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Binturong (Arctictis binturong) is a threatened carnivore that inhabits the forests of South and Southeast Asia. Despite its wide range, binturong is relatively scarce across its habitat distribution and is currently under the threat of poaching and illegal trade. Captive breeding has unfortunately been conducted rather haphazardly with a lack of origin record maintained, implicating potential risks to the management such as inbreeding or genetic swamping. This study thus aims to characterise the phylogenetic relationship of Indonesian binturong within the context of Southeast Asian binturong and further probe the distinctness of lineages originating from Java, Sumatra, Indonesian Borneo, and Bangka using Cytochrome B (CytB) and Cytochrome C Oxidase Subunit 1 (CO1). Genetic distance, phylogram topology, and haplotype analysis of both encoding genes further corroborate the distinctness of Java, Borneo, and Bangka binturong from other binturong from Indochinese regions such as India, Laos, and Myanmar. Search for prospective single nucleotide polymorphism markers to discriminate island lineages consistently found that each Java, Bangka, and Bornean binturong be distinct from each other and other lineages, especially when assessed using haplotype-based clustering. Assigning binturong originated from Sumatra is nonetheless more complicated, suggesting the possibility. Our findings substantiated the much-needed systematic research of Southeast Asian binturong as ex-situ insurance population management grows in Indonesia and other parts of the world to protect the diversity of binturong lineages and their corresponding unique evolutionary history. [ABSTRACT FROM AUTHOR]

Rapid anthropogenic climate change has elevated the interest in studying the biotic responses of species during the Last Glacial Maximum. During this period, species retreated to highly spatially restricted geographic regions where survival was possible, known as glacial micro-refugia, from which they migrated and expanded when conditions became more suitable. Several distinct sources of evidence have contributed to developing a new understanding of how these regions might have impacted the sustainability of the natural populations of many species. Pollen records in Eastern Beringia have been used to explore the possibility that the region harbored glacial refugia for several plants from the arctic tundra and/or the boreal forest biomes common to the region. Our study focuses on Alnus viridis and Picea glauca, two predominant species of arcto-boreal vegetation. We propose to integrate genomic, SDM, and existing fossil data in a hierarchical Bayesian modeling (HBM) framework to determine whether multiple refugia existed in isolated geographic areas. This study demonstrates how the flexibility of HBMs makes the formal synthesis of such disparate data sources feasible. Our results highlight the regions of plausible refugia that can guide future investigations into studying the role of glacial refugia during climate change. Supplementary materials accompanying this paper appear online. [ABSTRACT FROM AUTHOR]

Purpose: Rett syndrome is a rare neurodevelopmental disorder associated with methyl CpG binding protein 2 (MECP2) gene mutations. We aimed to characterize the long-term nutritional and gastrointestinal course of Rett syndrome in a large national patient population. Methods: We conducted a retrospective cohort study of patients followed during 1991–2021 at a national center for Rett syndrome. The data retrieved included clinical features, laboratory and genetic analyses. Continuous anthropometric measurements were calculated for the closest visit to the median ages: 2.5, 7.5, 12.5 and 17.5 years. Kaplan Meier curves were used to describe the appearance of clinical manifestations during the follow up period. Generalized estimating equation models were used to compare repeated measurements. Results: Included were 141 patients (139 females), the median age at the first visit was 3.2 years (interquartile range [IQR] 2.3–5.7), and the median length of follow-up was 94.5 months (IQR 28.6–153.3). Mean weight, height and BMI Z-scores were -1.09, -1.03 and -0.56, respectively, at median age 2.5 years; and deteriorated to -3.95, -3.01 and -1.19, respectively, at median age 17.5 years (P < 0.001). Gastrointestinal features included constipation (47.5%, 67/141) and chewing/feeding difficulties (20%, 28/141) at presentation; and an additional 47 (33.3%) and 24 (17.0%), respectively, during follow up. Twenty-eight patients (20%) developed aerophagia and 44 (31.2%) gastroesophageal reflux. No relation was found between genetic mutation types and clinical manifestations. GI manifestations were more prevalent in patients with typical form of Rett syndrome. Conclusions: Anthropometric parameters were shown to deteriorate with age, regardless of the specific genetic mutation. Chewing/feeding difficulties, constipation and gastroesophageal reflux are common in Rett patients. [ABSTRACT FROM AUTHOR]

Background: Twin studies revealed that genetic effects play a role in hand eczema (HE), but the responsible genetic factors are unknown. Objectives: To identify and characterise genetic loci associated with HE and to provide insight into the genetic overlap between HE and atopic dermatitis (AD). Methods: We used questionnaire‐derived and genotype data from the European population‐based Lifelines cohort and biobank. We performed a discovery genome‐wide association study (GWAS) of HE (2879 cases and 16 249 controls) and of AD (1706 cases and 17 190 controls). We replicated our findings in an independent Lifelines sample for HE (1188 cases and 6431 controls) and AD (757 cases and 6747 controls). We conducted several post‐GWAS analyses and performed genetic correlation analyses between our HE results and independent AD data. Results: The two‐step GWAS of HE, regardless of adjusting for AD, identified one independent locus 20q13.33, likely driven by a number of causal single‐nucleotide polymorphisms. For the AD GWAS, we replicated a known stop‐gained rs61816761 at locus 1q21.3 (FLG, FLGAS1). We found a strong genetic correlation (p < 0.01) between HE and AD (rg = 0.65), regardless of adjusting for AD (rg = 0.63). Conclusions: Locus 20q13.33 is associated with HE, and there is a large genetic overlap between HE and AD. [ABSTRACT FROM AUTHOR]

Maintaining good health is crucial, and exercise plays a vital role in achieving this goal. It offers a range of positive benefits for cognitive function, regardless of age. However, as our population ages and life expectancy increases, cognitive impairment has become a prevalent issue, often coexisting with age-related neurodegenerative conditions. This can result in devastating consequences such as memory loss, difficulty speaking, and confusion, greatly hindering one's ability to lead an ordinary life. In addition, the decrease in mental capacity has a significant effect on an individual's physical and emotional well-being, greatly reducing their overall level of contentment and causing a significant financial burden for communities. While most current approaches aim to slow the decline of cognition, exercise offers a non-pharmacological, safe, and accessible solution. Its effects on cognition are intricate and involve changes in the brain's neural plasticity, mitochondrial stability, and energy metabolism. Moreover, exercise triggers the release of cytokines, playing a significant role in the body–brain connection and its impact on cognition. Additionally, exercise can influence gene expression through epigenetic mechanisms, leading to lasting improvements in brain function and behavior. Herein, we summarized various genetic and epigenetic mechanisms that can be modulated by exercise in cognitive dysfunction. [ABSTRACT FROM AUTHOR]

