Li B, Li H, Shi M
… +47 more, Wang Q, Li H, Guo C, Hu J, Liu B, Tian Y, Liu S, Finch K, Wang S, Yang S, Cui L, Li J, Zhao X, Deng Z, Ma Y, Kim HJ, Wasser SK, Wang K, Lu H, Chen J, Guo H, Yao Y, Xie H, Wang Y, Fan J, Lin Y, Hou Y, Fu Y, Jiang C, Lu J, Li S, Qiu Z, Zhang W, Bai S, Han L, Wang Z, Wang C, Li J, Jiang Y, Liu S, Wang J, Yu L, Li Q, Li L, Hua Y, Lan T, Xu Y
Mol Biol Evol
· 2026 Feb · PMID 41543495
·
Full text
Archipelagos and oceanic islands have remarkably high levels of endemism, which is associated with rapid speciation. The Malayan pangolin (Manis javanica), one of critically endangered Asia pangolin species, occurs in so...Archipelagos and oceanic islands have remarkably high levels of endemism, which is associated with rapid speciation. The Malayan pangolin (Manis javanica), one of critically endangered Asia pangolin species, occurs in southern Yunnan, China, and on oceanic islands via the Malay peninsula. The question of whether the distribution of Malayan pangolins between the mainland and nearby marine islands has led to deep population differentiation is not well addressed. In-depth investigation of population structure and genetic consequences is of vital importance for protection and conservation of Malayan pangolins. Here we carried out a large-scale population genomic analysis for Malayan pangolins, which revealed three highly distinct genetic populations. The largest population was found to be distributed over a wide area extending from mainland China to almost the whole of South East Asia. The other two smaller populations reported in this study were inferred from Borneo. In addition, based on multiple lines of genomic and skull morphological evidences, we confirmed the existence of a fifth Asian pangolin species (M. mysteria). Genetic diversity and genome-wide inbreeding were at moderate levels, indicating that anthropogenic factors did not significantly weaken the basis of genetic sustainability for Malayan pangolins. However, Malayan pangolins from northeastern Borneo exhibited low genetic diversity, high levels of inbreeding and mutational load, thereby necessitating attention to their protection.
Mol Biol Evol
· 2026 Feb · PMID 41530943
·
Full text
Germline de novo mutations (DNMs) are the ultimate source of heritable variation, yet their patterns in highly heterozygous genomes remain poorly understood. Amphioxus, an early-branching chordate with exceptionally high...Germline de novo mutations (DNMs) are the ultimate source of heritable variation, yet their patterns in highly heterozygous genomes remain poorly understood. Amphioxus, an early-branching chordate with exceptionally high genomic heterozygosity (3.2% to 4.2% in sequenced species), offers a unique model to explore mutational dynamics in such contexts. It is unclear whether high heterozygosity in amphioxus is due to a large effective population size, an increased mutation rate, or both. Here, we perform deep short-read whole-genome sequencing of a two-generation pedigree of the amphioxus Branchiostoma floridae comprising two parents and 104 offspring and develop a framework based on allele-aware parental assemblies as the reference to accurately identify DNMs. We detect 242 high-confidence DNMs, yielding a genome-wide mutation rate of 5.89 × 10-9 per base per generation, which is comparable to that of vertebrates. Combining this estimate with observed nucleotide diversity, we obtain an effective population size of ∼1.7 million, indicating that the elevated heterozygosity mainly results from a large effective population size. We observe no sex bias when considering all DNMs but a paternal-origin bias for early-occurring ones. Amphioxus harbors a much smaller fraction of CpG>TpG DNMs relative to vertebrates, attributable to its low methylation levels. We also investigate putative postzygotic mutations in the offspring, revealing an unexpected paternal-origin bias. These suggest some distinct mutational mechanisms in amphioxus. Our study not only provides the first DNM measurement for amphioxus but also offers a generalizable strategy for studying DNMs in highly heterozygous genomes, facilitating mutation rate studies across chordates and other lineages.
