SEARCH · PubMed Health

Results for “regulatory evolution”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources

PubMed2026

Regulatory Evolution and the Genetic Basis of Human Brain Expansion.

The evolution of the human brain is characterized by profound changes in structure and function, despite relatively limited divergence in protein-coding genes compared to other primates. This paradox has led to increasing recognition of gene regulatory elements (GREs) as primary drivers of evolutionary innovation. In this review, we synthesize current knowledge on the role of conserved noncoding elements (CNEs), human accelerated regions (HARs), and transposable element (TE)-derived sequences in shaping gene regulatory networks (GRNs) underlying brain development. Comparative analyses across humans and closely related primates, including the chimpanzee, gorilla, and orangutan, reveal that while core regulatory architectures are highly conserved, subtle changes in regulatory elements drive species-specific gene expression patterns. We highlight how CNEs provide a stable regulatory framework, whereas HARs and TE-derived elements introduce lineage-specific modifications that fine-tune neurodevelopmental processes. Advances in functional genomics, including CRISPR-based perturbations, massively parallel reporter assays, and single-cell multi-omics, have enabled direct interrogation of regulatory function, linking sequence variation to cellular phenotypes. Furthermore, we discuss how regulatory evolution contributes to both cognitive innovation and susceptibility to neurological disorders. Despite significant progress, challenges remain in establishing causal relationships between regulatory variation and phenotypic outcomes. Future integration of multi-omics data and comparative models will be essential for resolving these complexities. Together, this review provides a comprehensive framework for understanding the molecular basis of primate brain evolution through the lens of gene regulation.

Brain evolution↗

PubMed2026

Cis-regulatory evolution of CsANS1 drives cultivar variation in anthocyanin accumulation in tea plants.

Anthocyanins, a ubiquitous class of water-soluble phytochemicals renowned for their chromatic diversity and potent bioactivity, are integral to the phenotypic and metabolic plasticity of higher plants. Using an integrative multi-omics approach that combines transcriptomic and metabolomic profiling, we identified anthocyanin synthase (CsANS1) as the key genetic determinant responsible for interspecific variation in anthocyanin accumulation among tea plants. Architectural comparison of promoter regions revealed a 192-bp variation insertion in the CsANS1 cis-regulatory region with potential functional significance. This insertion was strictly conserved in anthocyanin-rich (purple-leaf) cultivars, including both natural and hybrid genotypes, but entirely missing in anthocyanin-deficient (green-leaf) cultivars. Dual-luciferase assays confirmed that this insertion enhances promoter activity. Additionally, we delineated a tripartite regulatory axis comprising CsmiR156b, CsSPL9, and CsMYB75 which orchestrates the spatiotemporal modulation of CsANS1 expression and, consequently, anthocyanin biosynthesis. Collectively, these findings provide a mechanistic paradigm for anthocyanin polymorphism in tea plants, implicating both cis-regulatory evolution and transcriptional network synergy as pivotal drivers of phytochemical diversification.

Anthocyanins↗

PubMed2025

A mouse organoid platform for modeling cerebral cortex development and cis-regulatory evolution in vitro.

Natural selection has shaped the gene regulatory networks that orchestrate cortical development, leading to structural and functional variation across mammals, but the molecular and cellular mechanisms underpinning these changes have only begun to be characterized. Here, we develop a reproducible protocol for cerebral cortex organoid generation from mouse epiblast stem cells (EpiSCs), which recapitulates the timing and cellular differentiation programs of the embryonic cortex. We generated cortical organoids from F1 hybrid EpiSCs derived from crosses between laboratory mice (C57BL/6J) and four wild-derived inbred strains spanning ∼1 M years of evolutionary divergence to comprehensively map cis-acting transcriptional regulatory variation across developing cortical cell types, using single-cell RNA sequencing (scRNA-seq). We identify hundreds of genes that exhibit dynamic allelic imbalances, providing the first insight into the developmental mechanisms underpinning changes in cortical structure and function between subspecies. These experimental methods and cellular resources represent a powerful platform for investigating gene regulation in the developing cerebral cortex.

Organoids↗

PubMed2025

Cis-regulatory evolution of Wnt-family genes contributes to a morphological difference between silkworm species.

