BioProject

Human genome structural variants (SVs) are caused by diverse mutational mechanisms. More...

Human genome structural variants (SVs) are caused by diverse mutational mechanisms. We used orthogonal long- and short-read sequencing technologies to investigate end products of de novo chromosome 17p11.2 rearrangements and query the molecular mechanisms underlying both recurrent and non-recurrent events. For non-recurrent events we found microhomology and microhomeology at the breakpoint junctions, an excess of deletion rearrangements on paternally-derived haplotypes, and elucidated recalcitrant breakpoints. Our data indicate an increased rate of clustered single nucleotide variant mutation in cis that is not present with recurrent rearrangement of the genome at the same locus. Indel and single nucleotide mutations are associated with both copy number gains and losses of 17p11.2, occur up to ~1 Mb away from the breakpoint junctions, and favor C>G transversion substitutions; results suggesting that single stranded DNA is formed during the genesis of the SV and providing compelling support for a microhomology-mediated break-induced replication mechanism for SV formation. Overall design: To determine size, genomic extent and gene content for each rearrangement, we used a customized tiling-path oligonucleotide microarray spanning the 17p11.2 chromosomal region to query the genomic DNA of 55 individuals and their parents. This allowed us to discern the extent of the rearrangements, the copy number, and the de novo status of each rearrangement. Less...