Copy-number variation

Copy-number variation is defined as the presence of one or more extra or missing copies of a DNA segment, typically larger than 1 kb, relative to a reference genome.¹ CNVs include deletions, duplications, and more complex rearrangements such as insertions and multi-allelic copy-number polymorphisms.² They are distinguished from smaller variants like single-nucleotide polymorphisms (SNPs) by their size and structural nature.³

CNVs can be classified as either common (present in more than 1% of a population) or rare, and as either benign or pathogenic depending on their effect on gene dosage and phenotype.⁴ They often arise through non-allelic homologous recombination (NAHR) during meiosis, which is facilitated by segmental duplications flanking the rearranged regions.⁵

CNVs are detected using a variety of molecular and computational methods, including array comparative genomic hybridization (aCGH), SNP microarrays, and next-generation sequencing (NGS) approaches such as whole-genome sequencing and targeted read-depth analysis.⁶ Each method has trade-offs in resolution, sensitivity, and cost, with NGS offering the highest resolution for breakpoint mapping.⁷

Bioinformatics tools such as CNVnator, PennCNV, and DELLY are commonly used to call CNVs from sequencing data, but they vary in accuracy and require careful validation. The 1000 Genomes Project and the Database of Genomic Variants have cataloged thousands of CNVs, providing a reference for distinguishing benign from pathogenic variants.¹

CNVs are a major cause of genetic disorders, including microdeletion syndromes such as DiGeorge syndrome (22q11.2 deletion) and Charcot-Marie-Tooth disease type 1A (duplication of PMP22).⁴ They also contribute to neurodevelopmental conditions like autism spectrum disorder and schizophrenia, where rare, large CNVs confer significant risk.⁵

In cancer, somatic CNVs drive tumorigenesis by altering oncogene and tumor suppressor gene dosage, and they are used as biomarkers for diagnosis and prognosis.⁶ Prenatal testing increasingly employs CNV analysis to detect fetal anomalies, though interpretation of variants of uncertain significance remains a clinical challenge.⁷

Beyond disease, CNVs have shaped human evolution: the salivary amylase gene (AMY1) shows higher copy numbers in populations with starch-rich diets, an adaptation that arose independently in different regions.³ Similarly, the CCL3L1 gene copy number influences HIV susceptibility, with higher copies associated with reduced infection risk.

CNVs also occur in non-human organisms, including plants and microbes, where they contribute to environmental adaptation and drug resistance. In agriculture, CNVs in crop genomes affect traits like disease resistance and yield.² Additionally, CNVs can arise somatically during development, leading to mosaicism, which complicates genetic diagnosis and has been implicated in aging and cancer.⁶

Structural variation

Large genomic alterations, including deletions, duplications, inversions, and translocations, typically >1 kb.

Non-allelic homologous recombination (NAHR)

A recombination event between non-allelic homologous sequences, a major mechanism generating CNVs.

Microdeletion syndrome

A disorder caused by a small chromosomal deletion, often involving multiple genes.

Mosaicism

Presence of genetically distinct cell populations within an individual, often due to somatic CNVs.