Molecular Biology And Evolution[JOURNAL]
Sun
200 papers
Insights into human history and complex traits from the genomes of African populations.
Bitsue HK, Tang C, Yang Z
Mol Biol Evol · 2026 Jan · PMID 41432001 · Full text
Ancient and modern genomic data provide insights into continuous human migrations and subsequent admixture and gene flow throughout human history. These demographic events and natural selection contribute to the genetic...
Ancient and modern genomic data provide insights into continuous human migrations and subsequent admixture and gene flow throughout human history. These demographic events and natural selection contribute to the genetic and phenotypic variation that gives the African population its unique characteristics. This genomic data have provided scientists with insights into complex migratory events, patterns of admixture and the spatial distribution of ancestral lineages. For example, the return migration from western Eurasia to Africa introduced pastoralism, and the remarkable expansion of Bantu-speaking groups brought agricultural practices to a wider area of eastern and southern Africa. In addition, the continent's vast and diverse environmental conditions as well as complex human history and higher-level genetic diversity contribute to varying degrees of susceptibility and resistance to complex diseases. With all these complex demographic histories of African populations and a multi-ethnic genomic diversity, it remains essential to deepen our understanding of the genetic basis of complex traits and diseases. This review provides an overview of insights into population admixture and complex disease states based on data from ancient and modern genomes. These include the major waves of population movement and patterns of admixture that influence the diverse, complex traits observed among populations within the African continent. Overall, this review will provide a deep insight into prehistoric demographic events and the genomic profiles of modern Africans and highlights the importance of integrated international cooperation to strengthen African genomics research.
Cost of Altered Translation Accuracy Shapes Adaptation to Antibiotics in E. coli.
Samhita L, Tamhankar S, Miranda J … +2 more , Basu A, Agashe D
Mol Biol Evol · 2025 Nov · PMID 41406172 · Full text
Protein synthesis, while central to cellular function, is error-prone. The resulting mistranslation is generally costly, but we do not know how these costs compare or interact with the costs imposed by external selection...
Protein synthesis, while central to cellular function, is error-prone. The resulting mistranslation is generally costly, but we do not know how these costs compare or interact with the costs imposed by external selection pressures such as antibiotics. We also do not know whether and how these costs are compensated during evolution. It is important to answer these questions, since mistranslation is ubiquitous and antibiotic exposure is widespread. We quantified the growth cost of genetically increasing and decreasing mistranslation rates and exposure to low antibiotic concentrations in Escherichia coli. Mistranslation costs were generally lower than the cost imposed by antibiotics and exacerbated in a strain-specific manner under antibiotic exposure. All strains quickly compensated for the antibiotic cost during experimental evolution, via antibiotic- and genotype- specific mutations. In contrast, mistranslation costs were significantly reduced only in some cases, without clear causal mutations. Control populations that evolved without antibiotics consistently compensated for the cost of accuracy and evolved increased antibiotic resistance as a by-product. Our work demonstrates that even when the cost of mistranslation is weak, altered translation accuracy can shape adaptive outcomes and underlying genetic mechanisms, with strong collateral fitness effects for apparently unrelated phenotypes such as antibiotic resistance.
Evolution of the Tri-PDZ Domain in PSD95 (DLG-4 Gene).
Nilkant R, Mesrop LY, Lobo S … +5 more , Sakarya O, Shea JE, Shell S, Yi SV, Kosik KS
Mol Biol Evol · 2025 Nov · PMID 41404844 · Full text
Some genes encoding proteins within the co-evolved pre- and postsynaptic compartments are present in genomes long preceding the origination of the synapse within the animal kingdom. DLG4, gene encoding PSD-95, is one of...
