Genome-wide variability in recombination activity is associated with meiotic chromatin organization

Abstract

BackgroundRecombination enables reciprocal exchange of genomic information between parental chromosomes and successful segregation of homologous chromosomes during meiosis. Errors in this process lead to negative health outcomes, while variability in recombination rate affects genome evolution. In mammals, most crossovers occur in hotspots defined by PRDM9 motifs, though PRDM9 binding sites are not all equally hot. We hypothesize that dynamic patterns of meiotic genome folding are linked to recombination activity.ResultsWe apply an integrative bioinformatics approach to analyze how three-dimensional (3D) chromosomal organization during meiosis relates to rates of double-strandbreak (DSB) and crossover formation at PRDM9 hotspots. We show that active, spatially accessible genomic regions during meiotic prophase are associated with DSB-favoured hotspots, which further adopt a transient locally active configuration in early prophase. Conversely, crossover formation is depleted among DSBs in spatially accessible regions during meiotic prophase, particularly within gene bodies. We also find evidence that active chromatin regions have smaller average loop sizes in mammalian meiosis. Collectively, these findings establish that differences in chromatin architecture along chromosomal axes are associated with variable recombination activity.ConclusionsWe propose an updated framework describing how 3D organization of brush-loop chromosomes during meiosis may modulate recombination.

PRDM9 losses in vertebrates are coupled to those of paralogs ZCWPW1 and ZCWPW2

“…In mice and humans, and probably in most mammals, the localization of almost all DSBs is specified through the binding of PRDM9 [2][3][4]. Yet the presence of a PRDM9 binding site is far from sufficient for a DSB to be made: a number of additional factors modulate whether PRDM9 binds or act downstream of PRDM9 binding [5][6][7].…”

Chromosome Organization in Early Meiotic Prophase

“…In silico modeling using HiC data estimated the mean loop size of mouse zygotene and pachytene chromosomes to be between 0.8 and 2 Mbps ( Alavattam et al, 2019 ; Patel et al, 2019 ). This value may, however, mask variability that is detected when separating A and B compartments and revealing shorter predicted loop sizes in A compartments ( Jin et al, 2021 ). Electron microscopy and immuno-FISH experiments using female and male meiotic chromosome spreads estimated the loop size on several autosomes to be about 2.2 mm in leptotene, and about 6 μm in pachytene ( Novak et al, 2008 ; Kauppi et al, 2011 ).…”