De novo mutations (DNMs) cause a large proportion of severe rare diseases of childhood. DNMs that occur early may result in mosaicism of both somatic and germ cells. Such early mutations can cause recurrence of disease. We scanned 1,007 sibling pairs from 251 families and identified 878 DNMs shared by siblings (ssDNMs) at 448 genomic sites. We estimated DNM recurrence probability based on parental mosaicism, sharing of DNMs among siblings, parent-of-origin, mutation type and genomic position. We detected 57.2% of ssDNMs in the parental blood. The recurrence probability of a DNM decreases by 2.27% per year for paternal DNMs and 1.78% per year for maternal DNMs. Maternal ssDNMs are more likely to be T>C mutations than paternal ssDNMs, and less likely to be C>T mutations. Depending on the properties of the DNM, the recurrence probability ranges from 0.011% to 28.5%. We have launched an online calculator to allow estimation of DNM recurrence probability for research purposes.
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Access to these data is controlled, the DNMs are a subset of the sequence variants deposited to the European Nucleotide Archive (PRJEB15197).
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We thank all of the participants in this study. The study was performed in collaboration with Illumina.
Integrated supplementary information
a,b, The male and female germ cell lineages of a nine-offspring family. c,d, The paternal and maternal germ cell lineages of a nine-offspring family. Purple and green text correspond to DNMs determined by the trio and sibling approach, respectively. Percentages are paternal and maternal imbalances, respectively. The paternal imbalance serves as a background rate for the maternal DNMs, and vice versa. In addition to ssDNMs, we incorporated DNMs that are somatic mosaic in the parent (≥4 reads supporting the alternative allele in the parent). DNM sites are ordered according to carrier frequency, from high (top) to low (bottom) frequency.
a,b, The male and female germ cell lineages of a nine-offspring family. c,d, The paternal and maternal germ cell lineages of a nine-offspring family. Purple and green text correspond to DNMs determined by the trio and sibling approach, respectively. Percentages are paternal and maternal allelic imbalances, respectively. The paternal allelic imbalance serves as a background rate for the maternal DNMs, and vice versa. In addition to ssDNMs, we incorporated DNMs that are somatic mosaic in the parent (≥4 reads supporting the alternative allele in the parent). DNM sites are ordered according to carrier frequency, from high (top) to low (bottom) frequency.
a, Restricting to DNMs determined by the trio approach and DNMs from the sibling approach in which the allelic balance difference between carriers and parents was rejected. A two-sided Fisher test was used for the allelic balance test difference. The P values were adjusted with Holm multiple-testing correction using the number of DNMs found solely by the sibling approach. b, In addition to rejecting the null hypothesis as in a, we required DNMs determined by the sibling approach to have at least two siblings who were non-carriers despite having the same haplotype background as the DNM carriers (absent). For a and b, the analysis was restricted to deep-sequenced parents (13 parent pairs and 518 sibling pairs). c, Same as in a except that all sibling pairs were used (238 parent pairs and 518 sibling pairs). d, Same as in b except that all sibling pairs were used (238 parent pairs and 518 sibling pairs). The center values are means and error bars are 95% CIs.
The power of detecting a DNM segregating in the parental germline conditional on DNM transmission.
a, The allelic imbalance from targeted resequencing against carrier status determined from whole-genome sequencing. In a, sites with over 100× coverage were used, resulting in 657 genotypes from 27 offspring from two parent pairs. In a, the hinges are the first and third quantiles, and notches are ±1.58 × IQR/√n, where IQR is the interquartile range and n is the number in each category. b–e, Targeted resequenced imbalance of the parents against the imbalance from whole-genome sequencing.
The green and orange states represent the intermediate analysis steps and datasets, respectively.
The vertical error bars are the 95% CIs assessed by the jackknife procedure. The center values are the means. 13 parent pairs and 1,517 sibling trios were used in the 200× subset, and 54 parent pairs and 241 sibling trios were used in the 30× subset.
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Nature Ecology & Evolution (2019)