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Accessible, realistic genome simulation with selection using stdpopsim.
Selection is a fundamental evolutionary force that shapes patterns of genetic variation across species. However, simulations incorporating realistic selection along heterogeneous genomes in complex demographic histories are challenging, limiting our ability to benchmark statistical methods aimed at detecting selection and to explore theoretical predictions. stdpopsim is a community-maintained simulation library that already provides an extensive catalog of species-specific population genetic models. Here we present a major extension to the stdpopsim framework that enables simulation of various modes of selection, including background selection, selective sweeps, and arbitrary distributions of fitness effects (DFE) acting on annotated subsets of the genome (for instance, exons). This extension maintains stdpopsim 's core principles of reproducibility and accessibility while adding support for species-specific genomic annotations and published DFE estimates. We demonstrate the utility of this framework by benchmarking methods for demographic inference, DFE estimation, and selective sweep detection across several species and scenarios. Our results demonstrate the robustness of demographic inference methods to selection on linked sites, reveal the sensitivity of DFE-inference methods to model assumptions, and show how genomic features, like recombination rate and functional sequence density, influence power to detect selective sweeps. This extension to stdpopsim provides a powerful new resource for the population genetics community to explore the interplay between selection and other evolutionary forces in a reproducible, low-barrier framework.
Integration of Large-Scale Genomic Data Sources With Evolutionary History Reveals Novel Genetic Loci for Congenital Heart Disease.
BackgroundMost cases of congenital heart disease (CHD) are sporadic and nonsyndromic, with poorly understood etiology. Rare genetic variants have been found to affect the risk of sporadic, nonsyndromic CHD, but individual studies to date are of only moderate sizes, and none to date has incorporated the ohnolog status of candidate genes in the analysis. Ohnologs are genes retained from ancestral whole-genome duplications during evolution; multiple lines of evidence suggest ohnologs are overrepresented among dosage-sensitive genes. We integrated large-scale data on rare variants with evolutionary information on ohnolog status to identify novel genetic loci predisposing to CHD.MethodsWe compared copy number variants present in 4634 nonsyndromic CHD cases derived from publicly available data resources and the literature, and >27 000 healthy individuals. We analyzed deletions and duplications independently and identified copy number variant regions exclusive to cases. These data were integrated with whole-exome sequencing data from 829 sporadic, nonsyndromic patients with Tetralogy of Fallot. We placed our findings in an evolutionary context by comparing the proportion of vertebrate ohnologs in CHD cases and controls.ResultsNovel genetic loci in CHD cases were significantly enriched for ohnologs compared with the genome (χ2 test, P<0.0001, OR =1.253 [95% CI, 1.199-1.309]). We identified 54 novel candidate protein-coding genes supported by both: (1) copy number variant and whole-exome sequencing data; and (2) ohnolog status.ConclusionsWe have identified new CHD candidate loci, and show for the first time that ohnologs are overrepresented among CHD genes. Incorporation of evolutionary metrics may be useful in refining candidate genes emerging from large-scale genetic evaluations of CHD.
Noncoding variants are a rare cause of recessive developmental disorders in trans with coding variants.
PurposeIdentifying pathogenic noncoding variants is challenging. A single protein-altering variant is often identified in a recessive gene in individuals with developmental disorders (DD), but the prevalence of pathogenic noncoding "second hits" in trans with these is unknown.MethodsIn 4073 genetically undiagnosed rare-disease trio probands from the 100,000 Genomes project, we identified rare heterozygous protein-altering variants in recessive DD-associated genes. We identified rare noncoding variants on the other haplotype in introns, untranslated regions, promoters, and candidate enhancer regions. We clinically evaluated the top candidates for phenotypic fit and performed functional testing where possible.ResultsWe identified 3761 rare heterozygous loss-of-function or ClinVar pathogenic variants in recessive DD-associated genes in 2430 probands. For 1366 (36.3%) of these, we identified at least 1 rare noncoding variant in trans. Bioinformatic filtering and clinical review, revealed 7 to be a good clinical fit. After detailed characterization, we identified likely diagnoses for 3 probands (in GAA, NPHP3, and PKHD1) and candidate diagnoses in a further 3 (PAH, LAMA2, and IGHMBP2).ConclusionWe developed a systematic approach to uncover new diagnoses involving compound heterozygous coding/noncoding variants and conclude that this mechanism is likely to be a rare cause of DDs.