Emerling CA, Teullet S, Allio R
… +3 more, Gatesy J, Springer MS, Delsuc F
Mol Biol Evol
· 2026 Feb · PMID 41527362
·
Full text
Adaptation to ant and/or termite consumption (myrmecophagy) in mammals constitutes a textbook example of convergent evolution, being independently derived in several mammalian lineages. Myrmecophagous species are charact...Adaptation to ant and/or termite consumption (myrmecophagy) in mammals constitutes a textbook example of convergent evolution, being independently derived in several mammalian lineages. Myrmecophagous species are characterized by striking convergent morphological adaptations such as skull elongation, enlargement of salivary glands, and long claws to dig into ant and termite nests. These evolutionary modifications also include anatomical regression, such as dental simplification or loss, reduction of masticatory muscles, and possessing a reduced set of taste buds. To gain insights into the molecular changes underlying the regression of these morpho-anatomical traits, we investigated the functionality of candidate genes related to dentition, gustation, and mastication in nine convergent myrmecophagous mammalian lineages. We examined these genes in a comparative phylogenetic context, paired with molecular evolutionary analyses, to estimate the relative timing of loss of gene function over the evolutionary history of each convergent lineage. We found that gustatory reduction and pseudogenization of masticatory myosin were often associated with the regression of dental genes. Evidence of pseudogenization events linked to oral anatomy dates to as early as the Cretaceous/Paleogene boundary, and is an ongoing process including examples of incipient gene inactivations. Whereas we found evidence for gene inactivations across all three functional categories occurring during distinct temporal intervals, there was variation in the sets of genes lost and the relative timing of inactivation events. The combined evidence suggests that the convergent evolution of myrmecophagy has occurred as a protracted process with distinct phases of anatomical evolution, over timescales as long as 60 Myr.
Petrohilos C, Peel E, Silver LW
… +4 more, O'Neill RJ, Grady PGS, Hogg CJ, Belov K
Mol Biol Evol
· 2026 Feb · PMID 41521888
·
Full text
Cancer is ubiquitous in multicellular life, yet susceptibility varies significantly between species. Previous studies have shown a genetic basis for cancer resistance in many species, but few studies have investigated th...Cancer is ubiquitous in multicellular life, yet susceptibility varies significantly between species. Previous studies have shown a genetic basis for cancer resistance in many species, but few studies have investigated the inverse: why some species are particularly susceptible to cancer. The Dasyuridae are a family of carnivorous marsupials that are frequently reported as having high rates of cancer prevalence. We hypothesized that this high susceptibility also has a genetic basis. To investigate this, we generated reference genomes for the kowari (Dasyuroides byrnei), a dasyurid species with one of the highest rates of reported cancer prevalence among mammals, and a non-dasyurid marsupial, the eastern barred bandicoot (Perameles gunnii). We used these to perform a comparative genomics analysis alongside nine previously assembled reference genomes: four dasyurid species and five non-dasyurid marsupial species. Genomes were annotated using FGENESH++ and assigned to orthogroups for input to computational analysis of gene family evolution (CAFE) to identify gene families that had undergone significant expansions or contractions in each lineage. In the dasyurids, we identified large expansions in Ras genes, a family of oncogenes. Interestingly, a similar expansion of Ras genes was also identified in the bandicoot and bilby. These genes were primarily expressed in tissues such as testes, ovaries, and yolk sac, so we hypothesize they serve a reproductive role. Future work is required to identify the potential roles of oncogene expansions in cancer susceptibility in these marsupial species.
Chen Q, Li S, Wu X
… +14 more, Xu Q, Zhu R, Ruan Y, Lan A, Liu Z, Weng J, Zhao Y, Xu X, Qi X, Lai J, Xiao L, Lan P, Wu CI, Chen B
Mol Biol Evol
· 2026 Feb · PMID 41521784
·
Full text
The process of migration and colonization is important in evolution; for example, modern humans experienced multiple waves of migrations out of Africa. However, no data cover the spatio-temporal patterns sufficiently to...The process of migration and colonization is important in evolution; for example, modern humans experienced multiple waves of migrations out of Africa. However, no data cover the spatio-temporal patterns sufficiently to be truly informative. Metastatic cancer provides a unique in vivo model to study these processes through rapid somatic evolution. Here, we apply the high-resolution sampling technique (Dense 3D Crypt-scale Sampling) to analyze hundreds of spatially mapped micro-samples from the primary colorectal cancer and liver metastases in two representative cases. This would be analogous to recording the "out-of-Africa" events in two repeats. Our results support that liver metastases arise from polyphyletic and polyclonal seeding events where multiple, genetically distinct clones colonize a new site together. Following colonization, these multi-clonal populations can evolve into distinct spatial architectures: segregated territories formed by cells with low motility, or highly intermixed patterns driven by high motility. The colonization (or seeding) process begins within the first third of the primary tumor's progression, creating a large number of widespread but clinically undetectable micrometastatic colonies. These findings support a model where metastatic competence is not an intrinsic trait of a single "winner" clone but an emergent property of multiple concurrent clones. Collectively, our work supports metastasis as a multi-stage process initiated early in tumor development, characterized by continuous polyclonal dissemination and the formation of spatially distinct clonal architectures. This general pattern may echo the ecology of migration and colonization in organismal evolution.
Thomas WR, Lama TM, Baldoni C
… +21 more, Marín-Gual L, Moreno Santillán D, Farré M, Abueg L, Balacco J, Fedrigo O, Formenti G, Jain N, Mountcastle J, Tilley T, Sims Y, Tracey A, Wood J, Ray DA, von Elverfeldt D, Nieland J, Corthals AP, Ruiz-Herrera A, Dechmann DKN, Jarvis E, Dávalos LM
Mol Biol Evol
· 2026 Feb · PMID 41517999
·
Full text
Sorex araneus, the Eurasian common shrew, has seasonal brain size plasticity (Dehnel's phenomenon) and many intraspecific chromosomal rearrangements. Genomic contributions to these traits, however, remain unknown. We cou...Sorex araneus, the Eurasian common shrew, has seasonal brain size plasticity (Dehnel's phenomenon) and many intraspecific chromosomal rearrangements. Genomic contributions to these traits, however, remain unknown. We couple a chromosome-scale genome assembly with seasonal brain transcriptomes to discover relationships between molecular evolution and both traits. While Positively Selected Genes (PSGs) enriched the Fanconi anemia DNA repair pathway (FANCI, FAAP100), which is likely involved in chromosomal rearrangements by preventing the accumulation of chromosomal aberrations, genes under positive selection or showing seasonal differential expression in the brain implicate neurogenesis (PCDHA6, SOX9, Notch signaling) and metabolic regulation (VEGFA, SPHK2) as key mechanisms underlying Dehnel's phenomenon. We also find that both positively selected and differentially expressed genes in the hippocampus are overrepresented near S. araneus evolutionary breakpoints. This relates both positive selection and differential expression to accessible chromatin configuration, suggesting that chromosomal rearrangements are integral to adaptive evolution and the regulation of brain size plasticity.
Shimmura T, Kurachi T, Matsuda Y
… +13 more, Rafati N, Shimura K, Goto T, Kawakami SI, Maeda R, Yamada Y, Pettersson ME, Nakamura Y, Higashiura Y, Shimura NN, Bendesky A, Tsudzuki M, Andersson L
Mol Biol Evol
· 2026 Jan · PMID 41512112
·
Full text
Aggression is an essential animal behavior for survival, particularly in situations where fighting cannot be avoided. In such situations, the choice of fighting strategy (eg biting, charging, or defending) is critical. A...Aggression is an essential animal behavior for survival, particularly in situations where fighting cannot be avoided. In such situations, the choice of fighting strategy (eg biting, charging, or defending) is critical. Although the molecular bases of fighting and aggressiveness have been previously studied, how genetic, transcriptional, and neurobiological mechanisms contribute to the choice of fighting strategy remains largely unknown. Here, we use two subpopulations of chickens bred for cockfighting that show markedly different fighting strategies: offensive and defensive attack. A genome-wide screen comparing individuals from the two subpopulations indicated a polygenic background and we identified 15 candidate genes, five of which are implicated in neuronal development. Among these, the transcription factor gene FOXP1 was notable. FOXP1 is essential for neuronal development in the brain and has been implicated in the regulation of motor circuits. Transcriptomic analysis of the diencephalon also revealed differential expressions of genes involved in neurodevelopment, as well as in the synthesis and release of neurotransmitters. RNA-sequencing and immunohistochemistry suggested that activation of the indirect pathway of the brain motor circuit promotes the defensive fighting strategy. This was further supported by behavioral pharmacological experiments targeting dopaminergic signaling. Taken together, our results indicate that genomic variation and altered expression of neurodevelopment-related genes underlie differences in fighting strategies, and that the neuroendocrine changes in brain circuits further modulate these behavioral outcomes.
