Copy number variation

Mechanism:

Copy number variations occur during DNA replication. Homologous DNA regions can bind to each other, resulting in genetic alterations after the chromosomes pull apart. Researchers can map regions in which CNVs are likely to occur.

For example, about 82 percent of the population has a duplicated region on either side of the 16p12.1 chromosomal region, which puts them at risk for deletion of this stretch of the chromosome¹. Deletion of 16p12.1 is linked to developmental disability and autism when combined with other mutations².

Researchers have also mapped unique identifiers in the regions around human genes that are at risk for duplication or deletion. These results show that many of the human genes with the most CNVs play neurological roles and show no variation in primates. This suggests that CNVs could have contributed to the evolution of higher-order cognition³.

CNVs and disease:

CNVs are associated with several disorders, most notably autism and schizophrenia.

In general, large and non-inherited, or de novo, CNVs are the most likely to be associated with disease.

In an August 2011 study, researchers mapped CNVs from the genomes of 15,767 children with developmental disabilities compared with 8,329 adult controls. CNVs larger than 400 nucleotides are responsible for 14 percent of the disease burden in these children, the researchers estimate⁴.

The overall pattern of CNVs identified in the children with developmental disabilities is strikingly different from that of controls. In particular, CNVs larger than 400 nucleotides are much more common: 26 percent compared with 11.5 percent in controls. This effect is greater for larger CNVs. For example, 11 percent of the developmental disability group has CNVs larger than 1.5 megabases compared with 0.5 percent of controls.

CNV regions associated with neurological disorders include the following: 

• [16p11.2], the deletion of which is linked to autism^5,6 and duplication to symptoms that resemble schizophrenia.
• 15q11.13, deletion of which is associated with autism and epilepsy⁷ and duplication to Angelman syndrome.
• 7q11.23 deletion, which is associated with Williams syndrome
• 22q13 deletion, which leads to Phelan-McDermid syndrome
• 22q11 deletions, which are linked to schizophrenia
• 17q12 deletion, which is associated with autism and schizophrenia⁸

Other disorders associated with copy number variation include Charcot-Marie-Tooth disease, Parkinson disease Alzheimer’s-related dementia.

Because CNVs often contain several genes, researchers are working to hone in on the specific genes responsible for disease in many of these regions.

Relevance to autism:

As indicated above, several CNVs are associated with autism.

“CNVs are the most common cause of autism that we can identify today, by far,” notes Arthur Beaudet a geneticist at the Baylor College of Medicine in Houston.

Deletion of 16p11.2 is probably the most well-known copy number variant linked to autism. Deletions in this region have been detected in as many as one percent of individuals with autism spectrum disorders. However, a large clinical study of 3,450 people, published in October 2010, suggests that although 16p11.2 CNVs almost always result in some symptoms of autism, only about 30 percent of people with the deletion warrant an actual diagnosis⁹.

In a 2008 study, researchers identified 277 CNVs in 427 unrelated individuals with autism. In 27 of these individuals, the CNVs are de novo, meaning that they appear in children with autism, but not in their healthy parents¹⁰.

Two papers published in the same 2011 issue of Neuron in children from simplex families — in which one child in the family has autism but siblings and parents are unaffected — expand on these findings. One reported a de novo CNV mutation rate of 8 percent among affected children compared with 2 percent in unaffected siblings¹¹. The second study found a rate of 5.8 percent among affected children compared with 1.7 percent in unaffected siblings¹².

Both teams found that de novo CNVs in the affected individuals are larger than those in their siblings, and cover more genes. The studies also pinpoint several known autism-related regions, including 16p11.2, 7q11.23 and 15q13.2.

Although larger CNVs are more likely to be linked to disease, small CNVs are also likely to play a role in autism. A 2011 study found that CNVs as small as 10 kilobases are more common in individuals with autism than in controls¹³. Small CNVs are more likely to be inherited than are larger CNVs and probably lead to autism in combination with other mutations¹⁴.

Gene dosage:

Although people generally think of mutations as a lack of function in a particular gene, CNVs that are duplications show that varying the gene dosage can also lead to disease. Genes are generally present in two copies, one on each chromosome, or 2n. A deletion on a single chromosome leads to 1n, whereas duplication leads to 3n or more.

Duplications and deletions of the same region can often lead to different patterns of symptoms.

For example, deletion of 16p11.2 leads to autism and enlarged head size macrocephaly whereas duplication leads to symptoms that resemble schizophrenia and smaller head size (microcephaly)^15,16. By contrast, duplication of another genetic region, 1q21.1, seems to favor autism and macrocephaly whereas deletion of the region causes schizophrenia and microcephaly.

Similarly, duplication of 15q11.13 leads to Angelman syndrome, and duplication of 7q11.23, the Williams syndrome region, leads to symptoms that resemble autism.