Congenital vertebral malformations (CVMs) encompass formation, segmentation and mixed defects, with or without scoliosis. This narrative review relates human genetic findings to paraxial mesoderm specification, somitogenesis, sclerotome differentiation and vertebral morphogenesis. An author-defined evidence hierarchy distinguishes established disease relationships, emerging susceptibility mechanisms and hypothesis-generating observations; it is not a formal ClinGen classification. Replicated TBX6 dosage mechanisms and disease-specific segmentation disorders provide stronger etiological evidence than candidate-gene burden signals, regulatory hypotheses or accessible-tissue methylation associations. Evidence is assigned to a defined gene–disease or mechanism–phenotype relationship, not to a gene or pathway universally. Building on previous developmental and gene–environment models, we outline a conceptual spatiotemporal threshold framework in which dosage, developmental stage, tissue distribution and modifiers may influence vertebral anatomy. No numerical human threshold has been established. Explicit appraisal criteria, relationship-specific evidence summaries and proposed experimental tests separate demonstrated findings from extrapolation. Standardized vertebral and rib phenotyping, associated anomalies and inheritance remain essential for genomic interpretation. Molecular diagnosis may inform counseling and syndrome-specific evaluation but does not independently establish prognosis or surgical indications.
Background: Termites (epifamily Termitoidae) represent the oldest known lineage of eusocial insects, yet their higher-level phylogenetic relationships remain contentious. Methods: We sequenced ten new termite mitochondrial genomes (mitogenomes) from Australia and China and integrated them with published data to assemble a comprehensive dataset of 560 species, including 553 termite ingroup species representing all 13 extant families and seven Cryptocercus outgroups. Phylogenetic relationships were inferred using maximum likelihood analyses of mitochondrial protein-coding genes and ribosomal RNA genes under amino acid and nucleotide datasets. Results: All newly sequenced mitogenomes contained the canonical set of 37 mitochondrial genes, exhibited a pronounced A+T bias, and retained the ancestral insect gene order. Mastotermes darwiniensis (Mastotermitidae) was consistently recovered as the sister lineage to all other termites. Among the basal lineages, the relationship ((Hodotermopsidae + Stolotermitidae) + (Archotermopsidae + Hodotermitidae)) received strong support. Kalotermitidae was recovered as monophyletic and as the sister group to Neoisoptera. The traditional Rhinotermitidae was non-monophyletic, and the analyses supported the revised family-level classification that restricts Rhinotermitidae to Rhinotermitinae while recognizing Psammotermitidae, Termitogetonidae, and Heterotermitidae as separate lineages. Within Termitidae, Macrotermitinae was recovered as the sister group to the remaining termitid lineages, whereas Sphaerotermitinae formed a distinct lineage, consistent with its recognition as a separate subfamily. Conclusions: Our results substantially expand mitogenomic sampling across termites and provide further support for recent family- and subfamily-level taxonomic revisions. The inferred relationships broadly agree with recent molecular studies, while some unresolved relationships require denser taxon sampling and nuclear genomic data.
Autism spectrum disorder (ASD) and epilepsy frequently co-occur, with the clinical overlap particularly evident in individuals with intellectual disability, developmental impairment, and genetically defined neurodevelopmental disorders. Advances in genomic diagnostics have revealed substantial genetic and molecular convergence between ASD and epilepsy. This convergence encompasses both recurrent copy-number variants (CNVs), including 15q11–q13, 16p11.2, and 22q11.2 rearrangements, and sequence-level alterations in genes implicated in both epilepsy and ASD-related neurodevelopmental phenotypes, including SCN1A, SCN2A, GRIN2A, SYNGAP1, STXBP1, TSC1/TSC2, MECP2, and UBE3A. These diverse genetic alterations affect gene dosage, ion-channel function, synaptic organization and neurotransmission, intracellular signaling, and gene regulation, ultimately converging on disruption of circuit homeostasis, excitation–inhibition regulation, synaptic plasticity, and network dynamics. Importantly, the relationship between epilepsy and ASD is neither uniform nor necessarily causal: epileptic activity may aggravate neurodevelopmental dysfunction in some disorders, whereas in others, seizures and autistic features represent partially independent consequences of a shared genetic defect. This heterogeneity has major therapeutic implications. Emerging precision approaches increasingly incorporate variant-specific functional effects and include ion-channel modulation, pathway-directed treatments, metabolic correction, and gene- or RNA-targeted therapies. However, successful seizure control does not necessarily translate into normalization of neurodevelopmental outcomes, emphasizing the importance of developmental timing and of distinguishing seizure-directed benefit from modification of the underlying neurodevelopmental disorder. This review integrates clinical, genetic, molecular, cellular, and network-level evidence linking ASD and epilepsy and examines how these convergent mechanisms may guide precision therapeutics and future early-intervention strategies.
