A new highly penetrant form of obesity due to deletions on chromosome 16p11.2

Walters, Robin G.; Jacquemont, Sébastien; Valsesia, Armand; Smith, Adam J. de; Martinet, Danielle; Andersson, Jan-Erik; Falchi, Mario; Chen, Fei; Andrieux, Joris; Lobbens, Stéphane; Delobel, Bruno; Stutzmann, Fanny; Moustafa, Julia S. El-Sayed; Chèvre, Jean-Claude; Lecœur, Cécile; Vatin, Vincent; Bouquillon, Sonia; Buxton, Jessica L.; Boute, Odile; Holder‐Espinasse, Muriel; Cuisset, Jean‐Marie; Lemaître, M.; Ambresin, Anne‐Emmanuelle; Brioschi, Andrea; Gaillard, Muriel; Giusti, Vittorio; Fellmann, Florence; Ferrarini, Alessandra; Hadjikhani, Nouchine; Campion, Dominique; Guilmatre, Audrey; Goldenberg, Anna; Calmels, Nadège; Mandel, Jean‐Louis; Caignec, Cédric Le; David, Albert; Isidor, Bertrand; Cordier, Marie‐Pierre; Dupuis‐Girod, Sophie; Labalme, Audrey; Sanlaville, Damien; Béri-Dexheimer, Mylène; Jonveaux, Philippe; Leheup, Bruno; Õunap, Katrin; Bochukova, Elena G.; Henning, Elana; Keogh, Julia M.; Ellis, Richard J.; MacDermot, K D; Haelst, Mieke M. van; Vincent‐Delorme, Catherine; Plessis, Ghislaine; Touraine, Renaud; Philippe, Anne; Malan, Valérie; Mathieu‐Dramard, Michèle; Chiésa, Jean; Blaumeiser, Bettina; Kooy, R. Frank; Caïazzo, Robert; Pigeyre, Marie; Balkau, Beverley; Sladek, Robert; Bergmann, Sven; Mooser, Vincent; Waterworth, Dawn; Reymond, Alexandre; Vollenweider, Péter; Waeber, Gérard; Kurg, Ants; Palta, Priit; Esko, Tõnu; Metspalu, Andres; Nelis, Mari; Elliott, Paul; Hartikainen, Anna-Liisa; McCarthy, Mark I.; Peltonen, Leena; Carlsson, Lena; Jacobson, Peter; Sjöström, Lars; Huang, Ni; Hurles, Matthew E.; O’Rahilly, Stephen; Farooqi, I. Sadaf; Männik, Katrin; Järvelin, Marjo‐Riitta; Pattou, François; Meyre, David; Walley, Andrew J.; Coin, Lachlan; Blakemore, Alexandra I. F.; Froguel, Philippe; Beckmann, Jacques S.

doi:10.1038/nature08727

Cited by 500 publications

(434 citation statements)

References 37 publications

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“…1; Girirajan et al 2010;Walters et al 2010;Jacquemont et al 2011). These observations suggest that we should consider the possibility that the differences reported in regulatory footprints (Shulha et al 2012) might be associated with the specific genomic organization of these loci in human and/or with their localization to or closeness to highly plastic sections of the human genome.…”

Section: Resultsmentioning

confidence: 99%

Novel H3K4me3 marks are enriched at human- and chimpanzee-specific cytogenetic structures

2014

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Human and chimpanzee genomes are 98.8% identical within comparable sequences. However, they differ structurally in nine pericentric inversions, one fusion that originated human chromosome 2, and content and localization of heterochromatin and lineage-specific segmental duplications. The possible functional consequences of these cytogenetic and structural differences are not fully understood and their possible involvement in speciation remains unclear. We show that subtelomeric regions-regions that have a species-specific organization, are more divergent in sequence, and are enriched in genes and recombination hotspots-are significantly enriched for species-specific histone modifications that decorate transcription start sites in different tissues in both human and chimpanzee. The human lineage-specific chromosome 2 fusion point and ancestral centromere locus as well as chromosome 1 and 18 pericentric inversion breakpoints showed enrichment of human-specific H3K4me3 peaks in the prefrontal cortex. Our results reveal an association between plastic regions and potential novel regulatory elements.

