Frequency of mosaicism points towards mutation-prone early cleavage cell divisions.
Chad HarlandiD, Carole CharlieriD, Latifa Karim, Nadine Cambisano, Manon Deckers, Myriam Mni, Erik MullaartiD, Wouter Coppieters, Michel GeorgesiD
Abstract
It has recently become possible to directly estimate the germ-line de novo mutation (dnm) rate by sequencing the whole genome of father-mother-offspring trios, and this has been conducted in human1-5, chimpanzee6, mice7, birds8 and fish9. In these studies dnms are typically defined as variants that are heterozygous in the offspring while being absent in both parents. They are assumed to have occurred in the germ-line of one of the parents and to have been transmitted to the offspring via the sperm cell or oocyte. This definition assumes that detectable mosaicism in the parent in which the mutation occurred is negligible. However, instances of detectable mosaicism or premeiotic clusters are well documented in humans and other organisms, including ruminants10-12. We herein take advantage of cattle pedigrees to show that as much as [~]30% to [~]50% of dnms present in a gamete may occur during the early cleavage cell divisions in males and females, respectively, resulting in frequent detectable mosaicism and a high rate of sharing of multiple dnms between siblings. This should be taken into account to accurately estimate the mutation rate in cattle and other species.
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Abstract summary
Claude Opus 5.5 · xhigh effort · 18 Oct 2026 · from the abstract · CC BY-NC-ND 4.0
Cattle pedigrees indicate up to ~30% of de novo mutations in male gametes and ~50% in female gametes arise during early cleavage divisions, leaving parental mosaicism and sibling sharing.
Trio-based mutation rate estimates call any variant heterozygous in the offspring and absent from both parents a germline de novo mutation, which assumes parental mosaicism can be ignored. Using cattle pedigrees, the authors argue a substantial share of these events instead happen in the first cell divisions of the embryo, which would distort rate estimates and make siblings share mutations.
Key results
SuggestedA large share of the de novo mutations a gamete carries trace back to the earliest embryonic cell divisions rather than to later germline events.
Put at as much as ~30% for males and ~50% for females from cattle pedigrees; the abstract gives these as upper bounds and states no pedigree size or confidence interval. · Abstract
SuggestedMutations of this origin leave two observable traces: mosaicism detectable in the parent, and several mutations shared between siblings.
Both are reported as frequent in the cattle pedigrees, but no counts, frequencies or sibling-pair numbers appear in the abstract. · Abstract
ClaimedThe usual trio definition of a de novo mutation therefore mis-assigns a fraction of events, so published rate estimates need correction.
Argued from the assumption of negligible parental mosaicism that trio studies in human, chimpanzee, mice, birds and fish rely on; no corrected rate for cattle or any other species is reported here. · Abstract
Methods, data and reproducibility
Cattle pedigrees were used to ask what fraction of the de novo mutations present in a gamete arose during the early cleavage cell divisions rather than later in the germ line, with mosaicism detectable in the transmitting parent and the sharing of several mutations between siblings as the signal. The abstract describes no sequencing, variant-calling or statistical procedure.
- Cattle pedigrees used to detect de novo mutations, parental mosaicism and mutations shared between siblings · cattle
Limitations (2)
- The estimate comes from cattle alone; whether the same share holds in the human, chimpanzee, mouse, bird or fish trio studies the authors cite is not tested in this text. · noted in this summary
- No pedigree size, sequencing depth, mosaicism detection threshold or uncertainty is given, and the headline figures are stated as upper bounds rather than point estimates. · noted in this summary
Who should read:Read this if you estimate de novo mutation rates from sequenced trios and need to know how much early-embryo mosaicism can distort the counts.
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