Growth and reproductive performance traits are important economic indicators for analyzing the overall performance of breeding systems. This study aims to evaluate the comparative performance of two Algerian sheep (Rumbi and Hamra) in terms of growth and reproductive performance, and the effect of factors such as breed, season of birth, mode of birth and age of the mother on this performance in a semi-intensive breeding system. The reproductive performance of 577 Rumbi ewes and 1328 Hamra ewes bred at the Tiaret and Saïda experimental stations respectively, was analyzed using performance monitoring data. Fertility rates for the Rumbi and Hamra breeds of 87.14% and 78.8% respectively were practically similar (p > 0,05). Litter size at birth and weaning was significantly higher in the Hamra breed than in the Rumbi breed (p < 0,05). Weaning mortality was significantly higher in the Hamra breed than in the Rumbi breed, with an average of 22.60% versus 14.94% (p < 0,05). The effect of factors showed that there was a highly significant effect of the mother’s age and season of birth on the reproductive performance of the Hamra and Rumbi breeds with a p < 0.0001 on fertility, litter size at birth, litter size at weaning and fertility. There was a significant effect of the year factor on reproductive performance with p = 0,013 for the Hamra breed and p = 0,031 for the Rumbi breed. The results of this study showed that Rumbi lambs were heavier at birth than Hamra lambs. The values observed were 4,86 kg versus 3,10 kg for the Hamra breed, with a highly significant difference (p < 0,0001), so that the average daily pre-weaning weight gains of Rumbi lambs were higher than those of Hamra lambs, at 0,195 kg/day versus 0,113 kg/day for Hamra lambs, with a high significance (p < 0,0001). The effect of factors showed that there was a significant effect of the mother’s age on the ADGs (0–30), (30–70) and (70–90) of the Hamra and Rumbi breeds with a p = 0,034 and p = 0,02 respectively. There was also a highly significant effect of the birth mode effect on ADGs (0–30), (30–70) and (70–90) only for the Hamra breed with a p = 0,004. The effect of the birth weight on ADGs was not significant for both Hamra and Rumbi breeds with a p > 0,05. According to the findings of this study, the Hamra breed had superior reproductive potential and the Rumbi breed had superior growth. The Hamra breed showed better maternal skills in terms of fertility and prolificacy, while the Rumbi breed showed better lamb growth performance. Consequently, these results could be used for selective sheep breeding, taking into account the random effects of the environment and the potential of each breed. [ABSTRACT FROM AUTHOR]

This experiment evaluated growth traits and estimated genetic parameters of offspring (F2)crossbreed of exotic and local birds in University of Nigeria Nsukka farm. A total of 240 F2 hatched chicks from the genotype groups of F1 (offspring of first filial generation)were used for this experiment. The chicks were brooded in groups according to their genotypes for six weeks. Parameters measured include; body weight, body length, thigh length, and shank length from which heritability were estimated. The result shows that Amo cock x Isa brown hen genotype (AC x IBH f2) was significantly (p<0.05) higher in body weight than other genotypes in all the weeks considered with a mean weight of 46.67±0.33 at 1st week and 1365.00±56.75at 12thweeks of age, followed by Amo cock x heavy ecotype hen genotype (AC x HEH f2) with a mean weight of 41.00±1.00 and 1253.00±69.51 at 1stand 12thweeks respectively. Heritability in week one were found to be low in all the traits observed except in body weight and body length of AC x IBH f2 with h²s of 0.941 and 0.360 for body weight and body length respectively. It could be concluded therefore that crossbreeding of Nigeria local birds with a proven exotic birds increases production performance. Also additive gene effect was stronger than the nonadditive gene effect, epitasis or even environmental factors. [ABSTRACT FROM AUTHOR]

Background and Hypothesis Schizophrenia (SCZ) and anorexia nervosa (AN) are 2 severe and highly heterogeneous disorders showing substantial familial co-aggregation. Genetic factors play a significant role in both disorders, but the shared genetic etiology between them is yet to be investigated. Study Design Using summary statistics from recent large genome-wide association studies on SCZ (N cases = 53 386) and AN (N cases = 16 992), a 2-sample Mendelian randomization analysis was conducted to explore the causal relationship between SCZ and AN. MiXeR was employed to quantify their polygenic overlap. A conditional/conjunctional false discovery rate (condFDR/conjFDR) framework was adopted to identify loci jointly associated with both disorders. Functional annotation and enrichment analyses were performed on the shared loci. Study Results We observed a cross-trait genetic enrichment, a suggestive bidirectional causal relationship, and a considerable polygenic overlap (Dice coefficient = 62.2%) between SCZ and AN. The proportion of variants with concordant effect directions among all shared variants was 69.9%. Leveraging overlapping genetic associations, we identified 6 novel loci for AN and 33 novel loci for SCZ at condFDR <0.01. At conjFDR <0.05, we identified 10 loci jointly associated with both disorders, implicating multiple genes highly expressed in the cerebellum and pituitary and involved in synapse organization. Particularly, high expression of the shared genes was observed in the hippocampus in adolescence and orbitofrontal cortex during infancy. Conclusions This study provides novel insights into the relationship between SCZ and AN by revealing a shared genetic component and offers a window into their complex etiology. [ABSTRACT FROM AUTHOR]

Background The ganglionic eminences (GE) are fetal-specific structures that give rise to gamma-aminobutyric acid (GABA)- and acetylcholine-releasing neurons of the forebrain. Given the evidence for GABAergic, cholinergic, and neurodevelopmental disturbances in schizophrenia, we tested the potential involvement of GE neuron development in mediating genetic risk for the condition. Study Design We combined data from a recent large-scale genome-wide association study of schizophrenia with single-cell RNA sequencing data from the human GE to test the enrichment of schizophrenia risk variation in genes with high expression specificity for developing GE cell populations. We additionally performed the single nuclei Assay for Transposase-Accessible Chromatin with Sequencing (snATAC-Seq) to map potential regulatory genomic regions operating in individual cell populations of the human GE, using these to test for enrichment of schizophrenia common genetic variant liability and to functionally annotate non-coding variants-associated with the disorder. Study Results Schizophrenia common variant liability was enriched in genes with high expression specificity for developing neuron populations that are predicted to form dopamine D1 and D2 receptor-expressing GABAergic medium spiny neurons of the striatum, cortical somatostatin-positive GABAergic interneurons, calretinin-positive GABAergic neurons, and cholinergic neurons. Consistent with these findings, schizophrenia genetic risk was concentrated in predicted regulatory genomic sequence mapped in developing neuronal populations of the GE. Conclusions Our study implicates prenatal development of specific populations of GABAergic and cholinergic neurons in later susceptibility to schizophrenia, and provides a map of predicted regulatory genomic elements operating in cells of the GE. [ABSTRACT FROM AUTHOR]

In the realm of maritime emergencies, unmanned aerial vehicles (UAVs) play a crucial role in enhancing search and rescue (SAR) operations. They help in efficiently rescuing distressed crews, strengthening maritime surveillance, and maintaining national security due to their cost-effectiveness, versatility, and effectiveness. However, the vast expanse of sea territories and the rapid changes in maritime conditions make a single SAR center insufficient for handling complex emergencies. Thus, it is vital to develop strategies for quickly deploying UAV resources from multiple SAR centers for area reconnaissance and supporting maritime rescue operations. This study introduces a graph-structured planning model for the maritime SAR path planning problem, considering multiple rescue centers (MSARPPP-MRC). It incorporates workload distribution among SAR centers and UAV operational constraints. We propose a reinforcement learning-based genetic algorithm (GA-RL) to tackle the MSARPPP-MRC problem. GA-RL uses heuristic rules to initialize the population and employs the Q-learning method to manage the progeny during each generation, including their retention, storage, or disposal. When the elite repository's capacity is reached, a decision is made on the utilization of these members to refresh the population. Additionally, adaptive crossover and perturbation strategies are applied to develop a more effective SAR scheme. Extensive testing proves that GA-RL surpasses other algorithms in optimization efficacy and efficiency, highlighting the benefits of reinforcement learning in population management. [ABSTRACT FROM AUTHOR]

