Genetic factors have long been known to contribute to both normal human energy metabolism and the etiology of metabolic syndrome and obesity. However, the role of genomics and copy number variation (CNV) in these processes has not been studied until recently. Although many CNVs appear to be phenotypically benign, some have been found to play a role in disease susceptibility and in the pathogenesis of metabolic disorders as identified by several large-scale patient studies3-5
(summarized in ref. 6
). We recently applied an alternative approach to study metabolic traits associated with CNV of a specific genomic interval; heterozygous deletion of this genomic interval is known to cause a genomic disorder associated with obesity in humans, Smith-Magenis syndrome (SMS: MIM #182290; www.ncbi.nlm.gov.sites/entrez) and convey an obese phenotype in mice.7,8
In this paper, entitled “A duplication CNV that conveys traits reciprocal to metabolic syndrome and protects against diet-induced obesity in mice and men,” we describe diametric metabolic phenotypes observed in chromosome-engineered mice harboring reciprocal duplication or deletion CNVs, clearly demonstrating the functional link between CNV and metabolism.9
We analyzed the metabolic profiles of previously-generated mouse models for Smith-Magenis (SMS) and Potocki-Lupski (PTLS; MIM #610883) syndromes, respectively harboring either deletion or duplication of the mouse chromosomal region syntenic to human chromosome 17p11.2.10,11
While obesity and hypercholesterolemia were known to be associated with SMS,12
few formal studies had been performed, and the metabolic profiles had not been extensively described in either PTLS or SMS subjects.
We showed that duplication mice (modeling PTLS) have decreased body weight and body fat composition, reduced TC/LDL levels in the blood, and increased insulin sensitivity that cannot be attributed to either increased activity or reduced food intake. Rather, these mice have increased intrinsic metabolic activity that also confers protection from diet-induced obesity. This latter observation that mice fed a high-fat diet do not gain weight is a clear demonstration of gene X environmental interactions that can be very important in common, complex traits. Interestingly, the reciprocal deletion CNV (modeling SMS) results in a “mirror” or reciprocal phenotype, as the deletion mice are overweight with increased body fat, decreased HDL levels in the blood and reduced insulin sensitivity, corresponding with observations in SMS patients and consistent with the metabolic syndrome so common in the obese American population. The results of the metabolic phenotyping of duplication and deletion mice described in this study are summarized in .
Figure 1. A summary of the reciprocal metabolic phenotypes observed in mouse models of PTLS and SMS. TC, total cholesterol; ND, no difference, although there was a trend toward increased HDL/TC.
Further investigation into the genetic and biological mechanisms underlying these phenotypes revealed that they may not be due solely to the alteration of a single gene or genetic element. Rather they appear to be a consequence of the alteration of multiple genes/genetic elements by the CNV. The “genetic load” could potentially either act through cumulative effects on a single pathway or by each of the contributing genes affecting different downstream metabolic pathways.
The distinction between the metabolic phenotypes of mice harboring a duplication CNV vs. mice that transgenically overexpress the major candidate dosage-sensitive gene in the region, Rai1
or between mice harboring a deletion CNV vs. mice that have a targeted gene knockout of Rai1,
clearly demonstrates the central message of this study: structural genomic variation and the resultant alterations in downstream gene expression can be responsible for common, complex phenotypes, such as obesity or metabolic disorder. While these monogenic (transgenic Rai1
overexpression or targeted Rai1+/−
gene knockout) mouse models do display some abnormal metabolic phenotypes, they do not possess the full-spectrum of phenotypes identified in the mouse models harboring duplication or deletion CNVs, suggesting that epistatic interactions between the major dosage-sensitive gene, Rai1
, and other genes or regulatory elements within the CNV (i.e., deviation from the normal n = 2 diploid state) region are needed to manifest the full spectrum of metabolic phenotypes. Interestingly, Rai1
appears to have a greater influence on metabolism when its dosage is reduced (knockout/deletion) than when its dosage is increased (transgenic/duplication); the specificity of the CNV in this context is interesting, and it may be an indication that the precise pathways underlying leanness and resistance to diet-induced obesity may be distinct from those underlying obesity and metabolic syndrome, although some overlap is quite likely. Alternatively, the regulatory networks/pathways leading to obesity may be more susceptible to gene dosage perturbations.