Some genes encoding proteins within the co-evolved pre- and postsynaptic compartments are present in genomes long preceding the origination of the synapse within the animal kingdom. DLG4, gene encoding PSD-95, is one of the most abundant synaptic proteins. It is a MAGUK family member that shares a conserved domain structure comprised of one or multiple PDZ domains, a Src homology 3 (SH3), and a guanylate kinase (GK) domain. Here, we construct the phylogeny of the tri-PDZ domains in DLG4 to its deep ancestral origin in Filozoa, which includes animals and their nearest unicellular relatives. PDZ domain architecture appears to be a strong organizing feature of this gene lineage that originated with a single ancestral PDZ3-like domain in Capsaspora owczarzaki from which PDZ1 and PDZ2 were derived. The strong conservation of individual PDZ domain identities was captured by Evolutionary Scale Modeling (ESM2) across the boundary to the animal kingdom, corroborating distinct clades formed by the divergence of PDZ1, PDZ2, and PDZ3 in the phylogeny. CRIPT, PDZ3 ligand, is present in all Filozoa genomes studied here. AlphaFold2 Multimer demonstrates conserved binding function; however, conserved binding does not completely depend on either sequence motifs or hydrophobicity profiles. Rather, the most conserved feature is hydrogen bonds at the 0 and -2 positions of the ligand as an ancient foundational innovation for PDZ3 ligand interaction. Hydrogen bonds may loosen the sequence requirements for binding to allow a more extensive search space for protein-protein interactions that enhance fitness before the mutations that secure those interactions occur.
The loss of a supergene in obligately polygynous Formica wood ant species.
Sigeman H, Satokangas I, de Lamarre M … +7 more , Krapf P, Nouhaud P, Deshmukh R, Helanterä H, Chapuisat M, Kulmuni J, Viljakainen L
Mol Biol Evol · 2025 Nov · PMID 41401204 · Full text
Some of the most striking examples of phenotypic variation within species are controlled by supergenes. However, most research on supergenes has focused on their emergence and long-term maintenance, leaving the later sta...
Some of the most striking examples of phenotypic variation within species are controlled by supergenes. However, most research on supergenes has focused on their emergence and long-term maintenance, leaving the later stages of their life cycle largely unexplored. Specifically, what happens to a derived supergene haplotype when the trait it controls reaches fixation? Here we answer this question using the ancient supergene system of Formica ants, where (monogynous) single-queen colonies typically carry only the ancestral haplotype M while the derived haplotype P is exclusive to (polygynous) colonies with multiple queens. Through comparative population genomics of 264 individuals from all seven European wood ant species, we found that the P haplotype was present in only 1/3 obligately polygynous species (Formica polyctena). In the two others (Formica aquilonia and Formica paralugubris), the P haplotype was completely missing except for duplicated P-specific paralogs of two genes, Zasp52 and TTLL2, with Zasp52 being directly involved in wing muscle development. We hypothesize that these genes play a direct role in polygyny and contribute to differences in body size and/or dispersal behavior between monogynous and polygynous queens. A complete lack of P/P genotypes among the 261 workers suggests strong selection against such genotypes. While our analyses did not reveal evidence of increased mutation load on the P, it is possible that this skew in genotype distributions is driven by a few loci with strong fitness effects. We propose that selection to escape P-associated fitness costs underlies the loss of this haplotype in obligately polygynous wood ants.
Macroevolutionary changes in gene expression response to an immune stimulus across the diversity of fishes.
Flanagan BA, Fuess LE, Vrtílek M … +2 more , Roth-Monzón AJ, Bolnick DI
Mol Biol Evol · 2026 Jan · PMID 41392554 · Full text
Our understanding of the vertebrate immune system is dominated by a few model organisms such as mice. This use of a few model systems is reasonable if major features of the immune systems evolve slowly and are conserved...
Our understanding of the vertebrate immune system is dominated by a few model organisms such as mice. This use of a few model systems is reasonable if major features of the immune systems evolve slowly and are conserved across most vertebrates, but may be problematic if there is substantial macroevolutionary change in immune responses. Here, we present a test of the macroevolutionary stability, across 14 species of ray-finned fishes, of the transcriptomic response to a standardized immune challenge. Intraperitoneal injection of an immune adjuvant (alum) induces a fibrosis response in nearly all jawed fishes, which in some species contributes to anti-helminth protection. Despite this conserved phenotypic response, the underlying transcriptomic response is highly inconsistent across species. Although many gene orthogroups exhibit differential expression between saline versus alum-injected fish in at least one species, few orthogroups exhibit consistent differential expression across species. This result suggests that although the phenotypic response to alum (fibrosis) is highly conserved, the underlying gene regulatory architecture is very flexible and cannot readily be extrapolated from any one species to fishes (or vertebrates) more broadly. The vertebrate immune response is remarkably changeable over macroevolutionary time, requiring a diversity of model organisms to describe effectively.
