A Conserved Bicycle Model for Circadian Clock Control of Membrane Excitability.

Circadian clocks regulate membrane excitability in master pacemaker neurons to control daily rhythms of sleep and wake. Here, we find that two distinctly timed electrical drives collaborate to impose rhythmicity on Drosophila clock neurons. In the morning, a voltage-independent sodium conductance via the NA/NALCN ion channel depolarizes these neurons. This current is driven by the rhythmic expression of NCA localization factor-1, linking the molecular clock to ion channel function. In the evening, basal potassium currents peak to silence clock neurons. Remarkably, daily antiphase cycles of sodium and potassium currents also drive mouse clock neuron rhythms. Thus, we reveal an evolutionarily ancient strategy for the neural mechanisms that govern daily sleep and wake.

miR-9a minimizes the phenotypic impact of genomic diversity by buffering a transcription factor.

Gene expression has to withstand stochastic, environmental, and genomic perturbations. For example, in the latter case, 0.5%-1% of the human genome is typically variable between any two unrelated individuals. Such diversity might create problematic variability in the activity of gene regulatory networks and, ultimately, in cell behaviors. Using multigenerational selection experiments, we find that for the Drosophila proneural network, the effect of genomic diversity is dampened by miR-9a-mediated regulation of senseless expression. Reducing miR-9a regulation of the Senseless transcription factor frees the genomic landscape to exert greater phenotypic influence. Whole-genome sequencing identified genomic loci that potentially exert such effects. A larger set of sequence variants, including variants within proneural network genes, exhibits these characteristics when miR-9a concentration is reduced. These findings reveal that microRNA-target interactions may be a key mechanism by which the impact of genomic diversity on cell behavior is dampened.

A nondegenerate code of deleterious variants in Mendelian loci contributes to complex disease risk.

Although countless highly penetrant variants have been associated with Mendelian disorders, the genetic etiologies underlying complex diseases remain largely unresolved. By mining the medical records of over 110 million patients, we examine the extent to which Mendelian variation contributes to complex disease risk. We detect thousands of associations between Mendelian and complex diseases, revealing a nondegenerate, phenotypic code that links each complex disorder to a unique collection of Mendelian loci. Using genome-wide association results, we demonstrate that common variants associated with complex diseases are enriched in the genes indicated by this "Mendelian code." Finally, we detect hundreds of comorbidity associations among Mendelian disorders, and we use probabilistic genetic modeling to demonstrate that Mendelian variants likely contribute nonadditively to the risk for a subset of complex diseases. Overall, this study illustrates a complementary approach for mapping complex disease loci and provides unique predictions concerning the etiologies of specific diseases.

A comprehensive analysis of clinical and polygenic germline influences on somatic mutational burden.

Tumor mutational burden (TMB), the total number of somatic mutations in the tumor, and copy number burden (CNB), the corresponding measure of aneuploidy, are established fundamental somatic features and emerging biomarkers for immunotherapy. However, the genetic and non-genetic influences on TMB/CNB and, critically, the manner by which they influence patient outcomes remain poorly understood. Here, we present a large germline-somatic study of TMB/CNB with >23,000 individuals across 17 cancer types, of which 12,000 also have extensive clinical, treatment, and overall survival (OS) measurements available. We report dozens of clinical associations with TMB/CNB, observing older age and male sex to have a strong effect on TMB and weaker impact on CNB. We additionally identified significant germline influences on TMB/CNB, including fine-scale European ancestry and germline polygenic risk scores (PRSs) for smoking, tanning, white blood cell counts, and educational attainment. We quantify the causal effect of exposures on somatic mutational processes using Mendelian randomization. Many of the identified features associated with TMB/CNB were additionally associated with OS for individuals treated at a single tertiary cancer center. For individuals receiving immunotherapy, we observed a complex relationship between PRSs for educational attainment, self-reported college attainment, TMB, and survival, suggesting that the influence of this biomarker may be substantially modified by socioeconomic status. While the accumulation of somatic alterations is a stochastic process, our work demonstrates that it can be shaped by host characteristics including germline genetics.

Expanded encyclopaedias of DNA elements in the human and mouse genomes.

