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1.
Nat Methods ; 21(5): 835-845, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38374265

RESUMEN

Modern multiomic technologies can generate deep multiscale profiles. However, differences in data modalities, multicollinearity of the data, and large numbers of irrelevant features make analyses and integration of high-dimensional omic datasets challenging. Here we present Significant Latent Factor Interaction Discovery and Exploration (SLIDE), a first-in-class interpretable machine learning technique for identifying significant interacting latent factors underlying outcomes of interest from high-dimensional omic datasets. SLIDE makes no assumptions regarding data-generating mechanisms, comes with theoretical guarantees regarding identifiability of the latent factors/corresponding inference, and has rigorous false discovery rate control. Using SLIDE on single-cell and spatial omic datasets, we uncovered significant interacting latent factors underlying a range of molecular, cellular and organismal phenotypes. SLIDE outperforms/performs at least as well as a wide range of state-of-the-art approaches, including other latent factor approaches. More importantly, it provides biological inference beyond prediction that other methods do not afford. Thus, SLIDE is a versatile engine for biological discovery from modern multiomic datasets.


Asunto(s)
Aprendizaje Automático , Humanos , Biología Computacional/métodos , Animales , Análisis de la Célula Individual/métodos , Algoritmos
2.
J Immunol ; 207(11): 2710-2719, 2021 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-34740959

RESUMEN

The single-nucleotide polymorphism (SNP) rs3184504 is broadly associated with increased risk for multiple autoimmune and cardiovascular diseases. Although the allele is uniquely enriched in European descent, the mechanism for the widespread selective sweep is not clear. In this study, we find the rs3184504*T allele had a strong association with reduced mortality in a human sepsis cohort. The rs3184504*T allele associates with a loss-of-function amino acid change (p.R262W) in the adaptor protein SH2B3, a likely causal variant. To better understand the role of SH2B3 in sepsis, we used mouse modeling and challenged SH2B3-deficient mice with a polymicrobial cecal-ligation puncture (CLP) procedure. We found SH2B3 deficiency improved survival and morbidity with less organ damage and earlier bacterial clearance compared with control mice. The peritoneal infiltrating cells exhibited augmented phagocytosis in Sh2b3 -/- mice with enriched recruitment of Ly6Chi inflammatory monocytes despite equivalent or reduced chemokine expression. Rapid cycling of monocytes and progenitors occurred uniquely in the Sh2b3 -/- mice following CLP, suggesting augmented myelopoiesis. To model the hypomorphic autoimmune risk allele, we created a novel knockin mouse harboring a similar point mutation in the murine pleckstrin homology domain of SH2B3. At baseline, phenotypic changes suggested a hypomorphic allele. In the CLP model, homozygous knockin mice displayed improved mortality and morbidity compared with wild-type or heterozygous mice. Collectively, these data suggest that hypomorphic SH2B3 improves the sepsis response and that balancing selection likely contributed to the relative frequency of the autoimmune risk variant.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/inmunología , Sepsis/inmunología , Proteínas Adaptadoras Transductoras de Señales/genética , Adulto , Animales , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Congénicos , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Polimorfismo de Nucleótido Simple/genética , Sepsis/genética
3.
Am J Hum Genet ; 98(5): 1001-1010, 2016 05 05.
Artículo en Inglés | MEDLINE | ID: mdl-27108799

RESUMEN

Whole-exome sequencing of 13 individuals with developmental delay commonly accompanied by abnormal muscle tone and seizures identified de novo missense mutations enriched within a sub-region of GNB1, a gene encoding the guanine nucleotide-binding protein subunit beta-1, Gß. These 13 individuals were identified among a base of 5,855 individuals recruited for various undiagnosed genetic disorders. The probability of observing 13 or more de novo mutations by chance among 5,855 individuals is very low (p = 7.1 × 10(-21)), implicating GNB1 as a genome-wide-significant disease-associated gene. The majority of these 13 mutations affect known Gß binding sites, which suggests that a likely disease mechanism is through the disruption of the protein interface required for Gα-Gßγ interaction (resulting in a constitutively active Gßγ) or through the disruption of residues relevant for interaction between Gßγ and certain downstream effectors (resulting in reduced interaction with the effectors). Strikingly, 8 of the 13 individuals recruited here for a neurodevelopmental disorder have a germline de novo GNB1 mutation that overlaps a set of five recurrent somatic tumor mutations for which recent functional studies demonstrated a gain-of-function effect due to constitutive activation of G protein downstream signaling cascades for some of the affected residues.