Coexisting With Humans: Genomic and Behavioral Consequences in a Small and Isolated Bear Population.
Fabbri G, Biello R, Gabrielli M … +18 more , Torres Vilaça S, Sammarco B, Fuselli S, Santos P, Ancona L, Peretto L, Padovani G, Sollitto M, Iannucci A, Paule L, Balestra D, Gerdol M, Ciofi C, Ciucci P, Mahan CG, Trucchi E, Benazzo A, Bertorelle G
Mol Biol Evol · 2025 Nov · PMID 41392451 · Full text
Climate and land use change have increased human-wildlife interactions, potentially reducing wild species density and prompting behavioral adaptations to urbanized environments. It is still debated if behavioral response...
Climate and land use change have increased human-wildlife interactions, potentially reducing wild species density and prompting behavioral adaptations to urbanized environments. It is still debated if behavioral responses are mainly the result of phenotypic plasticity or if they were driven by anthropic selective pressures, especially in small populations where genetic drift is strong. Our study focused on the small Apennine brown bear population (Ursus arctos marsicanus), which has coexisted with humans in Central Italy for millennia. We characterized genomic diversity and identified adaptation signals distinctive to this population by comparing newly generated and published whole-genome resequencing data from Apennine, Central European, and North American brown bears. Apennine brown bears exhibited reduced genomic diversity, higher inbreeding, and larger realized genetic load compared to other brown bears. We showed that Apennine brown bears possess a unique genomic diversity pattern including selective signatures at genes associated with reduced aggressiveness (eg DCC, SLC13A5). Within these genes, most of the newly discovered variants were located in noncoding regions and some of them were predicted to alter splicing factor binding sites, highlighting the contribution of noncoding variation in shaping complex phenotypes. Our results support the hypothesis that human-induced selection has promoted behavioral changes even in small- and long-isolated populations, reducing conflicts and contributing to the long-term persistence of a large mammal species and its coexistence with humans.
On the robustness of Bayesian inference of gene flow to intragenic recombination and natural selection.
Thawornwattana Y, Rannala B, Yang Z
Mol Biol Evol · 2026 Jan · PMID 41388647 · Full text
The multispecies coalescent (MSC) model provides a framework for detecting gene flow using genomic data, including between sister species. However, the robustness of the inference to violations of model assumptions are p...
The multispecies coalescent (MSC) model provides a framework for detecting gene flow using genomic data, including between sister species. However, the robustness of the inference to violations of model assumptions are poorly understood. Here, we use simulation to study the false positive rate of a Bayesian test of gene flow under the MSC with multiple influencing factors including recombination, natural selection, discrete versus continuous gene flow, variable species divergence time, and gene flow involving sister versus nonsister lineages. We find that in almost all scenarios examined the test has very low false positives. However, the test of gene flow between sister lineages may be prone to high false positives in cases of very recent species divergence and very high recombination rate. At low recombination rates, the test is robust to selective sweeps, background selection and balancing selection, although prolonged balancing selection can lead to false signals of gene flow between sister lineages. The impact of excessive recombination on the test of gene flow between sisters may be assessed by using a smaller number of sequences for each species and by considering shorter sequences at each locus. Recent species divergence alone (with no recombination) does not cause false positives in tests of gene flow, contrary to previous claims. The test of gene flow between nonsister lineages is robust to recombination at all divergence levels. Our findings provide guidance for reliable inference of gene flow using coalescent methods and highlight the need for care in conducting and interpreting simulation experiments.
The green lacewing venom system and the complex mechanisms underlying its evolution.
Maurstad MF, Ramiro IBL, Oeyen JP … +5 more , Sombke A, Büsse S, Nachtigall PG, Jakobsen KS, Undheim EAB
Mol Biol Evol · 2026 Jan · PMID 41381409 · Full text
Venom has independently evolved across many lineages, yet relatively few have been studied in detail, particularly among insects. Of these, Neuroptera (lacewings, antlions, and relatives) remain largely unexplored, despi...
