Biology subjects

Lemieux, F. A.

Publications and source records attributed to Lemieux, F. A..

4 recordsLinked to original sources

bioRxiv2026

Evolutionary Divergence of mTOR-mediated Transcriptional Regulation Between Drosophila melanogaster and Drosophila simulans is Modulated by Sex and Tissue

Evolutionary divergence in gene regulation is a major source of phenotypic novelty, yet understanding how deeply conserved, pleiotropic signaling pathways evolve under selective constraint while maintaining essential cellular functions remains an important challenge. Here, we investigate the evolutionary divergence in transcriptional regulation mediated by the mechanistic target of rapamycin (mTOR) pathway in two related species, Drosophila melanogaster and Drosophila simulans. mTOR is a highly conserved central regulator of cellular growth and metabolism, making it well-suited for the study of regulatory evolution under functional constraint. Using a fully factorial RNA-seq design, we quantified transcriptional responses to mTOR inhibition by rapamycin across three tissues (head, thorax, and abdomen) and both sexes. Despite highly conserved tissue-specific expression - reflecting the close phylogenetic relationship between species - mTOR-mediated transcriptional responses showed clear evidence of evolutionary divergence. Divergence varied across tissues and sexes: heads of both sexes and female thoraces and abdomens showed the most rapid gene-level divergence, suggesting stronger directional selection, whereas male thorax and abdomen exhibited comparatively conserved responses, consistent with stabilizing selection. Gene-level divergence patterns were consistent across multiple metrics and generally mirrored pathway-level divergence, except in the female abdomen, which showed relative pathway-level conservation despite extensive gene-level divergence. Species-by-treatment interaction analyses further revealed divergence in core mTOR-regulated biological processes. Together, our results suggest that regulatory modularity may allow even highly conserved signaling pathways to evolve under context-specific selective pressures while maintaining critical functionality. Significance statementThe evolution of gene regulation is increasingly recognized as a major contributor to biological diversification. However, how highly pleiotropic and deeply conserved pathways evolve new regulatory effects without disrupting essential cellular functions remains an open question in evolutionary biology. Using the nutrient-sensing mTOR pathway as a model, we show that gene regulation mediated by this core, selectively-constrained signaling network has diverged between two closely related fruit fly species in a tissue- and sex-specific manner. Our findings suggest that even pleiotropic pathways like mTOR can diverge over short evolutionary timescales, and that regulatory modularity may facilitate the evolution of novel transcriptional effects in specific contexts while preserving essential functions.

evolutionary biology↗

bioRxiv2025

Absence of Mothers Curse for performance traits among divergent mtDNAs in heterozygous nuclear backgrounds in Drosophila

Maternal inheritance allows selection to act on mtDNA-encoded effects in females but prevents direct selection on mtDNA in males. Mutations that are deleterious in males but neutral or beneficial in females can persist in populations. This predicts that mtDNA-based phenotypic variation should be more common among males than among females, a pattern referred to as Mothers Curse (MC). Most studies of MC place alternative mtDNAs on common homozygous nuclear chromosomal backgrounds, a condition not common in nature. Moreover, it is not known whether MC effects accumulate as mtDNAs acquire nucleotide substitutions between populations or species. We tested the MC hypothesis using mtDNAs from Drosophila melanogaster (OreR, Zimbabwe or w1118), D. simulans (siI and siII) and D. yakuba each placed on several D. melanogaster nuclear backgrounds heterozygous for different chromosomal deficiencies paired with a common w1118 chromosome set. Females and males were tested for starvation resistance, climbing speed, and flight performance. In the majority of chromosomal backgrounds the variance among mtDNA genotypes was greater in females than in males, opposite from the central prediction of Mothers Curse. This suggests that additive and dominance variation across the nuclear genome may provide nuclear blessings that can counter the curse of maternally inherited mtDNA. Teaser textMothers Curse (MC) posits that selection on mtDNA should be stronger in females than in males due to maternal inheritance of mtDNA. This predicts that phenotypic variation among mtDNA genotypes should be lower for females and higher for males. There is conflicting experimental evidence for MC. Most studies of MC have used a common, homozygous nuclear background and have not explored the influence of divergent mtDNAs as strong predictors of MC effects. We address both issues by assaying performance traits among mtDNAs of varying levels of divergence on heterozygous backgrounds. The data fail to support the MC hypothesis and even reveal the opposite effect that females have greater phenotypic variation across mtDNAs. MC may operate in some contexts, but it is not a consistent force in evolutionary genetics.

evolutionary biology↗

bioRxiv2025

Genetic and environmental interactions outweigh mitonuclear coevolution for complex traits in Drosophila

The interdependent relationship between mitochondrial and nuclear genomes is a powerful model for understanding how epistasis shapes the architecture and evolution of complex traits. Once considered a neutral marker, mitochondrial DNA variation is now recognized as critical to phenotypic evolution because of its epistatic interactions and history of coevolution with the nuclear genome. A central challenge in evolutionary genetics is to quantify the relative importance of stabilizing and directional selection shaping complex trait distributions within and among species. Both can act on interacting and/or co-evolving genes contributing to quantitative traits, but resolving their relative roles is complicated by the complex architecture of most traits. Here, we use a panel of 90 Drosophila mitonuclear genotypes to quantify the relative contributions of mitochondrial, nuclear, and environmental variation and their interactions to four metabolically demanding complex traits. We sample both within-species and between-species mitochondrial variation and observe stronger interaction effects attributable to within-species variation, consistent with stabilizing selection maintaining mitonuclear function. Additionally, culturing the flies on a mitochondrial Complex I inhibitor, rotenone, reveals significant genotype x environment (GxE and GxGxE) interaction effects, providing insight into how genetic variation can be maintained across changing environments. Our results have broader implications in medicine, where mitochondrial DNA donors with longer purifying selection histories may be safer for mitochondrial replacement therapies.

evolutionary biology↗

bioRxiv2024

Natural variation in starvation sensitivity maps to a point mutation in phospholipase IPLA2-VIA in Drosophila melanogaster

Resistance to starvation is a classic complex trait where genetic and environmental variables can greatly modify an animals ability to survive without nutrients. Genetic analyses in Drosophila have shown that starvation resistance is highly polygenic with different genetic architectures in different mapping populations. In this study we sought to dissect the genetic basis of starvation resistance among a set of mitonuclear genotypes carrying different mtDNAs paired with specific nuclear genomes from the Drosophila Genetic Reference Panel (DGRP). We focused on differences between one of the most sensitive strains (DGRP-765) and a strain with more moderate resistance (DGRP-315) whose starvation phenotypes appeared to be modified by alternative mtDNAs. Using complementary pooled-sequencing and forward genetic mapping approaches, we identified regions of chromosomes 2L, 3L and 3R contributing to starvation sensitivity and localize a major effect locus modifying starvation resistance to the coding region of phospholipase iPLA2-VIA. These analyses further confirm that the alternative mtDNAs had little influence on variation in starvation resistance between the genotypes studied. The sensitive line shows a starvation-dependent depletion of glucose and glycogen that is modified by hemi- and heterozygosity in the iPLA2-VIA region. These findings contribute to our understanding of the complex genetic relationship between resistance to starvation stress and nutrient metabolism.

genetics↗