CoChat
Sign Up
Cited by 58

The DOI matches its Crossref record; 4 of the 4 references it cites were found in a registry or an index.

Mutation rates and the evolution of germline structure

Scally, Aylwyn·2016·Philosophical Transactions of the Royal Society B: Biological Sciences
DOI 10.1098/rstb.2015.0137PMC PMC4920338

Published version of a preprint

Open this paper in CoChat — free account

Abstract

Genome sequencing studies of de novo mutations in humans have revealed surprising incongruities in our understanding of human germline mutation. In particular, the mutation rate observed in modern humans is substantially lower than that estimated from calibration against the fossil record, and the paternal age effect in mutations transmitted to offspring is much weaker than expected from our long-standing model of spermatogenesis. I consider possible explanations for these discrepancies, including evolutionary changes in life-history parameters such as generation time and the age of puberty, a possible contribution from undetected post-zygotic mutations early in embryo development, and changes in cellular mutation processes at different stages of the germline. I suggest a revised model of stem-cell state transitions during spermatogenesis, in which ‘dark’ gonial stem cells play a more active role than hitherto envisaged, with a long cycle time undetected in experimental observations. More generally, I argue that the mutation rate and its evolution depend intimately on the structure of the germline in humans and other primates. This article is part of the themed issue ‘Dating species divergences using rocks and clocks'.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1098/rstb.2015.0137

