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A cross-platform approach identifies genetic regulators of human metabolism and health.

ABSTRACT: In cross-platform analyses of 174 metabolites, we identify 499 associations (P < 4.9 × 10^-10) characterized by pleiotropy, allelic heterogeneity, large and nonlinear effects and enrichment for nonsynonymous variation. We identify a signal at GLP2R (p.Asp470Asn) shared among higher citrulline levels, body mass index, fasting glucose-dependent insulinotropic peptide and type 2 diabetes, with β-arrestin signaling as the underlying mechanism. Genetically higher serine levels are shown to reduce the likelihood (by 95%) and predict development of macular telangiectasia type 2, a rare degenerative retinal disease. Integration of genomic and small molecule data across platforms enables the discovery of regulators of human metabolism and translation into clinical insights.

SUBMITTER: Lotta LA

PROVIDER: S-EPMC7612925 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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A cross-platform approach identifies genetic regulators of human metabolism and health.

Lotta Luca A LA Pietzner Maik M Stewart Isobel D ID Wittemans Laura B L LBL Li Chen C Bonelli Roberto R Raffler Johannes J Biggs Emma K EK Oliver-Williams Clare C Auyeung Victoria P W VPW Luan Jian'an J Wheeler Eleanor E Paige Ellie E Surendran Praveen P Michelotti Gregory A GA Scott Robert A RA Burgess Stephen S Zuber Verena V Sanderson Eleanor E Koulman Albert A Imamura Fumiaki F Forouhi Nita G NG Khaw Kay-Tee KT Griffin Julian L JL Wood Angela M AM Kastenmüller Gabi G Danesh John J Butterworth Adam S AS Gribble Fiona M FM Reimann Frank F Bahlo Melanie M Fauman Eric E Wareham Nicholas J NJ Langenberg Claudia C

Nature genetics 20210107 1

In cross-platform analyses of 174 metabolites, we identify 499 associations (P < 4.9 × 10<sup>-10</sup>) characterized by pleiotropy, allelic heterogeneity, large and nonlinear effects and enrichment for nonsynonymous variation. We identify a signal at GLP2R (p.Asp470Asn) shared among higher citrulline levels, body mass index, fasting glucose-dependent insulinotropic peptide and type 2 diabetes, with β-arrestin signaling as the underlying mechanism. Genetically higher serine levels are shown to ...[more]

PMID: 33414548

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Project description:The study of aflatoxin in Aspergillus spp. has garnered the attention of many researchers due to aflatoxin's carcinogenic properties and frequency as a food and feed contaminant. Significant progress has been made by utilizing the model organism Aspergillus nidulans to characterize the regulation of sterigmatocystin (ST), the penultimate precursor of aflatoxin. A previous forward genetic screen identified 23 A. nidulans mutants involved in regulating ST production. Six mutants were characterized from this screen using classical mapping (five mutations in mcsA) and complementation with a cosmid library (one mutation in laeA). The remaining mutants were backcrossed and sequenced using Illumina and Ion Torrent sequencing platforms. All but one mutant contained one or more sequence variants in predicted open reading frames. Deletion of these genes resulted in identification of mutant alleles responsible for the loss of ST production in 12 of the 17 remaining mutants. Eight of these mutations were in genes already known to affect ST synthesis (laeA, mcsA, fluG, and stcA), while the remaining four mutations (in laeB, sntB, and hamI) were in previously uncharacterized genes not known to be involved in ST production. Deletion of laeB, sntB, and hamI in A. flavus results in loss of aflatoxin production, confirming that these regulators are conserved in the aflatoxigenic aspergilli. This report highlights the multifaceted regulatory mechanisms governing secondary metabolism in Aspergillus Additionally, these data contribute to the increasing number of studies showing that forward genetic screens of fungi coupled with whole-genome resequencing is a robust and cost-effective technique.IMPORTANCE In a postgenomic world, reverse genetic approaches have displaced their forward genetic counterparts. The techniques used in forward genetics to identify loci of interest were typically very cumbersome and time-consuming, relying on Mendelian traits in model organisms. The current work was pursued not only to identify alleles involved in regulation of secondary metabolism but also to demonstrate a return to forward genetics to track phenotypes and to discover genetic pathways that could not be predicted through a reverse genetics approach. While identification of mutant alleles from whole-genome sequencing has been done before, here we illustrate the possibility of coupling this strategy with a genetic screen to identify multiple alleles of interest. Sequencing of classically derived mutants revealed several uncharacterized genes, which represent novel pathways to regulate and control the biosynthesis of sterigmatocystin and of aflatoxin, a societally and medically important mycotoxin.

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A cross-platform approach identifies genetic regulators of human metabolism and health.

Publications

A cross-platform approach identifies genetic regulators of human metabolism and health.

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