Differences in 5'untranslated regions highlight the importance of translational regulation of dosage sensitive genes.
BackgroundUntranslated regions (UTRs) are important mediators of post-transcriptional regulation. The length of UTRs and the composition of regulatory elements within them are known to vary substantially across genes, but little is known about the reasons for this variation in humans. Here, we set out to determine whether this variation, specifically in 5'UTRs, correlates with gene dosage sensitivity.ResultsWe investigate 5'UTR length, the number of alternative transcription start sites, the potential for alternative splicing, the number and type of upstream open reading frames (uORFs) and the propensity of 5'UTRs to form secondary structures. We explore how these elements vary by gene tolerance to loss-of-function (LoF; using the LOEUF metric), and in genes where changes in dosage are known to cause disease. We show that LOEUF correlates with 5'UTR length and complexity. Genes that are most intolerant to LoF have longer 5'UTRs, greater TSS diversity, and more upstream regulatory elements than their LoF tolerant counterparts. We show that these differences are evident in disease gene-sets, but not in recessive developmental disorder genes where LoF of a single allele is tolerated.ConclusionsOur results confirm the importance of post-transcriptional regulation through 5'UTRs in tight regulation of mRNA and protein levels, particularly for genes where changes in dosage are deleterious and lead to disease. Finally, to support gene-based investigation we release a web-based browser tool, VuTR, that supports exploration of the composition of individual 5'UTRs and the impact of genetic variation within them.
De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome.
Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here we identify the non-coding RNA RNU4-2 as a syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 base pair region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals in whom it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to RNU4-1 and other U4 homologues. Using RNA sequencing, we show how 5' splice-site use is systematically disrupted in individuals with RNU4-2 variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 base pair region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide.
Cancer inequalities in the United Kingdom and the data used to measure them: a scoping review.
Significant cancer inequalities may exist across the United Kingdom (UK). Data are required to delineate and quantify these inequalities. This scoping review was undertaken to map the research evidence on UK cancer inequalities and determine the current data available, and the data gaps, that, if filled, could inform a strategy to reduce them. 444 studies were included. Their distribution across inequality domains, care pathways and cancer sites was uneven. The majority of studies were based on administrative datasets, notably cancer registry data, with a wide-range of methods used to define inequality groups. No UK-wide population-based evidence was identified. The landscape of data available in the UK to study cancer inequalities is uneven. Although there is a large volume of evidence available, there remain major gaps in both the data available and the knowledge base they are deployed to generate. This deficit needs to be addressed as a matter of urgency.
wav2sleep: A Unified Multi-Modal Approach to Sleep Stage Classification from Physiological Signals
Accurate classification of sleep stages from less obtrusive sensor measurements such as the electrocardiogram (ECG) or photoplethysmogram (PPG) could enable important applications in sleep medicine. Existing approaches to this problem have typically used deep learning models designed and trained to operate on one or more specific input signals. However, the datasets used to develop these models often do not contain the same sets of input signals. Some signals, particularly PPG, are much less prevalent than others, and this has previously been addressed with techniques such as transfer learning. Additionally, only training on one or more fixed modalities precludes cross-modal information transfer from other sources, which has proved valuable in other problem domains. To address this, we introduce wav2sleep, a unified model designed to operate on variable sets of input signals during training and inference. After jointly training on over 10,000 overnight recordings from six publicly available polysomnography datasets, including SHHS and MESA, wav2sleep outperforms existing sleep stage classification models across test-time input combinations including ECG, PPG, and respiratory signals.
The efficacy and safety of lanreotide Autogel in patients with acromegaly previously treated with octreotide LAR.
ObjectiveLanreotide Autogel is a sustained-release aqueous gel formulation supplied in a prefilled syringe, with injection volume <0.5 ml. The aim of this study was to establish the efficacy and safety of Autogel in patients with acromegaly previously treated with octreotide LAR.DesignA 28-week, open, multicentre study.PatientsTwelve patients with acromegaly, treated with 20 mg octreotide LAR for >4 months, with serum GH levels <10.0 mU/l.MethodsAutogel (90 mg) was given every 28 days during weeks 0-12. At week 16 the dose was titrated based on GH levels at weeks 8 and 12. If GH levels were <2.0, 2.0-5.0, or >5.0 mU/l, Autogel was reduced to 60 mg, maintained at 90 mg, or increased to 120 mg respectively, for the next three injections. GH and IGF-I levels were reassessed at weeks 24 and 28.ResultsTen patients completed the study. Five remained on 90 mg Autogel throughout the study; in two patients the dose was reduced to 60 mg from week 16; in three patients it was increased to 120 mg. Mean GH levels were: baseline, 3.0+/-1.7 mU/l; week 12, 3.5+/-1.8 mU/l; week 28, 3.3+/-1.6 mU/l (NS). Mean IGF-I levels were: baseline, 212+/-70 microg/l; week 12, 185+/-91 microg/l; week 28: 154+/-61 microg/l (P=0.027). Six patients at baseline and eight at week 28 had normalised GH and IGF-I levels. Three patients reported adverse events: musculoskeletal pain (n=2) and injection-site symptoms (n=1).ConclusionsLanreotide Autogel is effective and well tolerated in patients with acromegaly. This study in a small group of patients with well-controlled acromegaly suggests that the majority of patients switched from 20 mg LAR to 90 mg Autogel will have equivalent or better disease control.
Low to Moderate Prenatal Alcohol Exposure and Facial Shape of Children at Age 6 to 8 Years.
ImportanceIn addition to confirmed prenatal alcohol exposure and severe neurodevelopmental deficits, three cardinal facial features are included in the diagnostic criteria for fetal alcohol spectrum disorder. It is not understood whether subtle facial characteristics occur in children without a diagnosis but who were exposed to a range of common pregnancy drinking patterns and, if so, whether these persist throughout childhood.ObjectiveTo determine whether subtle changes in facial shape with prenatal alcohol exposure found in 12-month-old children were evident at age 6 to 8 years using extended phenotyping methods and, if so, whether facial characteristics were similar to those seen in fetal alcohol spectrum disorder.Design, setting, and participantsIn a prospective cohort study in Melbourne, Victoria, Australia, commencing in July 2011 with follow-up through April 2021, pregnant women were recruited in the first trimester from low-risk, metropolitan, public maternity clinics over a period of 12 months. Three-dimensional craniofacial images from 549 children of European descent taken at age 12 months (n = 421 images) and 6 to 8 years (n = 363) were included. Data analysis was performed from May 2021 to October 2024.ExposuresPredominantly low to moderate prenatal alcohol exposure in the first trimester or throughout pregnancy compared with controls without prenatal alcohol exposure.Main outcomes and measuresFollowing hierarchical facial segmentation, phenotype descriptors were computed. Hypothesis testing was performed for 63 facial modules to analyze different facial parts independently using principal component analysis and response-based imputed predictor (RIP) scores. Comparison was made with a clinical discovery sample of facial images of children with a confirmed diagnosis of partial or full fetal alcohol syndrome.ResultsA total of 549 children took part in the 3-dimensional craniofacial image analysis, of whom 235 (42.8%) contributed an image at both time points. Time 1 included 421 children, comprising 336 children (159 [47.3%] female) with any prenatal alcohol exposure and 85 control children (45 [52.9%] female); time 2 included 363 children, comprising 260 children with any prenatal alcohol exposure (125 [48.1%] female; mean [SD] age, 6.9 [0.7] years) and 103 control children (53 [51.5%] female; mean [SD] age, 6.8 [0.7] years). At both time points, there was consistent evidence for an association between prenatal alcohol exposure and the shape of the eyes (eg, module 15: RIP partial Spearman ρ, 0.19 [95% CI, 0.10-0.29; P Conclusions and relevanceLow to moderate prenatal alcohol exposure was associated with characteristic changes in the face, which persisted until at least 6 to 8 years of age. A linear association between alcohol exposure levels and facial shape was not supported.
Tracking SARS-CoV-2 mutations and variants through the COG-UK-Mutation Explorer.
