Navigating the phenotype frontier: The Monarch Initiative

McMurry, Julie A.; Köhler, Sebastian; Balhoff, James P.; Borromeo, Charles; Brush, Matthew; Carbon, Seth; Conlin, Tom; Dunn, Nathan; Engelstad, Mark; Foster, Erin D.; Gourdine, Jean-Philippe; Jacobsen, Julius O. B.; Keith, Dan; Laraway, Bryan; Lewis, Suzanna; Xuan, Jeremy Nguyen; Shefchek, Kent; Vasilevsky, Nicole; Zhou, Yuan; Washington, Nicole; Hochheiser, Harry; Mungall, Christopher J.; Groza, Tudor; Smedley, Damian; Robinson, Peter N.; Haendel, Melissa

doi:10.1101/059204

Cited by 9 publications

(10 citation statements)

References 16 publications

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“…For this final self-organizing map we then annotated each unit with Ensembl (v75) genes based on association rules defined by GREAT 58 . Based on these unit/gene assignments we then determined enrichment of gene ontologies (http://geneontology.org/ontology/go.obo) and human phenotype ontologies from the Monarch Initiative 90 (http://purl.obolibrary.org/obo/hp.obo) as previously described 91 . Clusters of units, or metaclusters, were then determined with four separate trials testing for the presence of up to 250 metaclusters as previously described 66 .…”

Section: Methodsmentioning

confidence: 99%

High Resolution Epigenomic Atlas of Early Human Craniofacial Development

Wilderman

Kron²,

VanOudenhove³

et al. 2017

Preprint

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12 13 Defects in embryonic patterning resulting in craniofacial abnormalities are common birth 14 defects affecting up to 1 in 500 live births worldwide, and are mostly non-syndromic. 15 The regulatory programs that build and shape the craniofacial complex are thought to 16 be controlled by information encoded in the genome between genes and within intronic 17 sequences. Early stages of human craniofacial development have not been interrogated 18 with modern functional genomics techniques, preventing systematic analysis of genetic 19 associations with craniofacial-specific regulatory sequences. Here we describe a 20 comprehensive resource of craniofacial epigenomic annotations and systematic, 21 integrative analysis with a variety of human tissues and cell types. We identified 22 thousands of novel craniofacial enhancers and provide easily accessible genome 23 annotations for craniofacial researchers and clinicians. We demonstrate the utility of our 24 data to find likely causal variants for craniofacial abnormalities and identify a large 25 enhancer cluster that interacts with HOXA genes during craniofacial development.

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Section: Methodsmentioning

confidence: 99%

High Resolution Epigenomic Atlas of Early Human Craniofacial Development

Wilderman

Kron²,

VanOudenhove³

et al. 2017

Preprint

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“…Thus the Oca2 CRISPR knockout phenotypes that have been generated in frogs (16) do not have a dedicated Gephebase entry ; the cavefish Oca2 CRISPR/TALEN knockout phenotypes (17,18) do not have a dedicated entry either, but are used as Additional References to support the functionality of the two natural Oca2 null alleles in Gephebase. This makes Gephebase complementary to the Monarch Initiative database, which compiles gene-to-phenotype relationships in humans, as well as in laboratory organisms and mutants generated by reverse genetics, but does not include non-model species such as cavefishes and corn snakes (8,9) .…”

Section: Snapshot Summarymentioning

confidence: 99%

“…Advances in genome sequencing and editing are accelerating the rate of discovery of the loci of evolution at a quick pace, making data integration increasingly challenging, and it is now crucial to develop a universal, single resource integrating this body of knowledge. As of today, compilations of genotype-phenotype relationships are available for a limited number of species in taxon-specific databases, for example OMIA for domesticated animals (4) , OMIM for humans (5) , TAIR for Arabidopsis (6) , FlyBase for Drosophila (7) , or the Monarch Initiative across the main laboratory animal model species (8,9) . To date, there are no databases that consolidate genotype-phenotype relationships related to natural evolutionary cases across all Eukaryotes.…”

