Deletion and Duplication

Deletions and duplications are structural rearrangements that change the copy number of a chromosomal segment: a deletion removes a stretch of DNA so that it is present in fewer copies than normal, while a duplication adds an extra copy. Because they alter the amount of genetic material, they are forms of unbalanced rearrangement, and their effects depend heavily on which genes lie within the affected region and how sensitive those genes are to dosage.

Definition

A deletion is the loss of a chromosomal segment, leaving that region in reduced copy number; a duplication is the gain of an additional copy of a chromosomal segment. Both are copy-number changes and, by definition, unbalanced because they alter the total amount of genetic material.

Scope

This topic covers what deletions and duplications are, the molecular mechanisms that generate them, the size spectrum from microscopically visible segments to submicroscopic copy-number variants, and the dosage logic that links them to phenotype. It treats them as a methodological and conceptual topic within cytogenetics and structural rearrangements, not as clinical guidance about any specific syndrome.

Core questions

• Which chromosomal region is lost or gained, and how large is it?
• What mechanism produced the copy-number change?
• Do the affected genes show dosage sensitivity?
• Is the change microscopically visible or submicroscopic?

Key concepts

• Copy-number variant (CNV)
• Haploinsufficiency
• Triplosensitivity
• Microdeletion and microduplication
• Non-allelic homologous recombination
• Low-copy repeats (segmental duplications)
• Recurrent versus non-recurrent rearrangement

Mechanisms

Many recurrent deletions and duplications arise by non-allelic homologous recombination between flanking low-copy repeats (segmental duplications), which misalign during recombination so that the intervening segment is either lost or gained; non-recurrent events more often arise from non-homologous end joining or replication-based mechanisms, as reviewed by Hastings and colleagues. The phenotypic effect follows from gene dosage: losing a copy can cause haploinsufficiency when one functional copy is not enough, while gaining a copy can cause problems through triplosensitivity. Davoli and colleagues showed that the cumulative density of dosage-sensitive genes within a region helps explain which segmental gains and losses are recurrently selected in cancer genomes.

Clinical relevance

Deletions and duplications are a major class of finding in the evaluation of developmental disability, congenital anomalies, and tumors, and detecting them is central to genetic diagnosis. Chromosomal microarray is positioned as a first-tier test for individuals with unexplained developmental disabilities or congenital anomalies precisely because it resolves submicroscopic gains and losses. This entry describes how these changes are conceptualized and detected and is not a basis for individual diagnostic or treatment decisions.

Epidemiology

Copy-number variation is a pervasive feature of the human genome, and surveys using array and sequencing methods, as summarized by Alkan and colleagues, find that gains and losses of submicroscopic segments are common across individuals; only a subset overlaps dosage-sensitive regions and contributes to disease. Reported frequencies depend strongly on the resolution of the detection platform.

Evidence & guidelines

The Miller and colleagues (2010) consensus statement recommends chromosomal microarray as a first-tier clinical test for unexplained developmental disability or congenital anomalies, on the grounds that it detects clinically relevant deletions and duplications below the resolution of conventional karyotyping.

History

Visible deletions and duplications were recognized once chromosome banding allowed segments to be matched between homologues, but the scale of the phenomenon was transformed by array-based methods in the 2000s, which revealed that copy-number variation is widespread in the genome. Alkan and colleagues reviewed how successive technologies expanded the detectable size range from megabase-scale microscopic changes down to small submicroscopic variants.

Key figures

• James R. Lupski
• Evan E. Eichler
• Stephen J. Elledge

Seminal works

• hastings-2009
• alkan-2011
• davoli-2013

Frequently asked questions

Why are deletions and duplications considered unbalanced rearrangements?

Because they change the total amount of genetic material — a deletion removes a segment and a duplication adds an extra copy — they alter gene dosage, which is the defining feature of an unbalanced rearrangement.

Why does the same-sized deletion or duplication have different effects in different regions?

The effect depends on the genes in the affected segment and their dosage sensitivity; regions rich in haploinsufficient or triplosensitive genes produce phenotypes, while gene-poor or dosage-tolerant regions may have little or no effect.