A New Tool to Unravel the Mysteries of Metabolic Genes

A novel discovery platform has been created by a multidisciplinary research team to investigate the role of genes involved in metabolism, which is the culmination of all chemical reactions necessary for life.

Utilizing the recently developed GeneMAP (Gene-Metabolite Association Prediction) platform, the researchers were able to pinpoint a gene required for mitochondrial choline transport. The resource and the results it produced were published in the journal Nature Genetics.

We sought to gain insight into a fundamental question: How does genetic variation determine our “chemical individuality” — the inherited differences that make us biochemically unique?”

Eric Gamazon, Ph.D., Study Senior Author and Associate Professor, Division of Genetic Medicine, Vanderbilt University Medical Center

The synthesis of proteins, lipids, and nucleic acids as well as the absorption of nutrients, energy production, and waste disposal are all dependent on metabolic processes. According to Gamazon, metabolism accounts for 20% of all protein-coding genes, including those that code for enzymes and small-molecule transporters.

Metabolic abnormalities are linked to a variety of illnesses, such as cancer and neurodegenerative diseases.

Despite decades of research, many metabolic genes still lack known molecular substrates. The challenge is in part due to the enormous structural and functional diversity of the proteins.”

Eric Gamazon, Ph.D., Study Senior Author and Associate Professor, Division of Genetic Medicine, Vanderbilt University Medical Center

The GeneMAP discovery platform was created by the researchers in order to identify the roles of "orphan" transporters and enzymes, which are proteins that lack known substrates.

They showed with in silico validation that GeneMAP can both find new and identify known gene-metabolite associations using datasets from two independent large-scale human metabolome genome-wide/transcriptome-wide association studies.

Furthermore, they demonstrated that the biochemical identity of uncharacterized metabolites can be deduced from metabolic networks generated using GeneMAP.

The researchers used in vitro biochemical studies and their top finding, SLC25A48-choline, to experimentally validate new gene-metabolite associations. The mitochondrial transporter SLC25A48 lacked a specific substrate to transport.

A necessary nutrient, choline is involved in several metabolic processes as well as the production of lipids for cell membranes.

It was demonstrated by the researchers that plasma choline levels are genetically determined by SLC25A48. To show that loss of SLC25A48 affects mitochondrial choline transport and synthesis of the choline downstream metabolite betaine, they also carried out radioactive mitochondrial choline uptake assays and isotope tracing experiments.

Using extensive biobanks (UK Biobank and BioVU), they also looked into the effects of the association between SLC25A48 and choline on the human medical phenome, or the ailments, characteristics, and symptoms recorded in electronic health records. Eight associations with diseases were found.

What’s exciting about this study is its interdisciplinarity — the combination of genomics and metabolism to identify a long-sought mitochondrial choline transporter. We think, given the extensive in silico validation studies in independent datasets and the proof-of-principle experimental studies, our approach can help identify the substrates of a wide range of enzymes and transporters, and ‘deorphanize’ these metabolic proteins.”

Eric Gamazon, Ph.D., Study Senior Author and Associate Professor, Division of Genetic Medicine, Vanderbilt University Medical Center