Biology subjects

Janes, J.

Publications and source records attributed to Janes, J..

4 recordsLinked to original sources

bioRxiv2024

Predicted mechanistic impacts of human protein missense variants

Genome sequencing efforts have led to the discovery of tens of millions of protein missense variants found in the human population with the majority of these having no annotated role and some likely contributing to trait variation and disease. Sequence-based artificial intelligence approaches have become highly accurate at predicting variants that are detrimental to the function of proteins but they do not inform on mechanisms of disruption. Here we combined sequence and structure-based methods to perform proteome-wide prediction of deleterious variants with information on their impact on protein stability, protein-protein interactions and small-molecule binding pockets. AlphaFold2 structures were used to predict approximately 100,000 small-molecule binding pockets and stability changes for over 200 million variants. To inform on protein-protein interfaces we used AlphaFold2 to predict structures for nearly 500,000 protein complexes. We illustrate the value of mechanism-aware variant effect predictions to study the relation between protein stability and abundance and the structural properties of interfaces underlying trans protein quantitative trait loci (pQTLs). We characterised the distribution of mechanistic impacts of protein variants found in patients and experimentally studied example disease linked variants in FGFR1.

bioinformatics↗

bioRxiv2021

A structural biology community assessment of AlphaFold 2 applications

Most proteins fold into 3D structures that determine how they function and orchestrate the biological processes of the cell. Recent developments in computational methods have led to protein structure predictions that have reached the accuracy of experimentally determined models. While this has been independently verified, the implementation of these methods across structural biology applications remains to be tested. Here, we evaluate the use of AlphaFold 2 (AF2) predictions in the study of characteristic structural elements; the impact of missense variants; function and ligand binding site predictions; modelling of interactions; and modelling of experimental structural data. For 11 proteomes, an average of 25% additional residues can be confidently modelled when compared to homology modelling, identifying structural features rarely seen in the PDB. AF2-based predictions of protein disorder and protein complexes surpass state-of-the-art tools and AF2 models can be used across diverse applications equally well compared to experimentally determined structures, when the confidence metrics are critically considered. In summary, we find that these advances are likely to have a transformative impact in structural biology and broader life science research.

biophysics↗

bioRxiv2020

Tissue-specific profiling reveals distinctive regulatory architectures for ubiquitous, germline and somatic genes

Despite increasingly detailed knowledge of gene expression patterns, the regulatory architectures that drive them are not well understood. To address this, we compared transcriptional and regulatory element activities across five adult tissues of C. elegans, covering [~]90% of cells, and defined regulatory grammars associated with ubiquitous, germline and somatic tissue-specific gene expression patterns. We find architectural features that distinguish two major promoter types. Germline-specific and ubiquitously-active promoters have well positioned +1 and -1 nucleosomes associated with a periodic 10-bp WW signal. Somatic tissue-specific promoters lack these features, have wider nucleosome depleted regions, and are more enriched for core promoter elements, which surprisingly differ between tissues. A 10-bp periodic WW signal is also associated with +1 nucleosomes of ubiquitous promoters in fly and zebrafish but is not detected in mouse and human. Our results demonstrate fundamental differences in regulatory architectures of germline-active and somatic tissue-specific genes and provide a key resource for future studies.

genomics↗

bioRxiv2018

Chromatin accessibility dynamics across C. elegans development and ageing

An essential step for understanding the transcriptional circuits that control development and physiology is the global identification and characterization of regulatory elements. Here we present the first map of regulatory elements across the development and ageing of an animal, identifying 42,245 elements accessible in at least one C. elegans stage. Based on nuclear transcription profiles, we define 15,714 protein-coding promoters and 19,231 putative enhancers, and find that both types of element can drive orientation-independent transcription. Additionally, hundreds of promoters produce transcripts antisense to protein coding genes, suggesting involvement in a widespread regulatory mechanism. We find that the accessibility of most elements is regulated during development and/or ageing and that patterns of accessibility change are linked to specific developmental or physiological processes. The map and characterization of regulatory elements across C. elegans life provides a platform for understanding how transcription controls development and ageing.

genomics↗