Predicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila.

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 candi...

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Autores principales:	Neha Agrawal, Katherine Lawler, Catherine M Davidson, Julia M Keogh, Robert Legg, INTERVAL, Inês Barroso, I Sadaf Farooqi, Andrea H Brand
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/f33c9af2608e4f3c96edf0d646019c8a
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spelling	oai:doaj.org-article:f33c9af2608e4f3c96edf0d646019c8a2021-12-02T19:54:20ZPredicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila.1544-91731545-788510.1371/journal.pbio.3001255https://doaj.org/article/f33c9af2608e4f3c96edf0d646019c8a2021-11-01T00:00:00Zhttps://doi.org/10.1371/journal.pbio.3001255https://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885The 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.Neha AgrawalKatherine LawlerCatherine M DavidsonJulia M KeoghRobert LeggINTERVALInês BarrosoI Sadaf FarooqiAndrea H BrandPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 19, Iss 11, p e3001255 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Neha Agrawal Katherine Lawler Catherine M Davidson Julia M Keogh Robert Legg INTERVAL Inês Barroso I Sadaf Farooqi Andrea H Brand Predicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila.
description	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.
format	article
author	Neha Agrawal Katherine Lawler Catherine M Davidson Julia M Keogh Robert Legg INTERVAL Inês Barroso I Sadaf Farooqi Andrea H Brand
author_facet	Neha Agrawal Katherine Lawler Catherine M Davidson Julia M Keogh Robert Legg INTERVAL Inês Barroso I Sadaf Farooqi Andrea H Brand
author_sort	Neha Agrawal
title	Predicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila.
title_short	Predicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila.
title_full	Predicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila.
title_fullStr	Predicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila.
title_full_unstemmed	Predicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila.
title_sort	predicting novel candidate human obesity genes and their site of action by systematic functional screening in drosophila.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/f33c9af2608e4f3c96edf0d646019c8a
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Predicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila.

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