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. 2021 Sep;31(9):1513-1518.
doi: 10.1101/gr.271809.120. Epub 2021 Jul 23.

Differences in the number of de novo mutations between individuals are due to small family-specific effects and stochasticity

Jakob M Goldmann  1   2 , Juliet E Hampstead  1   2 , Wendy S W Wong  3 , Amy B Wilfert  4 , Tychele N Turner  4 , Marianne A Jonker  5 , Raphael Bernier  6 , Martijn A Huynen  7 , Evan E Eichler  4   8 , Joris A Veltman  9 , George L Maxwell  10 , Christian Gilissen  1   2
Affiliations

Differences in the number of de novo mutations between individuals are due to small family-specific effects and stochasticity

Jakob M Goldmann et al. Genome Res. 2021 Sep.

Abstract

The number of de novo mutations (DNMs) in the human germline is correlated with parental age at conception, but this explains only part of the observed variation. We investigated whether there is a family-specific contribution to the number of DNMs in offspring. The analysis of DNMs in 111 dizygotic twin pairs did not identify a substantial family-specific contribution. This result was corroborated by comparing DNMs of 1669 siblings to those of age-matched unrelated offspring following correction for parental age. In addition, by modeling DNM data from 1714 multi-offspring families, we estimated that the family-specific contribution explains ∼5.2% of the variation in DNM number. Furthermore, we found no substantial difference between the observed number of DNMs and those predicted by a stochastic Poisson process. We conclude that there is a small family-specific contribution to DNM number and that stochasticity explains a large proportion of variation in DNM counts.

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Figures

Figure 1.
Figure 1.
Comparing dizygotic twins and parental age–matched unrelated children (PAMUCs). (A) Number of DNMs in dizygotic twins in relation to age of the father. Twins are linked by lines. (B) Number of DNMs in parental age–matched unrelated children (PAMUCs) in relation to age of the father. (C) Absolute differences in the number of DNMs between twins and PAMUCs. Numbers indicate sizes of sets, boxes indicate interquartile range, and bold line indicates median.
Figure 2.
Figure 2.
Estimating familial variance components. The error bars denote the 95% confidence intervals. The diamonds indicating the estimates are scaled according to the mean number of children per family. The vertical green line indicates the weighted mean between the point estimates of the two cohorts (cohort #3 and cohort #4) based on the number of multi-offspring families each cohort contains. Variance component estimations for cohorts #1 and #2 were not included above due to small cohort size (Supplemental Fig. 2).
Figure 3.
Figure 3.
Modeling DNMs as a family-independent Poisson process. (A–D) Simulations from cohorts #1–#4, respectively. Red lines depict Poisson-based predictions, black dots denote observations. Supplemental Table 3 lists P-values for various tests comparing predictions to observations.
See this image and copyright information in PMC

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