A new study sheds light on de novo mutations (DNMs) – genetic changes present in an individual but absent in their parents. These mutations are crucial in understanding disease development and evolutionary processes. Researchers have overcome limitations of previous studies by utilizing advanced sequencing technologies and a more complete human genome reference.
The study focused on a four-generation family (CEPH 1463), extensively studied in genetics. Five sequencing technologies were applied to the genomes of 28 family members. The goal was to identify single-nucleotide variants (SNVs), insertions and deletions (indels), and structural variants in DNA from blood samples.
Researchers accessed 260 million more base pairs of the genome compared to previous studies. The estimated transmission rate is 98-206 DNMs per generation, higher than prior estimates. "About 16% of the DNMs were postzygotic and, whereas germline DNMs were 81.4% paternal in origin, postzygotic DNMs show no parent-of-origin bias."
The study revealed that DNM rates vary depending on the region's repeat content. "Overall, the parental germ line contributes 1.17 × 10 SNVs per base pair per generation, with this rate almost tripling in centromere repeats and almost doubling in repeated sequences called segmental duplications." High mutation rates were also observed in heterochromatin and tandem repeat regions.
Researchers identified 32 sites with recurrent mutations in the family. They assembled 288 complete centromeres and validated 18 de novo structural variants from 150 transmission events. The research provides valuable data on human genomics and intergenerational transmission of genetic variations, even in complex genomic regions.