Genome-wide identification of loss of heterozygosity reveals its association with spatial positioning of chromosomes

Abstract Loss of heterozygosity (LOH) is a genetic alteration that results from the loss of one allele at a heterozygous locus. Some LOH events are generated by mitotic homologous recombination after monoallelic defection, then the novel homozygous locus has two copies of the normal counterpart allele. This phenomenon can serve as a source of genome diversity and is associated with various diseases. To clarify the nature of the LOH such as the frequency, genomic distribution, and inheritance pattern, we made use of whole-genome sequencing data of the three-generation CEPH/Utah family cohort, with the pedigree consisting of grandparents, parents, and offspring. We identified an average of 40.7 LOH events per individual taking advantage of 285 healthy individuals from 33 families in the cohort. On average 65% of them were classified as gonosomal-mosaicism-associated LOH, which exists in both germline and somatic cells. We also confirmed that the incidence of the LOH has little to do with the parents’ age and sex. Furthermore, through the analysis of the genomic region including the LOH, we found that the chance of the occurrence of the LOH tends to increase at the GC-rich locus and/or on the chromosome having a relatively close inter-homolog distance. We expect that these results provide significant insights into the association between genetic alteration and spatial position of chromosomes as well as the intrinsic genetic property of the LOH. Author Summary Loss of heterozygosity (LOH) is a common genetic alteration that a heterozygous locus becomes a homozygous locus. In some cases, if a monoallelic defection accompanying homologous recombination between inter-homolog occurs, it results in copy-neutral LOH having two copies of the allele. Although the LOH is potentially important in understanding pathogenesis of various diseases, its fundamental features have received scant attention. To characterize the nature of the LOH, data from single individuals and their parents are required. This is because it would be difficult to discriminate between the LOH and a normal homozygous allelic state using genomic data obtained only from a single individual. Whole-genome sequencing data of 33 CEPH/Utah families, which comprise large three-generation family units, motivated us to perform a genome-wide identification of the LOH. Using this dataset, we successfully identified the LOH and analyzed its frequency, genomic distribution, and inheritance pattern. Moreover, we revealed that the occurrence of the LOH was affected by the inter-homolog distances, which reflect the chromosome territory. Our findings pertaining to the LOH provide insight into the association between genetic alteration and spatial positioning of chromosomes.