Cites

4 of 4 references verified0 citation errors · 0 not checkable

Statistics

Figures

Figure 1. Models of human mutation rate slowdown with changing life-history parameters. Dotted line: simple scaling of mutation rate with generation time; dashed line: including a paternal age effect but with fixed age of puberty; solid line: including a paternal age effect and with age of puberty scaling with generation time, assuming tpub = 14 yr when tgen = 30 yr. Overall rates per basepair are scaled to be 0.5×10–9 bp–1 yr–1 when tgen = 30 yr.
Figure 1. Models of human mutation rate slowdown with changing life-history parameters. Dotted line: simple scaling of mutation rate with generation time; dashed line: including a paternal age effect but with fixed age of puberty; solid line: including a paternal age effect and with age of puberty scaling with generation time, assuming tpub = 14 yr when tgen = 30 yr. Overall rates per basepair are scaled to be 0.5×10–9 bp–1 yr–1 when tgen = 30 yr.CC BY · PubMed Central
Figure 2. Variation of male age of sexual maturity with body mass and generation time in extant primates. (a) Variation with body mass suggests a scaling coefficient of 0.34. Data from [19,20]. (b) A zero-intercept regression of age of sexual maturity on tgen has slope 0.38. Data from [6,19,21–26]. Hominoids are labelled: Hsap, human; Ptro, chimpanzee; Ggor, gorilla, Ppyg, orangutan; Hlar, gibbon.
Figure 2. Variation of male age of sexual maturity with body mass and generation time in extant primates. (a) Variation with body mass suggests a scaling coefficient of 0.34. Data from [19,20]. (b) A zero-intercept regression of age of sexual maturity on tgen has slope 0.38. Data from [6,19,21–26]. Hominoids are labelled: Hsap, human; Ptro, chimpanzee; Ggor, gorilla, Ppyg, orangutan; Hlar, gibbon.CC BY · PubMed Central
Figure 3. Cellular genealogies in a two-offspring family. Solid black lines represent cellular lineages; germ cell populations are shaded green (in females) or blue (in males), somatic cells are shaded orange. Darker somatic populations represent the cellular ancestors of somatic cells sampled in a sequencing experiment. (a–d) Possible configurations of germ and sampled somatic cellular lineages at the early post-zygotic stage: (a) any cell ancestral to sampled somatic and germ cells is ancestral to all such cells; (b) cells may be ancestral to all germ cells but only some sampled somatic cells; (c) cells may be ancestral to all sampled somatic cells but only some germ cells; (d) cells may be ancestral to some germ cells and some sampled somatic cells (meaning that some germ cells may be more closely related to some somatic cells than to other germ cells, and vice versa).
Figure 3. Cellular genealogies in a two-offspring family. Solid black lines represent cellular lineages; germ cell populations are shaded green (in females) or blue (in males), somatic cells are shaded orange. Darker somatic populations represent the cellular ancestors of somatic cells sampled in a sequencing experiment. (a–d) Possible configurations of germ and sampled somatic cellular lineages at the early post-zygotic stage: (a) any cell ancestral to sampled somatic and germ cells is ancestral to all such cells; (b) cells may be ancestral to all germ cells but only some sampled somatic cells; (c) cells may be ancestral to all sampled somatic cells but only some germ cells; (d) cells may be ancestral to some germ cells and some sampled somatic cells (meaning that some germ cells may be more closely related to some somatic cells than to other germ cells, and vice versa).CC BY · PubMed Central
Figure 4. Cell states and possible transitions in models of human and mouse spermatogenesis, from primordial germ cell (PGC) to spermiogenesis. Dotted lines represent transitions involving one or more intermediate states (e.g. the initial transition from PGC to Ap is sometimes thought to pass through a temporary Ad state). Two human models are shown: model 1 is the established model originally due to Clermont [51], and model 2 an alternative model discussed in the text. In the mouse model, the double arrow from As to itself indicates that cell division is symmetric: As → As + As.
Figure 4. Cell states and possible transitions in models of human and mouse spermatogenesis, from primordial germ cell (PGC) to spermiogenesis. Dotted lines represent transitions involving one or more intermediate states (e.g. the initial transition from PGC to Ap is sometimes thought to pass through a temporary Ad state). Two human models are shown: model 1 is the established model originally due to Clermont [51], and model 2 an alternative model discussed in the text. In the mouse model, the double arrow from As to itself indicates that cell division is symmetric: As → As + As.CC BY · PubMed Central
Figure 5. Models of human mutation rate slowdown in which the seminiferous epithelial cycle time increases with generation time and age of puberty. Dotted line: cycle time is 0.5 times the present length when generation time is 15 years; dashed line: cycle time is 0.75 times the present length when generation time is 15 years; solid line: no change in cycle time (identical to the solid line in figure 1). Overall rates per basepairs are scaled to be 0.5×10–9 bp–1 yr–1 when tgen = 30 yr.
Figure 5. Models of human mutation rate slowdown in which the seminiferous epithelial cycle time increases with generation time and age of puberty. Dotted line: cycle time is 0.5 times the present length when generation time is 15 years; dashed line: cycle time is 0.75 times the present length when generation time is 15 years; solid line: no change in cycle time (identical to the solid line in figure 1). Overall rates per basepairs are scaled to be 0.5×10–9 bp–1 yr–1 when tgen = 30 yr.CC BY · PubMed Central
Figure 6. A possible finite state model for spermatogenesis. Germline lineages are traced through the model, entering at the START state, from which they can transition to either of the GSC states Ad or Ap. The cell death state (X) can be reached from either GSC state, whereas we assume here that spermiogenesis (S) is possible only from Ap. Transitions from the GSC states correspond to cell divisions, so the model describes a branching process representing an entire genealogy of spermatozoa, each descended from a single primordial germ cell (PGC) and having an associated age and total number of cell divisions (depth) from the root of the genealogy. In the established model (model 1 in figure 4), the transition Ap → Ad has zero probability under normal conditions.
Figure 6. A possible finite state model for spermatogenesis. Germline lineages are traced through the model, entering at the START state, from which they can transition to either of the GSC states Ad or Ap. The cell death state (X) can be reached from either GSC state, whereas we assume here that spermiogenesis (S) is possible only from Ap. Transitions from the GSC states correspond to cell divisions, so the model describes a branching process representing an entire genealogy of spermatozoa, each descended from a single primordial germ cell (PGC) and having an associated age and total number of cell divisions (depth) from the root of the genealogy. In the established model (model 1 in figure 4), the transition Ap → Ad has zero probability under normal conditions.CC BY · PubMed Central
Figure 7. Output from an implementation of the model in figure 6, for parameters fitting the observed paternal age effect and decline in sperm production. (Code available upon request.) (a) Joint distribution of paternal age and number of cell divisions as the zygote in simulated spermatozoa (colours indicate relative frequency from zero (dark blue) to high (red)) for a set of parameters in which the Ad cycle time td = 300 days and initial transition times t0 were sampled uniformly from the range 5000–5500 days, P(Ap → Ad) = 0.1, P(Ap → X) = 0.32, P(Ad → X) = 0.2. The white line shows the slope of the paternal age effect observed in humans. (b) Simulated relative daily sperm output as a function of age.
Figure 7. Output from an implementation of the model in figure 6, for parameters fitting the observed paternal age effect and decline in sperm production. (Code available upon request.) (a) Joint distribution of paternal age and number of cell divisions as the zygote in simulated spermatozoa (colours indicate relative frequency from zero (dark blue) to high (red)) for a set of parameters in which the Ad cycle time td = 300 days and initial transition times t0 were sampled uniformly from the range 5000–5500 days, P(Ap → Ad) = 0.1, P(Ap → X) = 0.32, P(Ad → X) = 0.2. The white line shows the slope of the paternal age effect observed in humans. (b) Simulated relative daily sperm output as a function of age.CC BY · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 4 references

