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Mutation rates and the evolution of germline structure.

Scally A - Philos. Trans. R. Soc. Lond., B, Biol. Sci. (2016)

Bottom Line: 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.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'.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK aos21@cam.ac.uk.

No MeSH data available.


Related in: MedlinePlus

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).
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RSTB20150137F3: 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).

Mentions: An alternative explanation for the discrepancy in rates may lie in how de novo sequencing experiments relate to the cellular genealogy of the germline, and the definition of germline mutation rate as the mean number of mutations acquired on a germline lineage from zygote to zygote. Mutations on somatic lineages are important in the context of diseases such as cancer, but such lineages do not as a rule extend beyond lifespan of the organism and thus make no direct contribution to evolutionary genetic processes. However, the detection of de novo mutations in trios is based on sequencing somatic cells in parents and offspring, not zygotes (or even other germ cells). To understand the implications of this and how these experiments relate to what we want to measure, we need to consider the cellular genealogy of the germline within a family (figure 3).Figure 3.


Mutation rates and the evolution of germline structure.

Scally A - Philos. Trans. R. Soc. Lond., B, Biol. Sci. (2016)

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).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4920338&req=5

RSTB20150137F3: 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).
Mentions: An alternative explanation for the discrepancy in rates may lie in how de novo sequencing experiments relate to the cellular genealogy of the germline, and the definition of germline mutation rate as the mean number of mutations acquired on a germline lineage from zygote to zygote. Mutations on somatic lineages are important in the context of diseases such as cancer, but such lineages do not as a rule extend beyond lifespan of the organism and thus make no direct contribution to evolutionary genetic processes. However, the detection of de novo mutations in trios is based on sequencing somatic cells in parents and offspring, not zygotes (or even other germ cells). To understand the implications of this and how these experiments relate to what we want to measure, we need to consider the cellular genealogy of the germline within a family (figure 3).Figure 3.

Bottom Line: 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.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'.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK aos21@cam.ac.uk.

No MeSH data available.


Related in: MedlinePlus