Łabędzka-Dmoch K, Bui THD, Piątkowski J
… +4 more, Dilling M, Jagiełło P, Kabza W, Golik P
Mol Biol Evol
· 2026 Feb · PMID 41508847
·
Full text
The pathway involving the paralogous transcription factors Rtg1 and Rtg3 was first described in Saccharomyces cerevisiae as the retrograde regulation that adapts cellular metabolism in response to the state of mitochondr...The pathway involving the paralogous transcription factors Rtg1 and Rtg3 was first described in Saccharomyces cerevisiae as the retrograde regulation that adapts cellular metabolism in response to the state of mitochondrial respiration. We investigated the evolution of this pathway by studying its target genes in respiratory-deficient mutants of Candida albicans-a phylogenetically distant and metabolically distinct yeast species. We show that in C. albicans the Rtg pathway is also responsible for adaptation to cellular stresses related to respiratory dysfunction, but the repertoire of its target genes is different than in S. cerevisiae, and includes genes encoding proteins involved in alternative respiration, oxidative stress, mitophagy, and other aspects of metabolism. We also traced the evolution of the main components of the Rtg pathway and its target genes in the budding yeast (Saccharomycotina) subphylum. We show that the system originated within this clade following a single duplication of the gene encoding the ancestor of Rtg1 and Rtg3, but employs other factors, like the regulatory proteins Rtg2 and Mks1 that were likely present in the last common ancestor of budding yeasts. The regulation of the Rtg transcription factors in C. albicans is different than in S. cerevisiae, as both Rtg2 and Mks1 were lost in the majority of Serinales. Among the target genes, of particular interest is the evolution of the alternative oxidase (Aox), which was either lost or duplicated in multiple independent events. The presence of Aox strongly correlates with the mitochondrially encoded Complex I-a major source of oxidative stress.
Mackintosh A, Brault M, Roze D
… +2 more, Lascoux M, Glémin S
Mol Biol Evol
· 2026 Feb · PMID 41502013
·
Full text
The effect of natural selection on linked sites has been suggested to be a major determinant of genetic diversity. While it is in principle possible to estimate this effect from genome sequence data, interactions between...The effect of natural selection on linked sites has been suggested to be a major determinant of genetic diversity. While it is in principle possible to estimate this effect from genome sequence data, interactions between selection, demography and inbreeding are expected to make inference less reliable. Here, we investigate whether the genome-wide reduction in diversity due to background selection (B¯) can be accurately estimated when populations are at demographic non-equilibrium and/or reproduce by partial self-fertilization. We show that the classic-BGS model is surprisingly robust to both demographic non-equilibrium and low rates of selfing, although both processes do lead to biased estimation of the distribution of fitness effects (DFE) of deleterious mutations. A high rate of selfing leads to poor estimation of both B¯ and DFE parameters. We propose an alternative approach where background selection, demography and partial selfing are jointly estimated from windowed site frequency spectra. This approach resolves most of the bias observed under the classic-BGS model and can also generate estimates of past demography that account for the effect of background selection and partial selfing. We apply the approach to genome sequence data from Capsella grandiflora and Capsella orientalis, which have contrasting mating systems and display a forty-fold difference in nucleotide diversity. Our results suggest that background selection has a weak effect on levels of genetic diversity in the outcrosser C. grandiflora (B¯=0.89) and a more substantial effect in the predominantly selfing species C. orientalis (B¯=0.44), but that background selection alone cannot explain their disparity in genetic diversity.