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Section: Resultsmentioning

confidence: 99%

Novel H3K4me3 marks are enriched at human- and chimpanzee-specific cytogenetic structures

2014

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“…[2][3][4][5][6][7] They are associated with Rolandic epilepsy 8 and mirror phenotypes on body mass index (BMI), head circumference (HC), and brain volume. [9][10][11][12] The deletion of the distal 16p11.2 220 kb BP2-BP3 locus (MIM: 613444) is likewise enriched in individuals with early-onset obesity and is also associated with developmental delay, intellectual disability, autism spectrum disorders (ASD), and schizophrenia. 3,[13][14][15][16] Moreover, the BP2-BP3 deletion and reciprocal duplication have mirror effects on BMI and HC, whereas the duplication of this interval, like the deletion, is associated with ASD.…”

Section: Introductionmentioning

confidence: 99%

The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

Loviglio

Arbogast

Jønch³

et al. 2017

The American Journal of Human Genetics

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Copy-number changes in 16p11.2 contribute significantly to neuropsychiatric traits. Besides the 600 kb BP4-BP5 CNV found in 0.5%-1% of individuals with autism spectrum disorders and schizophrenia and whose rearrangement causes reciprocal defects in head size and body weight, a second distal 220 kb BP2-BP3 CNV is likewise a potent driver of neuropsychiatric, anatomical, and metabolic pathologies. These two CNVs are engaged in complex reciprocal chromatin looping, intimating a functional relationship between genes in these regions that might be relevant to pathomechanism. We assessed the drivers of the distal 16p11.2 duplication by overexpressing each of the nine encompassed genes in zebrafish. Only overexpression of LAT induced a reduction of brain proliferating cells and concomitant microcephaly. Consistently, suppression of the zebrafish ortholog induced an increase of proliferation and macrocephaly. These phenotypes were not unique to zebrafish; Lat knockout mice show brain volumetric changes. Consistent with the hypothesis that LAT dosage is relevant to the CNV pathology, we observed similar effects upon overexpression of CD247 and ZAP70, encoding members of the LAT signalosome. We also evaluated whether LAT was interacting with KCTD13, MVP, and MAPK3, major driver and modifiers of the proximal 16p11.2 600 kb BP4-BP5 syndromes, respectively. Co-injected embryos exhibited an increased microcephaly, suggesting the presence of genetic interaction. Correspondingly, carriers of 1.7 Mb BP1-BP5 rearrangements that encompass both the BP2-BP3 and BP4-BP5 loci showed more severe phenotypes. Taken together, our results suggest that LAT, besides its well-recognized function in T cell development, is a major contributor of the 16p11.2 220 kb BP2-BP3 CNV-associated neurodevelopmental phenotypes.

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“…In three instances, de novo CNVs were identified in a pair of nonmonozygotic siblings representing potential germline mosaicism and were counted as single events. Several de novo CNVs occur both at loci previously associated with variable phenotypes, including autism (AmosLandgraf et al 1999;McDermid and Morrow 2002;Veltman et al 2005; The International Schizophrenia Consortium 2008; Kumar et al 2008;Mefford et al 2008;Weiss et al 2008;Ben-Shachar et al 2009;Bijlsma et al 2009;Miller et al 2009), as well as sites of recurrent CNV not previously associated with autism (Kurotaki et al 2002;Bochukova et al 2010;Walters et al 2010). …”

Section: Agre Autism Analysismentioning

confidence: 99%

De novo rates and selection of large copy number variation

et al. 2010

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While copy number variation (CNV) is an active area of research, de novo mutation rates within human populations are not well characterized. By focusing on large (>100 kbp) events, we estimate the rate of de novo CNV formation in humans by analyzing 4394 transmissions from human pedigrees with and without neurocognitive disease. We show that a significant limitation in directly measuring genome-wide CNV mutation is accessing DNA derived from primary tissues as opposed to cell lines. We conservatively estimated the genome-wide CNV mutation rate using single nucleotide polymorphism (SNP) microarrays to analyze whole-blood derived DNA from asthmatic trios, a collection in which we observed no elevation in the prevalence of large CNVs. At a resolution of~30 kb, nine de novo CNVs were observed from 772 transmissions, corresponding to a mutation rate of m = 1.2 3 10 -2 CNVs per genome per transmission (m = 6.5 3 10 -3 for CNVs >500 kb). Combined with previous estimates of CNV prevalence and assuming a model of mutation-selection balance, we estimate significant purifying selection for large (>500 kb) events at the genome-wide level to be s = 0.16. Supporting this, we identify de novo CNVs in 717 multiplex autism pedigrees from the AGRE collection and observe a fourfold enrichment (P = 1.4 3 10 -3 ) for de novo CNVs in cases of multiplex autism versus unaffected siblings, suggesting that many de novo CNV mutations contribute a subtle, but significant risk for autism. We observe no parental bias in the origin or transmission of CNVs among any of the cohorts studied.

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A new highly penetrant form of obesity due to deletions on chromosome 16p11.2

Cited by 500 publications

References 37 publications

Novel H3K4me3 marks are enriched at human- and chimpanzee-specific cytogenetic structures

Novel H3K4me3 marks are enriched at human- and chimpanzee-specific cytogenetic structures

The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

De novo rates and selection of large copy number variation

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