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. 2015 Mar 22;282(1803):20142898.
doi: 10.1098/rspb.2014.2898.

Elevated germline mutation rate in teenage fathers

Peter Forster  1 , Carsten Hohoff  2 , Bettina Dunkelmann  3 , Marianne Schürenkamp  4 , Heidi Pfeiffer  4 , Franz Neuhuber  3 , Bernd Brinkmann  5
Affiliations

Elevated germline mutation rate in teenage fathers

Peter Forster et al. Proc Biol Sci. .

Erratum in

Abstract

Men age and die, while cells in their germline are programmed to be immortal. To elucidate how germ cells maintain viable DNA despite increasing parental age, we analysed DNA from 24 097 parents and their children, from Europe, the Middle East and Africa. We chose repetitive microsatellite DNA that mutates (unlike point mutations) only as a result of cellular replication, providing us with a natural 'cell-cycle counter'. We observe, as expected, that the overall mutation rate for fathers is seven times higher than for mothers. Also as expected, mothers have a low and lifelong constant DNA mutation rate. Surprisingly, however, we discover that (i) teenage fathers already set out from a much higher mutation rate than teenage mothers (potentially equivalent to 77-196 male germline cell divisions by puberty); and (ii) ageing men maintain sperm DNA quality similar to that of teenagers, presumably by using fresh batches of stem cells known as 'A-dark spermatogonia'.

Keywords: ageing; immortality; molecular clock; oogenesis; spermatogenesis; stem cell.

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Figures

Figure 1.
Figure 1.
DNA strand slippage during replication of an STR locus. The boxes symbolize repetitive DNA units, typically tetramers such as GATAGATAGATA, which together constitute the STR locus. The arrows indicate the direction in which a new DNA strand (white boxes) is being replicated from the template strand (black boxes). Three different situations during DNA replication are depicted. (a) The DNA replication of the STR locus has proceeded without a mutation. (b) The DNA replication of the STR locus has led to a gain of one repeat unit owing to a loop in the new strand; the aberrant loop is stabilized by flanking repeat units complementary to the opposite strand. (c) The DNA replication of the STR locus has led to a loss of one repeat unit owing to a loop in the template strand; the aberrant loop is likewise stabilized by flanking repeat units.
Figure 2.
Figure 2.
Germline STR mutation rates for fathers (blue) and mothers (pink). Ages refer to the parent's age at conception, starting with 15 years and ending with 45 years for mothers and 50 years for fathers. The straight lines are linear regressions and the accompanying green lines are the 95% confidence intervals (CIs). Standard deviations for individual values are shown as bars. The graph is based on 325 paternal mutations determined from 142 354 meioses, and on 58 maternal mutations determined from 154 368 meioses.
See this image and copyright information in PMC

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