A familial, telomere-to-telomere reference for human de novo mutation and recombination from a four-generation pedigree

作者：David Porubskỳ, Harriet Dashnow, Thomas A. Sasani, Glennis A. Logsdon, Pille Hallast, Michelle D. Noyes, Zev Kronenberg, Tom Mokveld, Nidhi Koundinya, C. Nolan, Cody J. Steely, Andrea Guarracino, Egor Dolzhenko, William T. Harvey, William J. Rowell, Kirill Grigorev, Thomas J. Nicholas, Keisuke K. Oshima, Jiadong Lin, Peter Ebert, W. Scott Watkins, Tiffany Y. Leung, Vincent C. T. Hanlon, Sean McGee, Brent S. Pedersen, Michael E. Goldberg, Hannah C. Happ, Hyeonsoo Jeong, Katherine M. Munson, Kendra Hoekzema, Daniel D. Chan, Yanni Wang, Jordan Knuth, Gage H. Garcia, Cairbre Fanslow, Christine Lambert, Charles Lee, Joshua D. Smith, Shawn Levy, Christopher E. Mason, Erik Garrison, Peter M. Lansdorp, Deborah W. Neklason, Lynn B. Jorde, Aaron R. Quinlan, Michael A. Eberle, Evan E. Eichler · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2024 · DOI：10.1101/2024.08.05.606142 · 被引用次数：22 · 研究领域：Chromosomal and Genetic Variations、Genomic variations and chromosomal abnormalities、CRISPR and Genetic Engineering

ABSTRACT Using five complementary short- and long-read sequencing technologies, we phased and assembled >95% of each diploid human genome in a four-generation, 28-member family (CEPH 1463) allowing us to systematically assess de novo mutations (DNMs) and recombination. From this family, we estimate an average of 192 DNMs per generation, including 75.5 de novo single-nucleotide variants (SNVs), 7.4 non-tandem repeat indels, 79.6 de novo indels or structural variants (SVs) originating from tandem repeats, 7.7 centromeric de novo SVs and SNVs, and 12.4 de novo Y chromosome events per generation. STRs and VNTRs are the most mutable with 32 loci exhibiting recurrent mutation through the generations. We accurately assemble 288 centromeres and six Y chromosomes across the generations, documenting de novo SVs, and demonstrate that the DNM rate varies by an order of magnitude depending on repeat content, length, and sequence identity. We show a strong paternal bias (75-81%) for all forms of germline DNM, yet we estimate that 17% of de novo SNVs are postzygotic in origin with no paternal bias. We place all this variation in the context of a high-resolution recombination map (∼3.5 kbp breakpoint resolution). We observe a strong maternal recombination bias (1.36 maternal:paternal ratio) with a consistent reduction in the number of crossovers with increasing paternal (r=0.85) and maternal (r=0.65) age. However, we observe no correlation between meiotic crossover locations and de novo S...