Song W, Liu F, Song W
… +11 more, Li X, Xie Y, Yang R, Du M, Wang Y, Zhang F, Gao X, Qi J, Bao Z, Zhang Q, He Y
Mol Biol Evol
· 2026 Jan · PMID 41498217
·
Full text
Endogenous retroviral envelope (ERV env) genes, notably syncytins, are known for driving placental development in mammals and lizards. However, their broader contributions to non-mammalian vertebrates, particularly vivip...Endogenous retroviral envelope (ERV env) genes, notably syncytins, are known for driving placental development in mammals and lizards. However, their broader contributions to non-mammalian vertebrates, particularly viviparous fish, remain largely unexplored. Here, we present the discovery and functional characterization of three co-opted/captured ERV env gene clades, including a Percom-env clade comprising previously reported percomORF in the viviparous teleost Sebastes schlegelii. Our findings reveal that each gene clade plays a distinct and critical role in neural regulation, reproductive maturation, and viviparity. Notably, Percom-env percomORF retains fusogenic activity and its brain-specific expression is driven by conserved regulatory elements across Percomorpha. Meanwhile, Seb-env4 env genes, expressed uniquely in the testis, support seasonal gonadal maturation and Sertoli cell maintenance. Lastly, Seb-env3 env genes, localized at the maternofetal interface, retain a robust fusion capacity essential for follicular placentation, and have persisted for approximately 15 million years in the Sebastes genus, thus identified as candidate syncytin-Seb, likely underpinning the emergence of viviparity. These findings demonstrate env co-option/capture drives teleost adaptations, extending retroviral env-mediated placentation beyond mammals and lizards, and highlight conserved mechanisms in vertebrate reproductive evolution.
Mol Biol Evol
· 2026 Feb · PMID 41493011
·
Full text
Understanding the evolutionary dynamics of cell populations requires models that link observed phylogenetic patterns to the underlying processes of cell division, death, and mutation. Classical phylodynamic inference met...Understanding the evolutionary dynamics of cell populations requires models that link observed phylogenetic patterns to the underlying processes of cell division, death, and mutation. Classical phylodynamic inference methods-developed primarily for macroevolutionary settings-assume that mutations accrue in calendar time and often rely on a molecular clock. Here, we introduce a framework that ties mutations to discrete birth (division) events. In this setting, mutations accumulate via a compound Poisson process, capturing both visible and hidden cell divisions within the reconstructed phylogenetic tree. We present a computationally efficient dynamic programming algorithm to compute the likelihood based on tree topologies with associated mutations, integrating over latent variables such as branch durations and unobserved cell divisions. Our method is applicable to large-scale single-cell datasets, and we demonstrate its utility on simulated data and on single-cell phylogenies of hematopoietic stem cells.
Zhang J, Zhang X, Liu N
… +9 more, Hu J, Hiller M, Sharma V, Han F, Dai H, Tu X, Cooper DN, Wu DD, Zeng L
Mol Biol Evol
· 2026 Feb · PMID 41490039
·
Full text
Hibernation is an adaptive survival strategy used by animals to cope with extreme environmental conditions. Although this physiological process involves complex metabolic changes, its underlying biological mechanisms rem...Hibernation is an adaptive survival strategy used by animals to cope with extreme environmental conditions. Although this physiological process involves complex metabolic changes, its underlying biological mechanisms remain largely unknown. Through comparative genomic analysis of six hibernating species across five orders, we identified an ancient amino acid substitution in POMT2 (R708Q), exhibiting signals of both convergent and positive selection in hibernating mammals. Phylogenetic analysis using HeIST indicated hemiplasy as a possible explanation, though given mammalian divergence times and the broader evidence for convergence, this is best considered an alternative rather than the primary interpretation. Functional studies using transgenic mice demonstrated the contribution of this mutation to hypoxia adaptation. Notably, despite the absence of this mutation in Rodentia hibernators, we included Graphiurus kelleni as a positive control in physiological studies of transgenic mice carrying POMT2 (R708Q), given its remarkable hypoxia adaptation during hibernation. Our findings not only provide novel insights into the genetic basis of hypoxic adaptation in hibernating mammals but also suggest incomplete lineage sorting (hemiplasy) as a plausible evolutionary mechanism for this important adaptive trait.