The human and mouse genomes contain instructions that specify RNAs and proteins and govern the timing, magnitude, and cellular context of their production. To better delineate these elements, phase III of the Encyclopedia of DNA Elements (ENCODE) Project has expanded analysis of the cell and tissue repertoires of RNA transcription, chromatin structure and modification, DNA methylation, chromatin looping, and occupancy by transcription factors and RNA-binding proteins. Here we summarize these efforts, which have produced 5,992 new experimental datasets, including systematic determinations across mouse fetal development. All data are available through the ENCODE data portal (https://www.encodeproject.org), including phase II ENCODE1 and Roadmap Epigenomics2 data. We have developed a registry of 926,535 human and 339,815 mouse candidate cis-regulatory elements, covering 7.9 and 3.4% of their respective genomes, by integrating selected datatypes associated with gene regulation, and constructed a web-based server (SCREEN; http://screen.encodeproject.org) to provide flexible, user-defined access to this resource. Collectively, the ENCODE data and registry provide an expansive resource for the scientific community to build a better understanding of the organization and function of the human and mouse genomes.

Context-dependent ciliary regulation of hedgehog pathway repression in tissue morphogenesis.

A fundamental problem in tissue morphogenesis is identifying how subcellular signaling regulates mesoscale organization of tissues. The primary cilium is a paradigmatic organelle for compartmentalized subcellular signaling. How signaling emanating from cilia orchestrates tissue organization-especially, the role of cilia-generated effectors in mediating diverse morpho-phenotypic outcomes-is not well understood. In the hedgehog pathway, bifunctional GLI transcription factors generate both GLI-activators (GLI-A) and GLI-repressors (GLI-R). The formation of GLI-A/GLI-R requires cilia. However, how these counterregulatory effectors coordinate cilia-regulated morphogenetic pathways is unclear. Here we determined GLI-A/GLI-R requirements in phenotypes arising from lack of hedgehog pathway repression (derepression) during mouse neural tube and skeletal development. We studied hedgehog pathway repression by the GPCR GPR161, and the ankyrin repeat protein ANKMY2 that direct cAMP/protein kinase-A signaling by cilia in GLI-R generation. We performed genetic epistasis between Gpr161 or Ankmy2 mutants, and Gli2/Gli3 knockouts, Gli3R knock-in and knockout of Smoothened, the hedgehog pathway transducer. We also tested the role of cilia-generated signaling using a Gpr161 ciliary localization knock-in mutant that is cAMP signaling competent. We found that the cilia-dependent derepression phenotypes arose in three modes: lack of GLI-R only, excess GLI-A formation only, or dual regulation of either lack of GLI-R or excess GLI-A formation. These modes were mostly independent of Smoothened. The cAMP signaling-competent non-ciliary Gpr161 knock-in recapitulated Gpr161 loss-of-function tissue phenotypes solely from lack of GLI-R only. Our results show complex tissue-specific GLI-effector requirements in morphogenesis and point to tissue-specific GLI-R thresholds generated by cilia in hedgehog pathway repression. Broadly, our study sets up a conceptual framework for rationalization of different modes of signaling generated by the primary cilium in mediating morphogenesis in diverse tissues.

Genetic regulation of human brain proteome reveals proteins implicated in psychiatric disorders.

Psychiatric disorders are highly heritable yet polygenic, potentially involving hundreds of risk genes. Genome-wide association studies have identified hundreds of genomic susceptibility loci with susceptibility to psychiatric disorders; however, the contribution of these loci to the underlying psychopathology and etiology remains elusive. Here we generated deep human brain proteomics data by quantifying 11,608 proteins across 268 subjects using 11-plex tandem mass tag coupled with two-dimensional liquid chromatography-tandem mass spectrometry. Our analysis revealed 788 cis-acting protein quantitative trait loci associated with the expression of 883 proteins at a genome-wide false discovery rate <5%. In contrast to expression at the transcript level and complex diseases that are found to be mainly influenced by noncoding variants, we found protein expression level tends to be regulated by non-synonymous variants. We also provided evidence of 76 shared regulatory signals between gene expression and protein abundance. Mediation analysis revealed that for most (88%) of the colocalized genes, the expression levels of their corresponding proteins are regulated by cis-pQTLs via gene transcription. Using summary data-based Mendelian randomization analysis, we identified 4 proteins and 19 genes that are causally associated with schizophrenia. We further integrated multiple omics data with network analysis to prioritize candidate genes for schizophrenia risk loci. Collectively, our findings underscore the potential of proteome-wide linkage analysis in gaining mechanistic insights into the pathogenesis of psychiatric disorders.

Nuclear receptors in cancer - uncovering new and evolving roles through genomic analysis.

