In this study we use comparative genomics to uncover a gene with uncharacterized function (1700011H14Rik/C14orf105/CCDC198), which we hereby name FAME (Factor Associated with Metabolism and Energy). We observe that FAME shows an unusually high evolutionary divergence in birds and mammals. Through the comparison of single nucleotide polymorphisms, we identify gene flow of FAME from Neandertals into modern humans. We conduct knockout experiments on animals and observe altered body weight and decreased energy expenditure in Fame knockout animals, corresponding to genome-wide association studies linking FAME with higher body mass index in humans. Gene expression and subcellular localization analyses reveal that FAME is a membrane-bound protein enriched in the kidneys. Although the gene knockout results in structurally normal kidneys, we detect higher albumin in urine and lowered ferritin in the blood. Through experimental validation, we confirm interactions between FAME and ferritin and show co-localization in vesicular and plasma membranes.

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences 1090 Vienna Austria

Central European Institute of Technology Brno University of Technology Brno Czech Republic

Central European Institute of Technology Masaryk University Brno Czech Republic

Department of Applied Physics Royal Institute of Technology Science for Life Laboratory 171 65 Stockholm Sweden

Department of Histology and Embryology Faculty of Medicine Masaryk University Brno Czech Republic

Department of Molecular Neurosciences Center for Brain Research Medical University Vienna Vienna Austria

Department of Neuroimmunology Center for Brain Research Medical University Vienna Vienna Austria

Department of Neuroscience Karolinska Institutet Stockholm Sweden

Department of Orthodontics University Leipzig Medical Center Leipzig Germany

Department of Physiology and Pharmacology Karolinska Institutet Stockholm Sweden

Endocrinology Research Center Moscow Russia

Institute of Experimental Biology Faculty of Science Masaryk University Brno Czech Republic

Institute of Experimental Medicine and Systems Biology RWTH Aachen University Aachen Germany

Institute of Molecular Genetics of the Czech Academy of Science Czech Centre for Phenogenomics Vestec Czech Republic

Institute of Pathology and Electron Microscopy Facility RWTH Aachen University Hospital Aachen Germany

Intractable Disease Research Center Graduate School of Medicine Juntendo University Tokyo Japan

Laboratory of Integrative Neuroendocrinology Institute of Experimental Medicine 1083 Budapest Hungary

Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases 1090 Vienna Austria

Luxembourg Centre for Systems Biomedicine University of Luxembourg 6 avenue du Swing 4367 Belvaux Luxembourg

Max Planck Institute for Evolutionary Biology Plön 24306 Germany

Medical Gene Technology Unit Institute of Experimental Medicine Budapest Hungary

Regulatory Genomics Research Center Institute of Fundamental Medicine and Biology Kazan Federal University Kazan Russia

Translational Cancer Research Department of Laboratory Medicine Lund University Medicon Village Scheelevägen 2 Lund Sweden

University of Oxford MRC Weatherall Institute of Molecular Medicine Radcliffe Department of Medicine Oxford OX3 9DS UK

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Nat Commun. 2023 Jun 15;14(1):3565. doi: 10.1038/s41467-023-39373-w PubMed

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