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We examined more than 97,000 families from four neurodevelopmental disease cohorts and the UK Biobank to identify phenotypic and genetic patterns in parents contributing to neurodevelopmental disease risk in children. We identified within- and cross-disorder correlations between six phenotypes in parents and children, such as obsessive-compulsive disorder (R = 0.32-0.38, p < 10-126). We also found that measures of sub-clinical autism features in parents are associated with several autism severity measures in children, including biparental mean Social Responsiveness Scale scores and proband Repetitive Behaviors Scale scores (regression coefficient = 0.14, p = 3.38 × 10-4). We further describe patterns of phenotypic similarity between spouses, where spouses show correlations for six neurological and psychiatric phenotypes, including a within-disorder correlation for depression (R = 0.24-0.68, p < 0.001) and a cross-disorder correlation between anxiety and bipolar disorder (R = 0.09-0.22, p < 10-92). Using a simulated population, we also found that assortative mating can lead to increases in disease liability over generations and the appearance of "genetic anticipation" in families carrying rare variants. We identified several families in a neurodevelopmental disease cohort where the proband inherited multiple rare variants in disease-associated genes from each of their affected parents. We further identified parental relatedness as a risk factor for neurodevelopmental disorders through its inverse relationship with variant pathogenicity and propose that parental relatedness modulates disease risk by increasing genome-wide homozygosity in children (R = 0.05-0.26, p < 0.05). Our results highlight the utility of assessing parent phenotypes and genotypes toward predicting features in children who carry rare variably expressive variants and implicate assortative mating as a risk factor for increased disease severity in these families.
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Trastorno Autístico , Trastorno Bipolar , Niño , Humanos , Virulencia , Padres , Familia , Trastorno Autístico/genética , Trastorno Bipolar/genéticaRESUMEN
We examined more than 38,000 spouse pairs from four neurodevelopmental disease cohorts and the UK Biobank to identify phenotypic and genetic patterns in parents associated with neurodevelopmental disease risk in children. We identified correlations between six phenotypes in parents and children, including correlations of clinical diagnoses such as obsessive-compulsive disorder (R=0.31-0.49, p<0.001), and two measures of sub-clinical autism features in parents affecting several autism severity measures in children, such as bi-parental mean Social Responsiveness Scale (SRS) scores affecting proband SRS scores (regression coefficient=0.11, p=0.003). We further describe patterns of phenotypic and genetic similarity between spouses, where spouses show both within- and cross-disorder correlations for seven neurological and psychiatric phenotypes, including a within-disorder correlation for depression (R=0.25-0.72, p<0.001) and a cross-disorder correlation between schizophrenia and personality disorder (R=0.20-0.57, p<0.001). Further, these spouses with similar phenotypes were significantly correlated for rare variant burden (R=0.07-0.57, p<0.0001). We propose that assortative mating on these features may drive the increases in genetic risk over generations and the appearance of "genetic anticipation" associated with many variably expressive variants. We further identified parental relatedness as a risk factor for neurodevelopmental disorders through its inverse correlations with burden and pathogenicity of rare variants and propose that parental relatedness drives disease risk by increasing genome-wide homozygosity in children (R=0.09-0.30, p<0.001). Our results highlight the utility of assessing parent phenotypes and genotypes in predicting features in children carrying variably expressive variants and counseling families carrying these variants.
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Cleft lip with or without cleft palate (CL/P) is a common birth defect with a complex, heterogeneous etiology. It is well established that common and rare sequence variants contribute to the formation of CL/P, but the contribution of copy-number variants (CNVs) to cleft formation remains relatively understudied. To fill this knowledge gap, we conducted a large-scale comparative analysis of genome-wide CNV profiles of 869 individuals from the Philippines and 233 individuals of European ancestry with CL/P with three primary goals: first, to evaluate whether differences in CNV number, amount of genomic content, or amount of coding genomic content existed within clefting subtypes; second, to assess whether CNVs in our cohort overlapped with known Mendelian clefting loci; and third, to identify unestablished Mendelian clefting genes. Significant differences in CNVs across cleft types or in individuals with non-syndromic versus syndromic clefts were not observed; however, several CNVs in our cohort overlapped with known syndromic and non-syndromic Mendelian clefting loci. Moreover, employing a filtering strategy relying on population genetics data that rare variants are on the whole more deleterious than common variants, we identify several CNV-associated gene losses likely driving non-syndromic clefting phenotypes. By prioritizing genes deleted at a rare frequency across multiple individuals with clefts yet enriched in our cohort of individuals with clefts compared to control subjects, we identify COBLL1, RIC1, and ARHGEF38 as clefting genes. CRISPR-Cas9 mutagenesis of these genes in Xenopus laevis and Danio rerio yielded craniofacial dysmorphologies, including clefts analogous to those seen in human clefting disorders.
