23 November 2006. As psychiatric researchers are well aware from the examples of 22q11 deletion syndrome (22q11DS) and disrupted in schizophrenia 1 (DISC1), when it comes to disease-causing alterations in the human genome, single nucleotide polymorphisms are not the only game in town. Certainly, simple point mutations are responsible for a plethora of disorders, but more profound changes or rearrangements of the human genome may prove equally, or even more important for the understanding of disease (For an overview, see Lee and Lupski, 2006).
Writing in the November 22 Nature, Matthew Hurles from the Wellcome Trust Sanger Institute in Cambridge, England, and an international collaborative of academic and industry researchers report the first copy number variation (CNV) map of the human genome. They found a startling total of 1,447 copy number variable regions (CNVRs) covering 360 megabases of DNA (12 percent of the total genome), which means that CNVRs cover more nucleotide content per genome than SNPs, and this may be only a fraction of the number that will eventually be uncovered. Of special interest to schizophrenia research, CNVs were detected in both DISC1 and region deleted in 22q11DS.
“The data suggest that the greatest source of genetic diversity in our species lies not in millions of SNPs, but rather in larger segments of the genome whose presence or absence calls into question what exactly is a ‘normal’ human genome,” write Kevin Shianna and Huntington Willard, Duke University, Durham, North Carolina, in an accompanying Nature News & Views.
This color representation of CNVs in the International HapMap Project samples shows segments of DNA that are overrepresented (green) or underrepresented (red) in many individuals. Image credit: Matthew Hurles
Psychiatric research already has some examples of pathological gross genomic changes: for example, the balanced translocation between chromosomes 1 and 11 that breaks up DISC1 and appears to increase susceptibility to both affective disease and schizophrenia (Millar et al., 2000) and the loss of a stretch of chromosome 22 that causes 22q11DS (velocardiofacial syndrome), a developmental disorder that often includes psychiatric symptoms (see related SRF news story). Copy number variation may prove to be the next, and widest, frontier in psychiatric genetics.
In their survey of copy numbers across the human genome, first author Richard Redon and colleagues applied high-throughput detection and high-density DNA oligonucleotide arrays (described in two separate papers in today’s Genome Research—Komura et al., 2006, and Fiegler et al., 2006) to generate the CNVR map using the same DNA samples and cell lines used by the International HapMap Project (see SRF related news story). These samples cover four different ethnic populations: Nigerians, Europeans, Japanese, and Han Chinese. The researchers defined CNVs as segments of DNA 1 kb or larger in size that are present in variable copy number in comparison to a reference genome. Almost one-quarter of all CNVs were associated with segmental duplications, which is perhaps not surprising, given that natural selection tends to weed out deletions.
Though the vast majority of CNVs were found outside of coding sequences, thousands of putative functional segments of DNA fall within CNVs and 99 percent of them overlap with conserved non-coding sequences. Notably, CNVs were found in DISC1 and the neighborhood of 22q11 (and readers may find others of interest to psychiatric disorders in the extensive supplementary materials published online). The researchers determined that at least 10 percent of disease-related genes in the OMIM database are associated with CNVs.
“Given the limited set of reference samples assayed, the 1,500 CNVs reported by Redon et al. are probably the tip of the iceberg. As the results and the raw data from the first wave of genome-wide association studies become available, it will be essential to catalogue the full range of human CNVs,” write Shianna and Willard. To that end, the Wellcome Trust Sanger Institute has developed a CNV database called DECIPHER to share information on CNVs and rare, severe phenotypes.
In a related paper coauthored by many of the same researchers, Lars Feuk, University of Toronto, Canada, and colleagues describe a comparison of the two human genome assemblies: those produced by Celera Genomics and the Human Genome Sequencing Consortium. First author Razi Khaja and colleagues use the data to demonstrate that there are megabases of sequence information, specifically over 13,500 non-SNP events, that are absent, inverted, or polymorphic in one assembly compared to the other. The data indicate that there is substantial undescribed variation within the human genome and suggest that more comprehensive annotation will be needed as we enter the era of personalized, genomic-based medicine.—Tom Fagan.
Redon R, Ishikawa S, Fitch KR, Feuk L, Perry GH, Andrews TD, Fiegler H, Shapero MH, Carson AR, Chen W, Cho EK, Dallaire S, Freeman JL, Gonzalez JR, Gratacos M, Huang J, Kalaitzopoulos D, Komura D, MacDonald JR, Marshall CR, Mei R, Montgomery L, Nishimura K, Okamura K, Shen F, Somerville MJ, Tchinda J, Valesia A, Woodwark C, Yang F, Zhang J, Zerjal T, Zhang J, Armengol L, Conrad DF, Estivill X, Tyler-Smith C, Carter NP, Aburatani H, Lee C, Jones KW, Scherer SW, Hurles ME. Global variation in copy number in the human genome. Nature. November 23, 2006;444:444-454.
Fiegler H, Redon R, Andrews D, Scott C, Andrews R, Carder C, Clark R, Dovey O, Ellis P, Feuk L, French L, Hunt P, Kalaitzopoulos D, Larkin J, Montgomery L, Perry GH, Plumb BW, Porter K, Rigby RE, Rigler D, Valsesia A, Langford C, Humphray SJ, Scherer SW, Lee C, Hurles ME, Carter NP. Accurate and reliable high-throughput detection of copy number variation in the human genome. Genome Res. November 23, 2006;16:1566-1574.
Komura D, Shen F, Ishikawa S, Fitch KR, Chen W, Zhang J, Liu G, Ihara S, Nakamura H, Hurles ME, Lee C, Scherer SW, Jones KW, Shapero MH, Huang J, Aburatani H. Genome-wide detection of human copy number variations using high-density DNA oligonucleotide arrays. Genome Res. November 23, 2006;16:1575-1584.
Shianna KV, Willard HF. In search of normality. Nature. November 23, 2006;444:428-429.
Khaja R, Zhang J, MacDonald JR, He Y, Joseph-George AM, Wei J, Rafiq MA, Qian C, Shago M, Pantano L, Aburatani H, Jones K, Redon R, Hurles M, Armengol L, Estivill X, Mural RJ, Lee C, Scherer SW, Feuk L. Genome assembly comparison identifies structural variants in the human genome. Nat Genet. November 22, 2006. Advance online publication.