Scholar 

  6. Kelkar, Y. D., Tyekucheva, S., Chiaromonte, F. & Makova, K. D. The genome-wide determinants of human and chimpanzee microsatellite evolution. Genome Res. 18, 30–38 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Bois, P. & Jeffreys, A. J. Minisatellite instability and germline mutation. Cell. Mol. Life Sci. 55, 1636–1648 (1999).

    CAS  PubMed  Google Scholar 

  8. Lupski, J. R. & Stankiewicz, P. Genomic disorders: molecular mechanisms for rearrangements and conveyed phenotypes. PLoS Genet. 1, e49 (2005).

    PubMed  PubMed Central  Google Scholar 

  9. Inoue, K. & Lupski, J. R. Molecular mechanisms for genomic disorders. Annu. Rev. Genomics Hum. Genet. 3, 199–242 (2002).

    CAS  PubMed  Google Scholar 

  10. Sharp, A. J., Cheng, Z. & Eichler, E. E. Structural variation of the human genome. Annu. Rev. Genomics Hum. Genet. 7, 407–442 (2006).

    CAS  PubMed  Google Scholar 

  11. Sen, S. K. et al. Human genomic deletions mediated by recombination between Alu elements. Am. J. Hum. Genet. 79, 41–53 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Scherer, S. W. et al. Challenges and standards in integrating surveys of structural variation. Nature Genet. 39 (Suppl.), S7–S15 (2007).

    CAS  PubMed  Google Scholar 

  13. Turner, D. J. et al. Germline rates of de novo meiotic deletions and duplications causing several genomic disorders. Nature Genet. 40, 90–95 (2008).

    CAS  PubMed  Google Scholar 

  14. Babushok, D. V. & Kazazian, H. H. Jr. Progress in understanding the biology of the human mutagen LINE-1. Hum. Mutat. 28, 527–539 (2007).

    CAS  PubMed  Google Scholar 

  15. Chen, J. M., Stenson, P. D., Cooper, D. N. & Ferec, C. A systematic analysis of LINE-1 endonuclease-dependent retrotranspositional events causing human genetic disease. Hum. Genet. 117, 411–427 (2005).

    CAS  PubMed  Google Scholar 

  16. Cordaux, R., Hedges, D. J., Herke, S. W. & Batzer, M. A. Estimating the retrotransposition rate of human Alu elements. Gene 373, 134–137 (2006).

    CAS  PubMed  Google Scholar 

  17. Jacobs, P. A., Browne, C., Gregson, N., Joyce, C. & White, H. Estimates of the frequency of chromosome abnormalities detectable in unselected newborns using moderate levels of banding. J. Med. Genet. 29, 103–108 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Baptista, J. et al. Breakpoint mapping and array CGH in translocations: comparison of a phenotypically normal and an abnormal cohort. Am. J. Hum. Genet. 82, 927–936 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Chen, J.-M., Cooper, D. N., Chuzhanova, N., Ferec, C. & Patrinos, G. P. Gene conversion: mechanisms, evolution and human disease. Nature Rev. Genet. 8, 762–775 (2007).

    CAS  PubMed  Google Scholar 

  20. Vogel, F. & Motulsky, A. G. Human Genetics: Problems and Approaches (Springer, Berlin, 1997).

    Google Scholar 

  21. Crow, J. F. The origins, patterns and implications of human spontaneous mutation. Nature Rev. Genet. 1, 40–47 (2000).

    CAS  PubMed  Google Scholar 

  22. Glaser, R. L. et al. The paternal-age effect in Apert syndrome is due, in part, to the increased frequency of mutations in sperm. Am. J. Hum. Genet. 73, 939–947 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Tiemann-Boege, I. et al. The observed human sperm mutation frequency cannot explain the achondroplasia paternal age effect. Proc. Natl Acad. Sci. USA 99, 14952–14957 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Goriely, A., McVean, G. A., Rojmyr, M., Ingemarsson, B. & Wilkie, A. O. Evidence for selective advantage of pathogenic FGFR2 mutations in the male germ line. Science 301, 643–646 (2003).

