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. 2021 Apr 1;108(4):597-607.
doi: 10.1016/j.ajhg.2021.02.012. Epub 2021 Mar 5.

De novo structural mutation rates and gamete-of-origin biases revealed through genome sequencing of 2,396 families

Jonathan R Belyeu  1 , Harrison Brand  2 , Harold Wang  2 , Xuefang Zhao  2 , Brent S Pedersen  1 , Julie Feusier  3 , Meenal Gupta  1 , Thomas J Nicholas  1 , Joseph Brown  1 , Lisa Baird  1 , Bernie Devlin  4 , Stephan J Sanders  5 , Lynn B Jorde  6 , Michael E Talkowski  7 , Aaron R Quinlan  8
Affiliations

De novo structural mutation rates and gamete-of-origin biases revealed through genome sequencing of 2,396 families

Jonathan R Belyeu et al. Am J Hum Genet. .

Abstract

Each human genome includes de novo mutations that arose during gametogenesis. While these germline mutations represent a fundamental source of new genetic diversity, they can also create deleterious alleles that impact fitness. Whereas the rate and patterns of point mutations in the human germline are now well understood, far less is known about the frequency and features that impact de novo structural variants (dnSVs). We report a family-based study of germline mutations among 9,599 human genomes from 33 multigenerational CEPH-Utah families and 2,384 families from the Simons Foundation Autism Research Initiative. We find that de novo structural mutations detected by alignment-based, short-read WGS occur at an overall rate of at least 0.160 events per genome in unaffected individuals, and we observe a significantly higher rate (0.206 per genome) in ASD-affected individuals. In both probands and unaffected samples, nearly 73% of de novo structural mutations arose in paternal gametes, and we predict most de novo structural mutations to be caused by mutational mechanisms that do not require sequence homology. After multiple testing correction, we did not observe a statistically significant correlation between parental age and the rate of de novo structural variation in offspring. These results highlight that a spectrum of mutational mechanisms contribute to germline structural mutations and that these mechanisms most likely have markedly different rates and selective pressures than those leading to point mutations.

Keywords: autism; copy number variation; de novo mutation; genetic diversity; genomic structure; genomics; germline mutation; structural variation.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
dnSVs identified in SFARI SSC The count of dnSVs of each SV type found in 2,363 ASD probands and 2,372 unaffected samples.
Figure 2
Figure 2
Comparisons of dnSV rates (A) Comparison by Fisher’s exact test of dnSV rates in probands versus siblings. (B) Comparison by Fisher’s exact test of dnSV rates from variants phased to maternal or paternal gamete in probands and siblings.
Figure 3
Figure 3
Correlations of paternal age and dnSV rate Comparison by one-sided Wilcoxon rank-sum test for increased father’s age in samples with at least one dnSV versus those without. This test is performed for unaffected samples (left) and probands (right). Overlay highlights differences in father’s age distribution between samples with and samples without a dnSV. After Bonferroni multiple testing for two tests, the adjusted marginal significance for unaffected samples is p = 0.066, and for probands, the adjusted marginal significance is p = 1.
Figure 4
Figure 4
A comparison of dnSV breakpoint homology and size among probands and unaffected samples (A) Counts of phased variants grouped by predicted mechanism class, parent of origin, and affected status. Mechanism classes include those characterized by no sequence homology at breakpoints (NON-HOM), microhomology at breakpoints (MICRO-HOM), or macrohomology (matching segmental duplications) at breakpoints (MACRO-HOM). (B) Variants binned by size and compared between probands and unaffected samples. The fraction of dnSVs assigned to each bin is statistically similar except in the largest two bins where sizes are 100 kb to 1 Mb and ≥1 Mb. The difficulty of determining the size of insertion variants, especially mobile element insertions, led to exclusion of those variants from this figure.
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