Background and Objectives: The aim of the following cross-sectional study is to determine the association between human leukocyte antigen (HLA) alleles and outcomes in patients presenting to the emergency department (ED) with SARS-CoV-2 infection. Methods and Materials: Genotyping was made using the Axiom Human Genotyping SARS-CoV-2 Research Array. Statistical analysis was made with Fisher's exact test and multivariable logistic regression, adjusted for sex, age and clinical variables. Results: Of 190 patients, 11.1% were discharged from the ED; 57.9% were admitted to the COVID-19 ward, without intensive care unit (ICU) admission; 15.3% survived an ICU admission; and 15.8% died. After multivariable analysis, two HLA alleles protected against hospital admission (HLA-C*05:01, adjusted odds ratio [aOR] 0.2, 95% confidence interval [CI] 0.055–0.731; and HLA-DQB1*02:02, aOR 0.046, CI 0.002–0.871) and one was associated with higher risk for ICU admission or death (HLA-DQA1*05:01, aOR 2.517, CI 1.086–5.833). Conclusions: In this population, HLA-C*05:01 and HLA-DQB1*02:02 are associated with a protective effect against hospital admission and HLA-DQA1*05:01 is associated with higher risk of ICU admission or death in the multivariable analysis. This may help stratify risk in COVID-19 patients. [ABSTRACT FROM AUTHOR]

Preimplantation genetic testing for aneuploidy (PGT-A) has become a useful approach for embryo selection following IVF and ICSI. However, the biopsy process associated with PGT-A is expensive, prone to errors in embryo ploidy determination, and potentially damaging, impacting competence and implantation potential. Therefore, a less invasive method of PGT-A would be desirable and more cost-effective. Noninvasive methods for PGT-A (ni-PGT-A) have been well-studied but present limitations in terms of cf-DNA origin and diagnostic accuracy. Minimally invasive pre-implantation genetic testing (mi-PGT-A) for frozen-thawed embryo transfer is a promising, less studied approach that utilizes a combination of spent culture media (SCM) and blastocoelic fluid (BF)-derived cell-free (CF)-DNA for genetic testing. This study aimed to optimize the effectiveness of mi-PGT-A for aneuploidy diagnosis by investigating the optimal temporal sequence for this protocol. SCM+BF was collected at either 48 or 72 h of culture after thawing day 3 preimplantation embryos. cf-DNA in the SCM+BF was amplified, analyzed by next-generation sequencing (NGS) and compared with results from the corresponding whole embryos (WEs) obtained from human embryos donated for research. Fifty-three (42 expanded blastocysts, 9 early blastocysts, and 2 morula) WE and SCM+BF samples were analyzed and compared. The overall concordance rate between SCM+BF and WE was 60%. Gender and ploidy concordance improved with extended culture time from 48 h (73% and 45%) to 72 h (100% and 64%), respectively. These results demonstrate that SCM+BF-derived cf-DNA can be successfully used for mi-PGT-A. Our findings indicate that longer embryo culture time prior to SCM+BF-derived cf-DNA analysis improves DNA detection rate and concordance with WEs and decreases the proportion of false positive results. [ABSTRACT FROM AUTHOR]

Circulating vitamin B12 concentrations during pregnancy are associated with offspring health. Foetal DNA methylation changes could underlie these associations. Within the Pregnancy And Childhood Epigenetics Consortium, we meta-analysed epigenome-wide associations of circulating vitamin B12 concentrations in mothers during pregnancy (n = 2,420) or cord blood (n = 1,029), with cord blood DNA methylation. Maternal and newborn vitamin B12 concentrations were associated with DNA methylation at 109 and 7 CpGs, respectively (False Discovery Rate P-value

Teleost fishes, which are the largest and most diverse group of living vertebrates, have a rich history of ancient and recent polyploidy. Previous studies of allotetraploid common carp and goldfish (cyprinids) reported a dominant subgenome, which is more expressed and exhibits biased gene retention. However, the underlying mechanisms contributing to observed subgenome dominance remains poorly understood. Here we report high-quality genomes of twenty-one cyprinids to investigate the origin and subsequent subgenome evolution patterns following three independent allopolyploidy events. We identify the closest extant relatives of the diploid progenitor species, investigate genetic and epigenetic differences among subgenomes, and conclude that observed subgenome dominance patterns are likely due to a combination of maternal dominance and transposable element densities in each polyploid. These findings provide an important foundation to understanding subgenome dominance patterns observed in teleost fishes, and ultimately the role of polyploidy in contributing to evolutionary innovations.

Ancestral Coast Salish societies in the Pacific Northwest kept long-haired woolly dogs that were bred and cared for over millennia. However, the dog wool-weaving tradition declined during the 19th century, and the population was lost. In this study, we analyzed genomic and isotopic data from a preserved woolly dog pelt from Mutton, collected in 1859. Mutton is the only known example of an Indigenous North American dog with dominant precolonial ancestry postdating the onset of settler colonialism. We identified candidate genetic variants potentially linked with their distinct woolly phenotype. We integrated these data with interviews from Coast Salish Elders, Knowledge Keepers, and weavers about shared traditional knowledge and memories surrounding woolly dogs, their importance within Coast Salish societies, and how colonial policies led directly to their disappearance.

Genetic logic gates can be employed in metabolic engineering and synthetic biology to regulate gene expression based on diverse inputs. Design of tunable genetic logic gates with versatile dynamic performance is essential for expanding the usability of these toolsets. Here, using the p-coumaric acid biosensor system as a proof-of-concept, we initially investigated the parameters influencing the buffer (BUF) genetic logic gates. Subsequently, integrating binding sequences from the p-coumaric acid biosensor system and tetR or lacI regulation systems into a constitutive promoter yielded AND genetic logic gates. Additionally, characterized antisense RNAs (asRNAs) or single guide RNAs (sgRNAs) with various repression efficiencies were combined with BUF gates to construct a suite of p-coumaric acid-triggered NOT genetic logic gates. Finally, the designed BUF and NOT gates were combined to construct bifunctional genetic circuits that were subjected to orthogonality evaluation. The genetic logic gates established in this study can serve as valuable tools in future applications of metabolic engineering and synthetic biology.

Endogenous retroviruses (ERVs) are remnants of ancient parasitic infections and comprise sizable portions of most genomes. Although epigenetic mechanisms silence most ERVs by generating a repressive environment that prevents their expression (heterochromatin), little is known about mechanisms silencing ERVs residing in open regions of the genome (euchromatin). This is particularly important during embryonic development, where induction and repression of distinct classes of ERVs occur in short temporal windows. Here, we demonstrate that transcription-associated RNA degradation by the nuclear RNA exosome and Integrator is a regulatory mechanism that controls the productive transcription of most genes and many ERVs involved in preimplantation development. Disrupting nuclear RNA catabolism promotes dedifferentiation to a totipotent-like state characterized by defects in RNAPII elongation and decreased expression of long genes (gene-length asymmetry). Our results indicate that RNA catabolism is a core regulatory module of gene networks that safeguards RNAPII activity, ERV expression, cell identity, and developmental potency.

Maternal diabetes mellitus is among the most frequent environmental contributors to congenital birth defects, including heart defects and craniofacial anomalies, yet the cell types affected and mechanisms of disruption are largely unknown. Using multi-modal single cell analyses, here we show that maternal diabetes affects the epigenomic landscape of specific subsets of cardiac and craniofacial progenitors during embryogenesis. A previously unrecognized cardiac progenitor subpopulation expressing the homeodomain-containing protein ALX3 showed prominent chromatin accessibility changes and acquired a more posterior identity. Similarly, a subpopulation of neural crest-derived cells in the second pharyngeal arch, which contributes to craniofacial structures, displayed abnormalities in the epigenetic landscape and axial patterning defects. Chromatin accessibility changes in both populations were associated with increased retinoic acid signaling, known to establish anterior-posterior identity. This work highlights how an environmental insult can have highly selective epigenomic consequences on discrete cell types leading to developmental patterning defects.