    CAS  PubMed  Google Scholar 

  25. Cole, D. N., Carlson, J. A. & Wilson, V. L. Human germline and somatic cells have similar TP53 and Kirsten-RAS gene single base mutation frequencies. Environ. Mol. Mutagen. 49, 417–425 (2008).

    CAS  PubMed  Google Scholar 

  26. Choi, S. K., Yoon, S. R., Calabrese, P. & Arnheim, N. A germ-line-selective advantage rather than an increased mutation rate can explain some unexpectedly common human disease mutations. Proc. Natl Acad. Sci. USA 105, 10143–10148 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Qin, J. et al. The molecular anatomy of spontaneous germline mutations in human testes. PLoS Biol. 5, e224 (2007).

    PubMed  PubMed Central  Google Scholar 

  28. Liu, Q. & Sommer, S. S. Detection of extremely rare alleles by bidirectional pyrophosphorolysis-activated polymerization allele-specific amplification (Bi-PAP-A): measurement of mutation load in mammalian tissues. Biotechniques 36, 156–166 (2004).

    CAS  PubMed  Google Scholar 

  29. Nachman, M. W. & Crowell, S. L. Estimate of the mutation rate per nucleotide in humans. Genetics 156, 297–304 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. The Chimpanzee Sequencing and Analysis Consortium.Initial sequence of the chimpanzee genome and comparison with the human genome. Nature 437, 69–87 (2005).

  31. Ebersberger, I., Metzler, D., Schwarz, C. & Paabo, S. Genomewide comparison of DNA sequences between humans and chimpanzees. Am. J. Hum. Genet. 70, 1490–1497 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Chen, F. C. & Li, W. H. Genomic divergences between humans and other hominoids and the effective population size of the common ancestor of humans and chimpanzees. Am. J. Hum. Genet. 68, 444–456 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Kondrashov, A. S. Direct estimates of human per nucleotide mutation rates at 20 loci causing Mendelian diseases. Hum. Mutat. 21, 12–27 (2003).

    CAS  PubMed  Google Scholar 

  34. Orioli, I. M., Castilla, E. E., Scarano, G. & Mastroiacovo, P. Effect of paternal age in achondroplasia, thanatophoric dysplasia, and osteogenesis imperfecta. Am. J. Med. Genet. 59, 209–217 (1995).

    CAS  PubMed  Google Scholar 

  35. Horton, W. A., Hall, J. G. & Hecht, J. T. Achondroplasia. Lancet 370, 162–172 (2007).

    CAS  PubMed  Google Scholar 

  36. Cohen, M. M. et al. Birth prevalence study of the Apert syndrome. Am. J. Med. Genet. 42, 655–659 (1992).

    PubMed  Google Scholar 

  37. Tolarova, M. M., Harris, J. A., Ordway, D. E. & Vargervik, K. Birth prevalence, mutation rate, sex ratio, parents' age, and ethnicity in Apert syndrome. Am. J. Med. Genet. 72, 394–398 (1997).

    CAS  PubMed  Google Scholar 

  38. Rousseau, F. et al. Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature 371, 252–254 (1994).

    CAS  PubMed  Google Scholar 

  39. Shiang, R. et al. Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell 78, 335–342 (1994).

    CAS  PubMed  Google Scholar 

  40. Bellus, G. A. et al. Achondroplasia is defined by recurrent G380R mutations of FGFR3. Am. J. Hum. Genet. 56, 368–373 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Park, W. J. et al. Analysis of phenotypic features and FGFR2 mutations in Apert syndrome. Am. J. Hum. Genet. 57, 321–328 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Wilkie, A. O. et al. Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome. Nature Genet. 9, 165–172 (1995).