Research works printed but not linked: 66

  1. 10.1016/j.tig.2010.05.003 · DOI
  2. 10.1007/BF02717892 · DOI
  3. 10.1007/BF02717891 · DOI
  4. 10.1146/annurev-genom-031714-125740 · DOI · Paper page
  5. 10.1038/nature13679 · DOI
  6. 10.1038/nature12161 · DOI
  7. 10.1038/ng.3015 · DOI · Paper page
  8. 10.1073/pnas.82.6.1741 · DOI
  9. 10.1111/j.1558-5646.2011.01337.x · DOI
  10. Fleagle JG, 1998, Primate adaptation and evolution
  11. 10.1016/j.cub.2011.08.025 · DOI
  12. 10.1093/gerona/62.2.149 · DOI
  13. 10.1038/ng.2398 · DOI
  14. 10.1098/rspb.2014.2898 · DOI
  15. Saltzman W, 2011, Hormones and reproduction of vertebrates, 291
  16. Kingsley SR, 1988, Orang-utan biology, 123
  17. 10.1073/pnas.1211740109 · DOI
  18. Molur S Brandon-Jones DW. Dittus W Eudey A Kumar A Singh M et al. 2003 Status of South Asian primates: Conservation Assessment and Management Plan (C.A.M.P.) workshop report p. viii+432.
  19. 10.1002/(SICI)1098-2345(1996)38:2<157::AID-AJP4>3.0.CO;2-Y · DOI
  20. 10.1007/s10592-008-9584-3 · DOI
  21. 10.1016/B978-0-12-381365-7.00008-X · DOI
  22. 10.1186/1471-2148-10-105 · DOI
  23. 10.1016/j.yrtph.2012.05.003 · DOI
  24. 10.1002/em.2850250609 · DOI
  25. 10.1038/35049558 · DOI · Paper page
  26. 10.1016/j.ajhg.2015.05.008 · DOI
  27. Harland C, 2015, Biology of genomes
  28. 10.1038/nm.1924 · DOI · Paper page
  29. 10.1186/1477-7827-12-105 · DOI
  30. 10.1093/humupd/8.4.333 · DOI
  31. 10.1016/j.ajhg.2014.08.010 · DOI
  32. 10.3390/genes6020216 · DOI
  33. 10.1371/journal.pgen.1002477 · DOI
  34. 10.1016/j.ajhg.2015.10.006 · DOI
  35. Hartl DL, 1971, Recurrence risks for germinal mosaics, Am. J. Hum. Genet, 23, 124
  36. Wijsman EM, 1991, Recurrence risk of a new dominant mutation in children of unaffected parents, Am. J. Hum. Genet, 48, 654
  37. 10.1136/jmg.26.9.553 · DOI
  38. 10.1002/ajmg.a.31826 · DOI
  39. 10.1002/ajmg.a.30896 · DOI
  40. 10.1159/000438812 · DOI
  41. 10.1086/301928 · DOI
  42. 10.1002/gepi.4 · DOI
  43. 10.1002/bies.201100091 · DOI
  44. 10.1038/nrg1914 · DOI
  45. 10.1038/nature10842 · DOI
  46. 10.1073/pnas.1515798113 · DOI
  47. 10.1002/aja.1001260106 · DOI
  48. 10.1016/j.semcdb.2014.03.007 · DOI
  49. 10.1002/aja.1001120103 · DOI
  50. 10.1530/rep.1.01081 · DOI
  51. 10.1017/S1464793105006755 · DOI
  52. 10.1073/pnas.0912629107 · DOI · Paper page
  53. 10.2164/jandrol.107.004655 · DOI
  54. 10.1095/biolreprod35.1.199 · DOI
  55. 10.1210/jc.86.4.1814 · DOI
  56. 10.1530/REP-09-0255 · DOI
  57. 10.2164/jandrol.112.016832 · DOI
  58. 10.1016/j.stem.2014.01.019 · DOI
  59. 10.1242/dev.101063 · DOI
  60. 10.1002/(SICI)1521-1878(200005)22:5<423::AID-BIES4>3.0.CO;2-0 · DOI
  61. 10.1111/j.2047-2927.2013.00175.x · DOI
  62. 10.1371/journal.pbio.1002355 · DOI
  63. 10.1186/scrt487 · DOI
  64. 10.1371/journal.pbio.0050224 · DOI
  65. 10.1073/pnas.1311381110 · DOI
  66. 10.1095/biolreprod.113.108639 · DOI

Cited by

Sorted by citations

See all 58

Metadata

Authors
Scally, A.
Venue
Philosophical Transactions of the Royal Society B: Biological Sciences
Publisher
The Royal Society
Published
2016-07-19
Volume
371
Issue
1699
Pages
20150137
ISSN
  • 0962-8436
  • 1471-2970
DOI
10.1098/rstb.2015.0137
PMC
PMC4920338
Cited by
58
References
4
Language
en
Licence
royalsociety.org/journals/ethics-policies/data-sharing-mining/ (tdm)
Funders
Isaac Newton Trust/Wellcome Trust ISSF

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

How to cite

Cite CoChat for the checks on this page, and the paper for its own findings.

This page
CoChat. (2026). Citation check: Mutation rates and the evolution of germline structure. https://app.cochat.ai/papers/10.1098/rstb.2015.0137
The paper
Scally, A. (2016). Mutation rates and the evolution of germline structure. Philosophical Transactions of the Royal Society B: Biological Sciences. https://doi.org/10.1098/rstb.2015.0137