Gametes are the products of a meiotic programme in which diploid germ cells undergo one round of DNA replication followed by two successive rounds of cell division. During this process, gametes acquire chromosomes comprising new assortments of parental alleles. Subsequent fusion of two gametes during sexual reproduction results in the reconstitution of a diploid genome, yielding offspring that are genetically distinct from their parents.
In most sexually reproducing organisms, homologous recombination lies at the heart of meiosis by promoting proper segregation of HOMOLOGOUS CHROMOSOMES
(also referred to as homologues) (reviewed in REF. 1
). Prior to the first meiotic division, recombination begins when DNA double-strand breaks (DSBs) are deliberately introduced into each chromosome. The DSBs are then repaired by genetic exchange with allelic sequences, resulting in physical linkages between pairs of homologues. These connections ensure that homologues orient correctly on the meiotic spindle and migrate to opposite spindle poles. Meiotic recombination thus promotes genetic stability and faithful transmission of the genome by limiting the repair of each DSB primarily to DNA sequences at the allelic position on the homologue and ensuring the accurate distribution of chromosomes to gametes.
Errors in meiotic recombination can affect genome stability during gametogenesis. Research spanning several decades has shown that chromosome non-disjunction (that is, missegregation) in meiosis results in constitutive ANEUPLOIDY
, which can lead to spontaneous abortion or congenital birth defects (reviewed in REF. 2
). More recent work has uncovered a second process that influences genome stability in the germline: aberrant meiotic recombination between non-allelic DNA segments that share high sequence similarity. This process is known as non-allelic homologous recombination (NAHR); the synonymous term `ectopic recombination' is more prevalent in older literature and in yeast studies. NAHR is a more recent, mechanistically evocative term and is used in this Review. Because eukaryotic genomes from yeasts to human harbour repeated blocks of DNA3, 4
, a meiotic DSB formed within a repeat has the potential to induce genomic rearrangement through repair with non-allelic sequences. In humans, NAHR-mediated events leading to chromosomal alterations have been implicated in numerous disorders. It is thus important to understand the mechanisms behind NAHR in the germline.
This Review focuses on genome instability induced by meiotic NAHR. We begin with an overview of the mechanism of meiotic recombination and then discuss the types of chromosomal rearrangement and human disorder that are associated with NAHR between duplicated regions of the genome. We next examine insights into NAHR mechanisms obtained from studies in other organisms. Finally, we review cellular strategies that prevent meiotic NAHR and favour recombination between allelic sequences, and consider some of the future challenges in the field.