Established and Novel Mechanisms Leading to de novo Genomic Rearrangements in the Human Germline

Abstract

During gametogenesis, the human genome can acquire various de novo rearrangements. Most constitutional genomic rearrangements are created through 1 of the 4 well-known mechanisms, i.e., nonallelic homologous recombination, erroneous repair after double-strand DNA breaks, replication errors, and retrotransposition. However, recent studies have identified 2 types of extremely complex rearrangements that cannot be simply explained by these mechanisms. The first type consists of chaotic structural changes in 1 or a few chromosomes that result from "chromoanagenesis (an umbrella term that covers chromothripsis, chromoanasynthesis, and chromoplexy)." The other type is large independent rearrangements in multiple chromosomes indicative of "transient multifocal genomic crisis." Germline chromoanagenesis (chromothripsis) likely occurs predominantly during spermatogenesis or postzygotic embryogenesis, while multifocal genomic crisis appears to be limited to a specific time window during oogenesis and early embryogenesis or during spermatogenesis. This review article introduces the current understanding of the molecular basis of de novo rearrangements in the germline.

Keywords: Chromothripsis; Copy number variation; De novo mutation; Genomic rearrangement; Multifocal genomic crisis.