Biology subjects

Garcia, M. E.

Publications and source records attributed to Garcia, M. E..

6 recordsLinked to original sources

bioRxiv2026

DNA nullomers as a statistical phenomenon

Nullomers are sequences absent from a certain genome. Due to their unexpected occurrence in short sequences, a hypothesis is that they are avoided for evolutionary reasons or because they might have lethal consequences on organisms. However, we present evidence that the occurrence and frequency of nullomers in genomes is expected as a stochastic consequence of uneven base pair combination distributions in the genetic code. This is done by artificially constructing whole genomes from statistics with a Markov chain model. The number of nullomers in these artificial genomes is in good agreement with the nullomer counts in reference genomes. Additionally, we investigated the nullomers of over 200 human genomes and found large deviations in the nullomers between individuals, further supporting the hypothesis that a vast majority of nullomers is very unlikely to have lethal effects.

biophysics↗

bioRxiv2026

Linking UV-induced DNA damage with base pair sequences

Ultraviolet (UV) radiation induces DNA damage associated with cancer and aging, yet the sequence dependence of UV absorption remains to be investigated. Here, we present a systematic study of the UV absorption spectra of DNA based on all-electron Hartree-Fock calculations. We analyze all possible sequences up to four base pairs, as well as longer randomized sequences and genomic nullomers - motifs which are missing in a given genome. We observe a pronounced sequence dependence: cytosine- and guanine-rich motifs exhibit significantly enhanced absorption, whereas adenine-thymine-rich sequences absorb up to four times less in the mid-UV range. Notably, the human genome is biased toward adenine-thymine-rich sequences, giving it an increased susceptibility to UV-induced damage. In addition, we introduce a computational framework enabling spectral calculations of large DNA and RNA fragments, opening the door to large-scale optical analyses.

biophysics↗

bioRxiv2026

The Quantum Environment in Cryptochrome Enhances Light Absorption of FAD

The light absorption of the protein cryptochrome and its chromophore FAD is important for the regulation of circadian rhythms and in some species for sensing magnetic fields. To compute the absorption spectrum of chromophore, typically only a small region is treated quantum-mechanically due the high computational cost of spectroscopic calculations. We present a formalism that allows a quantum-mechanical treatment of not only the chromophore but also the neighbouring amino acids which differ from species to species. This is achieved by using the real-time time-dependent Hartree-Fock method. This method allows extending the quantum domain from typically only a few dozen atoms up to around 1,200 atoms for the largest calculations. The presented framework allows the treatment of neighbouring tryptophan residues or the cofactor molecule MTHF in the same calculation and allows to extract information of which regions absorb light depending on wavelength. The presented results also show that the environment around the chromophore FAD amplifies the light absorption in cryptochrome.

biophysics↗

bioRxiv2026

PRIZM: Combining Low-N Data and Zero-shot Models to Design Enhanced Protein Variants

Machine learning has repeatedly shown the ability to accelerate protein engineering, but many approaches demand large amounts of robust, high-quality training data as well as substantial computational expertise. While large pre-trained models can function as zero-shot proxies for predicting variant effects, selecting the best model for a given protein property is often non-trivial. Here, we introduce Protein Ranking using Informed Zero-shot Modelling (PRIZM), a two-phase workflow that first uses a high-quality low-N dataset to identify the most suitable pre-trained zero-shot model for a target protein property and then applies that model to rank and prioritize an in silico variant library for experimental testing. Across diverse benchmark datasets spanning multiple protein properties, PRIZM reliably separated low- from high-performing models using datasets of [~]20 labelled variants. We further demonstrate PRIZM in enzyme engineering case studies targeting sucrose synthase thermostability and glycosyltransferase activity, where PRIZM-guided selection identified improved variants, including gains of [~]3{degrees}C in apparent melting temperature and [~]20% higher relative activity. PRIZM provides an accessible, data-efficient route to leverage foundation models for protein design while requiring minimal experimental data.

bioinformatics↗

bioRxiv2025

Orco regulates the circadian activity of pheromone-sensitive olfactory receptor neurons in hawkmoths

