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Major Changes in Our DNA Lead to Major Changes in Our Thinking

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Major Changes in Our DNA Lead to Major Changes in Our Thinking COMMENTARY Major changes in our DNA lead to major changes in our thinking Jonathan Sebat Variability in the human genome has far exceeded expectations. In the course of the past three years, we have learned that much of our naturally occurring genetic variation consists of large-scale differences in genome structure, including copy-number variants (CNVs) and balanced rearrangements such as inversions. Recent studies have begun to reveal that structural variants are an important contributor to disease risk; however, structural variants http://www.nature.com/naturegenetics as a class may not conform well to expectations of current methods for gene mapping. New approaches are needed to understand the contribution of structural variants to disease. A subject that has gained much attention in on average than single nucleotide polymor- gene mapping approaches. What these stud- the field of human genetics has been the dis- phisms (SNPs), which account for approxi- ies have begun to reveal is that structural vari- covery that structural variation of the genome mately 2.5 Mb (1/1,200 bp)8–10. Therefore, the ants contribute to disease and the risk factors including large insertions and deletions of total genomic variability between humans is involved often do not conform to the expec- DNA, collectively termed copy-number vari- significantly greater than previously thought, tations of prevailing association-based meth- ants (CNVs), as well as balanced chromosomal amounting to a difference of at least 0.2%, ods. This has consequences for what methods rearrangements, such as inversions, contribute >0.12% at the structural level and 0.08% at should be used to study CNVs, and it also has Nature Publishing Group Group Nature Publishing 7 to a major proportion of genetic difference in the nucleotide level. implications for the respective contribution of humans. Following the first studies to report the In retrospect, perhaps it should not have common and rare CNVs in disease. 200 1,2 © widespread abundance of CNVs in humans , been so surprising to find our genome riddled Much of what was previously known about knowledge of structural variation has grown with deletions, duplications and inversions. the role of CNVs in disease comes from a rich rapidly, owing to steady improvements in Remarkable genomic plasticity had been literature on ‘genomic disorders’13. Genomic oligonucleotide microarray technology and observed in model organisms much earlier, for disorders are defined as a diverse group of the development of new sequencing-based3 example when cytogenetic studies by Barbara genetic diseases that are each caused by an and SNP-based4,5 structural variant detection McClintock found that transposition events alteration in DNA copy number. These muta- methods, and their use in large-scale proj- explained nonmendelian patterns of segre- tions can be relatively large, microscopically ects to map structural variation in different gation for certain maize phenotypes11. Later, visible imbalances, such as in Prader-Willi syn- populations6,7. studies of the human genome revealed the pres- drome14, or they may be much smaller, requir- It is now recognized that the genomes of any ence of cytogenetically visible polymorphisms ing higher resolution detection methods, such 12 15 two individuals in the human population differ in heterochromatin length . Nevertheless, this as in Williams Syndrome . Genomic disorders more at the structural level than at the nucleo- aspect of human variability was not unmis- are typically sporadic in nature because the tide sequence level. Conservative estimates sug- takable. The proverbial lamp post was firmly CNV in most cases is a de novo mutation with gest that CNVs between individuals amount fixed in the opposite direction because reliable nearly complete penetrance, and because the 3 to 4 Mb (1/800 bp) of genetic difference , and methods did not exist for ascertaining CNVs affected individuals have severe developmental less conservative estimates put this figure in genome wide, and because prevailing methods problems and are unlikely to have offspring. 7 the range of 5–24 Mb . By either measure, for gene mapping worked best in the context However, there are notable examples of men- CNVs account for more nucleotide variation of a static genome. delian disease traits associated with CNVs. For Technological innovations have opened example, duplications of the gene for peripheral Jonathan Sebat is at the Cold Spring Harbor the door to a fundamental aspect of human myelin protein 22 (PMP22) cause the dominant Laboratory, One Bungtown Road, Cold Spring genomic variation that was previously unrecog- neuropathy Charcot-Marie Tooth disease type Harbor, New York 11724, USA nized and have opened a new window into the 1A16, and deletions of the α-globin gene cluster e-mail: [email protected] genetic basis of disease. Methods for detecting cause the recessive anemia α-thalassemia17. CNVs genome-wide have the power to iden- Previous knowledge of genomic disorders Published online 27 June 2007; doi:10.1038/ tify risk factors for disease directly, and thereby was limited by the available methods: that ng2095 overcome some key limitations of traditional is, limited primarily to disorders that form NATURE GENETICS SUPPLEMENT | VOLUME 39 | JULY 2007 S3 COMMENTARY a distinct clinical entity and where genomic findings of early genetic studies of autism that reasons for this effect could include reduced imbalances are often cytogenetically visible or found evidence for linkage at many locations SNP coverage in CNP regions and in regions inherited in a dominant fashion. The applica- in the genome25. An important implication of rich in segmental duplications, or recurrent tion of high resolution genome-wide meth- the recent findings in autism is that the genetic copy-number mutations at individual loci. ods to sporadic disorders promises to greatly component of certain common disorders may Recurrent mutation is certainly evident at improve the power to detect CNVs that cause consist largely of a constellation of rare, highly some CNP loci, based on the existence of sev- disease18. In addition, these genetic findings penetrant mutations. This line of evidence also eral common alleles. For example, quantitative are proving helpful in informing physicians favors the notion that much of the sporadic PCR measurements of FCGR3B in a cohort of about the clinical features of a disorder. For nature of autism can be attributed to sponta- European ancestry showed four distinct dis- example, by identifying new clinically relevant neous mutation at individual loci, in contrast tributions of diploid copy number, indicating CNVs and correlating these changes with phe- to models that explain the lack of mendelian that at least three distinct genomic structures, notypic information, new genomic disorders segregation by the additive or multiplicative consisting of zero, one or two copies per chro- have been defined that had not been previously effects of alleles at multiple loci26. mosome, are common in the population35. The recognized as distinct clinical entities19–21. A high rate of structural mutation is not a distribution of CCL3L1 copy-number alleles Because each genomic disorder is a clinically property of autism or other neurodevelop- was found to be greater still, varying between defined syndrome linked with a single locus, mental disorders; it is a property of the human zero and seven copies per genome34. In both of and each is nearly 100% penetrant, these dis- genome. Therefore, frequent spontaneous the previous examples, disease risk was associ- eases are individually quite rare in the human copy-number mutation may play a prominent ated primarily with the dosage of a gene, rather population. However, it is not a great stretch role in adult-onset neuropsychiatric disorders than with any single allele. Thus, some CNPs of the imagination to envisage another type or indeed in any heritable disease whose effect constitute common variation that segregates of genomic disorder that is similar in many on reproductive fitness and its prevalence in independently of SNPs. 27 respects to those described above, but is instead the population seem to defy darwinian logic . In the past three years, it has become obvi- http://www.nature.com/naturegenetics a common disease. Consider, for instance, a There are several examples of familial genomic ous that the structure of the human genome is 28 disorder where the clinically defined pheno- disorders ; but one fact that is not well appre- not static. Furthermore, it is becoming increas- type is not associated with a single locus, but ciated is that they are invariably a result of ingly evident that copy-number variability is instead associated with the occurrence of a spontaneous mutation (occurring in recent differs from nucleotide variability in terms single dominant mutation involving any one of ancestry). For example, autosomal dominant of the rate at which copy-number mutations 37 50 autosomal genes. Assuming a spontaneous and sporadic forms of Charcot Marie-Tooth occur spontaneously in the genome and CNV mutation rate of 1/10,000 per locus on disease type 1 are caused by identical dupli- the allelic diversity that may occur as a result. average, a ‘complex genomic disorder’ of this cations of the gene PMP22, and are typically Therefore, CNVs require special consideration 38 kind would be relatively common, with a popu- inherited in the dominant pedigrees and de in large-scale genetic studies of disease . For
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