Closely related species often exhibit distinct morphologies that can contribute to species-specific adaptations and reproductive isolation. One example are Lepidopteran caterpillar appendages, such as the "caudal horn" of Bombycoidea moths, which have evolved substantial morphological diversity among species in this group. Using interspecific crosses, we identify the genetic basis of the caudal horn size difference between Bombyx mori and its closest relative B. mandarina. The three largest of eight QTL account for one third the mean horn length difference between the species. The largest of these, on chromosome 4, encompasses a conserved Wnt-family gene cluster, key upstream regulators that are well-known for their roles in morphological diversification in animals. Using allele-specific expression analysis and CRISPR/Cas9 knockouts, we show that tissue-specific cis-regulatory changes to Wnt1 and Wnt6 contribute to the species difference in caudal horn size. This kind of modularity enables highly pleiotropic genes, including key upstream growth regulators, to contribute to the evolution of morphological traits without causing widespread deleterious effects.

Journal Article↗

PubMed2026

Gene expression is stable despite widespread cis and trans regulatory divergence in Saccharomyces yeasts.

Regulatory evolution can alter phenotypes, but cis- and trans-regulatory mechanisms may also diverge extensively while total transcript abundance remains stable. Comparisons of parental expression with allele-specific expression in F1 hybrids provide a framework for separating cis- and trans-regulatory effects because both parental alleles are measured in a shared trans-regulatory environment. Here, we analyzed RNA sequencing data from Saccharomyces cerevisiae, Saccharomyces paradoxus, and their F1 hybrid. Among the 4,164 genes with sufficient allele-specific support for strict classification, 2,134 (51.2%) showed detectable cis and/or trans regulatory divergence. However, hybrid expression remained largely conserved, with 81.5% of genes not significantly different from either parent. Compensatory cis-trans divergence predominated over reinforcing divergence; cross-replicate estimation reduced the apparent magnitude of this excess, but opposite-sign effects remained predominant in all 20 non-overlapping replicate comparisons. To connect gene expression to genome sequence, we analyzed the strongly cis-diverged locus LYS2 and found species differences in promoter architecture, including an S. cerevisiae-specific AT-rich insertion, altered spacing among candidate regulatory features, and a promoter-proximal TATA-like element unique to S. cerevisiae. Sequence-based nucleosome prediction suggests that these differences create a broader promoter-proximal nucleosome-depleted region in S. cerevisiae than in S. paradoxus. We also quantified allele-resolved intron retention and found that allele-resolved intron retention was broadly conserved, with only rare locus-specific hybrid-associated shifts. Together, these results show that regulatory divergence is widespread but often buffered in the hybrid, whereas intron-retention divergence is comparatively limited.

Saccharomyces↗

PubMed2026

Gene expression is stable despite widespread cis and trans regulatory divergence in Saccharomyces yeasts.

Regulatory evolution can alter phenotypes, but cis- and trans-regulatory mechanisms may also diverge extensively while total transcript abundance remains stable. Comparisons of parental expression with allele-specific expression in F1 hybrids provide a framework for separating cis- and trans-regulatory effects because both parental alleles are measured in a shared trans-regulatory environment. Here, we analyzed RNA sequencing data from Saccharomyces cerevisiae, Saccharomyces paradoxus, and their F1 hybrid. Regulatory divergence was widespread, with 61.3% of tested orthologs showing significant divergence in at least one cis or trans component. However, hybrid expression remained largely conserved, with 81.6% of genes not significantly different from either parent. Compensatory cis-trans divergence predominated over reinforcing divergence, consistent with widespread buffering of transcript abundance. To connect genome-wide patterns to mechanism, we analyzed the strongly cis-diverged locus LYS2 and found species differences in promoter architecture, including an S. cerevisiae-specific AT-rich insertion, altered spacing among candidate regulatory features, and a promoter-proximal TATA-like element unique to S. cerevisiae. Sequence-based nucleosome prediction suggests that these differences create a broader promoter-proximal nucleosome-depleted region in S. cerevisiae than in S. paradoxus. We also quantified allele-resolved intron retention and found that splicing was broadly conserved, with only rare locus-specific hybrid-associated shifts. Together, these results show that regulatory divergence is widespread but often buffered in the hybrid, whereas post-transcriptional divergence is comparatively limited.

