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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

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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'.

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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

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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

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