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The Vagaries of Genome Variation: Do You Copy?

Comprehending Copy Number Variation makes an impressive debut. 

By Kevin Davies

May 19, 2009
| SAN DIEGO—The inaugural Comprehending Copy Number Variation conference featured many of the true pioneers in the field, and left attendees impressed not only with the sheer number and breadth of copy number variants (CNVs) in the human genome, but also emerging evidence for their role in the etiology of many complex diseases, including autism, epilepsy, and schizophrenia.

Re-discovered by two groups in 2004, CNVs are stretches of DNA of greatly differing size that may be duplicated, deleted or inverted in different genomes. The amount of genetic variation caused by CNVs is 7-10 times more than the 0.1% attributed to single nucleotide polymorphisms (SNPs). CNV study has exploded thanks to comprehensive CNV arrays from the likes of Agilent, Nimblegen, Illumina, and Affymetrix, although Jan Korbel (EMBL) noted that no single platform detects all structural variants. His group has found widespread CNVs in the human olfactory receptor genes.

Stephen Scherer (Hospital for Sick Children, Toronto) reviewed the current state-of-play, as chronicled at the Database of Genetic Variants (, which currently catalogues more than 21,000 CNVs at more than 6500 loci. “We’re leaving Kansas,” Scherer said, stressing that at least one third of human genes exhibit some sort of sequence variation. Some of the best characterized examples include SHANK3 on chromosome 22 and ANKRD11 on chromosome 16, implicated in several cases of autism.

Evan Eichler (HHMI/University of Washington) showed examples of CNVs with clinical relevance. A common inversion of a region on chromosome 17 in northern European populations acts as a pre-mutation state associated with mental retardation. Another 1.5-megabase deletion on chromosome 15 occurs in 0.2-0.3% cases of autism, mental retardation, and schizophrenia, and up to 1% epilepsy.

Eichler’s group is identifying CNVs in individual genomes by simply looking at the genome sequencing depth of coverage among the millions of sequence reads. First, they developed a new mapping algorithm that, unlike programs such as MAQ, could map reads into repetitive genomic regions. He pointed to a 70,000 stretch of DNA that exists in two copies in Craig Venter’s genome but three in James Watson’s. “One can only imagine what that type of sequence might do,” Eichler joked. The group can now accurately assess how many copies of a gene there are in a region in a more quantitative fashion than standard array comparative genome hybridization methods. “I’m very excited by this. I think this is the first time that we can look at duplicated regions of the genome and accurately assess copy number based on depth of coverage.”

Harvard Medical School’s Charles Lee presented remarkable variation in the amylase genes among people of different ethnic backgrounds. Lee’s group found that populations with high starch intake (European, Japanese) had more copies of the amylase 1 gene than other populations. Japanese subjects even had copies of the gene on a second chromosome. 

Lee said there is a need for a revised human reference genome. “No-one will really admit that the human genome is not really completed,” he said.

This article also appeared in the May-June 2009 issue of Bio-IT World Magazine.
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