Gene expression↗

PubMed2025

Interspecies Organoids Reveal Human-Specific Molecular Features of Dopaminergic Neuron Development and Vulnerability.

The disproportionate expansion of telencephalic structures during human evolution involved tradeoffs that imposed greater connectivity and metabolic demands on midbrain dopaminergic neurons. Despite the central role of dopaminergic neurons in human-enriched disorders, molecular specializations associated with human-specific features and vulnerabilities of the dopaminergic system remain unexplored. Here, we establish a phylogeny-in-a-dish approach to examine gene regulatory evolution by differentiating pools of human, chimpanzee, orangutan, and macaque pluripotent stem cells into ventral midbrain organoids capable of forming long-range projections, spontaneous activity, and dopamine release. We identify human-specific gene expression changes related to axonal transport of mitochondria and reactive oxygen species buffering and candidate cis- and trans-regulatory mechanisms underlying gene expression divergence. Our findings are consistent with a model of evolved neuroprotection in response to tradeoffs related to brain expansion and could contribute to the discovery of therapeutic targets and strategies for treating disorders involving the dopaminergic system.

Brain evolution↗

PubMed2025

Evolutionary Process Underlying Receptor Gene Expansion and Cellular Divergence of Olfactory Sensory Neurons in Honeybees.

Olfaction is crucial for animals' survival and adaptation. Unlike the strict singular expression of odorant receptor (OR) genes in vertebrate olfactory sensory neurons (OSNs), insects exhibit complex OR gene expression patterns. In honeybees (Apis mellifera), a significant expansion of OR genes implies a selection preference for the olfactory demands of social insects. However, the mechanisms underlying receptor expression specificity and their contribution to OSN divergence remain unclear. In this study, we used single-nucleus multiomics profiling to investigate the transcriptional regulation of OR genes and the cellular identity of OSNs in A. mellifera. We identified three distinct OR expression patterns, singular OR expression, co-expression of multiple OR genes with a single active promoter, and co-expression of multiple OR genes with multiple active promoters. Notably, ∼50% of OSNs co-expressed multiple OR genes, driven by polycistronic transcription of tandemly duplicated OR genes via a single active promoter. In these OSNs, their identity was determined by the first transcribed receptor. The divergent activation of the promoter for duplicated OR genes ensures the coordinated increased divergence of OSN population. By integrating multiomics data with genomic architecture, we illustrate how fundamental genetic mechanisms drive OR gene expansion and influence flanking regulatory elements, ultimately contributing to the cellular divergence of OSNs. Our findings highlight the interplay between gene duplication and regulatory evolution in shaping OSN diversity, providing new insights into the evolution and adaptation of olfaction in social insects. This study also sheds light on how genetic innovations contribute to the evolution of complex traits.

Animals↗

PubMed2025

Rapid Divergence of Visual Systems and Signaling Traits to Contrasting Light Regimes During Early Speciation of African Crater Lake Cichlid Fish.

Sensory adaptation is widely hypothesized to drive ecological speciation, yet empirical evidence from natural populations undergoing early stage divergence remains limited. In Lake Masoko, a young crater lake in East Africa, the haplochromine cichlid Astatotilapia calliptera is undergoing early stage sympatric speciation into shallow-water littoral and deep-water benthic ecotypes that experience contrasting light environments. Here, we integrate retinal transcriptomics, phenotypic analyses, and visual modeling to uncover rapid sensory divergence associated with this ecological transition. We find striking shifts in cone opsin expression, with the benthic ecotype exhibiting a switch from short-wavelength sensitive SWS2B to SWS2A and an overall narrowing of cone sensitivity toward the center of the light spectrum, consistent with changes in deep-water light environment. In contrast, coding sequence variation in opsin genes was limited and no significant differences in allele frequencies were detected across nine polymorphic sites, pointing to expression regulation as the primary axis of early divergence in visual systems. In parallel, we observed divergence in male signaling traits, with benthic males displaying deeper red egg-spots, aligning with predictions from visual modeling of signal efficiency in different light environments. These results demonstrate rapid transcriptomic and phenotypic divergence in associated signaling traits-within ∼1,000 years-supporting a potential role for regulatory evolution in sensory adaptation during early ecological speciation.

