Open AccessPredicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila
Author(s) -
Neha Agrawal,
Katherine Lawler,
Catherine M. Davidson,
Julia M. Keogh,
Robert G. Legg,
Interval,
Inês Barroso,
I. Sadaf Farooqi,
Andrea H. Brand
Publication year - 2021
Publication title -
plos biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.127
H-Index - 271
eISSN - 1545-7885
pISSN - 1544-9173
DOI - 10.1371/journal.pbio.3001255
Subject(s) - biology , hippo signaling pathway , genetics , gene , genetic screen , drosophila melanogaster , exome sequencing , candidate gene , exome , phenotype
The discovery of human obesity-associated genes can reveal new mechanisms to target for weight loss therapy. Genetic studies of obese individuals and the analysis of rare genetic variants can identify novel obesity-associated genes. However, establishing a functional relationship between these candidate genes and adiposity remains a significant challenge. We uncovered a large number of rare homozygous gene variants by exome sequencing of severely obese children, including those from consanguineous families. By assessing the function of these genes in vivo in Drosophila , we identified 4 genes, not previously linked to human obesity, that regulate adiposity ( itpr , dachsous , calpA , and sdk ). Dachsous is a transmembrane protein upstream of the Hippo signalling pathway. We found that 3 further members of the Hippo pathway, fat, four-jointed, and hippo, also regulate adiposity and that they act in neurons, rather than in adipose tissue (fat body). Screening Hippo pathway genes in larger human cohorts revealed rare variants in TAOK2 associated with human obesity. Knockdown of Drosophila tao increased adiposity in vivo demonstrating the strength of our approach in predicting novel human obesity genes and signalling pathways and their site of action.