Abstract
The functional contribution of CNV to human biology and disease pathophysiology has undergone limited exploration. Recent observations in humans indicate a tentative link between CNV and weight regulation. Smith-Magenis syndrome (SMS), manifesting obesity and hypercholesterolemia, results from a deletion CNV at 17p11.2, but is sometimes due to haploinsufficiency of a single gene, RAI1. The reciprocal duplication in 17p11.2 causes Potocki-Lupski syndrome (PTLS). We previously constructed mouse strains with a deletion, Df(11)17, or duplication, Dp(11)17, of the mouse genomic interval syntenic to the SMS/PTLS region. We demonstrate that Dp(11)17 is obesity-opposing; it conveys a highly penetrant, strain-independent phenotype of reduced weight, leaner body composition, lower TC/LDL, and increased insulin sensitivity that is not due to alteration in food intake or activity level. When fed with a high-fat diet, Dp(11)17/+ mice display much less weight gain and metabolic change than WT mice, demonstrating that the Dp(11)17 CNV protects against metabolic syndrome. Reciprocally, Df(11)17/+ mice with the deletion CNV have increased weight, higher fat content, decreased HDL, and reduced insulin sensitivity, manifesting a bona fide metabolic syndrome. These observations in the deficiency animal model are supported by human data from 76 SMS subjects. Further, studies on knockout/transgenic mice showed that the metabolic consequences of Dp(11)17 and Df(11)17 CNVs are not only due to dosage alterations of Rai1, the predominant dosage-sensitive gene for SMS and likely also PTLS. Our experiments in chromosome-engineered mouse CNV models for human genomic disorders demonstrate that a CNV can be causative for weight/metabolic phenotypes. Furthermore, we explored the biology underlying the contribution of CNV to the physiology of weight control and energy metabolism. The high penetrance, strain independence, and resistance to dietary influences associated with the CNVs in this study are features distinct from most SNP–associated metabolic traits and further highlight the potential importance of CNV in the etiology of both obesity and MetS as well as in the protection from these traits.
Highlights
The significance of copy number variation (CNV) in human genetic variation is indisputable [1,2]
Penetrant weight change phenotypes were recently observed in humans for two obesity-associated deletion CNVs on 16p11.2 and the reciprocal duplication of one of them associated with leanness [9,10,27]
Dp(11)17/+ mice have a significantly lower percentage of both whole body fat mass and epididymal white adipose tissue (EWAT) (Figure 2A, 2B), as well as a significantly higher percentage of lean mass (Figure 2A). These findings are in accordance with our previous reports of reduced abdominal fat in Dp(11)17/+ mice on different strain backgrounds (N7 [26] and N12 C57BL/6J [25]), further demonstrating the strain-independent manifestation of the metabolic phenotypes caused by the duplication CNV
Summary
The significance of copy number variation (CNV) in human genetic variation is indisputable [1,2]. In contrast to the revolutionary progress achieved in the discovery of CNVs and delineating the mechanisms for their formation, our current knowledge of the downstream functional mechanisms by which CNVs contribute to trait manifestations is limited. Functional contributions of CNV to human biology have only been examined in a few physiological systems including the neuropsychiatric/ behavioral fields [2,3]. About 400 million people worldwide are classified as obese [4] and are likely to suffer from premature mortality and obesityassociated morbidities, such as hyperglycemia, dyslipidemia, hypertension and metabolic syndrome (MetS) [5]. The etiologies for obesity include genetic contributions [4], but the identities of the specific genetic factors remain largely unknown. Single nucleotide polymorphisms (SNPs) identified through linkage and Author Summary
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