Nuclear receptors (NRs) have historically been at the forefront of cancer research, where they are known to act as critical regulators of disease. They also serve as biomarkers for tumour subclassification and targets for hormone therapy. However, most tumour types express extensive repertoires of NRs, whose interactions provide multiple paths for disease progression and offer potentially untapped mechanisms for therapeutic interventions. Recently, next-generation sequencing technologies have provided genome-wide insights into the complex interplay of NR transcriptional networks and their contribution to the development and progression of cancer. These findings have altered the traditional understanding of NR activities in oncogenesis.

Military accession guidelines: An allergy focus.

Medical evaluation for military applicants is an intricate process that requires an understanding of the terminology, standards, and guidelines. Allergy providers are often called to provide medical evaluations for patients who desire to join the military services. Without understanding the complexities and nuances of military medical evaluations, a provider may delay or not be able to assist their patient in obtaining the desired goal of joining the services. This article reviews the terminology of military medical evaluations and the guidelines and processes for these evaluations. We also focus our discussion on common allergic conditions that may be disqualifying for service and provide expert opinions of the subtleties of these conditions to provide the allergist with a practical approach to medical evaluations. Finally, we provide a list of resources that are accessible to any provider engaged in military medical evaluations for accessions.

Genomic antagonism between retinoic acid and estrogen signaling in breast cancer.

Retinoic acid (RA) triggers antiproliferative effects in tumor cells, and therefore RA and its synthetic analogs have great potential as anticarcinogenic agents. Retinoic acid receptors (RARs) mediate RA effects by directly regulating gene expression. To define the genetic network regulated by RARs in breast cancer, we identified RAR genomic targets using chromatin immunoprecipitation and expression analysis. We found that RAR binding throughout the genome is highly coincident with estrogen receptor alpha (ERalpha) binding, resulting in a widespread crosstalk of RA and estrogen signaling to antagonistically regulate breast cancer-associated genes. ERalpha- and RAR-binding sites appear to be coevolved on a large scale throughout the human genome, often resulting in competitive binding activity at nearby or overlapping cis-regulatory elements. The highly coordinated intersection between these two critical nuclear hormone receptor signaling pathways provides a global mechanism for balancing gene expression output via local regulatory interactions dispersed throughout the genome.

Fluorescence imaging to visualize the recurrent laryngeal nerve during thyroidectomy procedures: analysis of 65 cases and 81 nerves.

BACKGROUND: Recurrent laryngeal nerve (RLN) injury after thyroidectomy is relatively common. Locating the RLN prior to thyroid dissection is paramount to avoid injury. We developed a fluorescence imaging system that permits nerve autofluorescence. We aimed to determine the sensitivity and specificity of fluorescence imaging at detecting the RLN relative to thyroid and other background tissue and compared it to white light. METHODS: In this prospective study, 65 patients underwent thyroidectomy from January to April 2022 (16 bilateral thyroid resections) using white and fluorescent light. Fluorescence intensity [relative fluorescence units (RFU)] was recorded for RLN, thyroid, and background. RFU mean, minimum, and maximum values were calculated using Image J software. Thirty randomly selected pairs of white and fluorescent light images were independently reviewed by two examiners to compare RLN detection rate, number of branches, and length and minimum width of nerves visualized. Parametric and nonparametric statistical analysis was performed. RESULTS: All 81 RNLs observed were visualized more clearly under fluorescence (mean intensity, µ = 134.3 RFU) than either thyroid (µ = 33.7, p < 0.001) or background (µ = 14.4, p < 0.001). Forest plots revealed no overlap between RLN intensity and that of either other tissue. Sensitivity and specificity for RLN were 100%. All 30 RLNs and all 45 nerve branches were clearly visualized under fluorescence, versus 17 and 22, respectively, with white light (both p < 0.001). Visible nerve length was 2.5 × as great with fluorescence as with white light (µ = 1.90 vs. 0.76 cm, p < 0.001). CONCLUSIONS: In 65 patients and 81 nerves, RLN detection was markedly and consistently enhanced with autofluorescence neuro-imaging during thyroidectomy, with 100% sensitivity and specificity.

Metabolic Regulation of Gene Expression by Histone Lysine ß-Hydroxybutyrylation.