Cytosine DNA methylation is essential in brain development and is implicated in various neurological disorders. Understanding DNA methylation diversity across the entire brain in a spatial context is fundamental for a complete molecular atlas of brain cell types and their gene regulatory landscapes. Here we used single-nucleus methylome sequencing (snmC-seq3) and multi-omic sequencing (snm3C-seq)1 technologies to generate 301,626 methylomes and 176,003 chromatin conformation-methylome joint profiles from 117 dissected regions throughout the adult mouse brain. Using iterative clustering and integrating with companion whole-brain transcriptome and chromatin accessibility datasets, we constructed a methylation-based cell taxonomy with 4,673 cell groups and 274 cross-modality-annotated subclasses. We identified 2.6 million differentially methylated regions across the genome that represent potential gene regulation elements. Notably, we observed spatial cytosine methylation patterns on both genes and regulatory elements in cell types within and across brain regions. Brain-wide spatial transcriptomics data validated the association of spatial epigenetic diversity with transcription and improved the anatomical mapping of our epigenetic datasets. Furthermore, chromatin conformation diversities occurred in important neuronal genes and were highly associated with DNA methylation and transcription changes. Brain-wide cell-type comparisons enabled the construction of regulatory networks that incorporate transcription factors, regulatory elements and their potential downstream gene targets. Finally, intragenic DNA methylation and chromatin conformation patterns predicted alternative gene isoform expression observed in a whole-brain SMART-seq2 dataset. Our study establishes a brain-wide, single-cell DNA methylome and 3D multi-omic atlas and provides a valuable resource for comprehending the cellular-spatial and regulatory genome diversity of the mouse brain.

Antagonistic selection has long been considered a major driver of the formation and expansion of sex chromosomes. For example, sexually antagonistic variation on an autosome can select for suppressed recombination between that autosome and the sex chromosome, leading to a neo-sex chromosome. Autosomal supergenes, chromosomal regions containing tightly linked variants affecting the same complex trait, share similarities with sex chromosomes, raising the possibility that sex chromosome evolution models can explain the evolution of genome structure and recombination in other contexts. We tested this premise in a Formica ant species, wherein we identified four supergene haplotypes on chromosome 3 underlying colony social organization and sex ratio. We discovered a novel rearranged supergene variant (9r) on chromosome 9 underlying queen miniaturization. The 9r is in strong linkage disequilibrium with one chromosome 3 haplotype (P2) found in multi-queen (polygyne) colonies. We suggest that queen miniaturization is strongly disfavored in the single-queen (monogyne) background and is thus socially antagonistic. As such, divergent selection experienced by ants living in alternative social "environments" (monogyne and polygyne) may have contributed to the emergence of a genetic polymorphism on chromosome 9 and associated queen-size dimorphism. Consequently, an ancestral polygyne-associated haplotype may have expanded to include the polymorphism on chromosome 9, resulting in a larger region of suppressed recombination spanning two chromosomes. This process is analogous to the formation of neo-sex chromosomes and consistent with models of expanding regions of suppressed recombination. We propose that miniaturized queens, 16%-20% smaller than queens without 9r, could be incipient intraspecific social parasites.

BackgroundPolygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women.MethodsWe generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel.ResultsIn the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28).ConclusionsExtant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women.

Arboleda-Tham Syndrome (ARTHS) is a rare genetic disorder caused by heterozygous, de novo mutations in Lysine(K) acetyltransferase 6A (KAT6A). ARTHS is clinically heterogeneous and characterized by several common features, including intellectual disability, developmental and speech delay, and hypotonia, and affects multiple organ systems. KAT6A is the enzymatic core of a histone-acetylation protein complex; however, the direct histone targets and gene regulatory effects remain unknown. In this study, we use ARTHS patient (n = 8) and control (n = 14) dermal fibroblasts and perform comprehensive profiling of the epigenome and transcriptome caused by KAT6A mutations. We identified differential chromatin accessibility within the promoter or gene body of 23% (14/60) of genes that were differentially expressed between ARTHS and controls. Within fibroblasts, we show a distinct set of genes from the posterior HOXC gene cluster (HOXC10, HOXC11, HOXC-AS3, HOXC-AS2, and HOTAIR) that are overexpressed in ARTHS and are transcription factors critical for early development body segment patterning. The genomic loci harboring HOXC genes are epigenetically regulated with increased chromatin accessibility, high levels of H3K23ac, and increased gene-body DNA methylation compared to controls, all of which are consistent with transcriptomic overexpression. Finally, we used unbiased proteomic mass spectrometry and identified two new histone post-translational modifications (PTMs) that are disrupted in ARTHS: H2A and H3K56 acetylation. Our multi-omics assays have identified novel histone and gene regulatory roles of KAT6A in a large group of ARTHS patients harboring diverse pathogenic mutations. This work provides insight into the role of KAT6A on the epigenomic regulation in somatic cell types.

Early recognition of hereditary urological cancers may influence diagnostic and therapeutic decision-making, and potentially alter the fate of patients and family members. Here, we introduce readers to the current knowledge on germline genetic testing and clinical practice in prostate, bladder, renal, and testicular carcinoma. Considering all urological cancer patients, routine inquiries about familial cancer history should become a standard practice in clinical settings. If suspicion arises, patients can opt for two avenues: referral to genetic counseling or undergoing genetic tests after consultation with the treating urologist. Patient summary: Tumors of the urogenital tract (prostate, kidney, bladder, and testes) can sometimes be related to genetic mutations that are present in all the cells of the body. Such mutations can be inherited and run in families. Therefore, it is relevant to obtain information on the incidence of all cancers in the family history. The information obtained may initiate genetic testing, leading to the identification of mutations that are related to cancer in the current or next generation. In addition, these mutations may offer alternative treatment options for patients.

Breast cancer (BC) is a heterogeneous disease characterized by significant global mortality and incidence rates. Annually, approximately 1 million cases of BC are diagnosed worldwide, with over 170,000 classified as triple-negative. Triple-negative breast cancer (TNBC) is a particularly aggressive subtype lacking targeted therapeutic options, which contributes to poorer outcomes compared to other BC subtypes. The five-year survival rate for patients with TNBC is roughly 30% lower than that for patients with other subtypes. TNBC treatment options are limited to surgery, radiotherapy, and chemotherapy. There is a critical need for the development of targeted therapies. Enhancing early detection through effective diagnostic and prognostic biomarkers can significantly improve survival rates. This review explores recent advancements in clinically relevant proteomic, genetic, and metabolomic biomarkers for TNBC, highlighting their potential roles as prognostic, diagnostic, and predictive markers that could facilitate personalized treatment approaches.

ABSTRACT: As the proportion of prime carcasses originating from dairy herds increases, the focus is shifting to the beef merit of the progeny from dairy herds. Several dairy cow total merit indexes include a negative weight on measures of cow size. However, there is a lack of knowledge on the effect of genetic selection, solely for lighter or smaller-sized dairy cows, on the beef performance of their progeny. Therefore, the objective of this study was to quantify the genetic correlations among cow size traits (i.e., cow BW, cow carcass weight [CW]), cow BCS, cow carcass conformation (CC), and cow carcass fat cover (CF), as well as the correlations between these cow traits and a series of beef performance slaughter-related traits (i.e., CW, CC, CF, and age at slaughter [AS]) in their progeny. After data editing, there were 52,950 cow BW and BCS records, along with 57,509 cow carcass traits (i.e., CW, CC, and CF); carcass records from 346,350 prime animals along with AS records from 316,073 prime animals were also used. Heritability estimates ranged from moderate to high (0.18–0.62) for all cow and prime animal traits. The same carcass trait in cows and prime animals were strongly genetically correlated with each other (0.76–0.85), implying that they are influenced by very similar genomic variants. Selecting exclusively for cows with higher BCS (i.e., fatter) will, on average, produce more conformed prime animal carcasses, owing to a moderate genetic correlation (0.30) between both traits. Genetic correlations revealed that selecting exclusively for lighter BW or CW cows will, on average, result in lighter prime animal carcasses of poor CC, while also delaying slaughter age. Nonetheless, selective breeding through total merit indexes should be successful in breeding for smaller dairy cows and desirable prime animal carcass traits concurrently, because of the nonunity genetic correlations between the cow and prime animal traits; this will help to achieve a more ethical, environmentally sustainable, and economically viable dairy-beef industry.

