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Talk Highlights Utility of Copy Number Variant Studies

By Brian Chorley
February 2010

"Gene dosage is important to disease," Lupski explained, as he surveyed several examples in which deletion, duplication, or inversion of a genetic loci leads to clinically distinct disorders. (Photo courtesy of Steve McCaw)

Shay Covo, Ph.D.
Hosted by Visiting Fellow Shay Covo, Ph.D., above, a member of the NIEHS Chromosome Stability Group in the Laboratory of Molecular Genetics (LMG), the talk was the latest in the NIEHS Laboratory of Molecular Genetics Fellows Invited Lecture Series. (Photo courtesy of Steve McCaw)

Lupski's talk was well attended by NIEHS scientists. Shown above, right to left, are Staff Scientist Katarzyna Bebenek, Ph.D., Postdoctoral Fellow Michelle Heacock, Ph.D., Postdoctoral Fellow Jill Hesse, Ph.D., and Application Support Contractor Nick Staffa, Ph.D. (Photo courtesy of Steve McCaw)

Jan Drake, Ph.D.
LMG Laboratory Chief Jan Drake, Ph.D., above, was one of several LMG principal investigators who turned out to hear Lupski's talk. (Photo courtesy of Steve McCaw)

In a Jan 11 guest lecture at NIEHS, Baylor College of Medicine Professor James Lupski, M.D., Ph.D., explored the clinical impact of copy number variants (CNVs) in the human genome. Lupski's talk on "Genomic Disorders: Mechanisms and Assays for CNV That Cause Human Disease" presented multiple examples of CNV association with disease and underscored the value of using state-of-the art CNV arrays for investigating genetically based disorders.

In a diploid human genome, gene and non-coding DNA segments exist normally as two copies. Genomic rearrangement of these segments is caused by deletion, duplication, or inversion of the chromosomal DNA. As Lupski demonstrated, de novo genetic copy number variation - alterations occurring anew beyond primary sequence information - can have important implications for an individual's biology and health.

CNVs linked to human neurodegenerative disease

Lupski( Exit NIEHS has studied CNVs for twenty years and first linked abnormal gene copy number to human disease while studying the neurodegenerative disease Charcot-Marie-Tooth type 1A (CMT1A) - a disease characterized by distal muscle loss and weakness and reduced sensation, such as touch and temperature. Lupski's research team found that chromosomal segment duplication was a cause of CMT1A, one of the most common genetically autosomal dominant disorders in humans.

Lupski noted, "76 to 90 percent of sporadic CMT1A patients have the duplication as a de novo event, so the mutations are happening quite frequently."

Study of CNVs in patients leads to better diagnosis and treatment

In the early 2000s, the human genome sequence was used by researchers to identify CNV hotspots. This information helped scientists develop clinical CNV assays that were quickly used to identify multiple novel deletion- or duplication-causative diseases in patients of various clinical phenotypes.

Specifically, two of these deletions were later linked to schizophrenia in two independent Nature publications. Lupski said that schizophrenia patients who harbored these deletions responded well to anti-psychotic drug therapy. He was optimistic for the future clinical use of CNV assays "as ways to choose what drugs patients might respond better to, which is currently done by empirical trial-and-error methods" in complex diseases such as schizophrenia.

CNV-related mechanisms inform CNV assay design

Early clinical CNV arrays targeted approximately one hundred regions. Over a five-year period, the Baylor clinical diagnostic laboratory and Lupski's group significantly expanded the number of CNV targets to hundreds of regions interrogated by more than 180,000 oligonucleotides using better and cheaper technology, chromosome structural analyses, and CNV prediction (see text box). Predictions are based on identifying CNV hotspots that result from DNA recombination and replication mechanisms, which include non-allelic homologous recombination (NAHR), nonhomologous end joining (NHEJ), fork stalling and template switching (FoSTeS), and microhomology-mediated break-induced replication (MMBIR).

FoSTeS/MMBIR-mediated replication errors can result in exon drop out, or loss of one or more gene coding segments. However, Lupski noted that only about five percent of all genes have known functions. Interpreting the phenotypic effect of exon deletion is therefore limited, which reduces the number of informative targets on a clinical CNV assay.

In spite of these important advances, Lupski reminded his audience, current research leaves many questions unanswered - including which structural variations in the human genome are pathogenic and which benign, how frequently they occur, and what precisely are the molecular mechanisms involved in genomic rearrangements.

(Brian Chorley, Ph.D., is a postdoctoral fellow in the NIEHS Laboratory of Molecular Genetics Environmental Genomics Group.)

CNV Arrays versus Genome-Wide Association Studies

During his talk, Lupski argued for wider use of CNV arrays as opposed to genome-wide association studies (GWAS) for discovery of new genomic loci important to disease etiology.  GWAS associate single-nucleotide polymorphisms (SNPs) with a phenotype or clinical manifestation. Lupski contends that assaying specific CNV loci enhances schizophrenia and autism identification in patients four-fold and at one percent of the cost of GWAS, based on data collected from 2008 and 2009 publications.

Lupski summarized his argument poetically with the couplet, "SNPs SNPs SNPs so passé, CNVs are here to stay."

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