Variants in the human gene PSPH may help explain why some people develop severe neurological disorders linked to inadequate production of the amino acid L-serine. New research published in FEBS Open Bio suggests that the gene’s evolutionary history is functionally important: versions of PSPH reconstructed from ancient human genomes performed less efficiently than the modern human form, while disease-associated variants showed the greatest loss of activity.

The findings come from an approach that combines ancient DNA analysis with laboratory experiments in yeast. Rather than treating all naturally occurring genetic differences as equally important, the researchers used evolutionary comparisons to identify changes in the PSPH sequence that may have altered the enzyme’s performance. They then tested those versions directly, providing experimental evidence for differences that might otherwise be missed by genome sequencing alone.

The PSPH gene encodes phosphoserine phosphatase, an enzyme involved in the final step of the biosynthetic pathway that produces L-serine. In this reaction, phosphoserine phosphatase removes a phosphate group from 3-phosphoserine, generating L-serine. Although L-serine can also be obtained from food, the body’s internal production is especially important for tissues with high metabolic demands, including the developing and mature nervous system.

When damaging PSPH variants sharply reduce enzyme activity, cells may be unable to maintain adequate serine production. Individuals carrying such variants can develop neurological problems, including developmental abnormalities and other disorders affecting the nervous system. The severity of disease-associated changes can vary, depending on how much residual enzyme function remains and how the altered protein affects cellular metabolism.

To compare the different forms of the enzyme, the investigators used a yeast complementation assay. In this type of experiment, researchers create yeast cells that lack a functional version of the organism’s corresponding gene and then introduce a human gene variant. If the human protein restores the yeast cells’ ability to grow or carry out the disrupted metabolic process, its activity can be estimated from the degree of complementation.

This system allowed the team to compare the modern human PSPH protein with versions inferred from DNA sequences found in ancient hunter-gatherer genomes. The results revealed a consistent functional ranking. The modern human enzyme produced the strongest complementation, ancient protein versions showed reduced activity, and known disease-associated variants performed most poorly.

The results do not mean that ancient humans were generally unhealthy or unable to produce L-serine. The experiments examined specific reconstructed protein sequences under controlled laboratory conditions, not the complete physiology of ancient individuals. Human health depends on many interacting genes, environmental conditions, diet, development and cellular pathways. Nevertheless, the differences indicate that particular amino acid substitutions accumulated during human evolution can influence the biochemical behavior of an essential enzyme.

The work also illustrates why evolutionary information can be valuable in interpreting genetic variation. A DNA change that appears rare or unfamiliar may be difficult to classify using clinical databases alone. By examining whether a sequence resembles ancestral forms, modern human DNA or variants already linked to disease, researchers can establish a set of candidates for functional testing. Laboratory assays can then determine whether those candidates actually alter protein activity.

“Our study highlights the potential of combining evolution-guided variant prioritization with scalable heterologous assays to uncover functional differences that may otherwise remain overlooked,” said co-corresponding author Alexander DeLuna of the Center for Research and Advanced Studies, or CINVESTAV, in Mexico.

The study, titled “Evolution-guided yeast complementation reveals functional differences in human PSPH variants,” points to a broader strategy for investigating genetic disease. Ancient genomes are increasingly being used not only to reconstruct human history, but also to identify biologically meaningful variation. When paired with rapid experimental systems such as yeast complementation, these sequences can help researchers distinguish harmless genetic diversity from changes that affect protein function and may contribute to neurological disease.

Subject of Research: Functional differences among modern human, ancient human and disease-associated variants of the PSPH gene and their effects on phosphoserine phosphatase activity.

Article Title: Evolution-guided yeast complementation reveals functional differences in human PSPH variants

Web References: FEBS Open Bio: https://febs.onlinelibrary.wiley.com/journal/22115463

References: DOI: 10.1002/2211-5463.70308

Keywords: PSPH, phosphoserine phosphatase, L-serine, ancient DNA, ancient genomes, human genetics, genomics, yeast complementation, functional assays, neurological disease, developmental neuroscience

Tags: ancient DNA and enzyme efficiencyancient human genome analysisevolutionary gene functionevolutionary history of neurological genesgene variants linked to neurological disordersgenetic basis of neurodevelopmental diseasesgenetic variants and neurodevelopmental conditionsimpact of enzyme activity loss on brain developmentL-serine biosynthesislaboratory experiments with yeast for genetic testingNeurodevelopmental Disordersphosphoserine phosphatase enzyme