C. elegans as a model for inter-individual variation in metabolism

Bennett W. Fox, Olga Ponomarova, Yong-Uk Lee, Gaotian Zhang, Gabrielle E. Giese, Melissa Walker, Nicole M. Roberto, Huimin Na, Pedro R. Rodrigues, Brian J. Curtis, Aiden R. Kolodziej, Timothy A. Crombie, Stefan Zdraljevic, L. Safak Yilmaz, Erik C. Andersen (), Frank C. Schroeder () and Albertha J. M. Walhout ()
Additional contact information
Bennett W. Fox: Cornell University
Olga Ponomarova: University of Massachusetts Chan Medical School
Yong-Uk Lee: University of Massachusetts Chan Medical School
Gaotian Zhang: Northwestern University
Gabrielle E. Giese: University of Massachusetts Chan Medical School
Melissa Walker: University of Massachusetts Chan Medical School
Nicole M. Roberto: Northwestern University
Huimin Na: University of Massachusetts Chan Medical School
Pedro R. Rodrigues: Cornell University
Brian J. Curtis: Cornell University
Aiden R. Kolodziej: Cornell University
Timothy A. Crombie: Northwestern University
Stefan Zdraljevic: Northwestern University
L. Safak Yilmaz: University of Massachusetts Chan Medical School
Erik C. Andersen: Northwestern University
Frank C. Schroeder: Cornell University
Albertha J. M. Walhout: University of Massachusetts Chan Medical School

Nature, 2022, vol. 607, issue 7919, 571-577

Abstract: Abstract Individuals can exhibit differences in metabolism that are caused by the interplay of genetic background, nutritional input, microbiota and other environmental factors1–4. It is difficult to connect differences in metabolism to genomic variation and derive underlying molecular mechanisms in humans, owing to differences in diet and lifestyle, among others. Here we use the nematode Caenorhabditis elegans as a model to study inter-individual variation in metabolism. By comparing three wild strains and the commonly used N2 laboratory strain, we find differences in the abundances of both known metabolites and those that have not to our knowledge been previously described. The latter metabolites include conjugates between 3-hydroxypropionate (3HP) and several amino acids (3HP-AAs), which are much higher in abundance in one of the wild strains. 3HP is an intermediate in the propionate shunt pathway, which is activated when flux through the canonical, vitamin-B12-dependent propionate breakdown pathway is perturbed5. We show that increased accumulation of 3HP-AAs is caused by genetic variation in HPHD-1, for which 3HP is a substrate. Our results suggest that the production of 3HP-AAs represents a ‘shunt-within-a-shunt’ pathway to accommodate a reduction-of-function allele in hphd-1. This study provides a step towards the development of metabolic network models that capture individual-specific differences of metabolism and more closely represent the diversity that is found in entire species.

Date: 2022
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DOI: 10.1038/s41586-022-04951-3

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