    CAS  PubMed  Google Scholar 

  43. Goriely, A. et al. Gain-of-function amino acid substitutions drive positive selection of FGFR2 mutations in human spermatogonia. Proc. Natl Acad. Sci. USA 102, 6051–6056 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Crow, J. F. Age and sex effects on human mutation rates: an old problem with new complexities. J. Radiat. Res. 47 (Suppl. B), B75–B82 (2006).

    CAS  PubMed  Google Scholar 

  45. Kan, S. H. et al. Genomic screening of fibroblast growth-factor receptor 2 reveals a wide spectrum of mutations in patients with syndromic craniosynostosis. Am. J. Hum. Genet. 70, 472–486 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Morrison, S. J. & Kimble, J. Asymmetric and symmetric stem-cell divisions in development and cancer. Nature 441, 1068–1074 (2006).

    CAS  PubMed  Google Scholar 

  47. Knoblich, J. A. Mechanisms of asymmetric stem cell division. Cell 132, 583–597 (2008).

    CAS  PubMed  Google Scholar 

  48. Dakouane Giudicelli, M. et al. Increased achondroplasia mutation frequency with advanced age and evidence for G1138A mosaicism in human testis biopsies. Fertil. Steril. 89, 1651–1656 (2007).

    PubMed  Google Scholar 

  49. Eswarakumar, V. P., Lax, I. & Schlessinger, J. Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev. 16, 1139–1149 (2005).

    Google Scholar 

  50. Thisse, B. & Thisse, C. Functions and regulations of fibroblast growth factor signaling during embryonic development. Dev. Biol. 287, 390–402 (2005).

    CAS  PubMed  Google Scholar 

  51. Runeberg-Roos, P. & Saarma, M. Neurotrophic factor receptor RET: structure, cell biology, and inherited diseases. Ann. Med. 39, 572–580 (2007).

    CAS  PubMed  Google Scholar 

  52. Carlson, K. M. et al. Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B. Proc. Natl Acad. Sci. USA 91, 1579–1583 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Carlson, K. M. et al. Parent-of-origin effects in multiple endocrine neoplasia type 2B. Am. J. Hum. Genet. 55, 1076–1082 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Eng, C. et al. Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours. Hum. Mol. Genet. 3, 237–241 (1994).

    CAS  PubMed  Google Scholar 

  55. Wray, C. J. et al. Failure to recognize multiple endocrine neoplasia 2B: more common than we think? Ann. Surg. Oncol. 15, 293–301 (2008).

    PubMed  Google Scholar 

  56. Oatley, J. M. & Brinster, R. L. Regulation of spermatogonial stem cell self-renewal in mammals. Annu. Rev. Cell Dev. Biol. 24, 263–286 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Amir, R. E. et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nature Genet. 23, 185–188 (1999).

    CAS  PubMed  Google Scholar 

  58. Bird, A. The methyl-CpG-binding protein MeCP2 and neurological disease. Biochem. Soc. Trans. 36, 575–583 (2008).

    CAS  PubMed  Google Scholar 

  59. Percy, A. K. et al. Rett syndrome: North American database. J. Child. Neurol. 22, 1338–1341 (2007).

    PubMed  Google Scholar 

  60. Trappe, R. et al. MECP2 mutations in sporadic cases of Rett syndrome are almost exclusively of paternal origin. Am. J. Hum. Genet. 68, 1093–1101 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Malter, H. E. et al. Characterization of the full fragile-X-syndrome mutation in fetal gametes. Nature Genet. 15, 165–169 (1997).

    CAS  PubMed  Google Scholar 

  62. Moutou, C., Vincent, M. C., Biancalana, V. & Mandel, J. L. Transition from premutation to full mutation in fragile X syndrome is likely to be prezygotic. Hum. Mol. Genet. 6, 971–979 (1997).