Venom has independently evolved across many lineages, yet relatively few have been studied in detail, particularly among insects. Of these, Neuroptera (lacewings, antlions, and relatives) remain largely unexplored, despite being widespread with agriculturally important groups such as green lacewings. While adults are nonvenomous, neuropteran larvae are ferocious predators that use pincer-like mouthparts to inject paralyzing and liquefying venom to subdue and consume their prey. Here, we provide a comprehensive investigation of the venom system in Neuroptera by integrating a high-quality genome, long-read transcriptomes spanning all life stages, microCT-reconstruction of venom glands, tissue-specific expression analyses, venom proteomics, and functional assays of the common green lacewing Chrysoperla carnea. We provide a re-description of the neuropteran venom system, demonstrate the venom's insecticidal and cytotoxic activity, and show that the venom comprises diverse toxin gene families and is richer and more similar to the venom of antlions than previously proposed. We show that this toxin arsenal is the result of a multitude of evolutionary events that include co-option, recruitment following gene duplication, diversification of toxin-paralogs by gene duplication, and functional innovation of new paralogs through both small structural and large architectural changes. In addition, we find that alternative splicing of toxin genes is an important contributor to the biochemical arsenal, which is a mechanism rarely documented among venomous animals. Our results demonstrate how multiple genomic and evolutionary mechanisms together contribute to the emergence and evolution of a complex molecular trait, and provide new insights into the evolution of venom in insects.
Stepwise recombination suppression around the mating-type locus associated with a diploid-like life cycle in Schizothecium fungi.
De Filippo E, Chahine E, Legendre-Despas J … +10 more , Snirc A, Labat A, Michel P, Grognet P, Gautier V, Levert E, Lalanne C, Silar P, Giraud T, Hartmann FE
Mol Biol Evol · 2026 Jan · PMID 41381385 · Full text
Recombination suppression often evolves around sex-determining loci and extends stepwise, resulting in adjacent regions with different levels of divergence between sex chromosomes, called evolutionary strata. In Ascomyco...
Recombination suppression often evolves around sex-determining loci and extends stepwise, resulting in adjacent regions with different levels of divergence between sex chromosomes, called evolutionary strata. In Ascomycota fungi, evolutionary strata around the mating-type (MAT) locus have been reported only in pseudo-homothallic species, which have a diploid-like life cycle with mycelia carrying nuclei of both mating types. In contrast, no recombination suppression has been observed in heterothallic fungi, where colonies contain only a single mating type. Here, we investigated the evolution of recombination suppression in a clade of dung fungi encompassing 16 pseudo-homothallic and three heterothallic sibling species from the Schizothecium genus (Ascomycota, Sordariales). The analysis of genetic divergence based on genome sequencing indicated recombination suppression around the MAT locus in all 13 pseudo-homothallic species examined. The nonrecombining region ranged from 600 kb to 1.6 Mb and harbored multiple evolutionary strata, varying in size and number among species. The clustering of alleles according to mating type in gene genealogies, the high linkage disequilibrium, and an inversion in one species supported the lack of recombination in the MAT-proximal region in pseudo-homothallic species. The overall lack of trans-specific polymorphism suggested multiple independent recombination suppression events or occasional recombination/genic conversion. In heterothallic species, progeny analyses showed that recombination occurs in regions at physical distances from the MAT locus similar to those in which it is lacking in the pseudo-homothallic species. We thus revealed here multiple, likely independent evolutionary strata, associated with an extended diploid-like stage in Schizothecium fungi.
Abundant Recurrent Mitochondrial Mutations and Widespread Mitonuclear Epistasis in Caenorhabditis elegans.
Nguyen THM, Klein DA, Weklar OS … +2 more , Wengrow ER, Rockman MV
Mol Biol Evol · 2025 Nov · PMID 41367310 · Full text
Coordinated genetic and physical interactions between mitochondrial and nuclear gene products regulate ATP production in the mitochondria. Linking mitochondrial genotypes and mitonuclear genetic interactions to phenotype...
