A familial T2T reference for human de novo mutation and recombination across four generations
This study presents a comprehensive telomere-to-telomere reference of human de novo mutations (DNMs) and recombination, derived from a four-generation, 28-member family. We use a combination of short- and long-read sequencing technologies to phase and assemble over 95% of each diploid genome, including 288 centromeres and six Y chromosomes. This allows for a systematic assessment of genetic variation inheritance across generations. We estimate an average of 152 DNMs per generation, including single-nucleotide variants, indels, and structural variants, with a strong paternal bias observed. We place all this variation in the context of a high-resolution recombination map (~3.4 kbp breakpoint resolution). Our findings demonstrate that the DNM rate varies by an order of magnitude depending on repeat content, length, and sequence identity. We find short tandem repeats and variable number tandem repeats are the most mutable with 32 loci exhibiting recurrent mutation through the generations. Overall, this dataset offers a valuable resource for benchmarking algorithms and understanding fundamental processes underlying human genetic variation.