Figure 1.

Gene conversion leading to LOH events in tumour cells. (a) A potential tumour cell that has incurred a LOH will increase in frequency as a subpopulation within a tissue or tumour. (b) A cell repairing a DSB mediated via a crossover or non-crossover, giving rise to two daughter cells exhibiting LOH. The examples shown correspond to a model in which the DSB repair pathway is followed by the resolution of a double Holliday junction, although other mechanisms may lead to gene conversion (as described in [137–139]). Mismatched bases may originate via DNA synthesis when the sister chromatid is used as a template for repair, resulting in a non-reciprocal exchange between both DNA strands [140]. LOH occurs during gene conversion when germline variants are heterozygous (as shown). If homologous recombination occurs during a two-homologue chromatid invasion, as is more often the case, only a non-crossover model leads to LOH, whereas with a four chromatid invasion, crossovers and non-crossovers lead to LOH only when recombinant chromatids segregate to the same daughter cell. (c) LOH events can be captured by counting the number of sequencing reads from tumour samples carrying the alternative alleles at heterozygous sites identified in germline (or healthy tissue). Nevertheless, challenges are associated with the detection of LOH events from sequencing data. Owing to cell mixture in the tumour, the signal for LOH events can be lost, and may not distinguishable from sequencing errors and mapping bias effects.