    CAS  PubMed  Google Scholar 

  63. Temmerman, N. D. et al. Intergenerational instability of the expanded CTG repeat in the DMPK gene: studies in human gametes and preimplantation embryos. Am. J. Hum. Genet. 75, 325–329 (2004).

    PubMed  PubMed Central  Google Scholar 

  64. Moseley, M. L. et al. SCA8 CTG repeat: en masse contractions in sperm and intergenerational sequence changes may play a role in reduced penetrance. Hum. Mol. Genet. 9, 2125–2130 (2000).

    CAS  PubMed  Google Scholar 

  65. Silveira, I. et al. High germinal instability of the (CTG)n at the SCA8 locus of both expanded and normal alleles. Am. J. Hum. Genet. 66, 830–840 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. De Michele, G. et al. Parental gender, age at birth and expansion length influence GAA repeat intergenerational instability in the X25 gene: pedigree studies and analysis of sperm from patients with Friedreich's ataxia. Hum. Mol. Genet. 7, 1901–1906 (1998).

    CAS  PubMed  Google Scholar 

  67. Delatycki, M. B. et al. Sperm DNA analysis in a Friedreich ataxia premutation carrier suggests both meiotic and mitotic expansion in the FRDA gene. J. Med. Genet. 35, 713–716 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Salat, U., Bardoni, B., Wohrle, D. & Steinbach, P. Increase of FMRP expression, raised levels of FMR1 mRNA, and clonal selection in proliferating cells with unmethylated fragile X repeat expansions: a clue to the sex bias in the transmission of full mutations? J. Med. Genet. 37, 842–850 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Hulten, M. A. et al. On the origin of trisomy 21 Down syndrome. Mol. Cytogenet. 1, 21 (2008).

    PubMed  PubMed Central  Google Scholar 

  70. Hastings, I. M. Germline selection: population genetic aspects of the sexual/asexual life cycle. Genetics 129, 1167–1176 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Smith, N. G., Webster, M. T. & Ellegren, H. Deterministic mutation rate variation in the human genome. Genome Res. 12, 1350–1356 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Hellmann, I. et al. Why do human diversity levels vary at a megabase scale? Genome Res. 15, 1222–1231 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Ellegren, H., Smith, N. G. & Webster, M. T. Mutation rate variation in the mammalian genome. Curr. Opin. Genet. Dev. 13, 562–568 (2003).

    CAS  PubMed  Google Scholar 

  74. Green, P., Ewing, B., Miller, W., Thomas, P. J. & Green, E. D. Transcription-associated mutational asymmetry in mammalian evolution. Nature Genet. 33, 514–517 (2003).

    CAS  PubMed  Google Scholar 

  75. Touchon, M., Arneodo, A., d'Aubenton-Carafa, Y. & Thermes, C. Transcription-coupled and splicing-coupled strand asymmetries in eukaryotic genomes. Nucleic Acids Res. 32, 4969–4978 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Hanawalt, P. C. & Spivak, G. Transcription-coupled DNA repair: two decades of progress and surprises. 9, 958–970 (2008).

  77. Polak, P. & Arndt, P. F. Transcription induces strand-specific mutations at the 5′ end of human genes. Genome Res. 18, 1216–1223 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Majewski, J. Dependence of mutational asymmetry on gene-expression levels in the human genome. Am. J. Hum. Genet. 73, 688–692 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Webster, M. T., Smith, N. G., Lercher, M. J. & Ellegren, H. Gene expression, synteny, and local similarity in human noncoding mutation rates. Mol. Biol. Evol. 21, 1820–1830 (2004).

    CAS  PubMed  Google Scholar 

  80. Anagnostopoulos, T., Green, P. M., Rowley, G., Lewis, C. M. & Giannelli, F. DNA variation in a 5-Mb region of the X chromosome and estimates of sex-specific/type-specific mutation rates. Am. J. Hum. Genet. 64, 508–517 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Krawczak, M., Ball, E. V. & Cooper, D. N. Neighboring-nucleotide effects on the rates of germ-line single-base-pair substitution in human genes. Am. J. Hum. Genet. 63, 474–488 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Cooper, D. N. & Krawczak, M. The mutational spectrum of single base-pair substitutions causing human genetic disease: patterns and predictions. Hum. Genet. 85, 55–74 (1990).