Okholm S, Taieb A, Rezvani HR
… +1 more, Lemoine M
Mol Biol Evol
· 2026 Jan · PMID 41486485
·
Full text
Cancer as a selective force in human evolution remains largely unexplored in the field of cancer evolution and ecology. In this review, we examine one such proposal about the evolution of skin pigmentation in ancestral h...Cancer as a selective force in human evolution remains largely unexplored in the field of cancer evolution and ecology. In this review, we examine one such proposal about the evolution of skin pigmentation in ancestral humans. The skin cancer hypothesis posits that deaths from sun-induced skin cancers in part favored the evolution of darker skin in early hominins as they dispersed into savanna mosaics. Evolutionary mismatch, where migrants and albinos with fair or extremely pale skin settle in high-UVR environments, has been used to support the hypothesis, but only the case involving albinos has been subject to examination and discussion. Using current data on skin cancer rates in Australians, we test the case of migration-related mismatch and find that, although skin cancers with metastatic potential are common, their typical onset occurs after reproductive age. This suggests that the protective effects of dark skin in ancestral humans were likely selected not for protection against skin cancers, but for mitigating other UV-related risks, e.g. maintaining thermoregulation and water barrier integrity. We then discuss several ad hoc explanations, and their criticisms, to preserve the skin cancer hypothesis, concerning melanoma as a selection pressure, life history traits of ancestral humans, and the grandmother effect. We conclude that lethal skin cancers may have shaped human evolution indirectly, insofar as post-reproductive elderly contributed to ancestral social structures by providing alloparental care to their kin.
Zhou Y, Lin Y, Ma H
… +19 more, Wang R, Zhai H, Qin Z, Zeng Y, Lou Y, Xu Y, Chen H, Bai T, Shen W, Chen T, Yang X, Zheng J, Tao L, He H, Zhu K, Li J, Chen L, Yan F, Wang CC
Mol Biol Evol
· 2026 Jan · PMID 41479132
·
Full text
The Central Plain of China, the cradle of Chinese civilization, experienced major demographic upheavals during the Qing era (1644-1912 AD), yet its population's genetic history during this critical period remains largely...The Central Plain of China, the cradle of Chinese civilization, experienced major demographic upheavals during the Qing era (1644-1912 AD), yet its population's genetic history during this critical period remains largely uncharacterized. Here, we generated genome-wide data for 46 Qing Dynasty individuals from the Sanzhiyuan cemetery in Sanmenxia, Henan province. The Sanzhiyuan population exhibits remarkable genetic homogeneity and shows substantial genetic continuity with preceding populations of the Yellow River region dating back to the Late Neolithic. We successfully model them as direct descendants of Tang Dynasty populations. Notably, despite the Qing being ruled by the ethnically distinct Manchu elite, we detected no evidence of large-scale genetic admixture with Manchu, Mongol, or other northern or West Eurasian groups. Furthermore, we demonstrate that these Qing-era individuals are direct ancestors of the modern Han population in Henan, completing an unbroken multi-millennial genetic lineage. Our findings further demonstrate the stability of the genetic profile of the Central Plains population-a stability that has persisted for millennia and remained profoundly unaffected by major historical upheaval.
Shankar A, Moscoso E, Cowan D
… +4 more, Kelly R, Cintron R, Al-Naimi OA, Switzer WM
Mol Biol Evol
· 2026 Jan · PMID 41479018
·
Full text
MicrobeTrace is a free, secure, browser-based bioinformatics tool to integrate and visualize epidemiologic, laboratory, and molecular data for outbreak investigations, with over 14,000 users from 127 countries. Regular t...MicrobeTrace is a free, secure, browser-based bioinformatics tool to integrate and visualize epidemiologic, laboratory, and molecular data for outbreak investigations, with over 14,000 users from 127 countries. Regular testing, user feedback, and comparison with other bioinformatics tools identified areas for improvement, prompting major architectural and functional upgrades. In MicrobeTrace 2.0, we refactored the codebase using Angular to improve scalability, performance, and usability. We also replaced the D3.js visualization engine with Cytoscape.js for faster, more efficient rendering of large networks. The update adds enhanced visualizations, new analytical tools, and expanded functionality within existing views. It also supports seamless integration with external phylogenetic platforms, such as Nextstrain and UShER (Ultrafast Sample Placement on Existing Trees), enabling users to import phylogenetic trees, visualize them as genetic networks, and securely enrich them with epidemiological and demographic metadata. These enhancements position MicrobeTrace as a next-generation, interoperable tool for genomic epidemiology and data-driven public health response.
Mol Biol Evol
· 2026 Jan · PMID 41457019
·
Full text
Alternative splicing is a major driver of transcriptome and proteome variation, but the role of alternative splicing in regulatory evolution is often overlooked. Alternative splicing can also contribute to phenotypic pla...Alternative splicing is a major driver of transcriptome and proteome variation, but the role of alternative splicing in regulatory evolution is often overlooked. Alternative splicing can also contribute to phenotypic plasticity, which may be critical when taxa colonize new environments. Here, we investigate variation in alternative splicing among new wild-derived strains of mice from different climates in the Americas on both a standard and high-fat diet. We show that alternative splicing is widespread and highly context-dependent, underscoring its potential as a substrate for adaptation and plasticity. Comparisons between strains on different diets revealed abundant gene-by-environment interactions affecting alternative splicing. Most genes showed strain- and sex-specific diet responses, highlighting the importance of incorporating sex, genetic diversity, and environmental variation in studies of gene regulation. More often than not, genes that were differentially spliced between strains were not differentially expressed, adding to evidence that the 2 regulatory mechanisms often act independently. Moreover, patterns of expression and network analyses suggest that the 2 mechanisms differ in pleiotropic constraint. Importantly, divergence in alternative splicing was predominantly driven by cis-regulatory changes. However, trans changes affecting splicing may be central to plasticity, as they were impacted more by environmental variation. Finally, we performed scans for selection and found that, while genes with splicing divergence more often co-localized with genomic outliers associated with metabolic traits, they were not enriched for genomic outliers. Overall, our results provide evidence that alternative splicing plays an important role in gene regulation in house mice, contributing to divergence and plasticity.
Stanek TJ, Leung W, Shaffer CD
… +29 more, Genomics Education Partnership
, Olaveja I, Laughlin A, Hester J, Garrido D, Oh EK, Volski M, Panda N, Mo M, Cordes E, Dalling M, Kershaw K, Arnott M, Daly S, Valenzuela SG, Thompson P, Hastert KL, Sabb D, Karpinski K, Arora MN, Rius N, LoBello L, Jaramillo S, Sonavane O, Herrmann A, Reed LK, Elgin SCR, Arrigo C, Ellison CE
Mol Biol Evol
· 2025 Nov · PMID 41442496
·
Full text
Genome size varies widely, even among closely related species, yet much less is known about chromosome size variation. Here we use the fourth chromosome of Drosophila, also known as the "Muller F element" or "dot chromos...Genome size varies widely, even among closely related species, yet much less is known about chromosome size variation. Here we use the fourth chromosome of Drosophila, also known as the "Muller F element" or "dot chromosome", as a model to investigate chromosome-specific size expansion. The F element of most Drosophila species is small (∼1.3 Mb) and almost entirely heterochromatic, yet harbors approximately 80 protein-coding genes. Here, we study D. kikkawai, D. takahashii, D. ananassae, and D. bipectinata, whose F elements are 2- to 15-fold larger in size compared to D. melanogaster. Through manual gene curation and comparative genomic analysis, we find that their F elements have expanded primarily via accumulation of transposable elements (TEs) in introns and intergenic regions. Natural selection appears less efficient on these expanded F elements: they have smaller effective population sizes and their genes exhibit reduced usage of optimal codons, compared to D. melanogaster. We propose that F element size variation is driven by differences in F element recombination rates. The ultra-long (∼20 Mb) F elements of D. ananassae and D. bipectinata display high rates of rearrangement and sequence evolution and exhibit independent TE-driven expansions. Our results suggest that F elements of most Drosophila species likely recombine enough to prevent size expansion, while F element recombination in D. ananassae and D. bipectinata is either absent or rare enough to allow TEs and other deleterious mutations to accumulate via Muller's ratchet; thus, these chromosomes evolve more like a Y chromosome than a typical Drosophila F element.
