Hotspots for Initiation of Meiotic Recombination

Abstract

Homologous chromosomes must pair and recombine to ensure faithful chromosome segregation during meiosis, a specialized type of cell division that occurs in sexually reproducing eukaryotes. Meiotic recombination initiates by programmed induction of DNA double-strand breaks (DSBs) by the conserved type II topoisomerase-like enzyme SPO11. A subset of meiotic DSBs are resolved as crossovers, whereby reciprocal exchange of DNA occurs between homologous chromosomes. Importantly, DSBs are non-randomly distributed along eukaryotic chromosomes, forming preferentially in permissive regions known as hotspots. In many species, including plants, DSB hotspots are located within nucleosome-depleted regions. DSB localization is governed by interconnected factors, including cis-regulatory elements, transcription factor binding, and chromatin accessibility, as well as by higher-order chromosome architecture. The spatiotemporal control of DSB formation occurs within a specialized chromosomal structure characterized by sister chromatids organized into linear arrays of chromatin loops that are anchored to a proteinaceous axis. Although SPO11 and its partner proteins required for DSB formation are bound to the axis, DSBs occur preferentially within the chromatin loops, which supports the "tethered-loop/axis model" for meiotic recombination. In this mini review, we discuss insights gained from recent efforts to define and profile DSB hotspots at high resolution in eukaryotic genomes. These advances are deepening our understanding of how meiotic recombination shapes genetic diversity and genome evolution in diverse species.

Keywords: DSB; chromatin; crossover; epigenetics; hotspot; meiosis; nucleosomes; recombination.

Figure 1

Meiotic DNA double-strand break hotspots, chromatin and chromosome architecture in plants. (A) A representative histogram showing relative levels of meiotic DNA double-strand breaks (DSBs) generated by SPO11-1. Physical coordinates along a hypothetical locus are represented on the x-axis and DSB signal intensity derived from SPO11-1-oligo mapping is indicated on the y-axis. The depicted hypothetical DSB topology maps on to the chromatin diagram in (B). (B) A representative chromosomal region is shown based on data from Arabidopsis thaliana. This region contains an LTR retrotransposon which has heterochromatic modifications (blue), including H3K9me2, H2A.W, H3K27me1, and DNA methylation in CG, CHG, and CHH sequence contexts. Adjacent is an RNA polymerase II transcribed gene with transcriptional start site (TSS) and termination site (TTS) indicated. The 5′ nucleosome within the gene contains H2A.Z and is H3K4me3 modified (red). Within the transcribed region, nucleosomes located toward the 3′ end are H3K4me1, H3K4me2, and H3K36me3 modified, and DNA methylated in the CG sequence context (orange). The regions of highest meiotic DSB formation correspond to gene promoter, terminator and intron regions, which tend to be AT-rich, nucleosome-depleted and contain insertions of DNA transposable elements. (C) The chromatin region shown in (B) is represented in the context of the tethered-loop/axis model for meiotic chromosomes. SPO11-1 is represented as both a freely diffusing pool and an axis/cohesin-associated pool. Paired sister chromatids organize as a linear loop array on an axial polymer, which includes ASY1. As meiosis progresses from leptotene to zygotene to pachytene, the homologs become synapsed at a distance of ~100 nm, with ZYP1 installed as transverse filaments of the synaptonemal complex. During this process, DSBs can undergo repair using a homologous chromosome, resulting in a crossover (not shown).