Identification of an obesity quantitative trait locus on mouse chromosome 2 and evidence of linkage to body fat and insulin on the human homologous region 20q.

Lembertas, A V; Pérusse, Louis; Chagnon, Y. C.; Fisler, Janis S.; Warden, Craig H; Purcell-Huynh, D A; Dionne, F. T.; Gagnon, Jacques; Nadeau, André; Lusis, Aldons J.; Bouchard, Claude

doi:10.1172/jci119637

Cited by 213 publications

(138 citation statements)

References 57 publications

(61 reference statements)

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“…Lembertas et al 2 and Mehrabian et al 3 have localized a quantitative trait locus (QTL) for obesity on mouse chromosome 2 (Mob5), and sibling pair analyses of Quebec families found a suggestive linkage in the interval between the ADA and MC3R genes in the homologous region of human chromosome 20q. 2 A genome scan and subsequent saturation mapping by our group 4 found linkage to several markers on 20q13. There are at least two other mouse obesity models which map to this same region.…”

Section: Discussionmentioning

confidence: 99%

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Melanocortin 3 receptor (MC3R) gene variants in extremely obese women

Joo

Furlong³

et al. 2000

Int J Obes

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OBJECTIVE: Following several reports of linkage of obesity related phenotypes to human chromosome 20q we sought to determine whether variations of the melanocortin 3 receptor (MC3R) gene are associated with obesity. DESIGN: We screened the MC3R gene coding region and approximately 2 kb of 5 H and 3 H¯a nking sequences for DNA variants in unrelated extremely obese women and average weight controls using polymerase chain reaction (PCR) single strand conformation polymorphism (SSCP) analysis and DNA sequencing. SUBJECTS: 124 unrelated extremely obese women (body mass index, (BMI) ! 40 kgam 2 ) and 85 average weight controls (BMI`27 kgam 2 ). MEASUREMENTS: Radiation hybrid (RH) mapping was performed to localize the MC3R gene. 5 H and 3 H¯a nking sequences of MC3R gene were cloned. PCR-SSCP and DNA sequencing were used to detect mutations in the MC3R gene coding region and¯anking sequences. RESULTS: RH mapping localized the MC3R gene to 20q13, between markers D20S100 and D20S149. 1083 bp 5 H and 653 bp 3 H¯a nking region of the MC3R gene were cloned. A missense mutation ( 241, codon 81 ATTaGTT, Ile 3 Val) was found in the MC3R coding region. Four more variants were detected in the 5 H¯a nking sequence: À201(C 3 G), À239 (A 3 G), À762(A 3 T) and À769(T 3 C). Compared with controls, no signi®cant allele frequency differences were found. Racial differences were found for the 241, À201, À239 and À762 polymorphisms. CONCLUSIONS: Several sequence variants were found in the MC3R gene coding region and in 5 H¯a nking sequences. However, none of the variants were associated with obesity phenotypes. The linkage of extreme human obesity on 20q13 is likely caused by genes other than MC3R.

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Section: Discussionmentioning

confidence: 99%

“…As shown in Table 1, the mean BMI of extremely obese women was over 50 kgam 2 , and for averageweight women, less than 23 kgam 2 . Within the extremely obese group, 100 were Caucasians and 24 were African-Americans.…”

Section: Subjectsmentioning

confidence: 92%

Melanocortin 3 receptor (MC3R) gene variants in extremely obese women

Joo

Furlong³

et al. 2000

Int J Obes

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“…We assumed a two-sided test for [1], according to the authors instructions, and a one-sided test for [43,46] (i.e. p value doubled before further calculation).…”

Section: Methodsmentioning

confidence: 99%

Agreement among type 2 diabetes linkage studies but a poor correlation with results from genome-wide association studies

Lillioja

Wilton

2009

Diabetologia

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Aims/hypothesis Little of the genetic basis for type 2 diabetes has been explained, despite numerous genetic linkage studies and the discovery of multiple genes in genome-wide association (GWA) studies. To begin to resolve the genetic component of this disease, we searched for sites at which genetic results had been corroborated in different studies, in the expectation that replication among studies should direct us to the genomic locations of causative genes with more confidence than the results of individual studies. Methods We have mapped the physical location of results from 83 linkage reports (for type 2 diabetes and diabetes precursor quantitative traits [QTs, e.g. plasma insulin levels]) and recent large GWA reports (for type 2 diabetes) onto the same human genome sequence to identify replicated results in diabetes genetic 'hot spots'. Results Genetic linkage has been found at least ten times at 18 different locations, and at least five times in 56 locations. All replication clusters contained study populations from more than one ethnic background and most contained results for both diabetes and QTs. There is no close relationship between the GWA results and linkage clusters, and the nine best replication clusters have no nearby GWA result. Conclusions/interpretation Many of the genes for type 2 diabetes remain unidentified. This analysis identifies the broad location of yet to be identified genes on 6q, 1q, 18p, 2q, 20q, 17pq, 8p, 19q and 9q. The discrepancy between the linkage and GWA studies may be explained by the presence of multiple, uncommon, mildly deleterious polymorphisms scattered throughout the regulatory and coding regions of genes for type 2 diabetes.

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“…The power of human-mouse comparative mapping data is tapped most efficiently through consolidation of mouse genetics and human genome resources to create a single, unified system that aids gene discovery and functional analysis in both species. As genetic and genomic tools become more sophisticated, an increasing number of gene-discovery strategies based on the merger of human, mouse, and other mammalian maps are being reported (e.g., Grobet et al 1997;Kambadur et al 1997;Lembertas et al 1997).…”

mentioning

confidence: 99%

Zooming in on the Human–Mouse Comparative Map: Genome Conservation Re-examined on a High-Resolution Scale

Carver¹,

Stubbs²

1997

Genome Res.

117

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Over the past decade, conservation of genetic linkage groups has been shown in mammals and used to great advantage, fueling significant exchanges of gene mapping and functional information especially between the genomes of humans and mice. As human physical maps increase in resolution from chromosome bands to nucleotide sequence, comparative alignments of mouse and human regions have revealed striking similarities and surprising differences between the genomes of these two best-mapped mammalian species. Whereas, at present, very few mouse and human regions have been compared on the physical level, existing studies provide intriguing insights to genome evolution, including the observation of recent duplications and deletions of genes that may play significant roles in defining some of the biological differences between the two species. Although high-resolution conserved marker-based maps are currently available only for human and mouse, a variety of new methods and resources are speeding the development of comparative maps of additional organisms. These advances mark the first step toward establishment of the human genome as a reference map for vertebrate species, providing evolutionary and functional annotation to human sequence and vast new resources for genetic analysis of a variety of commercially, medically, and ecologically important animal models.

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Identification of an obesity quantitative trait locus on mouse chromosome 2 and evidence of linkage to body fat and insulin on the human homologous region 20q.

Cited by 213 publications

References 57 publications

Melanocortin 3 receptor (MC3R) gene variants in extremely obese women

Melanocortin 3 receptor (MC3R) gene variants in extremely obese women

Agreement among type 2 diabetes linkage studies but a poor correlation with results from genome-wide association studies

Zooming in on the Human–Mouse Comparative Map: Genome Conservation Re-examined on a High-Resolution Scale

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