Here we report the identification and verification of a ß-hydroxybutyrate-derived protein modification, lysine ß-hydroxybutyrylation (Kbhb), as a new type of histone mark. Histone Kbhb marks are dramatically induced in response to elevated ß-hydroxybutyrate levels in cultured cells and in livers from mice subjected to prolonged fasting or streptozotocin-induced diabetic ketoacidosis. In total, we identified 44 histone Kbhb sites, a figure comparable to the known number of histone acetylation sites. By ChIP-seq and RNA-seq analysis, we demonstrate that histone Kbhb is a mark enriched in active gene promoters and that the increased H3K9bhb levels that occur during starvation are associated with genes upregulated in starvation-responsive metabolic pathways. Histone ß-hydroxybutyrylation thus represents a new epigenetic regulatory mark that couples metabolism to gene expression, offering a new avenue to study chromatin regulation and diverse functions of ß-hydroxybutyrate in the context of important human pathophysiological states, including diabetes, epilepsy, and neoplasia.

An Update and Review of Clinical Outcomes Using Immunohistochemical Stains in Mohs Micrographic Surgery for Melanoma.

BACKGROUND: Mohs micrographic surgery (MMS) provides optimal margin control through complete peripheral and deep margin assessment. The treatment of melanoma using MMS has historically been limited by difficulty in interpreting melanocytes using frozen sections. Immunohistochemical (IHC) staining, a technique whereby chromogen-tagged antibodies are used to detect antigens of interest, has revolutionized the surgical treatment of melanoma. OBJECTIVES: This article provides an update and literature review of current IHC stains used in MMS for melanoma, their sensitivities and specificities, and clinical outcomes. MATERIALS AND METHODS: A PubMed search was performed using keywords including "immunohistochemistry," "staining," and "Mohs surgery." Articles related to the use of IHC staining for the treatment of melanoma with MMS were included. RESULTS: Six IHC stains met the criteria for the review including melanoma antigen recognized by T cells (MART-1), SRY-related HMG-box (SOX10), microphthalmia-associated transcription factor, HMB-45, MEL-5, S-100, and preferentially expressed antigen in melanoma. CONCLUSION: The adaptation of IHC methods to frozen sections has enabled MMS to become a preferred treatment option for melanoma in special-site areas. Future studies are needed to standardize IHC techniques and to define best practices when using frozen section in the treatment of melanoma.

Atypical cutaneous manifestations of methicillin resistant Staphylococcus aureus infections in two immunocompetent pediatric patients: Case reports and review of the literature.

Although many clinical variants of Staphylococcus aureus infection are well-recognized, atypical presentations may mimic other conditions. We describe two cases of atypical S. aureus infections in pediatric patients: a S. aureus infection presenting with a vesicopustular rash mimicking varicella zoster virus and a case of multifocal panniculitis. Both of these cases were specifically caused by methicillin-resistant S. aureus (MRSA). Additional cases of atypical S. aureus infections and presenting features from the current literature are also discussed.

Dopamine Measurement Using Engineered CNT-CQD-Polymer Coatings on Pt Microelectrodes.

This study aims to develop a microelectrode array-based neural probe that can record dopamine activity with high stability and sensitivity. To mimic the high stability of the gold standard method (carbon fiber electrodes), the microfabricated platinum microelectrode is coated with carbon-based nanomaterials. Carboxyl-functionalized multi-walled carbon nanotubes (COOH-MWCNTs) and carbon quantum dots (CQDs) were selected for this purpose, while a conductive polymer like poly (3-4-ethylene dioxythiophene) (PEDOT) or polypyrrole (PPy) serves as a stable interface between the platinum of the electrode and the carbon-based nanomaterials through a co-electrodeposition process. Based on our comparison between different conducting polymers and the addition of CQD, the CNT-CQD-PPy modified microelectrode outperforms its counterparts: CNT-CQD-PEDOT, CNT-PPy, CNT-PEDOT, and bare Pt microelectrode. The CNT-CQD-PPy modified microelectrode has a higher conductivity, stability, and sensitivity while achieving a remarkable limit of detection (LOD) of 35.20 ± 0.77 nM. Using fast-scan cyclic voltammetry (FSCV), these modified electrodes successfully measured dopamine's redox peaks while exhibiting consistent and reliable responses over extensive use. This electrode modification not only paves the way for real-time, precise dopamine sensing using microfabricated electrodes but also offers a novel electrochemical sensor for in vivo studies of neural network dynamics and neurological disorders.

Molecular profiling of a real-world breast cancer cohort with genetically inferred ancestries reveals actionable tumor biology differences between European ancestry and African ancestry patient populations.

