Navigating MARRVEL, a Web-Based Tool that Integrates Human Genomics and Model Organism Genetics Information

MARRVEL.org aggregates information that can provide an overview of the disease relevance of human genes, focusing mostly on rare genetic diseases. It also gathers biological information from model organism databases. MARRVEL can save a lot of time and effort.

Without this tool, users would spend hours searching different databases to gather information that MARRVEL can obtain in seconds. MARRVEL is actively used by physicians and scientists all over the world. It facilitates diagnosis and can be a starting point for exploring more information for therapeutic studies.

Although most of our users have a human genetics background, we have increasing numbers of users from a wide range of biomedical fields, including model organism researchers. For a human gene and variant-based search, open the MARRVEL home page. A search can be performed with gene information alone, variant information alone, or both gene and variant information.

Confirm that the candidate gene names are listed below the input box with each character entry. If the search comes back negative, use the HGNC website to make sure that the gene symbol used is up to date. Next, enter a human variant information to how variants are displayed on the Exome Aggregation Consortium and Genome Aggregation Database, or use a transcript-based nomenclature according to the Human Genome Variation Society guidelines.

For genomic location nomenclature, use the coordinates according to Homo sapiens genome assembly 19. To access the model organism data relative to the human gene of interest in MARRVEL, use the Gene Function Table to obtain each of the following for eight model organisms. As each gene name is hyperlinked to the gene pages on their respective model organism databases, click on the links to find out more about the phenotypic information and resources available for each model organism.

For example, on FlyBase, there will be a list of all of the alleles that have been generated, their respective phenotypes, and the availability of each allele from public stock centers. In the Gene Function Table, click the PubMed links to go to a list of publications that relates to the gene of interest in each organism. To see the confidence level that the model organism gene is likely to be the ortholog of the human gene of interest, check the DIOPT column to obtain a measure of the number of ortholog prediction algorithms that the model organism gene is likely to be an ortholog of the human gene of interest.

Uncheck the Show only best DIOPT score gene box to display all of the candidates that typically include paralogous genes and homologous genes that are not necessarily orthologs in each model organism. To determine the expression of the gene or protein of interest, check the Expression column for the list of tissues where the gene or protein of interest has been reported to be expressed in human or model organism databases. Human transcriptome data is obtained from Genotype-Tissue Expression, or GTEx, and human protein expression data is from the Human Protein Atlas.

In the Expression column, some data will have a button with pop-up links, such as for human and fly data, that display the gene or protein expression pattern using a heat map. Other data are hyperlinked to their respective model organism databases pages for further exploration. To access the Gene Ontology terms, check the Molecular function, Cellular component, and Biological process columns.

These data have been filtered by the experimental evidence codes and display Gene Ontology terms that are based on direct experimental evidence in each model organism. Use Monarch Initiative to navigate to the Phenogrid page for a specific human gene. A chart that provides a quick comparison between the phenotypes associated with the gene of interest to known human diseases and model organism mutants that have phenotypic overlaps will appear.

If a mouse gene has a knockout mouse made or planned by the International Mouse Phenotyping Consortium, clicking IMPC will link to the page that details the phenotype of the knockout mouse and its availability from public stock centers. To obtain information on predicted protein domains of the human protein of interest, click the Human Gene Protein Domains box. The data is derived from DIOPT, which uses protein families and Conserved Domains Databases.

A single residue may be annotated more than once due to some overlap in domains annotated in the two sources. Then use the Multiple Protein Alignment box to obtain the amino acid multiple alignment generated by DIOPT that uses multiple alignment program for amino acid or nucleotide sequences aligner for each protein. To highlight the amino acid of interest, scroll down to the bottom of the box and enter the amino acid numbers of interest.

To begin a search in MARRVEL based on model organism genes, click Model Organisms Search and select the model organism of choice. Enter a model organism gene symbol, click on the gene symbol as the name is auto-completed, and click Search. If the search result is negative, check the official gene symbol that is used in model organism databases.

If the search result is still negative, access DIOPT and the Orthology Predictions Search database to assess if there are no good predicted orthologs for the gene of interest. If the search is positive, check the DIOPT score and the best score from human gene to model organism column for the selection of the human gene. If the gene has a DIOPT score of three or more and the best score from human gene to model organism is marked Yes, it is likely that there is more than one gene that is orthologous to the model organism gene of interest.

Click the MARRVEL it link to display the search results for each human ortholog candidate. In this case, there is only one candidate. To interpret a MARRVEL human genetics output for a gene and variant of interest, click Online Mendelian Inheritance in Man, or OMIM.

Use the Human Gene Description box to obtain a short summary of what is known about the gene and gene product. Use the Gene-Phototype Relationships box to determine if the gene of interest is known to be a Mendelian disease-causing gene. This box will provide manually curated known diseases and other phenotype associations with the gene of interest.

The Reported Alleles From OMIM box can be used to obtain a list of pathogenic variants curated by this database to see if the variant of interest has been curated in OMIM as pathogenic. In this example, a search for human TBX2 was performed to assess the known biological function of this gene and the potential functional impact of a specific missense variant in the gene found to segregate in a small family with a rare disease that involves the skeletal, cardiac, and immune systems. Here, the output for the TBX2 search can be seen.

Based on the model organism information displayed in MARRVEL, it was quickly determined that this gene of interest is conserved from C.elegans and Drosophila to humans and that the amino acid of interest, arginine 20, is also highly conserved throughout evolution. Note that rat TBX2 does not align well in this region, likely due to the transcript that is used for the alignment. By looking at the Gene Ontology terms of the TBX2 orthologs within different species, it can be observed that TBX2 encodes a transcription factor that has been implicated in heart morphogenesis and other biological processes in mouse and zebrafish.

As human TBX2 is expressed in the heart-based genotype tissue expression and protein atlases and patients with a TBX2 variant exhibit heart defects, it can be concluded that this variant is a good candidate to explore experimentally. Gene names may change over time, so it is important to confirm that you're using the latest official gene symbols based on human or model organism databases. Please watch our accompanying JoVE video article titled In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila"for further experimental studies that can be performed.

MARRVEL has been supporting clinicians and researchers in facilitating disease diagnosis and mechanistic studies. We will continue to do so by adding new features to the program as we move forward. MARRVEL is continuously being upgraded, so we recommend that users read the What's New section to stay up to date about the new features that have been introduced.