Biology subjects

Raynes, Y.

Publications and source records attributed to Raynes, Y..

9 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↗

bioRxiv2025

The Population Genetics of Biological Noise

Information transmission is intrinsic to life, and noise is intrinsic to information transmission. Biological noise during development is essential for the flexibility and plasticity of individual organisms, but also underlies some diseases. Biological noise during reproduction is the fuel for evolution, including the evolution of therapy resistance in pathogenic microbes and in cancer. Recent technological advances in our ability to characterize many sources of biological noise have demonstrated that its amount is often heritable. Here, we frame the population genetics of loci that influence the amount of any source of biological noise. While analogous theory for heritable changes in mean trait values has been established for nearly a century, to our knowledge this is the first general approach for studying the evolution of heritable changes in their statistical distributions. This represents a critical theoretical contribution to an important and rapidly growing domain of intellectual inquiry. It also sheds light on the hypothesis that natural selection can increase evolvability, and generalizes modifier theory used in the tradition of Feldman and colleagues. Author summaryBiological noise is a fact of life. Genetically identical organisms reared in identical environments invariably exhibit random phenotypic differences. And siblings born of the same parent(s) in the same environment are endowed with inheritances that invariably differ at random. While the specific consequences of biological noise are unpredictable, extraordinary experimental advances now make clear that its amount can be influenced by an organisms genetics. For example, high- and low-noise promoter, and high- and low-noise DNA polymerase alleles are well known. This raises the question of when and how natural selection favors high- or low-noise alleles. While biological noise is on average deleterious, it can also occasionally induce high fitness phenotypes. Here, we solve a simple analytic model for the fitness difference between noise alleles that captures both these features. Our model predicts the existence of an evolutionary equilibrium in the amount of noise, whose location reflects just four features of an organisms biology. In light the clinical importance of biological noise, as well as its central role more broadly in both development and evolution, this work provides an urgently needed evolutionary framework for understanding its long-term determinants.

evolutionary biology↗

bioRxiv2023

Beyond the (geometric) mean: stochastic models undermine deterministic predictions of bet hedger evolution

Bet hedging is a ubiquitous strategy for risk reduction in the face of unpredictable environmental change where a lineage lowers its variance in fitness across environments at the expense of also lowering its arithmetic mean fitness. Classically, the benefit of bet hedging has been quantified using geometric mean fitness (GMF); bet hedging is expected to evolve if and only if it has a higher GMF than the wild-type. We build upon previous research on the effect of incorporating stochasticity in phenotypic distribution, environment, and reproduction to investigate the extent to which these sources of stochasticity will impact the evolution of real-world bet hedging traits. We utilize both individual-based simulations and Markov chain numerics to demonstrate that modeling stochasticity can alter the sign of selection for the bet hedger compared to deterministic predictions. We find that bet hedging can be deleterious at small population sizes and beneficial at larger population sizes. This non-monotonic dependence of the sign of selection on population size, known as sign inversion, exists across parameter space for both conservative and diversified bet hedgers. We apply our model to published data of bet hedging strategies to show that sign inversion exists for biologically relevant parameters in two study systems: Papaver dubium, an annual poppy with variable germination phenology, and Salmonella typhimurium, a pathogenic bacteria that exhibits antibiotic persistence. Taken together, our results suggest that GMF is not enough to predict when bet hedging is adaptive.

evolutionary biology↗

bioRxiv2021

Sign inversion in selection on ploidy

Ploidy - the number of homologous chromosome sets in a cell - is remarkably variable across the natural world, yet the evolutionary processes that have resulted in such diversity remain poorly understood. Here we use stochastic agent-based simulations to model ploidy evolution under the influence of indirect selection, i.e., selection mediated solely by statistical associations with fitness-affecting mutations. We find that in non-equilibrium asexual populations, the sign of selection on ploidy can change with population size - a phenomenon we have previously termed sign inversion. In large populations, ploidy dynamics are dominated by indirect effects of selection on beneficial mutations, which favors haploids over diploids. However, as population size declines, selection for beneficial mutations is neutralized by random genetic drift before drift can overwhelm selection against the cost of the deleterious mutational load. As a result, in small populations indirect selection is dominated by the cost of the deleterious load, which favors diploids over haploids. Our work adds to the growing body of evidence challenging established evolutionary theory that population size can affect only the efficiency, but not the sign, of natural selection.

evolutionary biology↗

bioRxiv2021

When good mutations go bad: how population size can change the direction of natural selection

Classical evolutionary theory holds that the efficiency, but not the direction, of natural selection depends on population size. In small populations, drift overwhelms selection, rendering all fitness-affecting mutations selectively neutral. Yet, beneficial mutations never become deleterious and deleterious mutations never become beneficial. Remarkably, several mutations, including in modifiers of recombination and mutation rate, have now been shown to be favored at some population sizes but disfavored at others, challenging established theory. Previously, we have designated this phenomenon sign inversion. Here we show that, unlike selected mutations in the classical framework, mutations susceptible to sign inversion confer both fitness costs and fitness benefits, that vary among their carriers. Furthermore, all such mutations can be classified based on whether their effects differ between or within mutant lineages. Using computer simulations, we demonstrate that both between-lineage and within-lineage variability can cause sign inversion and elucidate the common underlying mechanism. Our results confirm that variability in the sign of selective effects is necessary for sign inversion, which occurs because drift overwhelms selection on carriers bearing the cost and carriers enjoying the benefit at different population sizes.

evolutionary biology↗

bioRxiv2019

Selection on mutators is not frequency-dependent

The evolutionary fate of mutator mutations - i.e., genetic variants that raise the genome-wide mutation rate - in asexual populations is often described as being frequency (or number) dependent. This common intuition suggests that mutators can invade a population by hitchhiking with a sweeping beneficial mutation, but only when sufficiently frequent to produce such a mutation before non-mutators do. Here, we use stochastic, agent-based simulations to show that neither the strength nor the sign of selection on mutators depend on their initial frequency, and while the overall probability of hitchhiking increases predictably with frequency, the per-capita probability of fixation remains unchanged.

evolutionary biology↗

bioRxiv2017

Sign of selection on mutation rate modifiers depends on population size

The influence of population size (N) on natural selection acting on alleles that affect fitness has been understood for over half a century1. As N declines, genetic drift overwhelms selection and alleles with direct fitness effects are rendered neutral. Often, though, alleles experience so called indirect selection, meaning they affect not the fitness of an individual but the fitness distribution of its offspring. Some of the best studied examples of indirect selection include alleles that modify aspects of the genetic system such as recombination2 and mutation3 rates. Here we use analytics, simulations and experimental populations of S. cerevisiae to show that modifiers that increase the genomic mutation rate (mutators) are favored by indirect selection in large populations but become disfavored as N declines. This surprising phenomenon of sign inversion in selective effect demonstrates that indirect selection on a mutator exhibits a qualitatively novel dependence on N. Sign inversion may help understand the relatively sporadic distribution of mutators in nature despite their frequent emergence in laboratory populations. More generally, sign inversion may be broadly applicable to other instances of indirect selection, suggesting a previously unappreciated but critical role of population size in evolution.

evolutionary biology↗