BACKGROUND: Endocrine-resistant HR+/HER2- breast cancer (BC) and triple-negative BC (TNBC) are of interest for molecularly informed treatment due to their aggressive natures and limited treatment profiles. Patients of African Ancestry (AA) experience higher rates of TNBC and mortality than European Ancestry (EA) patients, despite lower overall BC incidence. Here, we compare the molecular landscapes of AA and EA patients with HR+/HER2- BC and TNBC in a real-world cohort to promote equity in precision oncology by illuminating the heterogeneity of potentially druggable genomic and transcriptomic pathways. METHODS: De-identified records from patients with TNBC or HR+/HER2- BC in the Tempus Database were randomly selected (N = 5000), with most having stage IV disease. Mutations, gene expression, and transcriptional signatures were evaluated from next-generation sequencing data. Genetic ancestry was estimated from DNA-seq. Differences in mutational prevalence, gene expression, and transcriptional signatures between AA and EA were compared. EA patients were used as the reference population for log fold-changes (logFC) in expression. RESULTS: After applying inclusion criteria, 3433 samples were evaluated (n = 623 AA and n = 2810 EA). Observed patterns of dysregulated pathways demonstrated significant heterogeneity among the two groups. Notably, PIK3CA mutations were significantly lower in AA HR+/HER2- tumors (AA = 34% vs. EA = 42%, P < 0.05) and the overall cohort (AA = 28% vs. EA = 37%, P = 2.08e-05). Conversely, KMT2C mutation was significantly more frequent in AA than EA TNBC (23% vs. 12%, P < 0.05) and HR+/HER2- (24% vs. 15%, P = 3e-03) tumors. Across all subtypes and stages, over 8000 genes were differentially expressed between the two ancestral groups including RPL10 (logFC = 2.26, P = 1.70e-162), HSPA1A (logFC = - 2.73, P = 2.43e-49), ATRX (logFC = - 1.93, P = 5.89e-83), and NUTM2F (logFC = 2.28, P = 3.22e-196). Ten differentially expressed gene sets were identified among stage IV HR+/HER2- tumors, of which four were considered relevant to BC treatment and were significantly enriched in EA: ERBB2_UP.V1_UP (P = 3.95e-06), LTE2_UP.V1_UP (P = 2.90e-05), HALLMARK_FATTY_ACID_METABOLISM (P = 0.0073), and HALLMARK_ANDROGEN_RESPONSE (P = 0.0074). CONCLUSIONS: We observed significant differences in mutational spectra, gene expression, and relevant transcriptional signatures between patients with genetically determined African and European ancestries, particularly within the HR+/HER2- BC and TNBC subtypes. These findings could guide future development of treatment strategies by providing opportunities for biomarker-informed research and, ultimately, clinical decisions for precision oncology care in diverse populations.

Long-term adherence to imported fire ant subcutaneous immunotherapy.

BACKGROUND: Imported fire ant (IFA) whole-body extract subcutaneous immunotherapy (IT) is a safe and effective treatment for IFA hypersensitivity, with a recommended length of treatment of 3 to 5 years. OBJECTIVE: To evaluate long-term IFA IT adherence in patients with IFA allergy living in an endemic area. METHODS: During 2007 to 2014, patients with IFA-sting systemic reactions and a recommendation to start IFA IT were prospectively enrolled in this study. Subjects were contacted annually for interval IT adherence. Institutional review board approval was obtained. RESULTS: A total of 87 subjects, ages 2 to 64 years, with a recommendation to initiate IFA IT, were enrolled. Subjects were predominantly adult (76%) and female (55%), and 30% had asthma. Of these patients, 77 (89%) initiated treatment within 1 year of recommendation; 18 (23%) adhered to a 3-year course; and 10 (13%) adhered to a 5-year course. At 3 years, there were no significant differences in adherence between male and female subjects (28% vs 19%, P = .33), children and adults (25% vs 22%, P = .79), or those with or without asthma (30% vs 20%, P = .31). Adherence in subjects with mild initial reactions was lower than in subjects with moderate-to-severe reactions (0% vs 25%, P = .05) at 3 years only. Conventional buildup and concurrent flying Hymenoptera venom immunotherapy were predictive of adherence. Reasons for discontinuation were relocation to a nonendemic area (29%) and inconvenience (27%). CONCLUSION: This study showed poor long-term adherence to IFA IT at 3 and 5 years. Initial sting severity, buildup protocol, and concurrent flying Hymenoptera venom immunotherapy were predictors for long-term IT adherence.

Fire ant Immunotherapy with inteRvals Extended to 12 weekS: The FIRES study.

