An integrative approach to ortholog prediction for disease-focused and other functional studies

Hu, Yanhui; Flockhart, Ian; Vinayagam, Arunachalam; Bergwitz, Clemens; Berger, Bonnie; Perrimon, Norbert; Mohr, Stephanie E.

doi:10.1186/1471-2105-12-357

Cited by 707 publications

(717 citation statements)

References 72 publications

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“…The "DRSC Interactive Ortholog Prediction Tool" was used to identify the human orthologs of Drosophila genes (31). Known and predicted protein interactions were assessed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING 9.0) (32).…”

Section: Methodsmentioning

confidence: 99%

Genome-wide RNAi screen identifies the Parkinson disease GWAS risk locusSREBF1as a regulator of mitophagy

Ivatt

Sánchez-Martínez

Godena

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

117

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Genetic analysis of Parkinson disease (PD) has identified several genes whose mutation causes inherited parkinsonism, as well as risk loci for sporadic PD. PTEN-induced kinase 1 (PINK1) and parkin, linked to autosomal recessive PD, act in a common genetic pathway regulating the autophagic degradation of mitochondria, termed mitophagy. We undertook a genome-wide RNAi screen as an unbiased approach to identify genes regulating the PINK1/Parkin pathway. We identified several genes that have a conserved function in promoting mitochondrial translocation of Parkin and subsequent mitophagy, most notably sterol regulatory element binding transcription factor 1 (SREBF1), Fbox and WD40 domain protein 7 (FBXW7), and other components of the lipogenesis pathway. The relevance of mechanisms of autosomal recessive parkinsonism to sporadic PD has long been debated. However, with the recent identification of SREBF1 as a risk locus for sporadic PD, our findings suggest a common mechanistic link between autosomal recessive and sporadic PD, and underscore the importance of mitochondrial homeostasis. P arkinson disease (PD) is an age-related neurodegenerative disease caused principally by the loss of midbrain dopaminergic neurons, resulting in motor disturbances, such as postural instability, resting tremor, and bradykinesia, as well as other nonmotor symptoms. Current therapeutic strategies alleviate symptoms by the replacement of dopamine, with variable efficacy and substantial side effects. However, there are currently no established curative, preventative, or disease-modifying interventions, stemming from a poor understanding of the molecular mechanisms of pathogenesis. Genetic analyses have identified causative mutations for autosomal dominant and recessive forms of familial parkinsonism. Functional studies of these genes have provided great insight into potential pathogenic mechanisms of inherited forms of PD; however, it is unclear how these may relate to the more common sporadic forms of PD. To gain insight into the genetic influence in sporadic PD, genome-wide association studies (GWASs) have revealed several loci that are significantly associated with the occurrence of PD, and so are considered potential risk factors. However, we lack mechanistic insight into how many of the associated risk loci may contribute to pathogenesis.Mitochondrial dysfunction has long been considered a key contributing factor in the pathogenesis of PD, with evidence from postmortem tissue, epidemiological studies, and genetics. In particular, a body of evidence indicates that two genes linked to recessive parkinsonism, PTEN-induced kinase 1 (PINK1) and parkin, act in a common pathway to regulate mitochondrial turnover, providing an attractive hypothesis for the impact of mitochondrial homeostasis on pathogenesis (1). The process of mitophagy to degrade dysfunctional mitochondria has been extensively studied using uncoupling agents to dissipate the mitochondrial membrane potential (ΔΨm) (2). Following loss of ΔΨm, PINK1 accumulates on the outer mit...

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Section: Methodsmentioning

confidence: 99%

Genome-wide RNAi screen identifies the Parkinson disease GWAS risk locusSREBF1as a regulator of mitophagy

Ivatt

Sánchez-Martínez

Godena

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

117

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“…Mammalian orthologs for those genes containing event(s) that met these criteria were obtained using DIPOT (Hu et al 2011). Analysis of conservation is further described in Supplemental Methods.…”

Section: Identification Of Ancient Coregulated Orthologsmentioning

confidence: 99%

Ancient antagonism between CELF and RBFOX families tunes mRNA splicing outcomes

Gazzara¹,

Mallory

Roytenberg

et al. 2017

Genome Res.