    CAS  PubMed  Google Scholar 

  83. Hwang, D. G. & Green, P. Bayesian Markov chain Monte Carlo sequence analysis reveals varying neutral substitution patterns in mammalian evolution. Proc. Natl Acad. Sci. USA 101, 13994–14001 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Arndt, P. F. & Hwa, T. Identification and measurement of neighbor-dependent nucleotide substitution processes. Bioinformatics 21, 2322–2328 (2005).

    CAS  PubMed  Google Scholar 

  85. Hess, S. T., Blake, J. D. & Blake, R. D. Wide variations in neighbor-dependent substitution rates. J. Mol. Biol. 236, 1022–1033 (1994).

    CAS  PubMed  Google Scholar 

  86. Zhao, Z. & Boerwinkle, E. Neighboring-nucleotide effects on single nucleotide polymorphisms: a study of 2.6 million polymorphisms across the human genome. Genome Res. 12, 1679–1686 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Hodgkinson, A., Ladoukakis, E. & Eyre-Walker, A. Cryptic variation in the human mutation rate. PLoS Biol. 7, e1000027 (2009).

    PubMed  PubMed Central  Google Scholar 

  88. Jeffreys, A. J. & Neumann, R. Reciprocal crossover asymmetry and meiotic drive in a human recombination hot spot. Nature Genet. 31, 267–271 (2002).

    CAS  PubMed  Google Scholar 

  89. Duret, L. & Arndt, P. F. The impact of recombination on nucleotide substitutions in the human genome. PLoS Genet. 4, e1000071 (2008).

    PubMed  PubMed Central  Google Scholar 

  90. Hardison, R. C. et al. Covariation in frequencies of substitution, deletion, transposition, and recombination during eutherian evolution. Genome Res. 13, 13–26 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Walser, J. C., Ponger, L. & Furano, A. V. CpG dinucleotides and the mutation rate of non-CpG DNA. Genome Res. 18, 1403–1414 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Lercher, M. J. & Hurst, L. D. Human SNP variability and mutation rate are higher in regions of high recombination. Trends Genet. 18, 337–340 (2002).

    CAS  PubMed  Google Scholar 

  93. Myers, S. et al. The distribution and causes of meiotic recombination in the human genome. Biochem. Soc. Trans. 34, 526–530 (2006).

    CAS  PubMed  Google Scholar 

  94. Spencer, C. C. et al. The influence of recombination on human genetic diversity. PLoS Genet. 2, e148 (2006).

    PubMed  PubMed Central  Google Scholar 

  95. Arnheim, N., Calabrese, P. & Tiemann-Boege, I. Mammalian meiotic recombination hot spots. Annu. Rev. Genet. 41, 369–399 (2007).

    CAS  PubMed  Google Scholar 

  96. Tyekucheva, S. et al. Human–macaque comparisons illuminate variation in neutral substitution rates. Genome Biol. 9, R76 (2008).

    PubMed  PubMed Central  Google Scholar 

  97. Tian, D. et al. Single-nucleotide mutation rate increases close to insertions/deletions in eukaryotes. Nature 455, 105–108 (2008).

    CAS  PubMed  Google Scholar 

  98. Honma, M. et al. Non-homologous end-joining for repairing I-SceI-induced DNA double strand breaks in human cells. DNA Repair 6, 781–788 (2007).

    CAS  Google Scholar 

  99. Rattray, A. J., Shafer, B. K., McGill, C. B. & Strathern, J. N. The roles of REV3 and RAD57 in double-strand-break-repair-induced mutagenesis of Saccharomyces cerevisiae. Genetics 162, 1063–1077 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Prendergast, J. G. et al. Chromatin structure and evolution in the human genome. BMC Evol. Biol. 7, 72 (2007).

