Human acrocentric chromosome short arm <i>de novo</i> mutation and recombination
The extraordinary repetitive content of human acrocentric short arms has prevented detailed investigations into recombination and <i>de novo</i> mutation. Integrating multiple sequencing technologies, we created 156 phased short arms and assessed 107 intergenerational transmissions from 23 samples in a four-generation pedigree. We observed a significant depletion (<i>P</i><0.0001) of p-arm allelic recombination but one ectopic chr13-chr21 recombination breakpoint mediated by a 630 kbp segmental duplication mapping 1.6 Mbp distal to the SST1 array. In contrast, 18 maternal-biased q-arm allelic recombinations are significantly enriched within 5 Mbp of the centromere. Compared to autosomal euchromatin, the overall p-arm <i>de novo</i> single-nucleotide variant rate (1.33×10<sup>-7</sup> per base pair per generation) is 10-fold higher, with a significant reduction of C>T but increased C>G and A>C mutations. We hypothesize that acrocentric sequence composition biases and the dearth of allelic recombination contribute to an elevated mutation rate and unique mutational signatures suggestive of mismatch repair defects and oxidative stress-induced DNA lesions.
Authors
- Evan E. Eichler (ORCID: https://orcid.org/0000-0002-8246-4014)
- Francesco Mastrorosa (ORCID: https://orcid.org/0000-0003-0579-1895)
- Deborah W. Neklason (ORCID: https://orcid.org/0000-0002-4546-7080)
- Michelle D. Noyes
- Kendra Hoekzema (ORCID: https://orcid.org/0000-0002-8058-0177)
- Arang Rhie (ORCID: https://orcid.org/0000-0002-9809-8127)
- Jiadong Lin (ORCID: https://orcid.org/0000-0002-8116-5901)
- Aaron R. Quinlan (ORCID: https://orcid.org/0000-0003-1756-0859)
- DongAhn Yoo (ORCID: https://orcid.org/0000-0003-0033-3721)
- Katherine M. Munson (ORCID: https://orcid.org/0000-0001-8413-6498)
- Adam M. Phillippy (ORCID: https://orcid.org/0000-0003-2983-8934)
- David Porubský (ORCID: https://orcid.org/0000-0001-8414-8966)
- W. Scott Watkins (ORCID: https://orcid.org/0000-0001-9105-1193)
- Lynn B. Jorde (ORCID: https://orcid.org/0000-0002-0606-1862)
- Nidhi Koundinya
Institutions
- National Institutes of Health (US)
- Howard Hughes Medical Institute (US)
- University of Washington (US)
- University of Utah (US)
- National Human Genome Research Institute (US)
- European Molecular Biology Laboratory (DE)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2025-12-17
- DOI
- https://doi.org/10.64898/2025.12.16.694519
- Citations
- 2
- Primary Topic
- Genetic factors in colorectal cancer
- Type
- article
- Field-Weighted Citation Impact
- 2.94