Abstract Background The growing body of research on kidney disease in children has identified a broad spectrum of genetic etiologies. Methods We conducted a prospective study to evaluate the efficacy of an optimized genetic test and subclinical changes in a real-world context before kidney transplantation. All cases involved recipients under the age of 18 who underwent whole exome sequencing (ES) between 2013 and 2022. Results The study population included 244 children, with a median age of 13.1 years at transplantation. ES provided a molecular genetic diagnosis in 114 (46.7%) probands with monogenic variants in 15 known disease-causing genes. ES confirmed the suspected clinical diagnosis in 74/244 (30.3%) cases and revised the pre-exome clinical diagnoses in 40/244 (16.4%) cases. ES also established a specific underlying cause for kidney failure for 19 patients who had previously had an unknown etiology. Genetic diagnosis influenced clinical management in 88 recipients (36.1%), facilitated genetic counseling for 18 families (7.4%), and enabled comprehensive assessment of living donor candidates in 35 cases (14.3%). Conclusions Genetic diagnosis provides critical insights into the pathogenesis of kidney disease, optimizes clinical strategies concerning risk assessment of living donors, and enhances disease surveillance of recipients.

Abstract Aims Hypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic cardiac disorder characterized by unexplained left ventricular hypertrophy. It can cause a wide spectrum of clinical manifestations, ranging from asymptomatic to heart failure and sudden cardiac death (SCD). Approximately half of HCM cases are caused by variants in sarcomeric proteins, including α‐tropomyosin (TPM1). In this study, we aimed to characterize the clinical and molecular phenotype of HCM in an Iranian pedigree with SCD. Methods and Results The proband and available family members underwent comprehensive clinical evaluations, including echocardiography, cardiac magnetic resonance (CMR) imaging and electrocardiography (ECG). Whole‐exome sequencing (WES) was performed in all available family members to identify the causal variant, which was validated, and segregation analysis was conducted via Sanger sequencing. WES identified a novel missense variant, c.761A>G:p.D254G (NM_001018005.2), in the TPM1 gene, in the proband, his father and one of his sisters. Bioinformatic analysis predicted it to be likely pathogenic. Clinical features in affected individuals were consistent with HCM. Conclusions The identification of a novel TPM1 variant in a family with HCM and SCD underscores the critical role of genetic screening in at‐risk families. Early detection of pathogenic variants can facilitate timely intervention and management, potentially reducing the risk of SCD in individuals with HCM.

BACKGROUND AND OBJECTIVES: Introducing crossbred cattle in both lowland and highland regions is anticipated to enhance the productivity of indigenous breeds. Tropical environments present challenges such as acclimatization problems and decreased productivity. This study aims to test the influence of the interaction between genetic factors (crossbred cattle and local breeds) and environmental factors. This study is unique in its contribution of valuable insights into the potential interplay between tropical climate conditions and the genetic makeup of crossbred cattle. It sheds light on how this interaction influences the physiological and reproductive capabilities of the cattle, as well as the alterations in reproductive hormone secretion within this specific population. The results will serve as the main consideration for the development of crossbred cattle in tropical climates.METHODS: A fully randomized design incorporating three variables was employed in this study: altitude (highland and lowland), cattle breed (crossbred and local), and observation time. The study involved 357 cattle: 116 crossbred in the lowland, 67 crossbred in the highland, 93 local breed in the lowland, and 81 local breed in the highland. The environmental conditions, physiological status, hormone concentration, and reproductive performance were all part of the observations. Data was gathered every other day during each month, except for the hormone data, which was collected based on the oestrus cycle. The enzyme-linked immunosorbent assay method was utilized to analyze hormone concentrations. The data was analyzed using factorial patterns with SPSS 26, with Duncan''s multiple-range test analysis.FINDINGS: The main finding of this study indicates that altitude influences the genetic traits of cattle relevant to the journal''s scope. Variations in altitude and breed significantly affect physiological parameters such as sweating rate, respiration, and pulse frequency, as well as hormone levels including follicle stimulating hormone and luteinizing hormone. Furthermore, reproductive metrics such as days open, service per conception, and calving interval are also impacted. The interaction between altitude, breed, and observation time, significantly affected physiological status, hormone concentration, and reproductive performances. In cattle with high body weight, the peak sweating rate occurs at 08:00 post meridiem – 02:00 ante meridiem (21.83-27.92 second per centimeter square); while the low body weight occurs at 12:00 ante meridiem – 06:00 ante meridiem (16.92-32.68 seconds per square meter). Crossbred cattle in lowland areas and at 02:00 ante meridiem – 02:00 post meridiem have the highest respiratory frequency (59.08-63.29 times per minutes), and during the day have the highest pulse rate (69.43 times per minutes). During peak estrus, crossbred cattle in highland areas demonstrate increased concentrations of follicle stimulating hormone (15.82 ng/mL) and luteinizing hormone (70.91 ng/mL). Crossbred cattle in the lowlands have longer days open (5.75 months), higher service per conception (1.62 times), and longer calving intervals (15.94 months).CONCLUSION: Crossbred cattle reared in lowland settings may encounter a decline in both physiological and reproductive capabilities, while indigenous cattle have the ability to adapt, resulting in superior physiological and reproductive performance compared to crossbred cattle. The physiology and reproduction of cattle are shaped by genetic factors and the tropical environment, including 1) Genetic influence, 2). Adaptation to altitude and climate, 3) Stress zones and breed differences, 4) Body temperature, 5) Reproductive performance,6) Hormone concentrations. It is recommended that the development of crossbred cattle be carried out in the highlands.

Abstract Background Despite a high incidence of colorectal carcinoma, data regarding genetic aberrations in colorectal carcinoma (CRC) patients in Pakistan is scarce. This study aimed to determine the frequency of BRAFV600E mutations in colorectal carcinoma tissue in the Pakistani population and to associate BRAFV600E expression with CD133, a marker of colorectal stem cells, and CDX2 marker of differentiation. Methods Sanger Sequencing of exon 15 (426 bp) including the hotspot V600E was performed on formalin-fixed-paraffin-embedded (FFPE) CRC tissue samples of 115 patients. The samples were subjected to immunohistochemistry (IHC) to assess the expression of BRAFV600E, CDX2, and CD133. Additionally, homology modelling and docking were performed to investigate novel deletions revealed in sequencing. Results Twenty-four (20.8%) BRAF variants were identified in the coding region, with V600E mutations detected in 14 (12.2% )cases (GenBank: PP003258.1; Pop Set: 2678087296). Moreover, a wide spectrum of novel non-V600E mutations (8.6%) were identified, including deletions and missense variations. In-silico analysis revealed that due to large deletions in the coding region of three samples, the affinity of the anti-BRAF drugs (Encorafenib and Vemurafenib) for the active site decreased in comparison to the wild type. The IHC analysis showed that BRAFV600E expression was significantly associated with CD133 expression (χ2 (1, n=115) = 26.351; p =

Abstract Background Juvenile sudden cardiac death (SCD) remains unexplained in approximately 40% of cases, leading to a significant emotional burden for the victims’ families and society. Comprehensive investigations are essential to uncover its elusive causes and enable cascade family screening. This study aimed to enhance the identification of likely causative variants in juvenile SCD cases (age ≤ 50 years), particularly when autopsy findings are inconclusive. Results Autopsy revealed diagnostic structural abnormalities in 46%, non-diagnostic findings in 23%, and structurally normal hearts in 31% of cases. Whole-exome sequencing (WES), refined through a customized virtual gene panel was used to identify variants. These variants were then evaluated using a multidisciplinary approach and a structured variant prioritization scheme. Our extended approach identified likely causative variants in 69% of cases, outperforming the diagnostic yields of both the cardio panel and standard susceptibility gene analysis (50% and 16%, respectively). The extended cardio panel achieved an 80% diagnostic yield in cases with structurally normal hearts, demonstrating its efficacy in challenging scenarios. Notably, half of the positive cases harboured a single variant, while the remainder had two or more variants. Conclusion This study highlights the efficacy of a multidisciplinary approach employing WES and a tailored virtual gene panel to elucidate the aetiology of juvenile SCD. The findings support the expansion of genetic testing using tailored gene panels and prioritization schemes as part of routine autopsy evaluations to improve the identification of causative variants and potentially facilitate early diagnosis in first-degree relatives.