    PubMed  PubMed Central  Google Scholar 

  101. Haldane, J. B. S. The mutation rate of the gene for haemophilia and its segregation ratios in males and females. Ann. Eugen. 13, 262–271 (1947).

    CAS  PubMed  Google Scholar 

  102. Hurst, L. D. & Ellegren, H. Sex biases in the mutation rate. Trends Genet. 14, 446–452 (1998).

    CAS  PubMed  Google Scholar 

  103. Glaser, R. L. & Jabs, E. W. Dear old dad. Sci. Aging Knowledge Environ. 2004, re1 (2004).

    PubMed  Google Scholar 

  104. Li, W. H., Yi, S. & Makova, K. Male-driven evolution. Curr. Opin. Genet. Dev. 12, 650–656 (2002).

    CAS  PubMed  Google Scholar 

  105. Ellegren, H. Characteristics, causes and evolutionary consequences of male-biased mutation. Proc. Biol. Sci. 274, 1–10 (2007).

    CAS  PubMed  Google Scholar 

  106. Grimm, T. et al. On the origin of deletions and point mutations in Duchenne muscular dystrophy: most deletions arise in oogenesis and most point mutations result from events in spermatogenesis. J. Med. Genet. 31, 183–186 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Becker, J. et al. Characterization of the factor VIII defect in 147 patients with sporadic hemophilia A: family studies indicate a mutation type-dependent sex ratio of mutation frequencies. Am. J. Hum. Genet. 58, 657–670 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Rossiter, J. P. et al. Factor VIII gene inversions causing severe hemophilia A originate almost exclusively in male germ cells. Hum. Mol. Genet. 3, 1035–1039 (1994).

    CAS  PubMed  Google Scholar 

  109. Kluwe, L. et al. The parental origin of new mutations in neurofibromatosis 2. Neurogenetics 3, 17–24 (2000).

    CAS  PubMed  Google Scholar 

  110. Sommer, S. S., Scaringe, W. A. & Hill, K. A. Human germline mutation in the factor IX gene. Mutat. Res. 487, 1–17 (2001).

    CAS  PubMed  Google Scholar 

  111. Zlotogora, J. Germ line mosaicism. Hum. Genet. 102, 381–386 (1998).

    CAS  PubMed  Google Scholar 

  112. Youssoufian, H. & Pyeritz, R. E. Mechanisms and consequences of somatic mosaicism in humans. Nature Rev. Genet. 3, 748–758 (2002).

    CAS  PubMed  Google Scholar 

  113. Erickson, R. P. Somatic gene mutation and human disease other than cancer. Mutat. Res. 543, 125–136 (2003).

    CAS  PubMed  Google Scholar 

  114. Hall, J. G. Review and hypotheses: somatic mosaicism: observations related to clinical genetics. Am. J. Hum. Genet. 43, 355–363 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Sippel, K. C. et al. Frequency of somatic and germ-line mosaicism in retinoblastoma: implications for genetic counseling. Am. J. Hum. Genet. 62, 610–619 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Leuer, M. et al. Somatic mosaicism in hemophilia A: a fairly common event. Am. J. Hum. Genet. 69, 75–87 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Evans, D. G. et al. Mosaicism in neurofibromatosis type 2: an update of risk based on uni/bilaterality of vestibular schwannoma at presentation and sensitive mutation analysis including multiple ligation-dependent probe amplification. J. Med. Genet. 44, 424–428 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Kehrer-Sawatzki, H. & Cooper, D. N. Mosaicism in sporadic neurofibromatosis type 1: variations on a theme common to other hereditary cancer syndromes? J. Med. Genet. 45, 622–631 (2008).

