The dynamics of loss of heterozygosity events in genomes

Abstract

Genomic instability is a hallmark of tumorigenesis, yet it also plays an essential role in evolution. Large-scale population genomics studies have highlighted the importance of loss of heterozygosity (LOH) events, which have long been overlooked in the context of genetic diversity and instability. Among various types of genomic mutations, LOH events are the most common and affect a larger portion of the genome. They typically arise from recombination-mediated repair of double-strand breaks (DSBs) or from lesions that are processed into DSBs. LOH events are critical drivers of genetic diversity, enabling rapid phenotypic variation and contributing to tumorigenesis. Understanding the accumulation of LOH, along with its underlying mechanisms, distribution, and phenotypic consequences, is therefore crucial. In this review, we explore the spectrum of LOH events, their mechanisms, and their impact on fitness and phenotype, drawing insights from Saccharomyces cerevisiae to cancer. We also emphasize the role of LOH in genomic instability, disease, and genome evolution.

Keywords: Saccharomyces cerevisiae; DNA Repair; Genome Instability; Loss of Heterozygosity; Mutation Accumulation.

Figure 1. Accumulation of LOH events.

Potential mechanisms leading to LOH. LOH can span large regions of the chromosome through mitotic non-disjunction, with or without duplicating the remaining chromosome, Crossovers (CO) or Break-induced replication (BIR) events. Small deletions, translocations and gene conversions may result in short LOH events. The numbers represent the frequency of events in S. cerevisiae genomes [CL-copy loss; CN-copy neutral].

Figure 2. Mitotic repair of DSBs by homologous recombination (HR).

Recombination repair of a DSB is initiated by the 5’ resection of the break to produce single-stranded 3’ ends. The 3’ end invades the intact homolog and initiates leading strand synthesis. If a chromosome fragment is lost, repair is facilitated by Break-induced replication (BIR). The invading end creates a migrating D-loop, and both leading and lagging strand synthesis take place. The classical double-strand break repair (DSBR) pathway involves the further synthesis of the invading strand which gets ligated back to the resected 5’ end of the broken DNA molecule, leading to the formation of a double Holliday junction (dHJ). The dHJ can be resolved as crossovers and non-crossovers by Holliday junction resolvases. Repair by synthesis-dependent strand annealing (SDSA) is very common during mitotic DSB repair and involves the displacement of the invading strand with little synthesis and anneals to the other end of the broken DNA molecule, this is followed by gap repair and ligation leading to the formation of non-crossovers (adapted from Symington et al, 2014).

Figure 3. Return-to-growth (meiotic abortions).

A hybrid diploid cell is induced to initiate meiosis upon transfer to the sporulation medium, leading to Spo11-induced meiotic double-strand breaks (meiotic DSBs). If these cells are subsequently transferred to rich growth medium before the meiotic commitment step, the meiotic program is reversed. This process bypasses DNA replication and allows the meiotic mother cell to produce a diploid “daughter” cell through budding. Both the mother and daughter cells inherit two of the four chromatids present in the meiotic cell at the time RTG was induced, which may be recombined or non-recombined. The boxes highlight LOH events in the mother and daughter cells. The extent of LOH depends upon the time point of RTG induction.