论文
论文标题：C. elegans as a model for inter-individual variation in metabolism
作者：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. Kolodzi, et al.
期刊：Nature
发表时间：2022/07/06
数字识别码：10.1038/s41586-022-04951-3
摘要：Individuals can exhibit differences in metabolism that are caused by the interplay of genetic background, nutritional input, microbiota and other environmental factors1,2,3,4. 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.
近日，美国马萨诸塞大学Albertha J. M. Walhout实验室、康奈尔大学Frank C. Schroeder实验室和西北大学Erik C. Andersen实验室合作在Nature杂志发表了题为 C. elegans as a model for inter-individual variation in metabolism 的研究文章，通过比较3种野生线虫和实验室线虫的代谢差异，作者发现不同线虫中已知代谢物与未知代谢物（metabolites that have not been previously described）的丰度存在明显差异，其中代谢酶HPHD-1的遗传变异导致野生线虫中丙酸分流途径的中间体3HP及由3HP和氨基酸构成的未知代谢复合物(3HP-AAs)的丰度明显升高。本研究以线虫的丙酸代谢为突破口，揭示了基因变异导致个体间代谢差异性的调控模式。
1. Wilcken, B., Wiley, V., Hammond, J. & Carpenter, K. Screening newborns for inborn errors of metabolism by tandem mass spectrometry. N. Engl. J. Med. 348, 2304–2312 (2003).
2. Deodato, F., Boenzi, S., Santorelli, F. M. & Dionisi-Vici, C. Methylmalonic and propionic aciduria. Am. J. Med. Genet. C 142C, 104–112 (2006).
