copynumber

Copy number refers to the number of copies of a particular genomic segment within an individual’s genome. Copy number variation (CNV) denotes segments whose copy number differs between individuals in the population, ranging from kilobases to megabases. CNVs can be inherited (germline) or acquired in somatic cells, as seen in cancer. They include deletions, duplications, and more complex rearrangements, and may be homozygous or heterozygous, with multi-allelic copy number variation also observed in some regions.

CNVs can alter gene dosage and gene expression, influencing phenotype. They are associated with developmental disorders, congenital anomalies, immune and metabolic conditions, and susceptibility to psychiatric disorders in some cases. In cancer, somatic copy number alterations (CNAs) can amplify oncogenes or delete tumor suppressor regions, contributing to tumorigenesis; mosaic CNVs can be present in subsets of cells.

Detection and interpretation rely on genome-wide measurement of copy number. Microarray-based comparative genomic hybridization and SNP arrays compare signal intensities to reference genomes to infer relative copy number. High-coverage sequencing uses read depth, split reads, and paired-end mapping to identify CNVs with higher resolution. Computational methods such as read-depth, model-based, or paired-end approaches call CNVs from sequencing data; interpretation involves overlap with genes, dosage sensitivity, and population frequency. Challenges include repetitive regions, segmental duplications, mosaicism, and tumor purity.

CNV maps from population studies and clinical databases underpin variant interpretation, with guidelines from clinical genetics communities to classify CNVs as benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic.