The project MinE databrowser: bringing large-scale whole-genome sequencing in ALS to researchers and the public

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Abstract

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive fatal neurodegenerative disease affecting one in 350 people. The aim of Project MinE is to elucidate the pathophysiology of ALS through whole-genome sequencing at least 15,000 ALS patients and 7500 controls at 30× coverage. Here, we present the Project MinE data browser ( databrowser.projectmine.com), a unique and intuitive one-stop, open-access server that provides detailed information on genetic variation analyzed in a new and still growing set of 4366 ALS cases and 1832 matched controls. Through its visual components and interactive design, the browser specifically aims to be a resource to those without a biostatistics background and allow clinicians and preclinical researchers to integrate Project MinE data into their own research. The browser allows users to query a transcript and immediately access a unique combination of detailed (meta)data, annotations and association statistics that would otherwise require analytic expertise and visits to scattered resources.

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Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles

A. Subramanian, P Tamayo, V K Mootha … (2005)

Although genomewide RNA expression analysis has become a routine tool in biomedical research, extracting biological insight from such information remains a major challenge. Here, we describe a powerful analytical method called Gene Set Enrichment Analysis (GSEA) for interpreting gene expression data. The method derives its power by focusing on gene sets, that is, groups of genes that share common biological function, chromosomal location, or regulation. We demonstrate how GSEA yields insights into several cancer-related data sets, including leukemia and lung cancer. Notably, where single-gene analysis finds little similarity between two independent studies of patient survival in lung cancer, GSEA reveals many biological pathways in common. The GSEA method is embodied in a freely available software package, together with an initial database of 1,325 biologically defined gene sets.

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A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3.

Pablo Cingolani, Adrian Platts, Le Lily Wang … (2012)

We describe a new computer program, SnpEff, for rapidly categorizing the effects of variants in genome sequences. Once a genome is sequenced, SnpEff annotates variants based on their genomic locations and predicts coding effects. Annotated genomic locations include intronic, untranslated region, upstream, downstream, splice site, or intergenic regions. Coding effects such as synonymous or non-synonymous amino acid replacement, start codon gains or losses, stop codon gains or losses, or frame shifts can be predicted. Here the use of SnpEff is illustrated by annotating ~356,660 candidate SNPs in ~117 Mb unique sequences, representing a substitution rate of ~1/305 nucleotides, between the Drosophila melanogaster w(1118); iso-2; iso-3 strain and the reference y(1); cn(1) bw(1) sp(1) strain. We show that ~15,842 SNPs are synonymous and ~4,467 SNPs are non-synonymous (N/S ~0.28). The remaining SNPs are in other categories, such as stop codon gains (38 SNPs), stop codon losses (8 SNPs), and start codon gains (297 SNPs) in the 5'UTR. We found, as expected, that the SNP frequency is proportional to the recombination frequency (i.e., highest in the middle of chromosome arms). We also found that start-gain or stop-lost SNPs in Drosophila melanogaster often result in additions of N-terminal or C-terminal amino acids that are conserved in other Drosophila species. It appears that the 5' and 3' UTRs are reservoirs for genetic variations that changes the termini of proteins during evolution of the Drosophila genus. As genome sequencing is becoming inexpensive and routine, SnpEff enables rapid analyses of whole-genome sequencing data to be performed by an individual laboratory.

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Is Open Access

The Genotype-Tissue Expression (GTEx) project.

John M. Lonsdale, Jeffrey Thomas, Mike Salvatore … (2014)

Genome-wide association studies have identified thousands of loci for common diseases, but, for the majority of these, the mechanisms underlying disease susceptibility remain unknown. Most associated variants are not correlated with protein-coding changes, suggesting that polymorphisms in regulatory regions probably contribute to many disease phenotypes. Here we describe the Genotype-Tissue Expression (GTEx) project, which will establish a resource database and associated tissue bank for the scientific community to study the relationship between genetic variation and gene expression in human tissues.

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Author and article information

Journal

Journal ID (nlm-journal-id): 101587185

Journal ID (pubmed-jr-id): 40726

Journal ID (nlm-ta): Amyotroph Lateral Scler Frontotemporal Degener

Journal ID (iso-abbrev): Amyotroph Lateral Scler Frontotemporal Degener

Title: Amyotrophic lateral sclerosis & frontotemporal degeneration

ISSN (Print): 2167-8421

ISSN (Electronic): 2167-9223

Publication date Nihms-submitted: 21 January 2021

Publication date (Print): August 2019

Publication date PMC-release: 19 February 2021

Volume: 20

Issue: 5-6

Pages: 432-440

Affiliations

[1 ]Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands

[2 ]Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands

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Correspondence: Jan H. Veldink, Department of Neurology and Neurosurgery, University Medical Centre Utrecht, G03.228, P.O. Box 85500, 3508 GA Utrecht, The Netherlands. J.H.Veldink@ 123456umcutrecht.nl

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RICK A.A. VAN DER SPEK http://orcid.org/0000-0001-9983-204X

WOUTER VAN RHEENEN http://orcid.org/0000-0002-5860-1533

SARA L. PULIT http://orcid.org/0000-0002-2502-3669

LEONARD H. VAN DEN BERG http://orcid.org/0000-0002-5203-9674

JAN H. VELDINK http://orcid.org/0000-0001-5572-9657

Article

Manuscript ID: NIHMS1658714

DOI: 10.1080/21678421.2019.1606244

PMC ID: 7893599

PubMed ID: 31280677

SO-VID: d32e840c-df04-47d4-adc4-010d3e6f7bbe

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This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License, which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.

The project MinE databrowser: bringing large-scale whole-genome sequencing in ALS to researchers and the public

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Most cited references 35

Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles

A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3.

The Genotype-Tissue Expression (GTEx) project.

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