Animals↗

PubMed2026

Diversity and evolution of chromatin regulatory states across eukaryotes.

Histone post-translational modifications (hPTMs) are key regulators of chromatin states, influencing gene expression, epigenetic memory and transposable element repression across eukaryotic genomes. While many hPTMs are evolutionarily conserved, the extent to which the chromatin states they define are similarly preserved remains unclear. Here we developed a combinatorial indexing chromatin immunoprecipitation followed by sequencing method to simultaneously profile specific hPTMs across diverse eukaryotic lineages, including amoebozoans, rhizarians, discobans and cryptomonads. Our analyses revealed highly conserved euchromatin states at active gene promoters and gene bodies. In contrast, we observed diverse configurations of repressive heterochromatin states associated with silenced genes and transposable elements, characterized by various combinations of hPTMs such as H3K9me3, H3K27me3 and/or different H3K79 methylations. These findings suggest that, while core hPTMs are ancient and broadly conserved, their functional readout has diversified throughout eukaryotic evolution, shaping lineage-specific chromatin landscapes.

Histones↗

PubMed2025

Genome-Wide Mining of lncRNAs Reveals Their Potential Regulatory Role in the Evolution of Viviparity.

Reproduction in vertebrates usually involves egg-laying (oviparity) or live-bearing (viviparity). Oviparity is the ancestral trait from which viviparity has independently evolved more than 100 times in squamate reptiles. This transition involves a series of physiological and structural changes, including the degeneration of eggshell and the evolution of a placenta and differences in the temporal and spatial expression patterns of some functional genes that drive the structural transformation. Long non-coding RNAs (lncRNAs) play important roles in the regulation of gene expression, yet it remains unclear whether they participate in gene expression shifts during the transition from oviparity to viviparity, and if so how. Therefore, we employ deep mining to identify novel lncRNAs of a closely related oviparous-viviparous pair of lizards (Phrynocephalus przewalskii and P. vlangalii). We construct cis- and trans-regulatory networks between lncRNAs and target genes using the transcriptomic data of oviduct or uteri tissues across reproductive periods. Results show that lncRNAs that regulate eggshell gland developmental genes in the oviparous lizard are lost or less expressed in the viviparous lizard. A number of lncRNAs involved in the regulation of placental development and embryo attachment in viviparous species have no orthologs in oviparous species, and others show little or no expression. Accordingly, lncRNAs may play important regulatory roles in the physiological and structural changes in the transition from oviparity to viviparity. These results open doors to the further elucidation of genetic regulatory networks.

Animals↗

PubMed2026

Comparative analysis of conserved non-coding elements identifies gene regulatory networks rewired during the water-to-land transition in vertebrates.

The conquest of land by vertebrates has been a pivotal moment in evolutionary history. Adapting to the new habitats necessitated numerous changes in vertebrate anatomy and physiology, creating an enduring imprint on the developmental gene regulatory networks (GRNs) of tetrapods. The increase of high-quality genomic resources over the past decade has made it possible to study the genomic legacy of the water-to-land transition. While much attention has been given to the highly conserved non-coding elements (CNEs) of the genome that share high levels of similarity across evolutionarily diverged clades, recent evidence suggests that perhaps comparable attention should be given to "missing" CNE-s, conserved sequence patches present in extant stem gnathostomes and actinopterygian fishes that have become undetectable in tetrapods during the adaptation to terrestrial life, whether through true sequence loss or divergence beyond alignability. These sequences could help us reveal the relaxation of certain developmental constraints, related to the aquatic lifestyle, that made reaching new adaptive peaks in the developmental landscape possible. In this paper, we search for such CNEs and characterize them in comparison with pan-Gnathostome CNEs, using the zebrafish (Danio rerio) genome as a reference. Our results suggest that the rewiring of developmental networks related to pigmentation and muscle structure formation has left the largest genomic imprint. We also find that components of canonical Wnt and Hedgehog signalling, are enriched among CNEs retained in fish.

cis-regulatory evolution↗

PubMed2026

Transcriptome mining and comparative genomics reveal 36 putative novel marafivirus species and conserved evolution of the marafibox regulatory element.