Coordinated genetic and physical interactions between mitochondrial and nuclear gene products regulate ATP production in the mitochondria. Linking mitochondrial genotypes and mitonuclear genetic interactions to phenotypes remains a complex challenge. Here, we have developed Caenorhabditis elegans as a model for mitonuclear epistasis studies. In a sample of 540 genetically distinct wild isolates, 10% of sites in the mitochondrial genome vary, with hundreds of missense mutations segregating in the species. Recurrent mutations and triallelic sites are common. Phylogenetic analyses of mitogenome sequences identified 8 distinct lineages, each with diagnostic variants. Principal component analysis of the nuclear genomes showed considerable concordance between mitochondrial and nuclear genomes in C. elegans populations, suggesting that disrupting coevolved mitonuclear genetic combinations could reveal substantial epistasis. We used GPR-1 overexpression, which disrupts the first mitotic division, to efficiently exchange nuclear and mitochondrial genomes between all pairs of 18 naturally isolated C. elegans strains, generating the largest-to-date animal mitonuclear exchange panel, with 323 unique viable mitonuclear genotypes. We phenotyped development of a subset of strains, with 30 unique genotypes, under 6 different environmental conditions, including high temperature and exposure to heavy metals. Mitonuclear epistasis contributed significantly to phenotypic variance across all tested conditions. We also tested for mitonuclear coadaptation by comparing the stress resistance of matched and mismatched cybrids. Interestingly, some mismatched strains exhibited greater resistance, highlighting the complexity and context dependence of mitonuclear interactions.
Widespread turnover of a conserved cis-regulatory code across 589 grass species.
Hale CO, Hsu SK, Zhai J … +15 more , Schulz A, Aubuchon-Elder T, Costa-Neto G, Gelfond A, El-Walid MZ, Hufford M, Kellogg EA, La T, Marand AP, Seetharam AS, Scheben A, Stitzer MC, Wrightsman T, Romay MC, Buckler ES
Mol Biol Evol · 2026 Jan · PMID 41365331 · Full text
The growing availability of genomes from non-model organisms offers new opportunities to identify functional loci underlying trait variation through comparative genomics. While cis-regulatory regions drive much of phenot...
The growing availability of genomes from non-model organisms offers new opportunities to identify functional loci underlying trait variation through comparative genomics. While cis-regulatory regions drive much of phenotypic evolution, linking them to specific functions remains challenging. We identified 514 cis-regulatory motifs enriched in regulatory regions of five diverse grass species, with 73% consistently enriched across all, suggesting a deeply conserved regulatory code. Leveraging 57 new contig-level genome assemblies, we then quantified shared occupancy of specific motif instances within gene-proximal regions across 589 grass species, revealing widespread gain and loss over evolutionary time. Shared occupancy declined rapidly over the first few million years of divergence, yet ∼50% of motif instances were shared back to the origin of grasses ∼100 million years ago. We used phylogenetic mixed models to identify motif gains and losses associated with ecological niche transitions. Our models revealed significant environmental associations across 1282 motif-orthogroup combinations, including convergent gains of HSF/GARP motifs at an alpha-N-acetylglucosaminidase gene associated with occurrence in temperate environments. Our findings support a "stable motifs, variable binding sites" model in which cis-regulatory evolution involves turnover of thousands of individual binding site instances while largely preserving transcription factors' binding preferences. Our results highlight the potential of comparative genomics and phylogenetic mixed models to reveal the genetic basis of complex traits.
Genomic architecture and evolution of heterostyly: new insights from Cordia subcordata (Boraginaceae).
Shi M, Barrett SCH, Zhang Y … +9 more , Zhang J, Zhao Z, Wang X, Yuan S, Luo Z, Gu S, Li S, Tu T, Zhang D
Mol Biol Evol · 2026 Jan · PMID 41364676 · Full text
Heterostyly is a floral polymorphism controlled by an S-locus supergene in several angiosperm families. Most heterostylous species are self-incompatible. Here, we investigate the genomic architecture of distyly in self-c...
