Karen Oliver | bioRxiv Science

bioRxiv2020

Template switching mechanism drives the tandem amplification of chromosome 20q11.21 in human pluripotent stem cells

Copy number variants (CNVs) are genomic rearrangements implicated in numerous congenital and acquired diseases, including cancer. In human pluripotent stem cells (PSC), the appearance of culture-acquired CNVs prompted concerns for their use in regenerative medicine applications. A particularly common problem in PSC is the occurrence of CNVs in the q11.21 region of chromosome 20. However, the exact mechanisms of origin of this amplicon remains elusive due to the difficulty in delineating its sequence and breakpoints. Here, we used long-range Nanopore sequencing on two examples of this CNV, present as a duplication in one and a triplication in another line. The CNVs were arranged in a head-to-tail orientation in both lines, with sequences of microhomologies flanking or overlapping both the proximal and distal breakpoints. These breakpoint signatures point to a specific mechanism of template switching in CNV formation, with surrounding Alu sequences likely contributing to the instability of this genomic region.

genomics↗

bioRxiv2016

Contrasting genome dynamics between domesticated and wild yeasts

Structural rearrangements have long been recognized as an important source of genetic variation with implications in phenotypic diversity and disease, yet their evolutionary dynamics are difficult to characterize with short-read sequencing. Here, we report long-read sequencing for 12 strains representing major subpopulations of the partially domesticated yeast Saccharomyces cerevisiae and its wild relative Saccharomyces paradoxus. Complete genome assemblies and annotations generate population-level reference genomes and allow for the first explicit definition of chromosome partitioning into cores, subtelomeres and chromosome-ends. High-resolution view of structural dynamics uncovers that, in chromosomal cores, S. paradoxus exhibits higher accumulation rate of balanced structural rearrangements (inversions, translocations and transpositions) whereas S. cerevisiae accumulates unbalanced rearrangements (large insertions, deletions and duplications) more rapidly. In subtelomeres, recurrent interchromosomal reshuffling was found in both species, with higher rate in S. cerevisiae. Such striking contrasts between wild and domesticated yeasts reveal the influence of human activities on structural genome evolution.

Genomics↗