Functional unknomics: Systematic screening of conserved genes of unknown function

The human genome encodes approximately 20,000 proteins, many still uncharacterised. It has become clear that scientific research tends to focus on well-studied proteins, leading to a concern that poorly understood genes are unjustifiably neglected. To address this, we have developed a publicly available and customisable Unknome database that ranks proteins based on how little is known about them. We applied RNA interference (RNAi) in Drosophila to 260 unknown genes that are conserved between flies and humans. Knockdown of some genes resulted in loss of viability, and functional screening of the rest revealed hits for fertility, development, locomotion, protein quality control, and resilience to stress. CRISPR/Cas9 gene disruption validated a component of Notch signalling and 2 genes contributing to male fertility. Our work illustrates the importance of poorly understood genes, provides a resource to accelerate future research, and highlights a need to support database curation to ensure that misannotation does not erode our awareness of our own ignorance.

Automated summary

The human genome encodes many uncharacterised proteins among the approximately 20,000 proteins. The focus of scientific research on well-studied proteins has raised concerns about the neglect of poorly understood genes. To address this issue, the researchers developed a publicly available Unknome database that ranks proteins based on the extent of their unknown functions. By using RNA interference in Drosophila, they identified genes related to fertility, development, locomotion, protein quality control, and stress resilience. The study emphasizes the importance of poorly understood genes, provides a resource for future research, and highlights the need for proper database curation to avoid misannotation.