Biology subjects

Sayadi, A.

Publications and source records attributed to Sayadi, A..

6 recordsLinked to original sources

bioRxiv2026

Experimental evolution unveils a role for structural variants and sex-specificity in the genetic architecture of lifespan

Insights into the genetic basis of lifespan evolution can link evolutionary theory with an understanding of health, disease and adaptation. We leverage the power of >200 generations of experimental evolution in a seed beetle to unveil the genomic architecture of lifespan evolution. Replicated populations evolved under regimes favoring either a short or long life, resulting in a near doubling of lifespan. Whole genome re-sequencing revealed that short- and long-lived lines were strongly differentiated (global FST = 0.41) and more than 700 genes showed consistent signs of divergent selection. Remarkably, short- and long-lived lines were consistently divergent in a large number of regions harboring copy-number variants (CNVs), involving >600 genes. The evolution of a long life involved many distinct biological processes, such as DNA fidelity, mitotic integrity, reproduction, metabolism, immunity and stress response. A pedigree-based genome scan for quantitative trait loci (QTLs) uncovered several QTLs with large effects on lifespan, but the genetic basis of a long life was dominated by a very large number of regions with medium and small effects. The genome-wide spatial association with QTL effects was, if anything, stronger for CNVs than for sequence variants. The genetic effects of QTLs on lifespan were positively correlated overall between the sexes, but four regions showed pronounced sex-differences. Our results show that structural variants play a significant role in the evolution of an extended lifespan and the highly polygenic genomic architecture is to some extent sex-specific, consistent with differences in physiology and life history tradeoffs between the sexes.

evolutionary biology↗

bioRxiv2022

A possible genomic footprint of polygenic adaptation on population divergence in seed beetles?

Efforts to unravel the genomic basis of incipient speciation are hampered by a mismatch between our toolkit and our understanding of the ecology and genetics of adaptation. While the former is focused on detecting selective sweeps involving few independently acting or linked speciation genes, the latter states that divergence typically occurs in polygenic traits under stabilizing selection. Here, we ask whether a role of stabilizing selection on polygenic traits in population divergence may be unveiled by using a phenotypically informed integrative approach, based on genome-wide variation segregating in divergent populations. We compare three divergent populations of seed beetles (Callosobruchus maculatus) where previous work has demonstrated a prominent role for stabilizing selection on, and population divergence in, key life history traits that reflect rate-dependent metabolic processes. We derive and assess predictions regarding the expected pattern of covariation between genetic variation segregating within populations and genetic differentiation between populations. Population differentiation was considerable (mean FST = 0.23 - 0.26) and was primarily built by genes showing high selective constraints and an imbalance in inferred selection in different populations (positive Tajimas DNS in one and negative in one) and this set of genes was enriched with genes with a metabolic function. Repeatability of relative population differentiation was low at the level of individual genes but higher at the level of broad functional classes, again spotlighting metabolic genes. Absolute differentiation (dXY) showed a very different general pattern at this scale of divergence, more consistent with an important role for genetic drift. Although our exploration is consistent with stabilizing selection on polygenic metabolic phenotypes as an important engine of genome-wide relative population divergence and incipient speciation in our study system, we note that it is exceedingly difficult to firmly exclude other scenarios.

evolutionary biology↗

bioRxiv2022

Large-scale phage-based screening reveals extensive pan-viral mimicry of host short linear motifs

Viruses mimic host short linear motifs (SLiMs) to hijack and deregulate cellular functions. Studies of motif-mediated interactions therefore provide insight into virus-host dependencies, and reveal targets for therapeutic intervention. Here, we describe the pan-viral discovery of 1,712 SLiM-based virus-host interactions using a phage peptidome tiling the intrinsically disordered protein regions of 229 RNA viruses. We find mimicry of host SLiMs to be a ubiquitous viral strategy, reveal novel host proteins hijacked by viruses, and identify cellular pathways frequently deregulated by viral motif mimicry. Using structural and biophysical analyses, we show that viral mimicry-based interactions have similar binding strength and bound conformations as endogenous interactions. Finally, we establish polyadenylate-binding protein 1 as a potential target for broad-spectrum antiviral agent development. Our platform enables rapid discovery of mechanisms of viral interference and the identification of potential therapeutic targets which can aid in combating future epidemics and pandemics.