    CAS  PubMed  Google Scholar 

  119. Winn, R. N. et al. Transgenic lambda medaka as a new model for germ cell mutagenesis. Environ. Mol. Mutagen. 49, 173–184 (2008).

    CAS  PubMed  Google Scholar 

  120. Dubrova, Y. E., Plumb, M., Gutierrez, B., Boulton, E. & Jeffreys, A. J. Transgenerational mutation by radiation. Nature 405, 37 (2000).

    CAS  PubMed  Google Scholar 

  121. Dubrova, Y. E. Radiation-induced transgenerational instability. Oncogene 22, 7087–7093 (2003).

    CAS  PubMed  Google Scholar 

  122. Makova, K. D. & Li, W. H. Strong male-driven evolution of DNA sequences in humans and apes. Nature 416, 624–626 (2002).

    CAS  PubMed  Google Scholar 

  123. Miyata, T., Hayashida, H., Kuma, K., Mitsuyasu, K. & Yasunaga, T. Male-driven molecular evolution: a model and nucleotide sequence analysis. Cold Spring Harb. Symp. Quant. Biol. 52, 863–867 (1987).

    CAS  PubMed  Google Scholar 

  124. Taylor, J., Tyekucheva, S., Zody, M., Chiaromonte, F. & Makova, K. D. Strong and weak male mutation bias at different sites in the primate genomes: insights from the human–chimpanzee comparison. Mol. Biol. Evol. 23, 565–573 (2006).

    CAS  PubMed  Google Scholar 

  125. Drost, J. B. & Lee, W. R. Biological basis of germline mutation: comparisons of spontaneous germline mutation rates among drosophila, mouse, and human. Environ. Mol. Mutagen. 25, 48–64 (1995).

    CAS  PubMed  Google Scholar 

  126. Shen, J. C., Rideout, W. M. 3rd & Jones, P. A. The rate of hydrolytic deamination of 5-methylcytosine in double-stranded DNA. Nucleic Acids Res. 22, 972–976 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Trasler, J. M. Gamete imprinting: setting epigenetic patterns for the next generation. Reprod. Fertil. Dev. 18, 63–69 (2006).

    PubMed  Google Scholar 

  128. Lees-Murdock, D. J. & Walsh, C. P. DNA methylation reprogramming in the germ line. Epigenetics 3, 5–13 (2008).

    PubMed  Google Scholar 

  129. Eckhardt, F. et al. DNA methylation profiling of human chromosomes 6, 20 and 22. Nature Genet. 38, 1378–1385 (2006).

    CAS  PubMed  Google Scholar 

  130. El-Maarri, O. et al. Methylation levels at selected CpG sites in the factor VIII and FGFR3 genes, in mature female and male germ cells: implications for male- driven evolution. Am. J. Hum. Genet. 63, 1001–1008 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Morgan, H. D., Dean, W., Coker, H. A., Reik, W. & Petersen-Mahrt, S. K. Activation-induced cytidine deaminase deaminates 5-methylcytosine in DNA and is expressed in pluripotent tissues. J. Biol. Chem. 279, 52353–52360 (2004).

    CAS  PubMed  Google Scholar 

  132. Schreck, S. et al. Activation-induced cytidine deaminase (AID) is expressed in normal spermatogenesis but only infrequently in testicular germ cell tumours. J. Pathol. 210, 26–31 (2006).

    CAS  PubMed  Google Scholar 

  133. Bransteitter, R., Pham, P., Scharff, M. D. & Goodman, M. F. Activation-induced cytidine deaminase deaminates deoxycytidine on single-stranded DNA but requires the action of RNase. Proc. Natl Acad. Sci. USA 100, 4102–4107 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Olsen, A.-K., Lindeman, B., Wiger, R., Duale, N. & Brunborg, G. How do male germ cells handle DNA damage? Toxicol. Appl. Pharmacol. 207 (Suppl. 2), 521–531 (2005).