Heterostyly is a floral polymorphism controlled by an S-locus supergene in several angiosperm families. Most heterostylous species are self-incompatible. Here, we investigate the genomic architecture of distyly in self-compatible Cordia subcordata in which incompatibility has apparently been lost. We assembled chromosome-level genomes of floral morphs and conducted population genomic analyses to locate the S-locus region. We used transcriptomic analyses of floral organs and functional validation by gene overexpression to identify genes controlling floral dimorphism. The tempo and mode of origin of S-locus genes was also investigated to determine whether gene duplication facilitated supergene assembly. The candidate S-locus in C. subcordata contained 12 genes, eight of which were restricted to the S-morph. CsGA2ox6 deactivates gibberellins and was exclusively expressed in S-morph pistils. Overexpression of CsGA2ox6 in transgenic tobacco produced flowers with shortened styles and an apparently functioning self-incompatibility system. The genomic locations of paralogs and estimations of duplication age suggested that the S-locus genes may have arisen through stepwise duplications, although an origin via segmental duplication could not be excluded. Our study revealed molecular convergence with several other distylous families in hemizygous structure and possibly in the mode of supergene origins. We also identified a molecular pathway for style-length control, likely through gibberellin deactivation by CsGA2ox6, which may have also controlled the expression of self-incompatibility in transgenic plants.
Correction to: UPrimer: A Clade-Specific Primer Design Program Based on Nested-PCR Strategy and Its Applications in Amplicon Capture Phylogenomics.
Mol Biol Evol · 2025 Nov · PMID 41364483 · Full text
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Phylogenetic Analysis of NEAT1 and MALAT1 Long Non-Coding RNAs Highlights Structure-Function Relationships in Paraspeckle Biology.
Arkhipova K, Drukker M
Mol Biol Evol · 2026 Feb · PMID 41363149 · Full text
Paraspeckles are nuclear bodies essential for gene regulation and stress response, and they are built upon the long non-coding RNA NEAT1. Together with the syntenic MALAT1, these are the only lncRNAs that use the tRNA-pr...
Paraspeckles are nuclear bodies essential for gene regulation and stress response, and they are built upon the long non-coding RNA NEAT1. Together with the syntenic MALAT1, these are the only lncRNAs that use the tRNA-processing machinery for maturation, yet they differ in function and evolutionary conservation. To investigate these differences, we identified NEAT1 and MALAT1 orthologs across 545 mammals. For NEAT1, we found that G-quadruplexes, short motifs interacting with DBHS proteins and TDP-43, long gene length, and self-complementary regions are highly conserved features that likely stabilize paraspeckle integrity. Transposable elements also contributed structural modules potentially recognized by DBHS proteins, underscoring their role in NEAT1 evolution. The NEAT1Short isoform was present in all orthologs, and the TDP-43-mediated isoform switch appears to be conserved. In contrast, MALAT1 function likely relies on its conserved primary sequence and regions under purifying selection. This is the first large-scale phylogenetic study of NEAT1-a lncRNA that lacks sequence similarity between orthologs while maintaining functional and syntenic conservation.
Sponges, ctenophores, and the statistical significance of syntenies.
Copley RR
Mol Biol Evol · 2025 Nov · PMID 41355550 · Full text
Shared fusions between ancestral chromosomal linkage groups have previously been used to support phylogenetic groupings, notably sponges with cnidarians and bilaterians to the exclusion of ctenophores, rendering ctenopho...
Shared fusions between ancestral chromosomal linkage groups have previously been used to support phylogenetic groupings, notably sponges with cnidarians and bilaterians to the exclusion of ctenophores, rendering ctenophores the sister group to all other animals. The linkage groups used to identify these fusions were assessed for statistical significance relative to a model of randomly shuffled genes. I argue that the method of random shuffling treated all species as equally distant from each other and so overestimated the significance of the observed linkages. I calculate alternative statistics and further argue that there are likely to be real linkage groups that are not identified as significant. If linkage groups are not supported statistically, they cannot reliably be used to identify shared derived chromosomal rearrangements, and hence phylogenetic hypotheses derived from them are suspect.
Evolution of Insulin, Insulin-like Growth Factors, and Their Cognate Receptors in Vertebrates, Invertebrates, and Viruses.
