Copy Number Variation and Gene Dosage

Genomes vary not only in single letters but in how many copies of a segment they contain. Copy number variation (CNV) — deletions and duplications of stretches of DNA, often spanning whole genes — changes gene dosage, the number of functional copies of a gene. Because the amount of a gene product can matter as much as its sequence, dosage changes are an important axis of genome variation and disease.

Definition

Copy number variation is the gain (duplication) or loss (deletion) of segments of DNA so that the number of copies differs between genomes; gene dosage is the number of functional copies of a gene, which influences how much of its product is made.

Scope

This topic covers copy number variation as a structural change to the genome and the concept of gene dosage it affects, including how CNVs are discovered and why dosage sensitivity makes some genes vulnerable to copy changes. It is reference and educational material and describes disease associations generally rather than as clinical guidance.

Core questions

• What is a copy number variant and how does it differ from a point mutation?
• How does changing gene copy number alter gene dosage and phenotype?
• Which genes are sensitive to dosage changes?
• How are copy number variants detected across the genome?

Key concepts

• Copy number variation (CNV)
• Deletion and duplication
• Gene dosage
• Dosage sensitivity (haploinsufficiency and triplosensitivity)
• Structural variation
• Copy number polymorphism
• Genomic disorders

Mechanisms

A CNV arises when a segment of DNA is duplicated or deleted, typically through recombination between similar sequences, so a genome carries more or fewer copies of the genes within that segment. Changing the copy number changes gene dosage: with fewer copies the cell may make too little of a product (relevant where a single working copy is insufficient, i.e., dosage sensitivity), and with extra copies it may make too much. For dosage-sensitive genes, these quantitative shifts can be enough to alter phenotype even though the gene's coding sequence is unchanged. CNVs are identified genome-wide by comparing the depth or intensity of sequence across genomes to detect regions present in abnormal numbers.

Clinical relevance

Copy number variants contribute to a range of genomic disorders, and assessing whether a deletion or duplication overlaps a dosage-sensitive gene is part of interpreting structural variation. This topic describes the structural and dosage concepts behind such interpretation for reference and education; it is not a basis for individual diagnosis or treatment.

Epidemiology

Surveys of human genomes show that copy number variation is common: every genome carries many CNVs, and collectively they account for a substantial share of the base pairs that differ between individuals — comparable to or exceeding single-nucleotide differences in total sequence affected — making dosage variation a widespread feature of normal human genetic diversity.

Evidence & guidelines

The recognition that copy number polymorphism is pervasive in healthy genomes came from microarray-based surveys, and methods for discovering and genotyping structural variation, including CNVs, have been systematized in the sequencing era; these provide the reference basis for how copy number is measured and interpreted.

History

Until the early 2000s genetic variation was framed mainly in terms of single nucleotides. Microarray surveys then revealed that large duplications and deletions are common even among healthy people, establishing copy number variation as a major class of genome variation; sequencing later refined its discovery and linked specific dosage changes to genomic disorders.

Key figures

• Jonathan Sebat
• Michael Wigler
• Evan Eichler

Seminal works

• sebat-2004
• alkan-2011

Frequently asked questions

How is a copy number variant different from a single-letter mutation?

A point mutation changes one base in a gene, whereas a copy number variant duplicates or deletes a whole stretch of DNA, changing how many copies of one or more genes are present rather than altering a single position.

Why does the number of gene copies matter?

For dosage-sensitive genes, the amount of product made is important; too few copies can yield too little and extra copies too much, so a change in gene dosage can affect phenotype even when each copy's sequence is normal.