    PubMed  Google Scholar 

  135. Jaroudi, S. & SenGupta, S. DNA repair in mammalian embryos. Mutat. Res. 635, 53–77 (2007).

    CAS  PubMed  Google Scholar 

  136. Menezo, Y. Jr, Russo, G., Tosti, E., El Mouatassim, S. & Benkhalifa, M. Expression profile of genes coding for DNA repair in human oocytes using pangenomic microarrays, with a special focus on ROS linked decays. J. Assist. Reprod. Genet. 24, 513–520 (2007).

    PubMed  PubMed Central  Google Scholar 

  137. Intano, G. W. et al. Base excision repair is limited by different proteins in male germ cell nuclear extracts prepared from young and old mice. Mol. Cell. Biol. 22, 2410–2418 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Xu, G. et al. Nucleotide excision repair activity varies among murine spermatogenic cell types. Biol. Reprod. 73, 123–130 (2005).

    CAS  PubMed  Google Scholar 

  139. Cortazar, D., Kunz, C., Saito, Y., Steinacher, R. & Schar, P. The enigmatic thymine DNA glycosylase. DNA Repair (Amst.) 6, 489–504 (2007).

    CAS  Google Scholar 

  140. Schroering, A. G., Edelbrock, M. A., Richards, T. J. & Williams, K. J. The cell cycle and DNA mismatch repair. Exp. Cell Res. 313, 292–304 (2007).

    CAS  PubMed  Google Scholar 

  141. Hardeland, U., Kunz, C., Focke, F., Szadkowski, M. & Schar, P. Cell cycle regulation as a mechanism for functional separation of the apparently redundant uracil DNA glycosylases TDG and UNG2. Nucleic Acids Res. 35, 3859–3867 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Crow, J. F. Spontaneous mutation in man. Mutat. Res. 437, 5–9 (1999).

    CAS  PubMed  Google Scholar 

  143. Risch, N., Reich, E. W., Wishnick, M. M. & McCarthy, J. G. Spontaneous mutation and parental age in humans. Am. J. Hum. Genet. 41, 218–248 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Ketterling, R. P. et al. Germline origins in the human F9 gene: frequent G:C-->A:T mosaicism and increased mutations with advanced maternal age. Hum. Genet. 105, 629–640 (1999).

    CAS  PubMed  Google Scholar 

  145. Wilkie, A. O. Bad bones, absent smell, selfish testes: the pleiotropic consequences of human FGF receptor mutations. Cytokine Growth Factor Rev. 16, 187–203 (2005).

    CAS  PubMed  Google Scholar 

  146. Edghill, E. L. et al. Origin of de novo KCNJ11 mutations and risk of neonatal diabetes for subsequent siblings. J. Clin. Endocrinol. Metab. 92, 1773–1777 (2007).

    CAS  PubMed  Google Scholar 

  147. Kubota, H. & Brinster, R. L. Culture of rodent spermatogonial stem cells, male germline stem cells of the postnatal animal. Methods Cell Biol. 86, 59–84 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. McLean, D. J. Spermatogonial stem cell transplantation, testicular function, and restoration of male fertility in mice. Methods Mol. Biol. 450, 149–162 (2008).

    CAS  PubMed  Google Scholar 

  149. Falciatori, I., Lillard-Wetherell, K., Wu, Z., Hamra, F. K. & Garbers, D. L. Deriving mouse spermatogonial stem cell lines. Methods Mol. Biol. 450, 181–192 (2008).

    CAS  PubMed  Google Scholar 

  150. Walsh, C. P. & Xu, G. L. Cytosine methylation and DNA repair. Curr. Top. Microbiol. Immunol. 301, 283–315 (2006).

    CAS  PubMed  Google Scholar 

  151. Klose, R. J. & Bird, A. P. Genomic DNA methylation: the mark and its mediators. Trends Biochem. Sci. 31, 89–97 (2006).

    CAS  PubMed  Google Scholar 

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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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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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