Chrudinová M, DaCosta JM, Dogru D … +4 more , Huang R, Reiners R, De Meyts P, Altindis E
Mol Biol Evol · 2026 Jan · PMID 41355291 · Full text
The insulin and insulin-like growth factor (IGF) system regulates essential biological functions such as growth, metabolism, and development. While its physiological roles are well characterized, the evolutionary origins...
The insulin and insulin-like growth factor (IGF) system regulates essential biological functions such as growth, metabolism, and development. While its physiological roles are well characterized, the evolutionary origins and molecular diversification of its ligands and receptors remain incompletely defined. Here, we present the most comprehensive phylogenetic and sequence conservation analysis of this system to date, using over 1,000 sequences from vertebrates, invertebrates, and viruses. Our analyses reveal that insulin, IGF-1, and IGF-2 form distinct monophyletic clades that diverged after the emergence of vertebrates, with IGF-1 being the most conserved ligand. We show that IGF1R-binding residues, especially in the A- and B-domains of IGF-1, are highly conserved across vertebrates, while insulin's Site 2 residues, which overlap with its dimerization and hexamerization surface, are more variable-correlating with the loss of hexamer formation in hystricomorphs, reptiles, and jawless fish. Unexpectedly, we identify a 12-amino acid insert in the insulin receptor (IR) of turtles and tortoises, previously thought to be unique to mammalian IR-B isoform, challenging the view that receptor isoform diversity is a mammalian innovation. We also show that marsupials and monotremes retain ancestral receptor domain features shared with reptiles and birds and that avian insulins, particularly A-chain residues, are unusually conserved. Viral insulin/IGF-like peptides fall into two distinct clades that resemble either IGFs or insulin. Together, these findings illuminate the evolutionary architecture of the insulin/IGF system, highlight unexpected lineage-specific adaptations, and provide a framework for understanding hormone-receptor function across biology and therapeutic design.
Comparing great apes reveals human-specific ZEB2 roles in neural development.
Lee JE, Jovanovic VM, Jager Fonseca A … +4 more , Streblow S, Ettig K, Berto S, Nowick K
Mol Biol Evol · 2025 Nov · PMID 41340546 · Full text
Humans differ from other primates in various traits, despite nearly identical protein-coding sequences. Understanding the evolution of these differences requires studying transcriptional regulation. Here, we examine ZEB2...
Humans differ from other primates in various traits, despite nearly identical protein-coding sequences. Understanding the evolution of these differences requires studying transcriptional regulation. Here, we examine ZEB2, a transcription factor crucial for immune and neural development, to explore its regulatory divergence across great apes. Using B-lymphoblastoid cells, chosen as experimental model system due to the availability of biological replicates for three great ape species, we show that, in addition to conserved ZEB2 targets, human ZEB2 is distinct in regulating a larger repertoire of genes implicated in neuronal development. ZEB2 knock-down in human, chimpanzee, and orangutan B-lymphoblastoid cells followed by transcriptome profiling uncovered human-specific regulatory differences, especially in nervous system-related genes. Additional analysis using single-cell RNA-Seq and brain organoid data identified cell-type-specific differences in ZEB2 expression and regulated genes between humans and other apes, most pronounced in ventral progenitors and neurons. Moreover, human-specific ZEB2 targets are enriched in non-coding genes, suggesting an expanded and possibly rewired regulatory network. Our study demonstrates that species differences in ZEB2 regulation can be detected in a controlled cell system and validated in neural contexts. More broadly, we provide new insights into the functional divergence of TFs across closely related species and how regulatory shifts can contribute to phenotypic evolution.
Life Cycle Simplifications in Aphids Drive Changes in Evolutionary Rates and Selection Regimes.
Vericel T, Gong G, Legeai F … +3 more , Etier A, Jaquiéry J, Simon JC
Mol Biol Evol · 2025 Nov · PMID 41325137 · Full text
Transitions toward simplified life cycles can reshape evolutionary trajectories, yet their impact on the rate of molecular evolution remains poorly understood. In aphids, host alternation (heteroecy) entails obligate sea...
