Gene copy-number alterations – a review

To ensure the species-specific karyotype is faithfully maintained thus upholding health and reproduction, numerous mechanisms have evolved to guarantee the integrity of genomic information. When errors happen, for instance from cell cycle checkpoint failures, the resulting DNA copy-number alterations can become detrimental, often identified as the cause of multiple diseases and developmental abnormalities in an organism. On the other hand, DNA copy-number alterations can contribute to enhancing adaptive potential, as revealed from microorganisms that were under selective pressure. Increasing evidence indicates that DNA copy-number alterations underlie many human diseases, including cancer, thus the design of specifically targeting aneuploidy status may serve as a new therapeutic strategy.

Review by HFSP Long-Term Fellow Yun-Chi Tang and colleagues
authored on Tue, 26 March 2013

Types of gene copy-number alterations and the consequences

Much progress has been made to identify DNA copy-number alterations and to determine their biological impact. Depending on their size, DNA copy-number alterations are referred to in different terms. Multiples of the entire genetic complement are referred to as polyploidies. Whole chromosome (34~230 Mbp) gains or losses are known as aneuploidies. Changes in copy number of sub-chromosomal regions that are visible by light microscopy are referred to as partial or segmental aneuploidies. Submicroscopic DNA copy-number alterations that are between 1 kbp and 1 Mbp in length are referred to as copy-number variations (CNVs). Smaller changes in DNA copy number—ranging 1 bp to 1 kbp in size—are called deletions or insertions depending on whether sequences are deleted or amplified, respectively.

Alterations in the gene copy number can have a dramatic impact on organismal and cellular fitness, caused by the gene-specific effect or non-gene-specific effects. A single gene can elicit the gene-specific effect. For example, amplification of the oncogene Myc is thought to be a driving factor in human acute myeloid leukemia (AML). Likewise, changes in the copy number of large genome regions can cause phenotypes that are the cumulative consequences of copy-number changed genes, which on their own have little phenotypic significance. Up to date, three general outcomes have been observed when cells or organisms experience large-scale gene copy alterations:   

1.     Whole-chromosome copy-number alterations interfere with cell proliferation. For example, studies of aneuploid yeast strains and MEF cells showed that aneuploidy impairs proliferation under standard growth conditions. In humans, hypomorphic mutations in BubR1 lead to mosaic-variegated aneuploidy, which is associated with growth deficiency and short stature, mental retardation, developmental defects, as well as a predisposition to cancer.

2.     Whole-chromosome copy-number alterations cause several cellular stresses, collectively called the ‘‘aneuploidy-associated stresses’’. Studies in aneuploid yeast and MEFs indicate that aneuploid cells experience metabolic stress. Simultaneous changes in gene copy number of many genes, occuring when entire chromosomes are lost or gained, profoundly alter the cell’s protein composition. This aneuploidy-induced change in the cell’s proteome places a burden on the cell’s protein quality-control pathways and hence impacts fitness.

3.     Large-scale changes in DNA copy number elicit a stress response. Whole-chromosomal aneuploidies have been shown to lead to a transcriptional response in all organisms where this has been analyzed. A gene-expression signature similar to the environmental stress response (ESR) has been found in budding yeast, fission yeast, Arabidopsis, mouse, and human cells with whole-chromosome gains.

DNA copy-number changes as a source of adaptive potential

Gene copy-number changes are not always detrimental. Experimental evolution studies demonstrate that under selection, gene copy-number changes increase the chance of survival of the organism under the imposed selection. Perhaps the best example of such beneficial effects, is the tissue-specific amplification of genes as part of normal development. Recent studies in mice indicate that aneuploidy could also be an effective way of adapting selective pressure in multicellular organisms. The liver is a naturally aneuploid organ (Duncan et al., 2010; Putkey et al., 2002; Weaver et al., 2007), providing an opportunity to determine the importance of aneuploidy in adaptation to selective pressure. Deficiency of fumarylacetoacetate hydrolase (FAH) causes chronic liver disease that is suppressed by the loss of enzymes functioning upstream of FAH, such as homogentisic acid dioxygenase (HPD). Mice lacking FAH function and heterozygous for a deletion in HPD develop disease resistance through loss of the chromosome encoding the functional copy of HPD (Duncan et al., 2012), illustrating the power of aneuploidy in providing adaptive potential even in multicellular organisms.

Mutations that suppress the adverse effects of large-scale DNA copy-number changes may enhance the adaptive potential of chromosome gains or losses. Aneuploidy-tolerating mutations have been found in yeast (Torres et al., 2010). Loss of p53 increases survival of cells following chromosome missegregation in mammalian cells (Janssen et al., 2011; Li et al., 2010; Thompson and Compton, 2010). It will be interesting to examine the contribution of different aneuploidy-tolerating mutations to disease progression in cancer where gene copy-number alterations are a key feature. Indeed, p53 inactivation is a major contributor to tumorigenesis (Dai and Gu, 2010; Kruse and Gu, 2009; Toledo and Wahl, 2006).

Future directions—gene copy-number alterations as a therapeutic target?

Evidence is mounting for the importance of gene copy-number changes for a wide variety of human diseases. A particularly exciting future direction is the pursuit of gene copy-number changes in developing therapies. For example, autistic individuals with CNV in the duplication of AUTS4, a gene encoding the GABAA receptor subunit, may benefit from compounds that down-regulate GABAA receptor function (Zhang et al., 2009). Similarly, disruptive CNVs in MYT1L, CTNND2, and ASTN2 found for Schizophrenia and copy-number reduction of HBD2 for Crohn’s disease, when treated with compounds to increase the function of the remaining copy or inhibiting the function of negative regulators in the pathways may have a significant therapeutic index.

Cancer is the prime example in which gene amplifications and deletions have been shown to drive disease (Gordon et al., 2012). Therapies targeting overexpressed or amplified oncogenic drivers have been developed. The gene encoding epidermal growth factor receptor (EGFR) is amplified in non-small-cell lung cancer. Small molecules such as gefitinib or erlotinib have been applied to inhibit EGFR with success (Carling, 2004; Paez et al., 2004). Trastuzumab, an anti-HER2 antibody, has been used in the therapy of HER2-amplified breast cancers with success (Baselga et al., 1998). Targeting amplified disease drivers provides exciting opportunities for therapy in cancer, psychiatric disorders, and autoimmune diseases, where effective treatments are scarce.

On the other hand, therapeutic challenges remain for diseases that are derived from large-scale DNA alterations. Commonly found in cancers, the contribution of multiple gene-dosage changes is augmenting the variability thus questioning whether the standard single-gene-targeting strategy is effective. Targeting the general stress phenotypes associated with aneuploid status is providing a new avenue in cancer treatment. Such compounds would offer increased efficacy against a broad spectrum of cancers. Compounds that preferentially inhibit the proliferation of aneuploid cell lines have been identified (i.e. 17-AAG and AICAR) and appear to exaggerate the general stress phenotypes associated with whole-chromosome copy-number changes (Tang et al., 2011). By using the compounds alone, or in combination with standard chemotherapeutics like Taxol, the strategy may provide better efficiency to treat cancer, especially for those which can benefit from genome instability.


Gene copy-number alterations: a cost-benefit analysis. Tang, Y-C. and Amon, A. (2013). Cell. 152(3): 394-405.

Pubmed link