Biology subjects

Domingo-Sananes, M. R.

Publications and source records attributed to Domingo-Sananes, M. R..

5 recordsLinked to original sources

bioRxiv2026

Reference-free clustering as an epidemiological tool for Mycobacterium tuberculosis lineage typing

Whole-genome sequencing (WGS) of Mycobacterium tuberculosis (Mtb) is widely used in the epidemiological investigation of recent transmission events, resulting in high-resolution strain typing. Accurate and rapid strain typing is essential for informing outbreak investigations and guiding tuberculosis control strategies. However, the gold-standard reference-guided SNP-calling pipeline currently used for strain typing relies on computationally intensive reference-mapping approaches, making it challenging to perform in many high-burden, resource-limited settings, where simplified and scalable genomic tools are urgently needed. To address these limitations, we explored reference-free methods for medium resolution epidemiology, namely Mtb strain (lineage) typing, using a dataset of 535 complete genomes spanning the human- and animal-adapted lineages. Illumina paired-end reads were simulated from each complete genome, assembled, and analysed using three reference-free, k-mer-based tools: MASH, PopPUNK, and SKA2 (Split K-mer Analysis). Genetic distances were generated for each method and compared with a ground truth lineage assignment from with TB Profiler. Our results demonstrated that reference-free methods can effectively distinguish Mtb lineages, with SKA2 showing the most promising performance across all datasets. SKA2 consistently recovered lineage and sub-lineage structure with high accuracy, demonstrating strong potential as an alternative to traditional WGS workflows. These findings highlight the utility of reference-free methods, particularly SKA2, for enabling accessible, scalable, and rapid Mtb strain typing, while supporting genomic epidemiology with low computational resources.

bioinformatics↗

bioRxiv2025

Regulation of cell proliferation by a novel feedback system on Cdk function

The proliferation of eukaryotic cells is regulated by a complex network of regulatory systems that promotes efficient cell cycle progression and ensures proper responses to the environment. Despite this complexity, the core inputs that are necessary and sufficient for robust alternation of DNA replication and mitosis are surprisingly simpler than anticipated. Indeed, fission yeast cells operating with an engineered minimal cell cycle network that lacks the highly conserved Wee1+Cdc25 feedback loops on Cdk1 function are viable, although slow growing. This provides a unique entry for evaluating how such simplified cells can evolve and improve their proliferation potential while exploring unknown mechanisms modulating cell cycle progression. Taking advantage of this model, we applied laboratory evolution assays to minimal fission yeast backgrounds and selected for the emergence of faster growing populations. We found that loss of the small disordered protein Spo12 brings about enhanced population growth in cells lacking the Wee1+Cdc25 mitotic switch. Importantly, we demonstrate that Spo12 defines a new and conserved family of inhibitors of the Cdk-counteracting phosphatase PP2A that are directly regulated by Cdk-dependent phosphorylation. Our results also reveal a trade-off associated with Spo12-dependent regulation, which may have implications for our understanding of the principles underlying the evolution of cell cycle control. Finally, our study highlights how combining simplified circuits with experimental evolution allows for uncovering regulatory elements that may be obscured by network complexity.

cell biology↗

bioRxiv2024

The Mycobacterium tuberculosis complex pangenome is small and driven by sub-lineage-specific regions of difference

The Mycobacterium tuberculosis complex (MTBC) is a group of bacteria causing tuberculosis (TB) in humans and animals. Understanding MTBC genetic diversity is crucial for insights into its adaptation and traits related to survival, virulence, and antibiotic resistance. While it is known that within-MTBC diversity is characterised by large deletions found only in certain lineages (regions of difference [RDs]), a comprehensive pangenomic analysis incorporating both coding and non-coding regions remains unexplored. We utilised a curated dataset representing various MTBC genomes, including under-represented lineages, to quantify the full diversity of the MTBC pangenome. The MTBC was found to have a small, closed pangenome with distinct genomic features and RDs both between lineages (as previously known) and between sub-lineages. The accessory genome was identified to be a product of genome reduction, showing both divergent and convergent deletions. This variation has implications for traits like virulence, drug resistance, and metabolism. The study provides a comprehensive understanding of the MTBC pangenome, highlighting the importance of genome reduction in its evolution, and underlines the significance of genomic variations in determining the pathogenic traits of different MTBC lineages.

evolutionary biology↗

bioRxiv2023

Contingency, Repeatability and Predictability in the Evolution of a Prokaryotic Pangenome.

Pangenomes exhibit remarkable variability in many prokaryotic species. This variation is maintained through the processes of horizontal gene transfer and gene loss. Repeated acquisitions of near-identical homologs can easily be observed across pangenomes, leading to the question of whether these parallel events potentiate similar evolutionary trajectories, or whether the remarkably different genetic background of the recipients mean that post-acquisition evolutionary trajectories end up being quite different. In this study, we present a machine learning method that predicts the presence or absence of genes in the Escherichia coli pangenome based on the presence of other accessory genes within the genome. We are, in effect, asking whether gene acquisitions potentiate similar evolutionary trajectories or not. Our analysis leverages the repeated transfer of genes through the E. coli pangenome to observe patterns of repeated evolution following similar events. The presence or absence of a substantial set of genes is highly predictable, from other genes alone, indicating that selection potentiates and maintains gene-gene co-occurrence and avoidance relationships deterministically over long-term bacterial evolution despite differences in host evolutionary history. We propose that the pangenome can be understood as a set of genes with relationships that govern their likely cohabitants, analogous to an ecosystems set of interacting organisms. Our findings highlight intra-genomic gene fitness effects as key drivers of prokaryotic evolution, with ensuing pangenome-wide emergence of repeated patterns of community structure.

evolutionary biology↗

bioRxiv2019

Selection-based model of prokaryote pangenomes

The genomes of different individuals of the same prokaryote species can vary widely in gene content, displaying different proportions of core genes, which are present in all genomes, and accessory genes, whose presence varies between genomes. Together, these core and accessory genes make up a species pangenome. The reasons behind this extensive diversity in gene content remain elusive, and there is an ongoing debate about the contribution of accessory genes to fitness, that is, whether their presence is on average advantageous, neutral, or deleterious. In order to explore this issue, we developed a mathematical model to simulate the gene content of prokaryote genomes and pangenomes. Our model focuses on testing how the fitness effects of genes and their rates of gene gain and loss would affect the properties of pangenomes. We first show that pangenomes with large numbers of low-frequency genes can arise due to the gain and loss of neutral and nearly neutral genes in a population. However, pangenomes with large numbers of highly beneficial, low-frequency genes can arise as a consequence of genotype-by-environment interactions when multiple niches are available to a species. Finally, pangenomes can arise, irrespective of the fitness effect of the gained and lost genes, as long as gene gain and loss rates are high. We argue that in order to understand the contribution of different mechanisms to pangenome diversity, it is crucial to have empirical information on population structure, gene-by-environment interactions, the distributions of fitness effects and rates of gene gain and loss in different prokaryote groups.

microbiology↗