Biology subjects

Simonti, C.

Publications and source records attributed to Simonti, C..

4 recordsLinked to original sources

bioRxiv2025

Nuclear-encoded tRNA genes harbor substantial allelic diversity in three nematode species

Cytosolic transfer RNAs, which are encoded as hundreds of genes in nuclear genomes, experience exceptionally high mutation rates and have been hypothesized to confer substantial mutational load in natural populations. Although this phenomenon appears universal across multicellular eukaryotes, a comprehensive characterization of standing variation in tRNA repertoires is still lacking in any system. Here, we resolve within-species allelic variation in nuclear-encoded tRNAs in three nematode species: Caenorhabditis elegans, C. briggsae, and C. tropicalis. We show that these genes carry signatures of high rates of historical transcription-associated mutagenesis and of purifying selection, resulting in allelic variation that includes pervasive instances of within-gene mismatches between the amino acid recognized by the tRNA backbone and that indicated by the anticodon. Furthermore, patterns of tRNA genomic organization and variation differ markedly from those of protein-coding regions. Individual genomes harbor distinct complements of tRNA genes with predicted functional differences, an observation that coincides with recent evidence that variation in tRNA expression and regulation contributes to human disease. Our findings offer an entry point for identifying the micro-evolutionary processes that act on tRNA repertoires, and in turn connecting those processes to the macro-evolutionary patterns that have more frequently been the focus of study. Significance statementTransfer RNAs (tRNAs) are ancient and essential molecules that deliver amino acids to the growing polypeptide chain during protein synthesis. Despite their importance, little is known about how the genes encoding tRNAs vary among individuals, even though they accumulate large numbers of mutations due to their high rates of expression. Here, we report that three nematode species, including the model organism C. elegans, show within-species variation in their tRNA gene repertoires, which may cause differences in protein synthesis across individuals. Our findings may represent patterns common across multicellular species and they set the stage for future investigation into how this diversity influences cellular function and organismal fitness.

genetics↗

bioRxiv2025

How much is Transcription-associated Mutagenesis Driving tRNA Microevolution?

Transfer RNAs (tRNAs) are among the most highly conserved and frequently transcribed genes. Recent studies have demonstrated that tRNAs experience exceptionally high rates of transcription-associated mutagenesis (TAM) as well as strong purifying selection. How the mutational input of TAM, which induces a non-uniform distribution of nucleotide substitutions, affects the fitness of tRNA molecules is unclear. Secondary structure in tRNAs is strongly conserved over macro-evolutionary time, suggesting that mutations that disrupt paired sites may be especially deleterious, but TAM-induced mutations primarily involve nucleotide transitions, which tend to preserve base-pairing stability. To examine how TAM affects tRNA molecule fitness and shapes tRNA evolution over short timescales, we analyzed tRNA allelic variation in contemporary Caenorhabditis elegans strains. We propose a model of tRNA microevolution driven by TAM and demonstrate that the observed secondary structure characteristics align with our predicted TAM-biased patterns. Furthermore, we developed a continuous Markov substitution model that incorporates TAM-specific mutational biases. This TAM-biased model fits the C. elegans tRNA data more effectively than standard models, such as the general time-reversible (GTR) model. Based on these results, we conclude that tRNAs in natural populations carry substantial levels of structure-destabilizing mutations, which may be tolerated but nevertheless likely induce meaningful fitness costs. Our findings are consistent with recent experimental studies on tRNA fitness in yeast but challenge prior theoretical and computational analyses that emphasize RNA base-pairing as a primary determinant in genotype-phenotype systems. 1 Significance StatementTransfer RNAs (tRNAs) are ancient molecules, encoded as genes in all living systems. tRNA genes are known to experience exceptionally high rates of both mutation and purifying selection, but how these opposing evolutionary forces shape tRNA evolution is unclear. We developed a sequence substitution model specific to tRNA mutagenesis and applied it to standing variation in a natural population in order to infer how mutation and selection affect the structural stability of tRNA molecules.

evolutionary biology↗

bioRxiv2019

Neanderthal introgression reintroduced functional alleles lost in the human out of Africa bottleneck

Neanderthal ancestry remains across modern Eurasian genomes, and introgressed sequences influence diverse phenotypes, including immune, skin, and neuropsychiatric diseases. Interpretation of introgressed sequences has focused on alleles derived in the Neanderthal lineage. Here, we demonstrate that Neanderthal introgression also reintroduced thousands of ancestral hominin alleles lost in the Eurasian out of Africa bottleneck. Combining evolutionary simulations, expression quantitative trait loci (eQTL), massively parallel reporter assay (MPRA) data, and in vitro validation, we show that reintroduced alleles (RAs) have different fitness effects than Neanderthal-derived alleles (NDAs) and that some RAs regulate gene expression independent of NDAs. Illustrating the broad potential influence of RAs, we find that over 70% of known phenotype associations with NDAs are equally associated with RAs. Finally, we discover enrichment for RA eQTL activity in several tissues, with strongest enrichment in the brain. In summary, our study reveals that Neanderthal introgression supplied Eurasians with many lost functional variants and demonstrates that RAs must be considered when evaluating the effects of introgression. ONE SENTENCE SUMMARYNeanderthal interbreeding with modern humans restored to Eurasians, hundreds of thousands of ancient alleles that were lost in the out of Africa bottleneck.

evolutionary biology↗

bioRxiv2017

Polygenic selection underlies evolution of human brain structure and behavioral traits

Seemingly paradoxical characteristics of psychiatric disorders, including moderate to high prevalence, reduced fecundity, and high heritability have motivated explanations for the persistence of common risk alleles for severe psychiatric phenotypes throughout human evolution. Proposed mechanisms include balancing selection, drift, and weak polygenic adaptation acting either directly, or indirectly through selection on correlated traits. While many mechanisms have been proposed, few have been empirically tested. Leveraging publicly available data of unprecedented sample size, we studied twenty-five traits (i.e., ten neuropsychiatric disorders, three personality traits, total intracranial volume, seven subcortical brain structure volume traits, and four complex traits without neuropsychiatric associations) for evidence of several different signatures of selection over a range of evolutionary time scales. Consistent with the largely polygenic architecture of neuropsychiatric traits, we found no enrichment of trait-associated single-nucleotide polymorphisms (SNPs) in regions of the genome that underwent classical selective sweeps (i.e., events which would have driven selected alleles to near fixation). However, we discovered that SNPs associated with some, but not all, behaviors and brain structure volumes are enriched in genomic regions under selection since divergence from Neanderthals ~600,000 years ago, and show further evidence for signatures of ancient and recent polygenic adaptation. Individual subcortical brain structure volumes demonstrate genome-wide evidence in support of a mosaic theory of brain evolution while total intracranial volume and height appear to share evolutionary constraints consistent with concerted evolution. We further characterized the biological processes potentially targeted by selection, through expression Quantitative Trait Locus (eQTL) and Gene Ontology (GO) enrichment analyses and found evidence for the role of regulatory functions among selected SNPs in immune and brain tissues. Taken together, our results suggest that alleles associated with neuropsychiatric, behavioral, and brain volume phenotypes have experienced both ancient and recent polygenic adaptation in human evolution, acting through neurodevelopmental and immune-mediated pathways.

evolutionary biology↗