BACKGROUND: There are no studies describing 12-week extended maintenance interval (EMI) immunotherapy (IT) efficacy in preventing anaphylaxis to imported fire ant (IFA) stings. OBJECTIVE: The purpose of this study was to determine the safety and efficacy of 12-week maintenance intervals in patients treated with IFA IT. METHODS: After a minimum of 3 months of conventional maintenance interval IT and verification of baseline efficacy, adults with IFA hypersensitivity were prospectively enrolled and extended their maintenance doses to 6-, 8-, and 12-week intervals. Efficacy was confirmed by means of an annual IFA sting challenge. RESULTS: A total of 25 patients initiated EMI. The severity of their initial systemic reactions was mild in 8 patients (32%), moderate in 10 patients (40%), and severe in 7 patients (28%). Maintenance IT duration at trial entry was less than 3 years in 18 patients (mean 11 months; range 3-28 months), 3 to 5 years in 4 patients (mean 46 months; range 36-57 months), and greater than 5 years in 5 patients (mean 111 months; range 67-197 months). The treatment cohort did not experience systemic reactions to extended interval injections, cluster refill injections, field stings, or sting challenges. CONCLUSION: This prospective longitudinal cohort study revealed that in adults 18 years old or older who have received at least 3 months of maintenance dose IFA-whole body extract IT with proven efficacy, extension to a 12-week EMI is a safe effective treatment option. The benefits of EMI include a reduced number of injections, clinic visits, and lapses in maintenance IT.

Spatial and Temporal Trends of Persistent Organic Pollutants across Europe after 15 Years of MONET Passive Air Sampling.

The Global Monitoring Plan of the Stockholm Convention on Persistent Organic Pollutants (POPs) was established to generate long-term data necessary for evaluating the effectiveness of regulatory measures at a global scale. After 15 years of passive air monitoring (2003-2019), MONET is the first network to produce sufficient data for the analysis of continuous long-term temporal trends of POPs in air across the entire European continent. This study reports long-term concentrations of 20 POPs monitored at 32 sites in 27 European countries. As of January 1, 2019, the concentration ranges (pg/m3) were 1.1-52.8 (∑6PCB), 0.3-8.5 (∑12dl-PCB), 0.007-0.175 (∑17PCDD/F), 0.02-2.2 (∑9PBDE), 0.4-24.7 (BDE 209), 0.5-247 (∑6DDT), 1.7-818 (∑4HCH), 15.8-74.7 (HCB), and 5.9-21.5 (PeCB). Temporal trends indicate that concentrations of most POPs have declined significantly over the past 15 years, with median annual decreases ranging from -8.0 to -11.5% (halving times of 6-8 years) for ∑6PCB, ∑17PCDD/F, HCB, PeCB, and ∑9PBDE. Furthermore, no statistically significant differences were observed in either the trends or the concentrations of specific POPs at sites in Western Europe (WEOG) compared to sites in Central and Eastern Europe (CEE), which suggests relatively uniform compound-specific distribution and removal at the continental scale.

Distinct genomic features in a retrospective cohort of mucosal, acral, and vulvovaginal melanomas.

BACKGROUND: Compared with sun-exposed melanomas, less is known regarding the pathogenesis of sun-protected melanomas. Sun-protected melanomas share many epidemiologic factors, but their genetic heterogeneity is not well studied. OBJECTIVE: We investigated the genomic profile of acral, mucosal, and vulvovaginal melanomas. We hypothesize that mucosal melanomas, recognized for their uniquely aggressive clinical behavior, have distinct genomic features. METHODS: We performed whole transcriptome messenger RNA and DNA (1711 genes) sequencing, messenger RNA expression profiling, tumor mutational burden, ultraviolet signature, and copy number variants analysis on 29 volar/digital acral, 7 mucosal, and 6 vulvovaginal melanomas. RESULTS: There was significant genetic heterogeneity, particularly in acral melanomas, with 36% having BRAF alterations, whereas other melanomas had none (P = .0159). Nonzero ultraviolet signatures were more frequent in acral melanomas, suggesting greater ultraviolet involvement. Mucosal melanomas formed a distinct group with increased expression of cell cycle and proliferation genes. Various targetable aberrations were identified, such as AURKA and ERBB2, in mucosal and acral melanomas, respectively. LIMITATIONS: The sample size was a small. CONCLUSION: There is significant genetic heterogeneity among sun-protected melanomas. Mucosal melanomas have upregulation in cell cycle and proliferation genes, which may explain their aggressive behavior. Ultraviolet radiation plays some role in a subset of acral but not other melanomas.