Introduction. For four years, SARS-CoV-2, the etiological agent of COVID-19, has been circulating among humans. By the end of the second year, an absence of immunologically naive individuals was observed, attributable to extensive immunization efforts and natural viral exposure. This study focuses on delineating the molecular and biological patterns that facilitate the persistence of SARS-CoV-2, thereby informing predictions on the epidemiological trajectory of COVID-19 toward refining pandemic countermeasures. The aim of this study was to describe the molecular biological patterns identified that contribute to the persistence of the virus in the human population. Materials and methods. For over three years since the beginning of the COVID-19 pandemic, molecular genetic monitoring of SARS-CoV-2 has been conducted, which included the collection of nasopharyngeal swabs from infected individuals, assessment of viral load, and subsequent whole-genome sequencing. Results. We discerned dominant genetic lineages correlated with rising disease incidence. We scrutinized amino acid substitutions across SARS-CoV-2 proteins and quantified viral loads in swab samples from patients with emerging COVID-19 variants. Our findings suggest a model of viral persistence characterized by 1) periodic serotype shifts causing substantial diminutions in serum virus-neutralizing activity ( 10-fold), 2) serotype-specific accrual of point mutations in the receptor-binding domain (RBD) to modestly circumvent neutralizing antibodies and enhance receptor affinity, and 3) a gradually increasing amount of virus being shed in mucosal surfaces within a single serotype. Conclusion. This model aptly accounts for the dynamics of COVID-19 incidence in Moscow. For a comprehensive understanding of these dynamics, acquiring population-level data on immune tension and antibody neutralization relative to genetic lineage compositions is essential.

Watermelon (Citrullus lanatus L.) is grown in tropical and temperate regions and an economically important crop. Characterization studies of watermelon may provide valuable information for breeding and research programs. The objectives of this study were to determined of morphological, phytochemical, genetic diversity and population structure among the watermelons. Morphological and phytochemical variations including sugar contents were determined in 96 watermelon genotypes grown in the field. The average number of fruits per plant was determined as 2.52 ± 0.06, and the average yield was determined as 6.2 ± 0.11 kg/m2. The mean total sugar was determined as 6.27 ± 0.12 %, and the lowest value was measured in genotype 234 (1.1%); the highest value was measured in genotype number 184 (8.66%). A total of 62 SSR (Simple Sequence Repeat) primers were used in the molecular characterization study. The similarity coefficients among the 96 genotypes varied between 0.23 and 0.99. This study indicates that there is a wide morphological and sugar parameters variation among watermelon genotypes but narrow molecular genetic diversity. It also provides useful information for watermelon breeding studies.

Abstract Background Human parainfluenza virus-1 (HPIV-1) is a notable pathogen instigating acute respiratory tract infections in children. The article is to elucidate the epidemiological and genetic characteristics of HPIV-1 circulating in Hangzhou during the period of 2021–2022. Methods A cohort of 2360 nasopharyngeal swabs were amassed and subsequently examined via RT-PCR, with HPIV-1 positive samples undergoing P gene sequencing. Results The highest HPIV-1 infection rates were found in children aged between 3 and 6 years. A pronounced positive rate persisted through the latter half of 2021, with a notable decline observed in the initial half of 2022. All HPIV-1 strains could be clustered into 2 groups: Cluster 1, with strains similar to those found in Japan (LC764865, LC764864), and Cluster 2, with strains similar to the Beijing strain (MW575643). Conclusion In conclusion, our study contributes to the comprehensive data on the epidemiological and genetic characteristics of HPIV-1 in pediatric patients from Hangzhou, post the COVID-19 peak.

Mouse models are a critical tool for studying human diseases, particularly developmental disorders1. However, conventional approaches for phenotyping may fail to detect subtle defects throughout the developing mouse2. Here we set out to establish single-cell RNA sequencing of the whole embryo as a scalable platform for the systematic phenotyping of mouse genetic models. We applied combinatorial indexing-based single-cell RNA sequencing3 to profile 101 embryos of 22 mutant and 4 wild-type genotypes at embryonic day 13.5, altogether profiling more than 1.6 million nuclei. The 22 mutants represent a range of anticipated phenotypic severities, from established multisystem disorders to deletions of individual regulatory regions4,5. We developed and applied several analytical frameworks for detecting differences in composition and/or gene expression across 52 cell types or trajectories. Some mutants exhibit changes in dozens of trajectories whereas others exhibit changes in only a few cell types. We also identify differences between widely used wild-type strains, compare phenotyping of gain- versus loss-of-function mutants and characterize deletions of topological associating domain boundaries. Notably, some changes are shared among mutants, suggesting that developmental pleiotropy might be 'decomposable' through further scaling of this approach. Overall, our findings show how single-cell profiling of whole embryos can enable the systematic molecular and cellular phenotypic characterization of mouse mutants with unprecedented breadth and resolution.

Although beta-endorphinergic neurons in the hypothalamic arcuate nucleus (ARC) synthesize beta-endorphin (β-EP) to alleviate nociceptive behaviors, the underlying regulatory mechanisms remain unknown. Here, we elucidated an epigenetic pathway driven by microRNA regulation of β-EP synthesis in ARC neurons to control neuropathic pain. In pain-injured rats miR-203a-3p was the most highly upregulated miRNA in the ARC. A similar increase was identified in the cerebrospinal fluid of trigeminal neuralgia patients. Mechanistically, we found histone deacetylase 9 was downregulated following nerve injury, which decreased deacetylation of histone H3 lysine-18, facilitating the binding of NR4A2 transcription factor to the miR-203a-3p gene promoter, thereby upregulating miR-203a-3p expression. Further, increased miR-203a-3p was found to maintain neuropathic pain by targeting proprotein convertase 1, an endopeptidase necessary for the cleavage of proopiomelanocortin, the precursor of β-EP. The identified mechanism may provide an avenue for the development of new therapeutic targets for neuropathic pain treatment.

One-carbon metabolism is an essential branch of cellular metabolism that intersects with epigenetic regulation. In this work, we show how formaldehyde (FA), a one-carbon unit derived from both endogenous sources and environmental exposure, regulates one-carbon metabolism by inhibiting the biosynthesis of S-adenosylmethionine (SAM), the major methyl donor in cells. FA reacts with privileged, hyperreactive cysteine sites in the proteome, including Cys120 in S-adenosylmethionine synthase isoform type-1 (MAT1A). FA exposure inhibited MAT1A activity and decreased SAM production with MAT-isoform specificity. A genetic mouse model of chronic FA overload showed a decrease n SAM and in methylation on selected histones and genes. Epigenetic and transcriptional regulation of Mat1a and related genes function as compensatory mechanisms for FA-dependent SAM depletion, revealing a biochemical feedback cycle between FA and SAM one-carbon units.