Asunto(s)
Discapacidades del Desarrollo/etiología , Subunidades beta de la Proteína de Unión al GTP/genética , Mutación de Línea Germinal/genética , Discapacidad Intelectual/etiología , Hipotonía Muscular/etiología , Convulsiones/etiología , Adolescente , Adulto , Niño , Preescolar , Discapacidades del Desarrollo/patología , Exoma/genética , Femenino , Subunidades beta de la Proteína de Unión al GTP/química , Humanos , Lactante , Discapacidad Intelectual/patología , Masculino , Hipotonía Muscular/patología , Fenotipo , Conformación Proteica , Convulsiones/patología , Transducción de Señal , Adulto Joven
4.
Front Immunol ; 15: 1349601, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38487540

RESUMEN

Type 1 diabetes (T1D) is an autoimmune disease in which pancreatic islet ß-cells are attacked by the immune system, resulting in insulin deficiency and hyperglycemia. One of the top non-synonymous single-nucleotide polymorphisms (SNP) associated with T1D is in the interferon-induced helicase C domain-containing protein 1 (IFIH1), which encodes an anti-viral cytosolic RNA sensor. This SNP results in an alanine to threonine substitution at amino acid 946 (IFIH1A946T) and confers an increased risk for several autoimmune diseases, including T1D. We hypothesized that the IFIH1A946T risk variant, (IFIH1R) would promote T1D pathogenesis by stimulating type I interferon (IFN I) signaling leading to immune cell alterations. To test this, we developed Ifih1R knock-in mice on the non-obese diabetic (NOD) mouse background, a spontaneous T1D model. Our results revealed a modest increase in diabetes incidence and insulitis in Ifih1R compared to non-risk Ifih1 (Ifih1NR) mice and a significant acceleration of diabetes onset in Ifih1R females. Ifih1R mice exhibited a significantly enhanced interferon stimulated gene (ISG) signature compared to Ifih1NR, indicative of increased IFN I signaling. Ifih1R mice exhibited an increased frequency of plasma cells as well as tissue-dependent changes in the frequency and activation of CD8+ T cells. Our results indicate that IFIH1R may contribute to T1D pathogenesis by altering the frequency and activation of immune cells. These findings advance our knowledge on the connection between the rs1990760 variant and T1D. Further, these data are the first to demonstrate effects of Ifih1R in NOD mice, which will be important to consider for the development of therapeutics for T1D.


Asunto(s)
Enfermedades Autoinmunes , Diabetes Mellitus Tipo 1 , Femenino , Animales , Ratones , Helicasa Inducida por Interferón IFIH1/genética , ARN Helicasas DEAD-box/metabolismo , Linfocitos T CD8-positivos/metabolismo , Predisposición Genética a la Enfermedad , Ratones Endogámicos NOD , Enfermedades Autoinmunes/genética , Interferones/genética
5.
bioRxiv ; 2024 Aug 06.
Artículo en Inglés | MEDLINE | ID: mdl-39211124

RESUMEN

Genome-wide association studies have identified SH2B3 as an important non-MHC gene for islet autoimmunity and type 1 diabetes (T1D). In this study, we found a single SH2B3 haplotype significantly associated with increased risk for human T1D, and this haplotype carries the single nucleotide variant rs3184504*T in SH2B3. To better characterize the role of SH2B3 in T1D, we used mouse modeling and found a T cell-intrinsic role for SH2B3 regulating peripheral tolerance. SH2B3 deficiency had minimal effect on TCR signaling or proliferation across antigen doses, yet enhanced cell survival and cytokine signaling including common gamma chain-dependent and interferon-gamma receptor signaling. SH2B3 deficient CD8+T cells showed augmented STAT5-MYC and effector-related gene expression partially reversed with blocking autocrine IL-2 in culture. Using the RIP-mOVA model, we found CD8+ T cells lacking SH2B3 promoted early islet destruction and diabetes without requiring CD4+ T cell help. SH2B3-deficient cells demonstrated increased survival post-transfer compared to control cells despite a similar proliferation profile in the same host. Next, we created a spontaneous NOD .Sh2b3 -/- mouse model and found markedly increased incidence and accelerated T1D across sexes. Collectively, these studies identify SH2B3 as a critical mediator of peripheral T cell tolerance limiting the T cell response to self-antigens. Article Highlights: The rs3184504 polymorphism, encoding a hypomorphic variant of the negative regulator SH2B3, strongly associates with T1D.SH2B3 deficiency results in hypersensitivity to cytokines, including IL-2, in murine CD4+ and CD8+ T cells.SH2B3 deficient CD8+ T cells exhibit a comparable transcriptome to wild-type CD8+ T cells at baseline, but upon antigen stimulation SH2B3 deficient cells upregulate genes characteristic of enhanced JAK/STAT signaling and effector functions.We found a T-cell intrinsic role of SH2B3 leading to severe islet destruction in an adoptive transfer murine T1D model, while global SH2B3 deficiency accelerated spontaneous NOD diabetes across sexes.