Section: Introductionmentioning

confidence: 99%

Gephebase, a Database of Genotype-Phenotype Relationships for natural and domesticated variation in Eukaryotes

Courtier‐Orgogozo

Arnoult

Prigent

et al. 2019

Preprint

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Gephebase is a manually-curated database compiling our accumulated knowledge of the genes and mutations that underlie natural, domesticated and experimental phenotypic variation in all Eukaryotes -mostly animals, plants and yeasts. Gephebase aims to compile studies where the genotype-phenotype association (based on linkage mapping, association mapping or a candidate gene approach) is relatively well supported or understood. Human disease and aberrant mutant phenotypes in laboratory model organisms are not included in Gephebase and can be found in other databases ( eg. OMIM, OMIA, Monarch Initiative). Gephebase contains more than 1700 entries. Each entry corresponds to an allelic difference at a given gene and its associated phenotypic change(s) between two species or between two individuals of the same species, and is enriched with molecular details, taxonomic information, and bibliographic information. Users can easily browse entries for their topic of interest and perform searches at various levels, whether phenotypic, genetic, taxonomic or bibliographic ( eg. transposable elements, cis-regulatory mutations, snakes, carotenoid content, an author name). Data can be searched using keywords and boolean operators and is exportable in spreadsheet format. This database allows to perform meta-analysis to extract general information and global trends about evolution, genetics, and the field of evolutionary genetics itself. Gephebase should also help breeders, conservationists and others to identify the most promising target genes for traits of interest, with potential applications such as crop improvement, parasite and pest control, bioconservation, and genetic diagnostic. It is freely available at www.gephebase.org .

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“…The Human Phenotype Ontology (HPO) project (60) also provides gene-to-phenotype mappings, which can be used in a similar manner (http://human-phenotype-ontology.org). HPO plays a key role in the Monarch Initiative (61), which provides tools for genotypephenotype analysis across broad areas of disease (https://monarchinitiative.org). Toolkits that have been built on top of these and other annotations primarily for the discovery of Mendelian genes include:

Exomiser (62), which has been shown to improve the prioritization of disease genes from WES variant calls through cross-species phenotype comparisons (www.sanger.ac.uk/science/tools/exomiser).

…”

Section: Knowledge-driven Variant Prioritizationmentioning

confidence: 99%

A Practical Guide To Filtering and Prioritizing Genetic Variants

Dashti

Gamieldien

2017

BioTechniques

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Next-generation sequencing (NGS) of whole genomes and exomes is a powerful tool in biomedical research and clinical diagnostics. However, the vast amount of data produced by NGS introduces new challenges and opportunities, many of which require novel computational and theoretical approaches when it comes to identifying the causal variant(s) for a disease of interest. While workflows and associated software to process raw data and produce high-confidence variant calls have significantly improved, filtering tens of thousands of candidates to identify a subset relevant to a specific study is still a complex exercise best left to bioinformaticists. However, as this prioritization procedure requires biological/biomedical reasoning, biologists and clinicians are increasingly motivated to handle the task themselves. Here, we describe a set of guidelines, tools, and online resources that can be used to identify functional variants from whole-genome and whole-exome variant calls and then prioritize these variants with potential associations to phenotypes of interest. Insights gained from a recently published analysis of protein-coding gene variation in >60,000 humans by the Exome Aggregation Consortium (ExAC) are also taken into account.

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Navigating the phenotype frontier: The Monarch Initiative

Cited by 9 publications

References 16 publications

High Resolution Epigenomic Atlas of Early Human Craniofacial Development

High Resolution Epigenomic Atlas of Early Human Craniofacial Development

Gephebase, a Database of Genotype-Phenotype Relationships for natural and domesticated variation in Eukaryotes

A Practical Guide To Filtering and Prioritizing Genetic Variants

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