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Labio Leporino , Fisura del Paladar , Variaciones en el Número de Copia de ADN , Humanos , Labio Leporino/genética , Fisura del Paladar/genética , Estudio de Asociación del Genoma Completo , Factores de Intercambio de Guanina Nucleótido/genética , Fenotipo , Factores de Transcripción/genéticaRESUMEN
Spaceflight poses risks to the central nervous system (CNS), and understanding neurological responses is important for future missions. We report CNS changes in Drosophila aboard the International Space Station in response to spaceflight microgravity (SFµg) and artificially simulated Earth gravity (SF1g) via inflight centrifugation as a countermeasure. While inflight behavioral analyses of SFµg exhibit increased activity, postflight analysis displays significant climbing defects, highlighting the sensitivity of behavior to altered gravity. Multi-omics analysis shows alterations in metabolic, oxidative stress and synaptic transmission pathways in both SFµg and SF1g; however, neurological changes immediately postflight, including neuronal loss, glial cell count alterations, oxidative damage, and apoptosis, are seen only in SFµg. Additionally, progressive neuronal loss and a glial phenotype in SF1g and SFµg brains, with pronounced phenotypes in SFµg, are seen upon acclimation to Earth conditions. Overall, our results indicate that artificial gravity partially protects the CNS from the adverse effects of spaceflight.
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Gravedad Alterada , Vuelo Espacial , Ingravidez , Animales , Drosophila/genética , Drosophila melanogaster , Ingravidez/efectos adversosRESUMEN
The essential micronutrient Selenium (Se) is co-translationally incorporated as selenocysteine into proteins. Selenoproteins contain one or more selenocysteines and are vital for optimum immunity. Interestingly, many pathogenic bacteria utilize Se for various biological processes suggesting that Se may play a role in bacterial pathogenesis. A previous study had speculated that Francisella tularensis, a facultative intracellular bacterium and the causative agent of tularemia, sequesters Se by upregulating Se-metabolism genes in type II alveolar epithelial cells. Therefore, we investigated the contribution of host vs. pathogen-associated selenoproteins in bacterial disease using F. tularensis as a model organism. We found that F. tularensis was devoid of any Se utilization traits, neither incorporated elemental Se, nor exhibited Se-dependent growth. However, 100% of Se-deficient mice (0.01 ppm Se), which express low levels of selenoproteins, succumbed to F. tularensis-live vaccine strain pulmonary challenge, whereas 50% of mice on Se-supplemented (0.4 ppm Se) and 25% of mice on Se-adequate (0.1 ppm Se) diet succumbed to infection. Median survival time for Se-deficient mice was 8 days post-infection while Se-supplemented and -adequate mice was 11.5 and >14 days post-infection, respectively. Se-deficient macrophages permitted significantly higher intracellular bacterial replication than Se-supplemented macrophages ex vivo, corroborating in vivo observations. Since Francisella replicates in alveolar macrophages during the acute phase of pneumonic infection, we hypothesized that macrophage-specific host selenoproteins may restrict replication and systemic spread of bacteria. F. tularensis infection led to an increased expression of several macrophage selenoproteins, suggesting their key role in limiting bacterial replication. Upon challenge with F. tularensis, mice lacking selenoproteins in macrophages (TrspM) displayed lower survival and increased bacterial burden in the lung and systemic tissues in comparison to WT littermate controls. Furthermore, macrophages from TrspM mice were unable to restrict bacterial replication ex vivo in comparison to macrophages from littermate controls. We herein describe a novel function of host macrophage-specific selenoproteins in restriction of intracellular bacterial replication. These data suggest that host selenoproteins may be considered as novel targets for modulating immune response to control a bacterial infection.