BACKGROUND: Marafiviruses are plant-infecting RNA viruses associated with several economically important crops, but their genomic diversity remains incompletely characterized. OBJECTIVE: This study aimed to identify previously unrecognized marafivirus genomes and investigate their genomic features and evolutionary relationships. METHODS: Publicly available plant transcriptome datasets were systematically mined to detect marafivirus-like sequences. Recovered genomes were analyzed using comparative sequence analysis, phylogenetic reconstruction, and genome organization characterization. RESULTS: A total of 62 marafivirus-like genomes were recovered from 33 independent sources representing diverse plant hosts. Polyprotein-based comparative and phylogenetic analyses grouped these genomes into 36 lineages likely representing novel species. All newly identified viruses clustered within the Marafivirus clade. Genome organization analysis revealed conserved polyprotein architecture and widespread presence of the marafibox promoter element. Conservation of additional open reading frames among closely related isolates aided identification of potentially functional genes. CONCLUSION: These findings substantially expand the known diversity of marafiviruses and demonstrate the effectiveness of transcriptome mining for discovering previously unrecognized plant viruses.

Phylogeny↗

PubMed2025

Molecular signature of primate astrocytes reveals pathways and regulatory changes contributing to human brain evolution.

Astrocytes contribute to the development and regulation of the higher-level functions of the brain, the critical targets of evolution. However, how astrocytes evolve in primates is unsettled. Here, we obtain human, chimpanzee, and macaque induced pluripotent stem-cell-derived astrocytes (iAstrocytes). Human iAstrocytes are bigger and more complex than the non-human primate iAstrocytes. We identify new loci contributing to the increased human astrocyte. We show that genes and pathways implicated in long-range intercellular signaling are activated in the human iAstrocytes and partake in controlling iAstrocyte complexity. Genes downregulated in human iAstrocytes frequently relate to neurological disorders and were decreased in adult brain samples. Through regulome analysis and machine learning, we uncover that functional activation of enhancers coincides with a previously unappreciated, pervasive gain of "stripe" transcription factor binding sites. Altogether, we reveal the transcriptomic signature of primate astrocyte evolution and a mechanism driving the acquisition of the regulatory potential of enhancers.

Astrocytes↗

PubMed2026

Evidence for dual pathways of Tc1/mariner domestication in Drosophila.

BACKGROUND: The domestication of transposable elements is a key source of evolutionary innovation, yet the pathways by which their functional modules are repurposed by the host remain poorly understood. The Tc1/mariner superfamily is a widespread group of DNA transposons, but the prevalence and patterns of their domestication are underexplored. RESULTS: We performed a systematic genomic screen across 43 drosophilid species using stringent criteria for molecular domestication. This analysis identified five high-confidence, evolutionarily conserved genes derived from Tc1/mariner transposases. Phylogenetic and structural analyses suggest domestication via two distinct molecular pathways: co-option of the DNA-binding module and co-option of the catalytic domain. The DNA-binding module pathway includes CG4570, the previously known genes cag and toy (the latter fused with a homeodomain), and a lineage-restricted gene in the Drosophila obscura group that exhibits signatures of recent domestication. In contrast, the catalytic domain pathway is represented solely by CG14478. Structural modeling reveals that CG14478 protein preserves a canonical DDE endonuclease fold. Co-expression network analysis suggests potential cellular roles of these genes: CG14478 is linked to RNA/chromatin-related processes, CG4570 to cell cycle/chromosome functions, cag to ciliary and nuclear functions, and toy to neuronal development. CONCLUSIONS: This study establishes a stringent framework for identifying domesticated TEs, demonstrating that Tc1/mariner elements are co-opted via two distinct pathways: retention of either catalytic or DNA-binding modules. Our findings suggest that domestication is a dynamic continuum, ranging from recent, lineage-specific events to ancient, conserved genes, and underscore how genomic conflict with TEs can drive eukaryotic evolution and regulatory complexity.

Animals↗

PubMed2025

The evolutionary trajectories and gene regulatory roles of nuclear-integrated plastid DNA: clues for enhancing environmental adaptation in Caryophyllales.

