A familial, telomere-to-telomere reference for humande novomutation and recombination from a four-generation pedigree DOI Creative Commons
David Porubský, Harriet Dashnow, Thomas A. Sasani

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 5, 2024

Using five complementary short- and long-read sequencing technologies, we phased 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) recombination. From this family, estimate an average 192 DNMs per generation, including 75.5 single-nucleotide variants (SNVs), 7.4 non-tandem repeat indels, 79.6 indels or structural (SVs) originating from tandem repeats, 7.7 centromeric SVs SNVs, 12.4 Y chromosome events generation. STRs VNTRs are the most mutable with 32 loci exhibiting recurrent mutation through generations. We accurately assemble 288 centromeres six chromosomes across generations, documenting SVs, demonstrate that DNM rate varies by order magnitude depending on content, length, sequence identity. show strong paternal bias (75-81%) for all forms germline DNM, yet 17% SNVs postzygotic origin no bias. place variation context high-resolution recombination map (~3.5 kbp breakpoint resolution). observe maternal (1.36 maternal:paternal ratio) consistent reduction number crossovers increasing (r=0.85) (r=0.65) age. However, correlation between meiotic crossover locations arguing against non-allelic homologous as predominant mechanism. The use multiple orthogonal near-telomere-to-telomere assemblies, multi-generation transmission has created comprehensive, publicly available "truth set" classes genomic variants. resource can be used test benchmark new algorithms technologies understand fundamental processes underlying genetic variation.

Language: Английский

A familial, telomere-to-telomere reference for humande novomutation and recombination from a four-generation pedigree DOI Creative Commons
David Porubský, Harriet Dashnow, Thomas A. Sasani

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 5, 2024

Using five complementary short- and long-read sequencing technologies, we phased 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) recombination. From this family, estimate an average 192 DNMs per generation, including 75.5 single-nucleotide variants (SNVs), 7.4 non-tandem repeat indels, 79.6 indels or structural (SVs) originating from tandem repeats, 7.7 centromeric SVs SNVs, 12.4 Y chromosome events generation. STRs VNTRs are the most mutable with 32 loci exhibiting recurrent mutation through generations. We accurately assemble 288 centromeres six chromosomes across generations, documenting SVs, demonstrate that DNM rate varies by order magnitude depending on content, length, sequence identity. show strong paternal bias (75-81%) for all forms germline DNM, yet 17% SNVs postzygotic origin no bias. place variation context high-resolution recombination map (~3.5 kbp breakpoint resolution). observe maternal (1.36 maternal:paternal ratio) consistent reduction number crossovers increasing (r=0.85) (r=0.65) age. However, correlation between meiotic crossover locations arguing against non-allelic homologous as predominant mechanism. The use multiple orthogonal near-telomere-to-telomere assemblies, multi-generation transmission has created comprehensive, publicly available "truth set" classes genomic variants. resource can be used test benchmark new algorithms technologies understand fundamental processes underlying genetic variation.

Language: Английский

Citations

12