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Francisella tularensis/inmunología , Interacciones Huésped-Patógeno/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Selenoproteínas/metabolismo , Tularemia/etiología , Tularemia/metabolismo , Animales , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Francisella tularensis/genética , Francisella tularensis/patogenicidad , Ratones , Neumonía/inmunología , Neumonía/metabolismo , Neumonía/microbiología , Neumonía/patología , Tularemia/mortalidad , Virulencia/genética , Factores de Virulencia/genéticaRESUMEN
BACKGROUND: Recent studies have suggested that individual variants do not sufficiently explain the variable expressivity of phenotypes observed in complex disorders. For example, the 16p12.1 deletion is associated with developmental delay and neuropsychiatric features in affected individuals, but is inherited in > 90% of cases from a mildly-affected parent. While children with the deletion are more likely to carry additional "second-hit" variants than their parents, the mechanisms for how these variants contribute to phenotypic variability are unknown. METHODS: We performed detailed clinical assessments, whole-genome sequencing, and RNA sequencing of lymphoblastoid cell lines for 32 individuals in five large families with multiple members carrying the 16p12.1 deletion. We identified contributions of the 16p12.1 deletion and "second-hit" variants towards a range of expression changes in deletion carriers and their family members, including differential expression, outlier expression, alternative splicing, allele-specific expression, and expression quantitative trait loci analyses. RESULTS: We found that the deletion dysregulates multiple autism and brain development genes such as FOXP1, ANK3, and MEF2. Carrier children also showed an average of 5323 gene expression changes compared with one or both parents, which matched with 33/39 observed developmental phenotypes. We identified significant enrichments for 13/25 classes of "second-hit" variants in genes with expression changes, where 4/25 variant classes were only enriched when inherited from the noncarrier parent, including loss-of-function SNVs and large duplications. In 11 instances, including for ZEB2 and SYNJ1, gene expression was synergistically altered by both the deletion and inherited "second-hits" in carrier children. Finally, brain-specific interaction network analysis showed strong connectivity between genes carrying "second-hits" and genes with transcriptome alterations in deletion carriers. CONCLUSIONS: Our results suggest a potential mechanism for how "second-hit" variants modulate expressivity of complex disorders such as the 16p12.1 deletion through transcriptomic perturbation of gene networks important for early development. Our work further shows that family-based assessments of transcriptome data are highly relevant towards understanding the genetic mechanisms associated with complex disorders.
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Variación Biológica Poblacional , Deleción Cromosómica , Expresión Génica , Ancirinas/genética , Trastorno Autístico/genética , Encéfalo , Familia , Factores de Transcripción Forkhead/genética , Humanos , Fenotipo , Monoéster Fosfórico Hidrolasas/genética , Proteínas Represoras/genética , Factores de Transcripción/genética , Secuenciación del Exoma , Secuenciación Completa del Genoma , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/genéticaRESUMEN
MOTIVATION: One of the many technical challenges that arises when scheduling bioinformatics analyses at scale is determining the appropriate amount of memory and processing resources. Both over- and under-allocation leads to an inefficient use of computational infrastructure. Over allocation locks resources that could otherwise be used for other analyses. Under-allocation causes job failure and requires analyses to be repeated with a larger memory or runtime allowance. We address this challenge by using a historical dataset of bioinformatics analyses run on the Galaxy platform to demonstrate the feasibility of an online service for resource requirement estimation. RESULTS: Here we introduced the Galaxy job run dataset and tested popular machine learning models on the task of resource usage prediction. We include three popular forest models: the extra trees regressor, the gradient boosting regressor and the random forest regressor, and find that random forests perform best in the runtime prediction task. We also present two methods of choosing walltimes for previously unseen jobs. Quantile regression forests are more accurate in their predictions, and grant the ability to improve performance by changing the confidence of the estimates. However, the sizes of the confidence intervals are variable and cannot be absolutely constrained. Random forest classifiers address this problem by providing control over the size of the prediction intervals with an accuracy that is comparable to that of the regressor. We show that estimating the memory requirements of a job is possible using the same methods, which as far as we know, has not been done before. Such estimation can be highly beneficial for accurate resource allocation. AVAILABILITY AND IMPLEMENTATION: Source code available at https://github.com/atyryshkina/algorithm-performance-analysis, implemented in Python. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.