Biology subjects

Desmarais, J. J.

Publications and source records attributed to Desmarais, J. J..

4 recordsLinked to original sources

bioRxiv2026

Genetic background shapes AI-predicted variant effects

Predicting the consequences of genetic variants remains a major goal in biomedicine. Conventional approaches typically assess single-nucleotide variants in the context of a single reference genome, without accounting for genetic diversity that can modulate variant effects. Here we introduce the personalized variant effect predictor (pVEP) framework, which quantifies how genetic background across thousands of human genomes from globally diverse populations shapes computational predictions of clinical variant effects. Across deep learning models spanning protein structure, splicing, and noncoding regulation, pVEP reveals that many clinical variants exhibit heterogeneous predicted effects across haplotypes, with the same variant predicted to be pathogenic in some genetic backgrounds and benign in others. We find support for underlying molecular mechanisms, including shifts in predicted protein contacts and changes in splice-site recognition. Overall, personalized genomic context emerges as a systematically underappreciated variable in variant annotation and clinical interpretation, with particular implications for genetically diverse populations.

genomics↗

bioRxiv2025

HENMT1 restricts endogenous retrovirus activity by methylation of 3'-tRNA fragments

Long terminal repeat (LTR) retroelements such as endogenous retroviruses (ERVs) utilize host tRNA as a primer for reverse transcription, and are thus susceptible to silencing by small RNAs derived from the 3'-end of mature tRNAs (3'-tRFs). Rigorous quantification reveals that 3-tRF amounts are not directly proportional to tRNA levels, instead, 3-tRFs of specific isodecoder tRNAs are highly enriched in a pattern conserved between mouse and human. We found that 3-tRFs are 2-O methylated by the small RNA methyltransferase HENMT1 protecting them from degradation and promoting ERV silencing. In the absence of HENMT1, 3-tRFs are subjected to non-templated tailing by the terminal nucleotidyltransferases TUT4 and TENT2 that regulate small RNA turnover. Due to the perfect sequence complementarity of 3-tRFs to endogenous retroviral sequences, they have thousands of targets in mammalian genomes. We conducted a massively parallel reporter assay using Mus musculus particle type D, a highly active murine ERV, to determine target site rules for 3-tRFs. Our results suggest that HENMT1 not only stabilizes germline integrity but also serves transposon control by 3-tRFs in the soma.

molecular biology↗

bioRxiv2022

Trajectories for the evolution of bacterial CO2-concentrating mechanisms

Cyanobacteria rely on CO2 concentrating mechanisms (CCMs) that depend on {approx}15 genes to produce two protein complexes: an inorganic carbon (Ci) transporter and a 100+ nm carboxysome compartment that encapsulates rubisco with a carbonic anhydrase (CA) enzyme. Mutations disrupting CCM components prohibit growth in todays atmosphere (0.04% CO2), indicating that CCMs evolved to cope with declining environmental CO2. Indeed, geochemical data and models indicate that atmospheric CO2 has been generally decreasing from high concentrations over the last {approx}3.5 billion years. We used a synthetic reconstitution of a bacterial CCM in E. coli to study the co-evolution of CCMs with atmospheric CO2. We constructed strains expressing putative ancestors of modern CCMs -- strains lacking one or more CCM components -- and evaluated their growth in a variety of CO2 concentrations. Partial forms expressing CA or Ci uptake genes grew better than controls in intermediate CO2 levels ({approx}1%); we observed similar phenotypes in genetic studies of two autotrophic bacteria, H. neapolitanus and C. necator. To explain how partial CCMs improve growth, we advance a model of co-limitation of autotrophic growth by CO2 and HCO3-, as both are required to produce biomass. Our model and results delineated a viable trajectory for bacterial CCM evolution where decreasing atmospheric CO2 induces an HCO3- deficiency that is alleviated by acquisition of CAs or Ci uptake genes, thereby enabling the emergence of a modern CCM. This work underscores the importance of considering physiology and environmental context when studying the evolution of biological complexity. SignificanceThe greenhouse gas content of the ancient atmosphere is estimated using models and measurements of geochemical proxies. Some inferred high ancient CO2 levels using models of biological CO2 fixation to interpret the C isotopes found in preserved organic matter. Others argued that elevated CO2 could reconcile a faint young Sun with evidence for liquid water on Earth. We took a complementary "synthetic biological" approach to understanding the composition of the ancient atmosphere by studying present-day bacteria engineered to resemble ancient autotrophs. By showing that it is simpler to rationalize the emergence of modern bacterial autotrophs if CO2 was once high, these investigations provided independent evidence for the view that CO2 concentrations were significantly elevated in the atmosphere of early Earth.

microbiology↗

bioRxiv2018

Genome-wide screening reveals a novel class of carbonic anhydrase-like inorganic carbon transporters in chemoautotrophic bacteria

Many bacterial autotrophs rely on CO2 concentrating mechanisms (CCMs) to assimilate carbon. Although many CCM proteins have been identified, including a 200+ MDa protein organelle called the carboxysome, a systematic screen of CCM components has not been carried out. Here, we performed a genome-wide barcoded transposon screen to identify essential and CCM-related genes in the {gamma}-proteobacterium H. neapolitanus. Our screen revealed an operon encoding a domain of unknown function (PFAM:PF10070) and putative cation transporter subunit (PFAM:PF00361) is critical for CCM function. These two proteins, which we name DabA and DabB for \"DABs accumulate bicarbonate,\" function as a heterodimeric, energy-coupled inorganic carbon pump in E. coli. Furthermore, DabA has distant homology to a {beta}-carbonic anhydrase and binds a zinc ion necessary for activity. Based on these results, we propose that DABs function as vectorial CAs coupled to cation gradients and serve as inorganic carbon pumps throughout prokaryotic phyla.

molecular biology↗