biochemistry↗

bioRxiv2021

Large scale discovery of coronavirus-host factor protein interaction motifs reveals SARS-CoV-2 specific mechanisms and vulnerabilities

Viral proteins make extensive use of short peptide interaction motifs to hijack cellular host factors. However, current methods do not identify this important class of protein-protein interactions. Uncovering peptide mediated interactions provides both a molecular understanding of viral interactions with their host and the foundation for developing novel antiviral reagents. Here we describe a scalable viral peptide discovery approach covering 229 RNA viruses that provides high resolution information on direct virus-host interactions. We identify 269 peptide-based interactions for 18 coronaviruses including a specific interaction between the human G3BP1/2 proteins and an {Phi}xFG peptide motif in the SARS-CoV-2 nucleocapsid (N) protein. This interaction supports viral replication and through its {Phi}xFG motif N rewires the G3BP1/2 interactome to disrupt stress granules. A peptide-based inhibitor disrupting the G3BP1/2-N interaction blocks SARS-CoV-2 infection showing that our results can be directly translated into novel specific antiviral reagents.

biochemistry↗

bioRxiv2021

Proteome-scale amino-acid resolution footprinting of protein-binding sites in the intrinsically disordered regions of the human proteome

Specific protein-protein interactions are central to all processes that underlie cell physiology. Numerous studies using a wide range of experimental approaches have identified tens of thousands of human protein-protein interactions. However, many interactions remain to be discovered, and low affinity, conditional and cell type-specific interactions are likely to be disproportionately under-represented. Moreover, for most known protein-protein interactions the binding regions remain uncharacterized. We previously developed proteomic peptide phage display (ProP-PD), a method for simultaneous proteome-scale identification of short linear motif (SLiM)-mediated interactions and footprinting of the binding region with amino acid resolution. Here, we describe the second-generation human disorderome (HD2), an optimized ProP-PD library that tiles all disordered regions of the human proteome and allows the screening of ~1,000,000 overlapping peptides in a single binding assay. We define guidelines for how to process, filter and rank the results and provide PepTools, a toolkit for annotation and analysis of identified hits. We uncovered 2,161 interaction pairs for 35 known SLiM-binding domains and confirmed a subset of 38 interactions by biophysical or cell-based assays. Finally, we show how the amino acid resolution binding site information can be used to pinpoint functionally important disease mutations and phosphorylation events in intrinsically disordered regions of the human proteome. The HD2 ProP-PD library paired with PepTools represents a powerful pipeline for unbiased proteome-wide discovery of SLiM-based interactions.

biochemistry↗

bioRxiv2020

Sexual conflict drives micro- and macroevolution of sexual dimorphism in immunity

BackgroundSexual selection can have major effects on mating rates and sex-specific costs of mating and may thereby influence sex-differences in immunity as well as associated host-pathogen dynamics. Yet, experimental evidence linking the mating system to evolved sexual dimorphism in immunity are scarce and the direct effects of mating rate on immunity are not well established. Here, we use transcriptomic analyses, experimental evolution and phylogenetic comparative methods to study the association between the mating system and sexual dimorphism in immunity in seed beetles, where mating causes internal injuries in females. ResultsWe demonstrate that female phenoloxidase (PO) activity, involved in wound healing and defence against parasitic infections, is elevated relative to males. This difference is accompanied by concomitant sex-differences in the expression of genes in the pro-phenoloxidase activating cascade. We document substantial phenotypic plasticity in female PO activity in response to mating and show that experimental evolution under enforced monogamy (resulting in low remating rates and sexual conflict relative to natural polygamy) rapidly decreases female (but not male) PO activity. Moreover, monogamous females have evolved increased tolerance to bacterial infection unrelated to mating, implying that female responses to costly mating may trade off with other aspects of immune defence, an hypothesis which broadly accords with the documented sex differences in gene expression. Finally, female (but not male) PO activity shows correlated evolution with the perceived harmfulness of male genitalia across 12 species of seed beetles, suggesting that sexual conflict has a significant influence on sexual dimorphisms in immunity in this group of insects. ConclusionsOur study provides insights into the links between sexual conflict and sexual dimorphism in immunity at the molecular and phenotypic level and suggests that selection pressures moulded by mating interactions can lead to a sex-specific mosaic of immune responses with important implications for host-pathogen dynamics in sexually reproducing organisms.

evolutionary biology↗