Molecular clock models undergird modern methods of divergence-time estimation. Local clock models propose that the rate of molecular evolution is constant within phylogenetic subtrees. Current local clock inference procedures exhibit one or more weaknesses, namely they achieve limited scalability to trees with large numbers of taxa, impose model misspecification, or require a priori knowledge of the existence and location of clocks. To overcome these challenges, we present an autocorrelated, Bayesian model of heritable clock rate evolution that leverages heavy-tailed priors with mean zero to shrink increments of change between branch-specific clocks. We further develop an efficient Hamiltonian Monte Carlo sampler that exploits closed form gradient computations to scale our model to large trees. Inference under our shrinkage clock exhibits a speed-up compared to the popular random local clock when estimating branch-specific clock rates on a variety of simulated datasets. This speed-up increases with the size of the problem. We further show our shrinkage clock recovers known local clocks within a rodent and mammalian phylogeny. Finally, in a problem that once appeared computationally impractical, we investigate the heritable clock structure of various surface glycoproteins of influenza A virus in the absence of prior knowledge about clock placement. We implement our shrinkage clock and make it publicly available in the BEAST software package.

Intrinsically disordered proteins (IDPs) have been closely studied during the past decade due to their importance in many biological processes. The disordered nature of this group of proteins makes it difficult to observe its full span of the conformational space using either experimental or computational studies. In this article, we explored the conformational space of the C-terminal domain (CTD) of RNA polymerase II (Pol II), which is also an intrinsically disordered low complexity domain, using enhanced sampling methods. We provided a detailed conformational analysis of model systems of CTD with different lengths; first with the last 44 residues of the human CTD sequence and finally the CTD model with 2-heptapeptide repeating units. We then investigated the effects of phosphorylation on CTD conformations by performing simulations at different phosphorylated states. We obtained broad conformational spaces in nonphosphorylated CTD models, and phosphorylation has complex effects on the conformations of the CTD. These complex effects depend on the length of the CTD, spacing between the multiple phosphorylation sites, ion coordination, and interactions with the nearby residues.

Growing evidence suggests that social relationship quality can influence age-related health outcomes, although how the quality of ones relationships directly relates to the underlying aging process is less clear. We hypothesized that the absence of close relationships as well as lower support and higher strain within existing relationships would be associated with an accelerated epigenetic aging profile among older adults in the Health and Retirement Study. Adults (N = 3,647) aged 50-100 years completed ratings of support and strain in relationships with their spouse, children, other family members, and friends. They also provided a blood sample that was used for DNA methylation profiling to calculate a priori-specified epigenetic aging measures: Horvath, Hannum, PhenoAge, GrimAge, and Dunedin Pace of Aging methylation (DunedinPoAm38). Generalized linear models that adjusted for chronological age, sex, and race/ethnicity and applied a false discovery rate correction revealed that the absence of marital and friend relationships related to an older GrimAge and faster DunedinPoAm38. Among those with existing relationships, lower support from a spouse, child, other family, and friends and higher strain with friends related to an older PhenoAge and GrimAge and faster DunedinPoAm38. In secondary analyses that further adjusted for socioeconomic and lifestyle factors, lower support from other family members and friends was associated with greater epigenetic aging. Findings suggest that the absence of close relationships and lower support within existing relationships-particularly with family members and friends-relate to accelerated epigenetic aging in older adulthood, offering one mechanism through which social relationships might influence risk for age-related declines and disease.

BACKGROUND AND PURPOSE: The impact of radiotherapy (RT) at ultra high vs conventional dose rate (FLASH vs CONV) on the generation and repair of DNA double strand breaks (DSBs) is an important question that remains to be investigated. Here, we tested the hypothesis as to whether FLASH-RT generates decreased chromosomal translocations compared to CONV-RT. MATERIALS AND METHODS: We used two FLASH validated electron beams and high-throughput rejoin and genome-wide translocation sequencing (HTGTS-JoinT-seq), employing S. aureus and S. pyogenes Cas9 bait DNA double strand breaks (DSBs) in HEK239T cells, to measure differences in bait-proximal repair and their genome-wide translocations to prey DSBs generated after various irradiation doses, dose rates and oxygen tensions (normoxic, 21% O2; physiological, 4% O2; hypoxic, 2% and 0.5% O2). Electron irradiation was delivered using a FLASH capable Varian Trilogy and the eRT6/Oriatron at CONV (0.08-0.13 Gy/s) and FLASH (1x102-5x106 Gy/s) dose rates. Related experiments using clonogenic survival and γH2AX foci in the 293T and the U87 glioblastoma lines were also performed to discern FLASH-RT vs CONV-RT DSB effects. RESULTS: Normoxic and physioxic irradiation of HEK293T cells increased translocations at the cost of decreasing bait-proximal repair but were indistinguishable between CONV-RT and FLASH-RT. Although no apparent increase in chromosome translocations was observed with hypoxia-induced apoptosis, the combined decrease in oxygen tension with IR dose-rate modulation did not reveal significant differences in the level of translocations nor in their junction structures. Furthermore, RT dose rate modality on U87 cells did not change γH2AX foci numbers at 1- and 24-hours post-irradiation nor did this affect 293T clonogenic survival. CONCLUSION: Irrespective of oxygen tension, FLASH-RT produces translocations and junction structures at levels and proportions that are indistinguishable from CONV-RT.

Aging is a nearly inescapable trait among organisms yet lifespan varies tremendously across different species and spans several orders of magnitude in vertebrates alone. This vast phenotypic diversity is driven by distinct evolutionary trajectories and tradeoffs that are reflected in patterns of diversification and constraint in organismal genomes. Age-specific impacts of selection also shape allele frequencies in populations, thus impacting disease susceptibility and environment-specific mortality risk. Further, the mutational processes that spawn this genetic diversity in both germline and somatic cells are strongly influenced by age and life history. We discuss recent advances in our understanding of the evolution of aging and lifespan at organismal, population, and cellular scales, and highlight outstanding questions that remain unanswered.

Admixture, the exchange of genetic information between distinct source populations, is thought to be a major source of adaptive genetic variation. Unlike mutation events, which periodically generate single alleles, admixture can introduce many selected alleles simultaneously. As such, the effects of linkage between selected alleles may be especially pronounced in admixed populations. However, existing tools for identifying selected mutations within admixed populations only account for selection at a single site, overlooking phenomena such as linkage among proximal selected alleles. Here, we develop and extensively validate a method for identifying and quantifying the individual effects of multiple linked selected sites on a chromosome in admixed populations. Our approach numerically calculates the expected local ancestry landscape in an admixed population for a given multi-locus selection model, and then maximizes the likelihood of the model. After applying this method to admixed populations of Drosophila melanogaster and Passer italiae, we found that the impacts between linked sites may be an important contributor to natural selection in admixed populations. Furthermore, for the situations we considered, the selection coefficients and number of selected sites are overestimated in analyses that do not consider the effects of linkage among selected sites. Our results imply that linkage among selected sites may be an important evolutionary force in admixed populations. This tool provides a powerful generalized method to investigate these crucial phenomena in diverse populations.

