CNV; obesity; gene expression; mouse model; medical genetics
Reinthaler Eva M, Lal Dennis, Lebon Sebastien, Hildebrand Michael S, Dahl Hans-Henrik M, Regan Brigid M, Feucht Martha, Steinböck Hannelore, Neophytou Birgit, Ronen Gabriel M, Roche Laurian, Gruber-Sedlmayr Ursula, Geldner Julia, Haberlandt Edda, Hoffmann Per, Herms Stefan, Gieger Christian, Waldenberger Melanie, Franke Andre, Wittig Michael, Schoch Susanne, Becker Albert J, Hahn Andreas, Männik Katrin, Toliat Mohammad R (2014), 16p11.2 600 kb Duplications confer risk for typical and atypical Rolandic epilepsy., in Human molecular genetics
, 23(22), 6069-80.
Giannuzzi Giuliana, Migliavacca Eugenia, Reymond Alexandre (2014), Novel H3K4me3 marks are enriched at human-and chimpanzee-specific cytogenetic structures, in GENOME RESEARCH
, 24(9), 1455-1468.
Zufferey Flore, Sherr Elliott H., Beckmann Noam D., Hanson Ellen, Maillard Anne M., Hippolyte Loyse, Mace Aurelien, Ferrari Carina, Kutalik Zoltan, Andrieux Joris, Aylward Elizabeth, Barker Mandy, Bernier Raphael, Bouquillon Sonia, Conus Philippe, Delobel Bruno, Faucett WAndrew, Goin-Kochel Robin P., Grant Ellen, Harewood Louise, Hunter Jill V., Lebon Sebastien, Ledbetter David H., Martin Christa Lese, Maennik Katrin (2012), A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders, in JOURNAL OF MEDICAL GENETICS
, 49(10), 660-668.
Zufferey Flore, Sherr Elliott H, Beckmann Noam D, Hanson Ellen, Maillard Anne M, Hippolyte Loyse, Macé Aurélien, Ferrari Carina, Kutalik Zoltán, Andrieux Joris, Aylward Elizabeth, Barker Mandy, Bernier Raphael, Bouquillon Sonia, Conus Philippe, Delobel Bruno, Faucett W Andrew, Goin-Kochel Robin P, Grant Ellen, Harewood Louise, Hunter Jill V, Lebon Sébastien, Ledbetter David H, Martin Christa Lese, Männik Katrin (2012), A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders., in Journal of medical genetics
, 49(10), 660-8.
Golzio Christelle, Willer Jason, Talkowski Michael E., Oh Edwin C., Taniguchi Yu, Jacquemont Sebastien, Reymond Alexandre, Sun Mei, Sawa Akira, Gusella James F., Kamiya Atsushi, Beckmann Jacques S., Katsanis Nicholas (2012), KCTD13 is a major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number variant, in NATURE
, 485(7398), 363-363.
Jacquemont Sébastien, Reymond Alexandre, Zufferey Flore, Harewood Louise, Walters Robin G, Kutalik Zoltán, Martinet Danielle, Shen Yiping, Valsesia Armand, Beckmann Noam D, Thorleifsson Gudmar, Belfiore Marco, Bouquillon Sonia, Campion Dominique, de Leeuw Nicole, de Vries Bert B A, Esko Tõnu, Fernandez Bridget A, Fernández-Aranda Fernando, Fernández-Real José Manuel, Gratacòs Mònica, Guilmatre Audrey, Hoyer Juliane, Jarvelin Marjo-Riitta, Kooy R Frank (2011), Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus., in Nature
, 478(7367), 97-102.
Copy number variation (CNV) has recently gained considerable interest as a source of genetic variation likely to play a role in phenotypic diversity and evolution. Much effort has been invested into the identification and mapping of regions that vary in copy number among seemingly healthy/normal individuals in humans and a number of model organisms. These have uncovered associations between copy number changes and complex diseases in whole-genome association studies, as well as identified new genomic disorders. We have, for example, recently demonstrated that hemizygosity for a ~600 kb region on the short arm of human chromosome 16 was associated with obesity, defined by a body mass index (BMI) greater than 30. This genomic rearrangement was also shown to be associated with autism and macrocephaly, while its reciprocal duplication was linked to schizophrenia and microcephaly leading to hypothesize that these conditions may represent mirror states at different end of the same continuum.Obesity results from a greater intake of calories than the body requires. Its prevalence has dramatically increased worldwide in the last decades for both sexes and for all ages and ethnic groups. For example, the World Health Organization estimates that over 400 million people are now obese on the planet and that in some countries as much as 20% of the population is affected. As obesity is a major risk factor for several diseases that include cardiovascular diseases, hypertension, type 2 diabetes, dyslipidemia, sleep apnea and some cancer types, it poses one of the greatest current healthcare problems.Although the rise in obesity prevalence is driven by environmental factors, there is considerable evidence that weight or BMI are highly heritable. Few genetics causes of obesity have been identified thus far, and in each case, the take-home messages were important allowing one to infer new, unsuspected pathophysiological processes linking central brain functions to eating behaviors. Thus the study of rearrangements on the short arm of human chromosome 16 represents a unique opportunity to explore molecular, cognitive and behavioral correlates and to assess if autism and schizophrenia are two sides of the same coin, as recently proposed. Both syndrome provide excellent windows to explore the etiology of obesity and possibly to identify the underlying pathophysiological pathways.The specific aims of our project are:Aim 1: Expand the cohorts of 16p11.2 deletion or duplication syndromes’ patientsAim 2: Characterize the phenotype of patients with 16p11.2 rearrangements at multiple levelsAim 3: Fine mapping of 16p11.2 rearrangement breakpointsAim 4: Characterize the transcriptome of 16p11.2 rearrangementsAim 5: Engineer mouse models of the 16p11.2 deletion and duplication syndromesAim 6: Establish a cohort of obese patients in LausanneThe goals of the proposed research is to better define these clinical entities, the genes underlying these conditions and the pathways leading to morbidity, thereby providing potential targets for better patient management and care or treatment.