Summary: A new study examines how the phosphoserine phosphatase (PSPH) gene has changed in function over human history. PSPH encodes the enzyme phosphoserine phosphatase, which catalyzes the final step in L-serine biosynthesis. L-serine is an amino acid essential for central nervous system development and maintenance; insufficient synthesis caused by pathogenic PSPH variants results in severe neurological disorders.
The research reveals a clear functional gradient: contemporary human PSPH variants show the strongest enzymatic activity, ancient hunter-gatherer sequences display reduced function, and known disease-associated variants perform the poorest in laboratory assays.
Key Facts
- Functional evolutionary gradient: Modern human PSPH sequences exhibit the highest enzymatic activity compared with ancient hunter-gatherer variants.
- Reduced ancient function: PSPH proteins reconstructed from ancient hunter-gatherer genomes provided noticeably less enzymatic rescue than modern PSPH in experimental tests.
- Disease variants are weakest: Clinically pathogenic PSPH alleles tested showed the lowest functional output in yeast complementation assays.
- Neurological relevance: Impaired L-serine synthesis due to PSPH dysfunction is directly linked to a spectrum of serious nervous system conditions, including developmental and seizure disorders.
- Methodological advance: The study demonstrates the value of combining evolution-guided variant prioritization with scalable heterologous screening to detect subtle but meaningful functional differences among human gene variants.
Source: Wiley
Certain PSPH variants, which alter the enzyme phosphoserine phosphatase, reduce the body’s ability to produce L-serine and thereby cause a range of neurological problems.
Published in FEBS Open Bio, the study compares modern, ancient, and disease-associated human PSPH sequences, using evolutionary analyses to prioritize variants and yeast complementation assays to measure functional impact.
The investigators identified differences between the modern human PSPH sequence and sequences recovered from ancient hunter-gatherer genomes. When tested in an evolution-guided yeast complementation system, the modern PSPH allele consistently produced the strongest enzymatic rescue, ancient variants delivered moderate and more condition-dependent activity, and disease-associated variants showed the weakest function.
“Our study highlights the potential of combining evolutionary prioritization with scalable heterologous assays to uncover functional differences that may otherwise remain overlooked,” said co–corresponding author Alexander DeLuna, PhD, of the Center for Research and Advanced Studies (CINVESTAV), Mexico.
Key Questions Answered:
A: L-serine is a necessary precursor for neuromodulators such as D-serine and for complex lipids that support brain development, synaptic plasticity, and the myelin sheath. When L-serine production is insufficient, neurodevelopment can be disrupted, leading to conditions including microcephaly, seizures, and developmental delays.
A: The team used yeast complementation assays. Human PSPH variants were expressed in Saccharomyces cerevisiae strains lacking the native SER2 gene, which performs the final step of L-serine synthesis in yeast. By measuring how well each human variant restored yeast growth under different conditions, the researchers obtained direct, quantitative comparisons of enzymatic function.
A: The stepwise increase in PSPH enzymatic activity from ancient hunter-gatherer variants to modern human alleles suggests that selective pressures favored enhanced L-serine synthesis. This biochemical improvement could have supported increasing metabolic and neurodevelopmental demands during human evolution.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full.
- Additional context was provided by our editorial staff.
About this genetics and evolutionary neuroscience research news
Author: Sara Henning-Stout
Source: Wiley
Contact: Sara Henning-Stout – Wiley
Image: Image credited to Neuroscience News
Original Research: Open access.
“Evolution-guided yeast complementation reveals functional differences in human PSPH variants” by Mauricio Campa-Álvarez, Diana Ascencio, Miguel Vallebueno-Estrada, Eduardo González-Orozco, Christian Eduardo Martínez-Guerrero, Rafael Montiel, Alexander DeLuna. FEBS Open Bio. DOI: 10.1002/2211-5463.70308
Abstract
Evolution-guided yeast complementation reveals functional differences in human PSPH variants
Understanding how human genetic variants alter conserved metabolic enzymes is crucial for interpreting both their evolutionary history and clinical consequences. This study combines sequence analysis of temporally stratified human genomes with a quantitative Saccharomyces cerevisiae complementation assay to examine functional variation among human PSPH alleles.
Population-genomic comparisons between ancient hunter-gatherers and present-day humans highlighted two PSPH exons with elevated nucleotide diversity. Those signals guided the selection of two ancient-genome-prioritized variants (R27S and Q83H) for functional testing alongside a modern allele and two disease-associated alleles (D32N and A35T).
Each human PSPH variant was expressed individually in a yeast strain lacking SER2, the yeast gene required for the final step of L-serine biosynthesis. By measuring how effectively each variant complemented the yeast deletion across multiple environmental conditions, the authors obtained reproducible, quantitative differences among alleles.
Overall, the modern human allele provided the strongest complementation. Ancient variants supported measurable, but more environment-dependent, rescue. Disease-associated alleles displayed the weakest complementation. These patterns were generally robust across tested conditions, although certain environmental perturbations changed the magnitude of allele effects.
Together, these results establish a scalable framework linking evolutionary genomics and experimental functional assays to identify and evaluate human metabolic enzyme variants with measurable in vivo effects, improving our ability to prioritize variants for further clinical and evolutionary study.