Loss of Heterozygosity and Its Importance in Evolution

Abstract

Loss of heterozygosity (LOH) is a mitotic recombination event that converts heterozygous loci to homozygous loci. This mutation event is widespread in organisms that have asexual reproduction like budding yeasts, and is also an important and frequent mutation event in tumorigenesis. Mutation accumulation studies have demonstrated that LOH occurs at a rate higher than the point mutation rate, and can impact large portions of the genome. Laboratory evolution experiments of heterozygous yeasts have revealed that LOH often unmasks beneficial recessive alleles that can confer large fitness advantages. Here, I highlight advances in understanding dominance, fitness, and phenotypes in laboratory evolved heterozygous yeast strains. I discuss best practices for detecting LOH in intraspecific and interspecific evolved clones and populations. Utilizing heterozygous strain backgrounds in laboratory evolution experiments offers an opportunity to advance our understanding of this important mutation type in shaping adaptation and genome evolution in wild, domesticated, and clinical populations.

Hybrid adaptation is hampered by Haldane’s sieve

“…These regions have been previously identified to be susceptible for t-LOHs 65 . Certain t-LOHs were found to cluster around particular positions enriched with repetitive loci, such as the rDNA locus on chromosome XII 62,66 or the STE4 gene, another common t-LOH-target on chromosome XV 67 . We found a much larger number of hybrid lines with t-LOHs when evolved under UV mimetic conditions (96% of the lines) compared to control conditions (8% of the lines) (Fig.…”

“…3), revealing the presence of reciprocal crossovers between chromosomes. These tracts that extend to the telomeres and usually measure between 50-100 kb correspond to Terminal-Loss of Heterozygosity (t-LOH) regions 62,63,66 . To quantitatively assess the number of t-LOH events in hybrid lines, we identified regions with simultaneous increases and decreases in read depth (deviation of 30% with respect to the genome-wide median read depth) in both chromosomal copies exceeding a size threshold of 20 kb.…”

Elucidating the clonal relationship of esophageal second primary tumors in patients with laryngeal squamous cell carcinoma

“…Frequent allelic deletions were observed at chromosomal positions 3p, 4q, 9p (p16 INK4a ), 11q, 13q (Rb), 14q and 17p (TP53) in LSCC patients [ 10 ]. Additionally, LOH analysis provides valuable insights into the identification and characterization of tumor suppressor genes and their cloning process [ 17 ]. It is worth noting that microsatellite DNA can be inherited across generations.…”

Ploidy evolution in a wild yeast is linked to an interaction between cell type and metabolism

“…Unexpectedly, all SNPs in the evolved isolates were represented by a single, non-reference allele (S2 Fig) . Although mitotic recombination can generate losses of heterozygosity at new or standing variation during adaptive evolution [69][70][71][72][73][74][75], our results differed significantly from 2 recent large-scale experimental evolution studies in S. cerevisiae, which found approximately 5% to 10% of mutations to be homozygous in diploid or autodiploid clones after 4,000 generations [7,9]. In comparison, our observed allele frequencies at mutated sites are highly improbable under the null expectation of diploidy (binomial tests: p = 5.3 × 10 −6 , p = 1 × 10 −4 , respectively).…”