1The mating behavior of nocturnal Manduca sexta hawkmoths is under strict temporal control. It is orchestrated via circadian and ultradian oscillations in sex-pheromone stimuli as social Zeitgeber. The extremely sensitive pheromone-detecting olfactory receptor neurons (ORNs) that innervate the long trichoid sensilla on the males antennae are peripheral circadian clocks. They express the transcriptional-translational feedback loop (TTFL) circadian clockwork, best characterized in Drosophila melanogaster. In hawkmoths, it is still unknown whether or how the ORN TTFL clockwork regulates the daily rhythms in pheromone sensitivity and in temporal resolution of ultradian pheromone pulses as prerequisites to the temporal regulation of hawkmoth mating behavior. We hypothesize that, rather than the slow TTFL clock, a more rapidly adaptive post-translational feedback loop (PTFL) clockwork, assembled in a signalosome in the ORN plasma membrane, allows for temporal control of pheromone detection via generation of multiscale endogenous membrane potential oscillations. The potential oscillations of the PTFL clock could rapidly synchronize to oscillations of pheromone stimuli at different time scales, thus enabling the prediction of stimulus patterns as a mechanism for active sensing. With in vivo long-term tip recordings of long trichoid sensilla of male hawkmoths, we analyzed the spontaneous spiking activity indicative of the ORNs endogenous membrane potential oscillations. Consistent with our hypothesis of a multiscale PTFL clock in hawkmoth ORNs, spontaneous spiking was modulated on ultradian and circadian time scales, with maximum activity at night. When we blocked the evolutionarily conserved olfactory receptor coreceptor (Orco), the circadian modulation was abolished but the ultradian frequency modulation of the spontaneous activity remained. Consistent with PTFL control, Orco was not under the transcriptional control of the TTFL clock, but its modulation of spontaneous spiking activity was dependent on cAMP. We could replicate the experimental data in a conductance-based computational model of an ORN. In this model, Orco conductance changed as a function of fluctuating 2nd messenger levels. This study demonstrates that a PTFL clock is sufficient to impose a circadian pattern on ORN sensitivity. Future experiments are necessary to further challenge our novel hypothesis. 2. Significance statementIt is generally assumed that all circadian rhythms in an organism are driven by a transcriptional-translational feedback loop (TTFL) clock. In this study, we demonstrate with in vivo recordings of hawkmoth pheromone-sensitive olfactory receptor neurons (ORNs) that the olfactory receptor coreceptor (Orco) is the key pacemaker channel for controlling circadian rhythms in spontaneous spiking activity. Since Orco expression is not driven by the TTFL clock, we put forward the novel hypothesis that Orco is a core element of a post-translational feedback loop (PTFL) membrane clock assembled in a signalosome controlling interlinked oscillations in 2nd messengers and membrane potential. Accordingly, our computational model predicts that ORN sensitivity is tuned by circadian changes in the conductance of an Orco ion channel, which is mediated by cycling levels of cyclic nucleotides. Our novel hypothesis that highlights the contribution of feedback-controlled post-translational modifications to the generation of endogenous circadian rhythmicity should spark further challenges.

physiology↗

bioRxiv2021

Epigenetic regulation clocks the multigenerational olfactory imprinting in C. elegans

Imprinting is an early sensory life experience that induces adult behaviours, such as mother recognition or homing. In a previous study, we demonstrated a striking olfactory imprinting in C. elegans that can be inherited over generations. When exposed to specific odorants during a timely controlled post-hatch period, C. elegans worms display during adulthood an enhanced migration towards these molecules. In order to unveil some of the genetic and epigenetic factors that are responsible for such a behavioural plasticity, we assessed the role of heterochronic genes using a candidate gene approach. We report here that translation of the Hunchback-Like 1 (HBL1) transcription factor in the sensory processing interneuron AIY, is a determining factor for olfactory plasticity timing in C.elegans. HBL1 may associate to the SPR1/CoREST co-repressor, the lysine demethylase SPR5/LSD1 and the histone deacetylase HDA3 to lengthen the plasticity period, whereas the translation initiation factor IFE-4 and the histone deacetylase HDA2 abridge it. We also observed that lengthened plasticity periods allow proportionally faster stable behavioral adaptation of C. elegans populations. We conclude that plasticity timing is a key factor, not only to transiently adapt individuals but also to stably adapt animal populations via multigenerational accumulation of experience.

animal behavior and cognition↗