Environmental stimuli can induce the transfer of chloroplast DNA to the nuclear genome, resulting in nuclear-integrated plastid DNAs (NUPTs). However, their role in plant adaptability remains unclear. Species within the Caryophyllales order, known for their adaptation to extreme environments, provide an ideal model for studying the evolutionary dynamics and functions of NUPTs. In this study, we analyzed NUPTs in 24 Caryophyllales species to investigate their evolution and regulatory roles in gene expression, particularly in response to environmental stimuli. We found significant interspecies variation in NUPT abundance, ranging from 566 insertions in Amaranthus cruentus to 3585 in Beta vulgaris, with sizes spanning from 100 bp to over 100 kb. Approximately 62% of NUPTs were inserted within the last 20 million years, while some species exhibit insertion peaks dating back 49 million years. NUPT presence/absence polymorphisms in six related species suggest that NUPT insertions and deletions are dynamic processes influenced by phylogeny. NUPTs predominantly integrate into intergenic regions but also insert into genes and promoters, with certain regions acting as hotspots. Notably, NUPTs introduce numerous environmental-responsive cis-acting elements in promoter regions. Genes with NUPT insertions in their promoters are significantly enriched for functions related to environmental response. Further luciferase assays in Spinacia oleracea demonstrated that NUPT insertions can regulate the expression of genes related to environmental responses, indicating their potential role in adaptive evolution. Overall, our study provides insights into NUPT evolution and their influence on gene function and plant adaptability to environmental stimuli.

Plastids↗

PubMed2026

Comparative metabolomic and transcriptomic profiling of flavonoid diversity and antioxidant capacity in three Isatis species.

Flavonoids are key bioactive compounds in plants with significant health benefits. This study employs an integrated multi-omics approach to investigate flavonoid diversity and antioxidant capacity across three Isatis species: I. oblongata, I. tinctoria, and I. indigotica. Metabolomic profiling identified 200 flavonoids, with glycosides being the most abundant class. I. tinctoria exhibited the highest total flavonoid content and antioxidant activity, strongly correlated with the accumulation of 53 core differential flavonoid metabolites, most of which were glycosylated derivatives. Transcriptomic analysis revealed coordinated upregulation of phenylpropanoid pathway genes and specific UDP-glycosyltransferases (UGTs) in I. tinctoria, providing a genetic basis for its enhanced glycoside production. The study establishes a clear genotype-metabolite-phenotype linkage, highlighting glycosylation as a key mechanism underlying flavonoid-driven antioxidant superiority in Isatis. Although the current evidence is primarily correlative, the consistent and strong associations across independent transcriptomic, metabolomic, and antioxidant datasets provide a robust foundation for this conclusion. These findings offer new insights into the metabolic evolution and regulatory networks of flavonoids, with implications for breeding and metabolic engineering of high-value medicinal plants.

Flavonoids↗

PubMed2026

Transposable element-driven expansion of enhancer RNA repertoires underlies regulatory innovation and polyploid adaptation in cereal crops.

Cereal genomes have undergone repeated polyploidization and transposable element (TE) proliferation, collectively generating complex regulatory landscapes. However, the evolutionary trajectories and functional implications of these landscapes remain largely unexplored. Using chromatin-bound RNA sequencing across seven cereal species, we systematically mapped 45,952 regulatory element transcripts (RETs), including 32,867 distal RETs corresponding to enhancer RNAs (eRNAs). Our analysis revealed that 56% of lineage-specific eRNAs originated from TE expansions, indicating that TEs serve as major reservoirs of species-specific regulatory innovation in cereals. Notably, we identified remarkable conservation in defense-related functions, root-specific expression, and TE-derived origins of eRNAs across both ancient and recent evolutionary layers of Triticeae, suggesting recurrent recruitment of TE-derived, root-associated regulatory elements throughout Triticeae evolution. Furthermore, we found that young eRNA pairs in hexaploid wheat with high sequence similarity, many originating from RLG_famc8.3 and DTC_famc4.3, exhibited pronounced root specificity and coordinated expression, suggesting targeted amplification and refinement of successful ancestral regulatory strategies established after Triticeae divergence. To facilitate community access, we developed Cereal-eRNAdb (http://bioinfo.cemps.ac.cn/Cereal-eRNAdb/), a comprehensive database integrating 69,426 eRNAs with functional annotations across 296 samples. Our findings suggest that TE-mediated innovation of root-specific eRNAs may contribute to Triticeae adaptation and provide a foundational resource for exploiting regulatory variation in cereal crop breeding.

Enhancer RNAs↗