6.
J Exp Med ; 218(5)2021 05 03.
Artículo en Inglés | MEDLINE | ID: mdl-33724365

RESUMEN

SAMD9L is an interferon-induced tumor suppressor implicated in a spectrum of multisystem disorders, including risk for myeloid malignancies and immune deficiency. We identified a heterozygous de novo frameshift variant in SAMD9L in an infant with B cell aplasia and clinical autoinflammatory features who died from respiratory failure with chronic rhinovirus infection. Autopsy demonstrated absent bone marrow and peripheral B cells as well as selective loss of Langerhans and Purkinje cells. The frameshift variant led to expression of a truncated protein with interferon treatment. This protein exhibited a gain-of-function phenotype, resulting in interference in global protein synthesis via inhibition of translational elongation. Using a mutational scan, we identified a region within SAMD9L where stop-gain variants trigger a similar translational arrest. SAMD9L variants that globally suppress translation had no effect or increased mRNA transcription. The complex-reported phenotype likely reflects lineage-dominant sensitivities to this translation block. Taken together, our findings indicate that interferon-triggered SAMD9L gain-of-function variants globally suppress translation.


Asunto(s)
Mutación del Sistema de Lectura , Regulación de la Expresión Génica/genética , Mutación de Línea Germinal , Biosíntesis de Proteínas/genética , Proteínas Supresoras de Tumor/genética , Células A549 , Linfocitos B/metabolismo , Linfocitos B/patología , Resultado Fatal , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Células HEK293 , Heterocigoto , Humanos , Recién Nacido , Interferones/farmacología , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Secuenciación Completa del Genoma
7.
Pediatr Rheumatol Online J ; 18(1): 80, 2020 Oct 16.
Artículo en Inglés | MEDLINE | ID: mdl-33066778

RESUMEN

BACKGROUND: Heme oxygenase-1 (HMOX1) catalyzes the metabolism of heme into carbon monoxide, ferrous iron, and biliverdin. Through biliverdin reductase, biliverdin becomes bilirubin. HMOX1-deficiency is a rare autosomal recessive disorder with hallmark features of direct antibody negative hemolytic anemia with normal bilirubin, hyperinflammation and features similar to macrophage activation syndrome. Clinical findings have included asplenia, nephritis, hepatitis, and vasculitis. Pulmonary features and evaluation of the immune response have been limited. CASE PRESENTATION: We present a young boy who presented with chronic respiratory failure due to nonspecific interstitial pneumonia following a chronic history of infection-triggered recurrent hyperinflammatory flares. Episodes included hemolysis without hyperbilirubinemia, immunodeficiency, hepatomegaly with mild transaminitis, asplenia, leukocytosis, thrombocytosis, joint pain and features of macrophage activation with negative autoimmune serologies. Lung biopsy revealed cholesterol granulomas. He was found post-mortem by whole exome sequencing to have a compound heterozygous paternal frame shift a paternal frame shift HMOX1 c.264_269delCTGG (p.L89Sfs*24) and maternal splice donor HMOX1 (c.636 + 2 T > A) consistent with HMOX1 deficiency. Western blot analysis confirmed lack of HMOX1 protein upon oxidant stimulation of the patient cells. CONCLUSIONS: Here, we describe a phenotype expansion for HMOX1-deficiency to include not only asplenia and hepatomegaly, but also interstitial lung disease with cholesterol granulomas and inflammatory flares with hemophagocytosis present in the bone marrow.


Asunto(s)
Anemia Hemolítica Congénita , Anemia Hemolítica , Trastornos del Crecimiento , Hemo-Oxigenasa 1/deficiencia , Hepatomegalia/diagnóstico por imagen , Trastornos del Metabolismo del Hierro , Insuficiencia Respiratoria , Bazo , Anemia Hemolítica/diagnóstico , Anemia Hemolítica/genética , Anemia Hemolítica Congénita/sangre , Anemia Hemolítica Congénita/diagnóstico , Anemia Hemolítica Congénita/fisiopatología , Anemia Hemolítica Congénita/terapia , Bilirrubina/sangre , Examen de la Médula Ósea/métodos , Niño , Deterioro Clínico , Cuidados Críticos/métodos , Diagnóstico , Resultado Fatal , Trastornos del Crecimiento/diagnóstico , Trastornos del Crecimiento/genética , Hemo-Oxigenasa 1/genética , Humanos , Trastornos del Metabolismo del Hierro/diagnóstico , Trastornos del Metabolismo del Hierro/genética , Enfermedades Pulmonares Intersticiales/diagnóstico por imagen , Enfermedades Pulmonares Intersticiales/etiología , Enfermedades Pulmonares Intersticiales/patología , Enfermedades Pulmonares Intersticiales/fisiopatología , Activación de Macrófagos , Masculino , Nefritis/diagnóstico , Nefritis/etiología , Insuficiencia Respiratoria/diagnóstico , Insuficiencia Respiratoria/etiología , Bazo/diagnóstico por imagen , Bazo/patología
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