Transitions toward simplified life cycles can reshape evolutionary trajectories, yet their impact on the rate of molecular evolution remains poorly understood. In aphids, host alternation (heteroecy) entails obligate seasonal migration between highly distinct plant hosts-typically woody and herbaceous species-and has been repeatedly lost, giving rise to monoecious species with simplified life cycles. Using comparative genomics across 46 aphid species, we tested whether transitions from heteroecy to monoecy alter evolutionary dynamics at the gene level. We identified 9,304 orthologs and estimated evolutionary rates (dN/dS) and shifts in selection regimes in the diverse Aphidinae subfamily. We found that 715 orthologs evolved faster in monoecious species, primarily due to relaxed selection, while heteroecious species showed signatures of intensified selection. Genes under relaxed selection in monoecious species were enriched for functions related to environmental sensing, signaling, nutritional adjustments, morph determination, and migration related-traits likely central for host alternation. These results suggest that the loss of a complex life cycle leads to reduced selective constraints as a consequence of ecological simplification. This study provides a robust evolutionary framework for understanding how life cycle transitions shape molecular evolution and drive gene decay following trait loss.
Unraveling the Prevalence and Multifaceted Roles of Accessory Peptide Deformylases in Bacterial Adaptation and Resistance.
Lambérioux M, Ducos-Galand M, Kaminski PA … +5 more , Littner E, Betton JM, Mechaly A, Haouz A, Mazel D
Mol Biol Evol · 2025 Nov · PMID 41316864 · Full text
Peptide deformylases (PDFs) are enzymes that are essential for bacterial viability and attractive targets for antibiotic development. Yet, despite their conserved function, many bacteria encode multiple PDFs, a genomic f...
Peptide deformylases (PDFs) are enzymes that are essential for bacterial viability and attractive targets for antibiotic development. Yet, despite their conserved function, many bacteria encode multiple PDFs, a genomic feature whose prevalence and implications remain largely unexplored. Here, we reveal that nearly half of all bacterial genomes carry more than one PDF gene, frequently embedded within mobile genetic elements such as plasmids and integrons. In Vibrio cholerae, the accessory PDF (Def2VCH) confers reduced susceptibility to actinonin (ACT), the most studied PDF inhibitor, while still supporting bacterial growth in the absence of the canonical PDF copies (Def1VCH). Crystallographic analysis shows that this reduced susceptibility stems from an arginine-to-tyrosine substitution that probably reduces ACT binding. Strikingly, this resistance signature is shared by integron-encoded PDFs, and transfer of an integron-encoded PDF cassette from Pseudoxanthomonas into a susceptible V. cholerae is sufficient to abolish ACT susceptibility. These findings reveal a hidden reservoir of resistance within the bacterial mobilome and shed light on potential mechanisms of bacterial resilience to environmental PDF inhibitors.
Structural Mutations Set an Equilibrium Noncoding Genome Fraction.
Luiselli J, Banse P, Mazet O … +2 more , Lartillot N, Beslon G
Mol Biol Evol · 2025 Nov · PMID 41315007 · Full text
The evolution of noncoding genome size remains poorly understood. While part of noncoding DNA arguably plays a regulatory role, a significant portion does not appear to have a detectable phenotypic effect. The abundance...
The evolution of noncoding genome size remains poorly understood. While part of noncoding DNA arguably plays a regulatory role, a significant portion does not appear to have a detectable phenotypic effect. The abundance of nonfunctional DNA in genomes, observed across the Tree of Life, challenges purely adaptationist explanations. Several nonadaptive theories have been proposed to explain its presence and identify its determinants, emphasizing either the mutational processes or the mutational hazard entailed by noncoding and nonfunctional DNA. However, those theories have not yet been integrated into a common framework, and the exact nature of the mutational hazard is not yet fully understood. In this work, we introduce a simple mathematical model of genome size evolution. Our model shows that the noncoding fraction of the genome is shaped by two fundamental forces: (i) inherent biases in mutational neutrality-adding base pairs being more likely to be neutral than removing some and (ii) robustness selection arising from the mere existence of structural mutations-larger genomes being more prone to double-strand breaks that generate such mutations, thereby imposing a second-order selection on robustness. Together, these forces establish an equilibrium noncoding fraction that depends solely on mutation biases and the product of population size and mutation rate.
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