Metabolic diseases are a worldwide problem but the underlying genetic factors and their relevance to metabolic disease remain incompletely understood. Genome-wide research is needed to characterize so-far unannotated mammalian metabolic genes. Here, we generate and analyze metabolic phenotypic data of 2016 knockout mouse strains under the aegis of the International Mouse Phenotyping Consortium (IMPC) and find 974 gene knockouts with strong metabolic phenotypes. 429 of those had no previous link to metabolism and 51 genes remain functionally completely unannotated. We compared human orthologues of these uncharacterized genes in five GWAS consortia and indeed 23 candidate genes are associated with metabolic disease. We further identify common regulatory elements in promoters of candidate genes. As each regulatory element is composed of several transcription factor binding sites, our data reveal an extensive metabolic phenotype-associated network of co-regulated genes. Our systematic mouse phenotype analysis thus paves the way for full functional annotation of the genome.

Identification of genetic elements in metabolism by high-throughput mouse phenotyping

Chiani F;Di Pietro C;Di Segni G;Ermakova O;Ferrara F;Fruscoloni P;Gambadoro A;Gastaldi S;Golini E;La Sala G;Mandillo S;Marazziti D;Massimi M;Matteoni R;Orsini T;Pasquini M;Raspa M;Rauch A;Rossi G;Rossi N;Putti S;Scavizzi F;TocchiniValentini GD;
2018

Abstract

Metabolic diseases are a worldwide problem but the underlying genetic factors and their relevance to metabolic disease remain incompletely understood. Genome-wide research is needed to characterize so-far unannotated mammalian metabolic genes. Here, we generate and analyze metabolic phenotypic data of 2016 knockout mouse strains under the aegis of the International Mouse Phenotyping Consortium (IMPC) and find 974 gene knockouts with strong metabolic phenotypes. 429 of those had no previous link to metabolism and 51 genes remain functionally completely unannotated. We compared human orthologues of these uncharacterized genes in five GWAS consortia and indeed 23 candidate genes are associated with metabolic disease. We further identify common regulatory elements in promoters of candidate genes. As each regulatory element is composed of several transcription factor binding sites, our data reveal an extensive metabolic phenotype-associated network of co-regulated genes. Our systematic mouse phenotype analysis thus paves the way for full functional annotation of the genome.
2018
Istituto di Biochimica e Biologia Cellulare - IBBC
mouse phenotyping
IMPC
Metabolic diseases
File in questo prodotto:
File Dimensione Formato  
prod_383374-doc_130692.pdf

accesso aperto

Descrizione: Identification of genetic elements in metabolism by high-throughput mouse phenotyping
Tipologia: Versione Editoriale (PDF)
Licenza: Creative commons
Dimensione 2.4 MB
Formato Adobe PDF
2.4 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.14243/371847
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact