What drives recombination hotspots to repeat DNA in humans?

Abstract

Recombination between homologous, but non-allelic, stretches of DNA such as gene families, segmental duplications and repeat elements is an important source of mutation. In humans, recent studies have identified short DNA motifs that both determine the location of 40 per cent of meiotic cross-over hotspots and are significantly enriched at the breakpoints of recurrent non-allelic homologous recombination (NAHR) syndromes. Unexpectedly, the most highly penetrant form of the motif occurs on the background of an inactive repeat element family (THE1 elements) and the motif also has strong recombinogenic activity on currently active element families including Alu and LINE2 elements. Analysis of genetic variation among members of these repeat families indicates an important role for NAHR in their evolution. Given the potential for double-strand breaks within repeat DNA to cause pathological rearrangement, the association between repeats and hotspots is surprising. Here we consider possible explanations for why selection acting against NAHR has not eliminated hotspots from repeat DNA including mechanistic constraints, possible benefits to repeat DNA from recruiting hotspots and rapid evolution of the recombination machinery. I suggest that rapid evolution of hotspot motifs may, surprisingly, tend to favour sequences present in repeat DNA and outline the data required to differentiate between hypotheses.

Figure 1.

The fine-scale structure of recombination-rate variation around repeat elements in the human genome. For each of the repeat element families shown, the average autosomal recombination rate, measured over 1 kb intervals from the centre of repeats, is shown for all repeats (blue) and those containing the degenerate 13 mer motif CCNCCNTNNCCNC (red). Note the markedly different recombination profiles across repeat families. In each case, however, the presence of the 13 mer motif leads to marked local increase in recombination rate. The fraction of repeats containing the degenerate motif varies from approximately 2 per cent (THE1B, L2, L1) to over 10 per cent (AluY).