<?xml version="1.0" encoding="UTF-8"?><xml><records><record><source-app name="Biblio" version="7.x">Drupal-Biblio</source-app><ref-type>17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Campa‐Álvarez, Mauricio</style></author><author><style face="normal" font="default" size="100%">Ascencio, Diana</style></author><author><style face="normal" font="default" size="100%">Vallebueno‐Estrada, Miguel</style></author><author><style face="normal" font="default" size="100%">González‐Orozco, Eduardo</style></author><author><style face="normal" font="default" size="100%">Martínez‐Guerrero, Christian Eduardo</style></author><author><style face="normal" font="default" size="100%">Montiel, Rafael</style></author><author><style face="normal" font="default" size="100%">DeLuna, Alexander</style></author></authors></contributors><titles><title><style face="normal" font="default" size="100%">Evolution‐guided yeast complementation reveals functional differences in human                    &lt;scp&gt;                      &lt;i&gt;PSPH&lt;/i&gt;                    &lt;/scp&gt;                    variants</style></title><secondary-title><style face="normal" font="default" size="100%">FEBS Open Bio</style></secondary-title></titles><dates><year><style  face="normal" font="default" size="100%">2026</style></year><pub-dates><date><style  face="normal" font="default" size="100%">2026/08/05</style></date></pub-dates></dates><urls><web-urls><url><style face="normal" font="default" size="100%">https://febs.onlinelibrary.wiley.com/doi/10.1002/2211-5463.70308</style></url></web-urls></urls><isbn><style face="normal" font="default" size="100%">2211-54632211-5463</style></isbn><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">&lt;p&gt;&lt;meta charset=&quot;UTF-8&quot; /&gt;Deciphering how human genetic variants affect conserved metabolic enzymes is essential for understanding their evolutionary and clinical significance. Here, we combine sequence analyses of temporally stratified human genomes with a quantitative&amp;nbsp;&lt;i&gt;Saccharomyces cerevisiae&lt;/i&gt;&amp;nbsp;complementation assay in a strain lacking&amp;nbsp;&lt;i&gt;SER2&lt;/i&gt;, the yeast gene required for the final step of L-serine biosynthesis, to examine functional differences among human phosphoserine phosphatase (PSPH) variants. Population-genomic comparisons between ancient hunter-gatherers and present-day humans identified two&amp;nbsp;&lt;i&gt;PSPH&lt;/i&gt;&amp;nbsp;exons with elevated differences in nucleotide diversity, guiding the selection of two ancient-genome-prioritized variants (R27S and Q83H) for functional testing. To place their effects in functional context, we expressed each variant individually and compared complementation with the modern&amp;nbsp;&lt;i&gt;PSPH&lt;/i&gt;&amp;nbsp;allele and two disease-associated alleles (D32N and A35T) across multiple environmental conditions. Human&amp;nbsp;&lt;i&gt;PSPH&lt;/i&gt;&amp;nbsp;enhanced growth of the&amp;nbsp;&lt;i&gt;SER2&lt;/i&gt;&amp;nbsp;deletion mutant and revealed reproducible quantitative differences among alleles. The modern allele generally conferred the strongest complementation, while the ancient genome variants supported measurable but more condition-dependent rescue, and the disease-associated alleles showed the weakest complementation. These differences were broadly consistent across conditions, while specific environmental perturbations revealed context-dependent shifts in effect size. Together, our results establish a scalable framework that links evolutionary genomics with experimental functional assays to identify and evaluate human metabolic enzyme variants with measurable&amp;nbsp;&lt;i&gt;in vivo&lt;/i&gt;&amp;nbsp;effects.&lt;/p&gt;
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