Background/Objectives: High-throughput RNA sequencing enables transcript discovery and quantification, but the resulting coverage profiles often contain substantial transcriptional noise, making it difficult to distinguish genuine transcript features from spurious signals. These noisy signals can propagate into transcriptome assemblies, increasing the number of false transcript models and reducing annotation precision. Methods: We present SpliceCOV, a supervised framework for filtering RNA-Seq-derived transcript features. Rather than performing general-purpose segmentation of RNA-Seq coverage, SpliceCOV uses coverage- and junction-derived features to distinguish likely genuine splice sites and transcript boundaries from noisy candidates. We benchmarked SpliceCOV against established changepoint methods and evaluated whether SpliceCOV-filtered features improve downstream transcriptome assembly with StringTie. Results: Across human GTEx tissue datasets, SpliceCOV substantially reduced likely false-positive splice sites while retaining most annotated sites. We included segmentation-based methods as baselines to assess whether generic coverage changepoints can support RNA-Seq transcript-feature filtering. Because these methods are unsupervised whereas SpliceCOV is trained using annotation-derived labels, the comparisons are intended to assess suitability for this specific filtering task rather than to provide a general ranking of the underlying algorithms. Under this evaluation framework, SpliceCOV retained more annotation-supported splice sites at comparable levels of filtering. For transcript start and end sites, SpliceCOV reduced the majority of false positives while retaining substantial overlap with reference annotations. When SpliceCOV-filtered splice sites and transcript boundaries were supplied to StringTie, transcript-level precision increased across the evaluated tissues while the number of reference-matching transcripts remained broadly similar. The model also showed transferability across tissues and chromosomes, and could be applied to mouse RNA-Seq without retraining, although downstream assembly performance was lower than in human datasets. Conclusions: SpliceCOV provides a supervised approach for filtering noisy RNA-Seq-derived transcript features before transcriptome assembly. By improving the quality of splice-site and transcript-boundary evidence supplied to downstream assembly, SpliceCOV can increase transcript-level precision while preserving transcript recovery.
Master sex-determining genes (MSDGs) occupy the top of developmental hierarchies and act as molecular switches that initiate female or male differentiation. Despite their essential roles, MSDGs exhibit rapid evolutionary turnover across vertebrates. In this review, we examine the molecular evolutionary trajectories of three independently evolved vertebrate MSDGs—Sry in mammals, dmy in medaka fishes, and dm-W in Xenopus frogs—and assess the extent to which their evolutionary histories are consistent with initial functional innovation followed by relaxed functional constraint, possible tolerated functional decline, and potential replacement or loss. Regulatory rewiring, structural innovation, or key amino acid substitutions can generate a functional “Jump” that enables a newly arisen gene to cross the threshold required for sex determination and become established as a master regulator. Once the new sex-determining system is established, further increases in MSDG activity may provide little additional fitness advantage, allowing purifying selection to relax. Nearly neutral or mildly deleterious substitutions can then accumulate while residual activity remains sufficient for normal sex determination, producing a tolerated functional “Decline.” Importantly, replacement need not await a decline in ancestral MSDG activity below the functional threshold. A newly emerging MSDG may become established through competition within a population while the ancestral determinant still retains sufficient sex-determining activity, thereby rendering the ancestral MSDG dispensable and permitting its subsequent functional decay or loss. Together, these cases suggest that the switch-like, threshold-dependent architecture of sex determination can permit initial innovation followed by relaxed functional constraint and, in some lineages, turnover of upstream master regulators. We propose “Jump-Decline” evolution as a testable conceptual framework linking the birth, functional relaxation, and potential turnover of vertebrate MSDGs.