COG-UK Mutation Explorer (COG-UK-ME, https://sars2.cvr.gla.ac.uk/cog-uk/-last accessed date 16 March 2022) is a web resource that displays knowledge and analyses on SARS-CoV-2 virus genome mutations and variants circulating in the UK, with a focus on the observed amino acid replacements that have an antigenic role in the context of the human humoral and cellular immune response. This analysis is based on more than 2 million genome sequences (as of March 2022) for UK SARS-CoV-2 data held in the CLIMB-COVID centralised data environment. COG-UK-ME curates these data and displays analyses that are cross-referenced to experimental data collated from the primary literature. The aim is to track mutations of immunological importance that are accumulating in current variants of concern and variants of interest that could alter the neutralising activity of monoclonal antibodies (mAbs), convalescent sera, and vaccines. Changes in epitopes recognised by T cells, including those where reduced T cell binding has been demonstrated, are reported. Mutations that have been shown to confer SARS-CoV-2 resistance to antiviral drugs are also included. Using visualisation tools, COG-UK-ME also allows users to identify the emergence of variants carrying mutations that could decrease the neutralising activity of both mAbs present in therapeutic cocktails, e.g. Ronapreve. COG-UK-ME tracks changes in the frequency of combinations of mutations and brings together the curated literature on the impact of those mutations on various functional aspects of the virus and therapeutics. Given the unpredictable nature of SARS-CoV-2 as exemplified by yet another variant of concern, Omicron, continued surveillance of SARS-CoV-2 remains imperative to monitor virus evolution linked to the efficacy of therapeutics.
Assessing the impact of COmorbidities and Sociodemographic factors on Multiorgan Injury following COVID-19: rationale and protocol design of COSMIC, a UK multicentre observational study of COVID-negative controls.
IntroductionSARS-CoV-2 disease (COVID-19) has had an enormous health and economic impact globally. Although primarily a respiratory illness, multi-organ involvement is common in COVID-19, with evidence of vascular-mediated damage in the heart, liver, kidneys and brain in a substantial proportion of patients following moderate-to-severe infection. The pathophysiology and long-term clinical implications of multi-organ injury remain to be fully elucidated. Age, gender, ethnicity, frailty and deprivation are key determinants of infection severity, and both morbidity and mortality appear higher in patients with underlying comorbidities such as ischaemic heart disease, hypertension and diabetes. Our aim is to gain mechanistic insights into the pathophysiology of multiorgan dysfunction in people with COVID-19 and maximise the impact of national COVID-19 studies with a comparison group of COVID-negative controls.Methods and analysisCOmorbidities and Sociodemographic factors on Multiorgan Injury following COVID-19 (COSMIC) is a prospective, multicentre UK study which will recruit 200 subjects without clinical evidence of prior COVID-19 and perform extensive phenotyping with multiorgan imaging, biobank serum storage, functional assessment and patient reported outcome measures, providing a robust control population to facilitate current work and serve as an invaluable bioresource for future observational studies.Ethics and disseminationApproved by the National Research Ethics Service Committee East Midlands (REC reference 19/EM/0295). Results will be disseminated via peer-reviewed journals and scientific meetings.Trial registration numberCOSMIC is registered as an extension of C-MORE (Capturing Multi-ORgan Effects of COVID-19) on ClinicalTrials.gov (NCT04510025).
Acute neural effects of fluoxetine on emotional regulation in depressed adolescents.
BackgroundAdolescent major depressive disorder (MDD) is associated with disrupted processing of emotional stimuli and difficulties in cognitive reappraisal. Little is known however about how current pharmacotherapies act to modulate the neural mechanisms underlying these key processes. The current study therefore investigated the neural effects of fluoxetine on emotional reactivity and cognitive reappraisal in adolescent depression.MethodsThirty-one adolescents with MDD were randomised to acute fluoxetine (10 mg) or placebo. Seventeen healthy adolescents were also recruited but did not receive any treatment for ethical reasons. During functional magnetic resonance imaging (fMRI), participants viewed aversive images and were asked to either experience naturally the emotional state elicited ('Maintain') or to reinterpret the content of the pictures to reduce negative affect ('Reappraise'). Significant activations were identified using whole-brain analysis.ResultsNo significant group differences were seen when comparing Reappraise and Maintain conditions. However, when compared to healthy controls, depressed adolescents on placebo showed reduced visual activation to aversive pictures irrespective of the condition. The depressed adolescent group on fluoxetine showed the opposite pattern, i.e. increased visuo-cerebellar activity in response to aversive pictures, when compared to depressed adolescents on placebo.ConclusionsThese data suggest that depression in adolescence may be associated with reduced visual processing of aversive imagery and that fluoxetine may act to reduce avoidance of such cues. This could reflect a key mechanism whereby depressed adolescents engage with negative cues previously avoided. Future research combining fMRI with eye-tracking is nonetheless needed to further clarify these effects.