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Over 95% of human multi-exon genes undergo alternative splicing, a process important in normal development and often dysregulated in disease. We sought to analyze the global splicing regulatory network of CELF2 in human T cells, a well-studied splicing regulator critical to T cell development and function. By integrating high-throughput sequencing data for binding and splicing quantification with sequence features and probabilistic splicing code models, we find evidence of splicing antagonism between CELF2 and the RBFOX family of splicing factors. We validate this functional antagonism through knockdown and overexpression experiments in human cells and find CELF2 represses RBFOX2 mRNA and protein levels. Because both families of proteins have been implicated in the development and maintenance of neuronal, muscle, and heart tissues, we analyzed publicly available data in these systems. Our analysis suggests global, antagonistic coregulation of splicing by the CELF and RBFOX proteins in mouse muscle and heart in several physiologically relevant targets, including proteins involved in calcium signaling and members of the MEF2 family of transcription factors. Importantly, a number of these coregulated events are aberrantly spliced in mouse models and human patients with diseases that affect these tissues, including heart failure, diabetes, or myotonic dystrophy. Finally, analysis of exons regulated by ancient CELF family homologs in chicken, Drosophila, and Caenorhabditis elegans suggests this antagonism is conserved throughout evolution.

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“…Biological and genetic features of human genes and their putative orthologous genes, including tissue expression pattern and Gene Ontology (GO) terms, are extracted from the following model organism databases: Saccharomyces Genome Database (SGD) 19 27 an online tool integrating 14 ortholog prediction tools to provide a homology score for each predicted ortholog pair. Additionally, DIOPT is used to display a multiple protein alignment that is generated with MAFFT and human gene functional domains.…”

Section: Gene Function Databasesmentioning

confidence: 99%

“…Additionally, DIOPT is used to display a multiple protein alignment that is generated with MAFFT and human gene functional domains. 27 …”

Section: Gene Function Databasesmentioning

confidence: 99%

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MARRVEL: Integration of Human and Model Organism Genetic Resources to Facilitate Functional Annotation of the Human Genome

Wang¹,

Al‐Ouran²,

Hu³

et al. 2017

The American Journal of Human Genetics

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198

146

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One major challenge encountered with interpreting human genetic variants is the limited understanding of the functional impact of genetic alterations on biological processes. Furthermore, there remains an unmet demand for an efficient survey of the wealth of information on human homologs in model organisms across numerous databases. To efficiently assess the large volume of publically available information, it is important to provide a concise summary of the most relevant information in a rapid user-friendly format. To this end, we created MARRVEL (model organism aggregated resources for rare variant exploration). MARRVEL is a publicly available website that integrates information from six human genetic databases and seven model organism databases. For any given variant or gene, MARRVEL displays information from OMIM, ExAC, ClinVar, Geno2MP, DGV, and DECIPHER. Importantly, it curates model organism-specific databases to concurrently display a concise summary regarding the human gene homologs in budding and fission yeast, worm, fly, fish, mouse, and rat on a single webpage. Experiment-based information on tissue expression, protein subcellular localization, biological process, and molecular function for the human gene and homologs in the seven model organisms are arranged into a concise output. Hence, rather than visiting multiple separate databases for variant and gene analysis, users can obtain important information by searching once through MARRVEL. Altogether, MARRVEL dramatically improves efficiency and accessibility to data collection and facilitates analysis of human genes and variants by cross-disciplinary integration of 18 million records available in public databases to facilitate clinical diagnosis and basic research.

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An integrative approach to ortholog prediction for disease-focused and other functional studies

Cited by 707 publications

References 72 publications

Genome-wide RNAi screen identifies the Parkinson disease GWAS risk locusSREBF1as a regulator of mitophagy

Genome-wide RNAi screen identifies the Parkinson disease GWAS risk locusSREBF1as a regulator of mitophagy

Ancient antagonism between CELF and RBFOX families tunes mRNA splicing outcomes

MARRVEL: Integration of Human and Model Organism Genetic Resources to Facilitate Functional Annotation of the Human Genome

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