Zdral S, Bordignon SG, Meyer A
… +2 more, Ros MA, Woltering JM
Mol Biol Evol
· 2026 Jan · PMID 41437880
·
Full text
Limbs exhibit adaptive differentiation along their dorsal-ventral (DV) axis, determined by the dorsal expression of the LIM homeobox gene Lmx1b. The paired appendages (ie the pectoral and pelvic fins from which limbs evo...Limbs exhibit adaptive differentiation along their dorsal-ventral (DV) axis, determined by the dorsal expression of the LIM homeobox gene Lmx1b. The paired appendages (ie the pectoral and pelvic fins from which limbs evolved) arose in an early jawless ancestor via co-option of a midline-fin genetic program including modules for anterior-posterior (AP) and proximal-distal (PD) patterning. Unlike the AP and PD axes, median fins lack an unambiguous DV axis, leaving the origin of this DV pattern in paired appendages unresolved. Here, we describe Lmx1b expression in the posterior midline fins of cichlids, sturgeons, catsharks, and lampreys, revealing an ancestral role for this gene predating the origin of paired appendages. In median fins, Lmx1b activation depends on shh from the ZPA, whereas in paired fins it relies on ectodermal wnt signaling, indicating the evolution of novel regulatory inputs for dorsal patterning. We observe that ephA4b, a putative Lmx1b target, is co-expressed with Lmx1b in dorsal pectoral and posterior midline fins and downregulated alongside Lmx1b, suggesting a role in both fin types related to axon guidance. We propose that novel regulation drove the repurposing of Lmx1b from posterior to dorsal fin determinant, with co-option of conserved downstream targets. Altogether, our findings demonstrate that the DV axis of paired appendages represents an evolutionary innovation arising from the integration of ancestral midline fin and flank determinants with novel regulatory inputs.
Mol Biol Evol
· 2026 Jan · PMID 41436042
·
Full text
Eukarya resemble Archaea in DNA replication. Analysis of the DNA replication machinery of Asgard archaea may provide a valuable test of the hypothesis that this phylum is the origin of Eukarya. Among the replication prot...Eukarya resemble Archaea in DNA replication. Analysis of the DNA replication machinery of Asgard archaea may provide a valuable test of the hypothesis that this phylum is the origin of Eukarya. Among the replication proteins, primase, which comprises the catalytic subunit PriS and the non-catalytic subunit PriL, synthesizes primers for extension by DNA polymerase. Here, we show that Asgard primases fall into two major groups, denoted the Heimdall group and the Loki group, which are phylogenetically and structurally more closely related to eukaryotic primases and to primases from non-Asgard archaea, respectively. Notably, like human PriL, PriL of the Heimdall group possesses an extra C-terminal domain, which, absent in archaeal PriL of the non-Heimdall group, presumably serves to enhance the stability of the conserved iron-sulfur cluster in PriL. We overproduced and purified the PriS and PriL subunits of the Heimdall group from the Candidatus Gerdarchaeota archaeon B18_G1 in Escherichia coli. Biochemical characterization reveals that the B18_G1 primase is capable of primer synthesis and extension, preferentially using dNTPs as substrates, as shown for primases from non-Asgard archaea; however, unlike non-Asgard archaeal primases, it produces short primers, a feature typical of eukaryotic primases. These results shed significant light on the evolutionary pathway of primase and are consistent with the hypothesis of the Asgard origin of Eukarya.