The first human mitotic nonallelic homologous recombination hotspot associated with genetic disease


Nonallelic homologous recombination (NAHR) is an important mutational mechanism in humans, giving rise to deletions, duplications, inversions and translocations. The study of disease-causing NAHR has so far largely focused on those events which have occurred during meiosis. Such studies have led to the identification of several meiotic NAHR hotspots in a number of different genomic disorders and have provided insights into the DNA sequence features that promote meiotic NAHR. In this issue, the Kehrer-Sawatzki group in Ulm and international colleagues have reported new findings from the study of another type of disease-causing NAHR, namely mitotic NAHR (Vogt et al., Hum Mutat 33:1599–1609, 2012). Molecular characterization of the breakpoints of a large number of type-2 NF1 NAHR-mediated deletions that apparently occurred postzygotically during early embryonic development (as evidenced by mosaicism with normal cells) enabled them to define the first human mitotic NAHR hotspot.

Importantly, but not unexpectedly, this mitotic NAHR hotspot is not associated with the 13-mer motif CCNCCNTNNCCNC that binds meiosis-specific histone H3 methyltransferase PRDM9, a major determinant of meiotic recombination hotspots in humans and mice. Rather, the authors found overrepresentation of the consensus SAR2 sequence motif, among others, within the recurrent type-2 NF1 deletion breakpoint regions. Since the SAR2 motif is frequently located within chromosomal scaffold and/or matrix attachment regions (S/MARs), Vogt et al. suggested that a combination of an open chromatin conformation and short non-B DNA-forming repeats may predispose to recurrent mitotic NAHR events in the NF1 locus. Although it remains to be seen whether mitotic NAHR hotspots in other loci share similar sequence features, this study has provided the first proof of concept that mitotic NAHR, like meiotic NAHR, is also highly sequence-directed.