Trimethylation of histone H3 lysine 9 (H3K9me3) is crucial for the regulation of gene repression and heterochromatin formation, cell-fate determination and organismal development1. H3K9me3 also provides an essential mechanism for silencing transposable elements1-4. However, previous studies have shown that canonical H3K9me3 readers (for example, HP1 (refs. 5-9) and MPP8 (refs. 10-12)) have limited roles in silencing endogenous retroviruses (ERVs), one of the main transposable element classes in the mammalian genome13. Here we report that trinucleotide-repeat-containing 18 (TNRC18), a poorly understood chromatin regulator, recognizes H3K9me3 to mediate the silencing of ERV class I (ERV1) elements such as LTR12 (ref. 14). Biochemical, biophysical and structural studies identified the carboxy-terminal bromo-adjacent homology (BAH) domain of TNRC18 (TNRC18(BAH)) as an H3K9me3-specific reader. Moreover, the amino-terminal segment of TNRC18 is a platform for the direct recruitment of co-repressors such as HDAC-Sin3-NCoR complexes, thus enforcing optimal repression of the H3K9me3-demarcated ERVs. Point mutagenesis that disrupts the TNRC18(BAH)-mediated H3K9me3 engagement caused neonatal death in mice and, in multiple mammalian cell models, led to derepressed expression of ERVs, which affected the landscape of cis-regulatory elements and, therefore, gene-expression programmes. Collectively, we describe a new H3K9me3-sensing and regulatory pathway that operates to epigenetically silence evolutionarily young ERVs and exert substantial effects on host genome integrity, transcriptomic regulation, immunity and development.

The identification of catalytic RNAs is typically achieved through primarily experimental means. However, only a small fraction of sequence space can be analyzed even with high-throughput techniques. Methods to extrapolate from a limited data set to predict additional ribozyme sequences, particularly in a human-interpretable fashion, could be useful both for designing new functional RNAs and for generating greater understanding about a ribozyme fitness landscape. Using information theory, we express the effects of epistasis (i.e., deviations from additivity) on a ribozyme. This representation was incorporated into a simple model of the epistatic fitness landscape, which identified potentially exploitable combinations of mutations. We used this model to theoretically predict mutants of high activity for a self-aminoacylating ribozyme, identifying potentially active triple and quadruple mutants beyond the experimental data set of single and double mutants. The predictions were validated experimentally, with nine out of nine sequences being accurately predicted to have high activity. This set of sequences included mutants that form a previously unknown evolutionary bridge between two ribozyme families that share a common motif. Individual steps in the method could be examined, understood, and guided by a human, combining interpretability and performance in a simple model to predict ribozyme sequences by extrapolation.

UNLABELLED: Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle-related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction. SIGNIFICANCE: The clinical, radiographic, and molecular analyses included in this study demonstrate the efficacy of ONC201 in H3K27M-mutant DMG and support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction. This article is featured in Selected Articles from This Issue, p. 2293.

ImportanceIn this study, we developed a correlative approach that combined DNA immunoprecipitation-seq and RNA-seq analyses to define the regulon of the Chlamydia trachomatis transcription factor Euo. We confirmed the proposed role of Euo as a transcriptional repressor of late chlamydial genes but also showed that Euo activates transcription of a subset of midcycle genes and autoregulates its own expression via negative feedback. This study validates and expands the role of Euo as an important developmental regulator in C. trachomatis. In addition, this genome-wide correlative approach can be applied to study transcription factors in other pathogenic bacteria.

Analyses of genome sequence data have revealed pervasive interspecific gene flow and enriched our understanding of the role of gene flow in speciation and adaptation. Inference of gene flow using genomic data requires powerful statistical methods. Yet current likelihood-based methods involve heavy computation and are feasible for small datasets only. Here, we implement the multispecies-coalescent-with-migration model in the Bayesian program bpp, which can be used to test for gene flow and estimate migration rates, as well as species divergence times and population sizes. We develop Markov chain Monte Carlo algorithms for efficient sampling from the posterior, enabling the analysis of genome-scale datasets with thousands of loci. Implementation of both introgression and migration models in the same program allows us to test whether gene flow occurred continuously over time or in pulses. Analyses of genomic data from Anopheles mosquitoes demonstrate rich information in typical genomic datasets about the mode and rate of gene flow.

BACKGROUND: During gestation, stressors to the fetus, including viral exposure or maternal psychological distress, can fundamentally alter the neonatal epigenome, and may be associated with long-term impaired developmental outcomes. The impact of in utero exposure to the COVID-19 pandemic on the newborn epigenome has yet to be described. METHODS: This study aimed to determine whether there are unique epigenetic signatures in newborns who experienced otherwise healthy pregnancies that occurred during the COVID-19 pandemic (Project RESCUE). The pre-pandemic control and pandemic cohorts (Project RESCUE) included in this study are part of a prospective observational and longitudinal cohort study that evaluates the impact of elevated prenatal maternal stress during the COVID-19 pandemic on early childhood neurodevelopment. Using buccal swabs collected at birth, differential DNA methylation analysis was performed using the Infinium MethylationEPIC arrays and linear regression analysis. Pathway analysis and gene ontology enrichment were performed on resultant gene lists. RESULTS: Widespread differential methylation was found between neonates exposed in utero to the pandemic and pre-pandemic neonates. In contrast, there were no apparent epigenetic differences associated with maternal COVID-19 infection during pregnancy. Differential methylation was observed among genomic sites that underpin important neurological pathways that have been previously reported in the literature to be differentially methylated because of prenatal stress, such as NR3C1. CONCLUSIONS: The present study reveals potential associations between exposure to the COVID-19 pandemic during pregnancy and subsequent changes in the newborn epigenome. While this finding warrants further investigation, it is a point that should be considered in any study assessing newborn DNA methylation studies obtained during this period, even in otherwise healthy pregnancies.

Social behaviours are typically modelled using neighbour-modulated fitness, which focuses on individuals having their fitness altered by neighbours. However, these models are either interpreted using inclusive fitness, which focuses on individuals altering the fitness of neighbours, or not interpreted at all. This disconnect leads to interpretational mistakes and obscures the adaptive significance of behaviour. We bridge this gap by presenting a systematic methodology for constructing inclusive-fitness models. We find a behaviours inclusive-fitness effect by summing primary and secondary deviations in reproductive value. Primary deviations are the immediate result of a social interaction; for example, the cost and benefit of an altruistic act. Secondary deviations are compensatory effects that arise because the total reproductive value of the population is fixed; for example, the increased competition that follows an altruistic act. Compared to neighbour-modulated fitness methodologies, our approach is often simpler and reveals the models inclusive-fitness narrative clearly. We implement our methodology first in a homogeneous population, with supplementary examples of help under synergy, help in a viscous population and Creels paradox. We then implement our methodology in a class-structured population, where the advantages of our approach are most evident, with supplementary examples of altruism between age classes, and sex-ratio evolution.

R-loops and guanine quadruplexes (G4s) are secondary structures of nucleic acids that are ubiquitously present in cells and are enriched in promoter regions of genes. By employing a bioinformatic approach based on overlap analysis of transcription factor chromatin immunoprecipitation sequencing (ChIP-seq) data sets, we found that many splicing factors, including U2AF1 whose recognition of the 3 splicing site is crucial for pre-mRNA splicing, exhibit pronounced enrichment at endogenous R-loop- and DNA G4-structure loci in promoter regions of human genes. We also revealed that U2AF1 binds directly to R-loops and DNA G4 structures at a low-nM binding affinity. Additionally, we showed the ability of U2AF1 to undergo phase separation, which could be stimulated by binding with R-loops, but not duplex DNA, RNA/DNA hybrid, DNA G4, or single-stranded RNA. We also demonstrated that U2AF1 binds to promoter R-loops in human cells, and this binding competes with U2AF1s interaction with 3 splicing site and leads to augmented distribution of RNA polymerase II (RNAPII) to promoters over gene bodies, thereby modulating cotranscriptional pre-mRNA splicing. Together, we uncovered a group of candidate proteins that can bind to both R-loops and DNA G4s, revealed the direct and strong interactions of U2AF1 with these nucleic acid structures, and established a biochemical rationale for U2AF1s occupancy in gene promoters. We also unveiled that interaction with R-loops promotes U2AF1s phase separation, and our work suggests that U2AF1 modulates pre-mRNA splicing by regulating RNAPIIs partition in transcription initiation versus elongation.