Study of structural chromosome abnormalities to increase the understanding of human genetic diversity: a commentary on signature of backward replication slippage at the copy number variation junction

In an earlier issue of Journal of Human Genetics, Ohye et al.¹ reported, at the sequence level, the chromosomal structure of a 2.8-Mb interstitial deletion of 2q. In this manuscript, two important implications of their report have been proposed. First, an unreported unbalanced chromosomal abnormality (UBCA) was detected with G-banding and confirmed with chromosomal microarray (CMA) and metaphase fluorescence in situ hybridization (FISH) in a subject who was a phenotypically normal adult female but suffering from recurrent miscarriage, although the relationship between UBCA and her recurrent miscarriage was uncertain. Second, the authors determined the genome structure of the junction of a microscopically visible interstitial chromosomal deletion in the subject and identified the complex repair resulting from sequence repeats with microhomology events, attributing it to a backward replication slippage mechanism. Their results suggest that such complex rearrangements of the genome may occur not only in patients but also in other phenotypically normal individuals.

Regarding chromosomal imbalances, along with recent technological advances in whole-genome analysis (WGA) using chromosomal microarray (CMA) and next-generation sequencing (NGS), humans certainly have more genomic structural variations (SVs), such as single-nucleotide variations (SNVs), insertion/deletion variations (indels) and copy number variations (CNVs), than suspected before. Some of these genomic changes have been identified as deleterious mutations of some diseases, termed ‘pathogenic’. Various so-called ‘benign’ genomic changes thought to represent innocuous individual variation have also been identified. We are faced with the fact that the nature of many genomic changes is unknown; such variants are tentatively called ‘variants of uncertain clinical significance (VOUS or VUS)’. Many submicroscopic CNVs (detectable only by molecular cytogenetic methods or CMA: MG-CNVs²) have been published in reports and databases such as Database of Genomic Variants and Phenotype in Humans using Ensembl Resources (DECIPHER) (http://decipher.sanger.ac.uk) and International Standards for Cytogenomic Arrays (ISCA) (https://www.iscaconsortium.org) of patients as well as Database of Genomic Variants (DGV) (http://dgv.tcag.ca) of healthy control samples, and this number has been increasing. However, there are larger CNVs (UBCAs or cytogenetically visible CNVs (CG-CNVs)²) that are difficult to identify even with current NGS technologies.

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