The Molecular Signatures Database Hallmark Gene Set Collection

Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of disease.

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“…17a). Additional candidate target genes (at 20% FDR) were enriched in multiple immune pathways from MsigDB 57 (Extended Data Fig. 17b).…”

Section: Expression Qtls and Complex Disease Associationsmentioning

confidence: 99%

Genetic effects on gene expression across human tissues

groups

Fund

Nhgri³

et al. 2017

Nature

3,677

2,412

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“…2B, in red; Supplemental Table S9). Additionally, various cancer hallmarks (Liberzon et al 2015) are enriched in differentially spliced events but not in differentially expressed genes ( Fig. 2C; Supplemental Fig.…”

Section: Rbp Mutations Associate With Abnormal Splicing Patterns In Cmentioning

confidence: 99%

Large-scale analysis of genome and transcriptome alterations in multiple tumors unveils novel cancer-relevant splicing networks

et al. 2016

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Alternative splicing is regulated by multiple RNA-binding proteins and influences the expression of most eukaryotic genes. However, the role of this process in human disease, and particularly in cancer, is only starting to be unveiled. We systematically analyzed mutation, copy number, and gene expression patterns of 1348 RNA-binding protein (RBP) genes in 11 solid tumor types, together with alternative splicing changes in these tumors and the enrichment of binding motifs in the alternatively spliced sequences. Our comprehensive study reveals widespread alterations in the expression of RBP genes, as well as novel mutations and copy number variations in association with multiple alternative splicing changes in cancer drivers and oncogenic pathways. Remarkably, the altered splicing patterns in several tumor types recapitulate those of undifferentiated cells. These patterns are predicted to be mainly controlled by MBNL1 and involve multiple cancer drivers, including the mitotic gene NUMA1. We show that NUMA1 alternative splicing induces enhanced cell proliferation and centrosome amplification in nontumorigenic mammary epithelial cells. Our study uncovers novel splicing networks that potentially contribute to cancer development and progression.

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“…DMPs were annotated to genomic regions based on the NCBI reference genome (hg19) and enrichment of genomic regions was calculated using HOMER version 3.9 59 . Functional annotation of jmmlDMPs was performed using GSEA on gene sets available from the Molecular Signature Database 60,61 .…”

Section: Methodsmentioning

confidence: 99%

Ras-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia

Lipka

Witte

Tóth

et al. 2017

Experimental Hematology

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Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of early childhood characterized by mutations activating RAS signaling. Established clinical and genetic markers fail to fully recapitulate the clinical and biological heterogeneity of this disease. Here we report DNA methylome analysis and mutation profiling of 167 JMML samples. We identify three JMML subgroups with unique molecular and clinical characteristics. The high methylation group (HM) is characterized by somatic PTPN11 mutations and poor clinical outcome. The low methylation group is enriched for somatic NRAS and CBL mutations, as well as for Noonan patients, and has a good prognosis. The intermediate methylation group (IM) shows enrichment for monosomy 7 and somatic KRAS mutations. Hypermethylation is associated with repressed chromatin, genes regulated by RAS signaling, frequent co-occurrence of RAS pathway mutations and upregulation of DNMT1 and DNMT3B, suggesting a link between activation of the DNA methylation machinery and mutational patterns in JMML.

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The Molecular Signatures Database Hallmark Gene Set Collection

Cited by 9,448 publications

References 33 publications

Genetic effects on gene expression across human tissues

Genetic effects on gene expression across human tissues

Large-scale analysis of genome and transcriptome alterations in multiple tumors unveils novel cancer-relevant splicing networks

Ras-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia

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