Biology subjects

Perez, R. M.

Publications and source records attributed to Perez, R. M..

4 recordsLinked to original sources

bioRxiv2025

Effects of ancestry, agriculture, and lactase persistence on the stature of prehistoric Europeans

Ancient DNA has revolutionized our understanding of human evolutionary history, but studies focusing solely on genetic variation tell an incomplete story by neglecting phenotypic outcomes. The relationships between genotype and phenotype can change over time, making it desirable to study them directly in ancient populations rather than present-day data. Here, we present a large-scale integration of ancient genomic and phenotypic data, analyzing femur length as a proxy for stature in 568 individuals with published whole-genome ancient DNA data across western Eurasia. Polygenic scores derived from modern European and East Asian genome-wide association studies retain predictive power in ancient populations, explaining up to 10% of phenotypic variance. Contrary to longstanding archaeological hypotheses, we find that Neolithic populations were only modestly shorter than preceding Mesolithic groups, with differences at least partly attributable to genetic rather than environmental factors, challenging narratives of systematic stature decline following the transition to agriculture. Finally, we find that the lactase persistence allele had a large positive effect on stature in ancient individuals (0.24 standard deviations), even though it shows no association with height in modern populations. This gene-environment interaction highlights the limitation of using present-day genetic data to infer past phenotypic relationships. Our results underscore the value of integrating genetic and morphological data from ancient populations to reconstruct the dynamics of human adaptation.

genetics↗

bioRxiv2025

Complementary Structural and Chemical Biology Methods Reveal the Basis for Selective Radioligand Binding to α-Synuclein in MSA Tissue

Fibrillar aggregation of -synuclein (Syn) is a hallmark of Parkinsons disease (PD) and related disorders, including multiple system atrophy (MSA) and dementia with Lewy bodies (DLB). Despite advances in Syn fibril structural characterization, the relevance of in vitro and ex vivo structures to patient aggregates remains unclear, particularly for developing therapeutic or diagnostic molecules. Cryo-electron microscopy (cryo-EM) studies of Syn fibrils with ligands often reveal binding at multiple sites, likely due to high ligand concentrations. Here, various structural and chemical biology techniques were used to characterize Syn fibrils in the presence of EX-6, a candidate ligand for positron emission tomography (PET) imaging of synucleinopathies. Transmission electron microscopy (TEM) and cryo-EM revealed no significant fibril core changes upon binding. Forster resonance energy transfer (FRET) further demonstrated that the disordered C-terminus was unaltered. Cryo-EM and crosslinking mass spectrometry (XL-MS) identified consistent binding sites, with one (Site 2*) providing a well-defined pocket for high-resolution analysis. Site 2* showed similar residue positioning in MSA patient-derived structures, suggesting MSA selectivity. [3H]-EX-6 binding assays demonstrated a 10-fold preference for MSA over PD tissue, with autoradiography further confirming MSA selectivity. Taken together, the combined use of structural and chemical biology techniques provides a comprehensive understanding of EX-6 binding that would not be possible with any single method. Optimization of ligand-protein and ligand-ligand interactions observed in the cryo-EM structure will enable the development of EX-6 as a PET imaging probe for MSA.

neuroscience↗

bioRxiv2025

Ankyrins are essential for synaptic integrity of photoreceptors in the mouse outer retina

Retinal circuit assembly relies on the precise timing and positioning of key molecules between neuronal partners to mediate proper synapse formation. In the outer retina, horizontal cells are important interneurons that make the first contacts to photoreceptors and begin to segregate visual information into two distinct pathways by selectively forming synapses to the different types of photoreceptors. Dendrites of horizontal cells synapse exclusively to cone photoreceptors whereas the axon terminal synapses to rod photoreceptors. Failure to properly form these early connections disrupts the downstream connectivity of other postsynaptic neurons and leads to abnormal visual function. Although these early events are critical for proper synapse development, little is known about the molecular mechanisms that establish horizontal cell to photoreceptor connectivity during development. In the present study, we performed single-cell RNA sequencing and uncovered new molecules that are highly expressed in horizontal cells. These include different members of the cytoskeletal scaffolding family of Ankyrins that are known to form specialized regions within neurons by recruiting different molecules to the membrane and linking them to the cytoskeleton. Specifically, we found Ankyrin-B to be highly expressed in horizontal cells at early time points and Ankyrin-G to be expressed at later stages. Loss of both Ankyrin-B and Ankyrin-G leads to synaptic defects between horizontal cells and photoreceptors and disrupts in vivo retinal responses. In summary, our findings uncovered a new role for Ankyrins in mediating synaptic connectivity between horizontal cells and photoreceptors required for normal visual function. SIGNIFICANCE STATEMENTIn the mammalian retina, the first synapse between photoreceptors and their downstream targets begins to separate visual information into two distinct pathways. During retinal development, photoreceptors first make contacts to horizontal cells in a temporal- and spatial-specific manner. Although this initial contact is critical for synaptogenesis, little is known about the key molecules responsible for selective wiring of horizontal cells to photoreceptors. In this study, we performed single-cell RNA sequencing and identified the family of cytoskeletal scaffolding proteins Ankyrins to be differentially expressed in horizontal cells. Loss of Ankyrins impairs synaptic connectivity between horizontal cells and their photoreceptor partners leading to abnormal visual responses. Taken together, our work uncovered a new function of Ankyrins at photoreceptor synapses.

neuroscience↗

bioRxiv2023

Proteins Need Extra Attention: Improving the Predictive Power of Protein Language Models on Mutational Datasets with Hint Tokens

In this computational study, we introduce "hint token learning," a novel machine learning approach designed to enhance protein language modeling. This method effectively addresses the unique challenges of protein mutational datasets, characterized by highly similar inputs that may differ by only a single token. Our research highlights the superiority of hint token learning over traditional fine-tuning methods through three distinct case studies. We first developed a highly accurate free energy of folding model using the largest protein stability dataset to date. Then, we applied hint token learning to predict a biophysical attribute, the brightness of green fluorescent protein mutants. In our third case, hint token learning was utilized to assess the impact of mutations on RecA bioactivity. These diverse applications collectively demonstrate the potential of hint token learning for improving protein language modeling across general and specific mutational datasets. To facilitate broader use, we have integrated our protein language models into the HuggingFace ecosystem for downstream, mutational fine-tuning tasks.

bioinformatics↗