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

Loss of heterozygosity (LOH) is a genetic alteration that results from the loss of one allele at a heterozygous locus. In particular, copy neutral LOH (CN-LOH) events are generated, for example, by mitotic homologous recombination after monoallelic defection or gene conversion, resulting in novel homozygous locus having 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 CN-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 CN-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 CN-LOH, which exists in both germline and somatic cells. We also confirmed that the incidence of the CN-LOH has little to do with the parents’ age and sex. Furthermore, through the analysis of the genomic region including the CN-LOH, we found that the chance of the occurrence of the CN-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 CN-LOH.