GeneFriends: An RNA-seq co-expression tool for functional annotation and candidate gene prioritization

Over the past decade, and in part thanks to the sequencing of the human genome, research in the field of genetics has rapidly expanded leading to the identification of many genes associated with multiple human diseases and traits. Even though science has gained a broader understanding of most human diseases, many unanswered questions remain and the genetic basis of the majority of human common diseases and most human traits is only partly understood.

This project aims to construct a new online tool to help researchers infer the functions of unknown genes as well as identify candidate new players for roles in diseases and in biological processes. This tool will be based on data obtained from the state-of-the-art RNA sequencing technology (RNA-seq). This technology allows researchers to measure the activity of genes in a given sample with greater accuracy than previous methods and is capable of measuring genes that to not encode proteins. A growing number of researchers currently employ RNA-seq, yet many genes associated with diseases and processes have unknown functions, which impedes understanding the mechanisms involved. To address this issue, our proposed tool, entitled GeneFriends, employs a guilt-by-association methodology to the analysis of genes. This approach identifies which genes tend to be activated simultaneously across multiple samples. Based on the idea that genes that are activated at the same time are functionally related, it is possible to predict the functions of previously unstudied genes based on the functions of the known genes they are co-activated with. To determine how genes tend to be co-activated, thousands of publicly available samples of previously measured gene levels using RNA-seq will be combined. This way a map will be generated that describes which genes generally tend to act together.

GeneFriends will allow scientists and clinicians to infer the function of unknown genes. Additionally, GeneFriends can be used to associate new genes with diseases and processes based on the fact that they were active at the same time as other genes previously identified as important for that disease or process. The corresponding tool created in this project will then allow researchers to relate new factors to diseases, identify candidate drug targets, potentially leading to new types of diagnosis and treatments. GeneFriends will be initially created for humans and mice and will be made freely available online for researchers, clinicians and commercial companies to use.

Sequencing the transcriptome (RNA-seq) is a powerful and emerging technology that allows researchers to measure differential expression of genes more accurately than with microarrays. One major advantage of RNA-seq is that it allows the measurement of different splice variants as well as non-coding RNAs (ncRNAs), which can play important biological roles and be involved in various diseases. However, a bottleneck in RNA-seq analyses is that even though many transcripts can be found differentially expressed, often most have not been well studied and it is often unclear which possible functions, for example, ncRNAs may have. The complexity of the already challenging analysis of RNA-seq data would be greatly reduced by the availability of information on the putative functions of all these transcripts.

Co-expression tools created from microarray data have successfully allowed researchers to assign putative functions to poorly annotated genes and identify candidate genes related to various diseases and biological processes using a guilt-by-association approach. In this project, we will create the first RNA-seq-based co-expression tool, focused on mice and humans. It will be entitled GeneFriends and it will allow researchers to assign putative functions to new and unstudied transcripts, such as ncRNAs and splice variants. Employing a guilt-by-association approach, GeneFriends will also allow researchers to identify new candidates for a role in a given disease or process. Given the growing importance of next-generation sequencing, GeneFriends will greatly benefit the research community. Overall, GeneFriends will be a new approach for the analysis and interpretation of genetics and genomics data from different types of studies. The resulting RNA-seq based co-expression tool will be and made freely available online for everyone to use.

Although many diseases have been well characterized at the molecular level, the underlying mechanisms are often unknown. The tool created in this project will allow researchers to relate previously unstudied transcripts to functions, diseases and biological processes, allowing candidate genes to be identified and testable hypothesis to be generated. It will also help infer the function of many unstudied transcripts.

This project will primarily benefit a wide range of researchers, as described in the Academic Beneficiaries section. Given the growing number of high-throughput technologies, including next-generation sequencing, employed in clinical genetic testing, inferring putative functions and interaction partners of poorly studied genes will have applications in the clinic. Numerous companies may also benefit from GeneFriends. Companies focused on personalized medicine services may benefit from having an online tool to infer function(s) of unknown genes. Besides, numerous pharmaceutical companies are focused on identifying novel targets for drug development. By providing and prioritizing candidates for further studies, GeneFriends may have applications in industry.