Certain variants in the PSPH gene, which encodes an enzyme called phosphoserine phosphatase, prevent the body from making sufficient amounts of amino acid L-serine, leading to a range of nervous system problems. New research in FEBS Open Bio reveals that PSPH in ancient human genomes differed functionally from modern and disease-associated versions of the gene.

Investigators found that the modern human DNA sequence of PSPH differs from sequences identified in ancient hunter-gatherers. In evolution-guided yeast complementation assays, modern-day human phosphoserine phosphatase had the greatest function, with ancient proteins showing diminished function and disease-associated variants exhibiting the weakest function.

Our study highlights the potential of combining evolution-guided variant prioritization with scalable heterologous assays to uncover functional differences that may otherwise remain overlooked."

Alexander DeLuna, PhD, co-corresponding author, Center for Research and Advanced Studies (CINVESTAV), Mexico

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Journal reference:

Campa‐Álvarez, M., et al. (2026). Evolution‐guided yeast complementation reveals functional differences in human PSPH variants. FEBS Open Bio. DOI: 10.1002/2211-5463.70308. https://febs.onlinelibrary.wiley.com/doi/10.1002/2211-5463.70308