Senior Principal Scientist, Computational Biology & Translation
Genentech
My research interests lie at the intersection of computational genomics, machine learning and human disease. I'm currently a Principal Scientist at Genentech, studying gene dysregulation in cancer. Formerly a postdoc in the Blencowe lab at the University of Toronto.
Accurate detection and quantification of mRNA isoforms from nanopore long-read sequencing remains challenged by technical noise, particularly in single cells. To address this, we introduce Isosceles, a computational toolkit that outperforms other methods in isoform detection sensitivity and quantification accuracy across single-cell, pseudo-bulk and bulk resolution levels, as demonstrated using synthetic and biologically-derived datasets.
Short-read RNA-seq datasets are expanding rapidly, while existing alternative splicing (AS) analysis tools are computationally inefficient and ineffective at handling complex splicing patterns. To address this, we've created a light-weight method for the rapid quantitative profiling of AS from raw RNA-seq reads at the event-level (Whippet.jl). In conjunction with investigations of RNA cis-regulatory elements, transcriptome profiling in multiple vertebrate species and tissues will to help identify conserved and clade-specific modes of isoform-specific gene regulation and dysregulation.
Local and long-range RNA structures are essential to the regulation of protein-coding mRNAs as well as short and long non-coding RNAs. Yet, identifying functional long-range and intermolecular RNA structures in vivo remains a major challenge in the field. To address this we have been developing high-throughput methods for the global-scale mapping of RNA duplexes, such as the ligation and sequencing of interacting RNA (LIGR-Seq).
As an orthogonal approach to biochemical RNA duplex mapping, algorithms for the efficient large-scale folding of local and long-range RNA duplexes can help us to study RNA structure from theoretical and evolutionary directions. Integrating multiple sources of computational (folding energetics, phylogenetic analysis) and experimental data (RNA structure probing, RNA duplex mapping) will facilitate prioritization and classification of functional RNA duplexes.
Kabza M., Ritter A., Byrne A., Sereti K., Le D., Stephenson W., Sterne-Weiler T.. (2024) “Accurate long-read transcript discovery and quantification at single-cell, pseudo-bulk and bulk resolution with Isosceles”. Nature Communications. 15, 15, 7316.
Sterne-Weiler T.* , Weatheritt RJ.*, Ha K., Blencowe BJ . (2018) “Efficient and accurate quantitative profiling of alternative splicing patterns of any complexity on a laptop”. Molecular Cell. 72(1), 187–200.
Sharma, E.*, Sterne-Weiler, T.*, O’Hanlon D., Blencowe, BJ. (2016) “Global mapping of human RNA:RNA interactions.” Molecular Cell. 62(4):618-26.
Weatheritt RJ., Sterne-Weiler T., Blencowe BJ. (2016) “The ribosome-engaged landscape of alternative splicing.” Nature Structural and Molecular Biology. doi: 10.1038/nsmb.3317.
Sterne-Weiler T, Sanford JR. (2014) "Exon identity crisis: disease-causing mutations that disrupt the splicing code." Genome Biology 15(1):201.
Mort M, Sterne-Weiler T, Li B, Ball EV, Cooper DN, Radivojac P, Sanford JR, Mooney SD. (2014) "MutPred Splice: machine learning-based prediction of exonic variants that disrupt splicing." Genome Biology 15(1):R19.
Sterne-Weiler T*, Martinez-Nunez RT*, Howard JM, Cvitovik I, Katzman S, Tariq MA, Pourmand N, Sanford JR. (2013) "Frac-seq reveals isoform-specific recruitment to polyribosomes." Genome Research 23(10):1615-23.
Sterne-Weiler T, Howard J, Mort M, Cooper DN, Sanford JR. (2011) "Loss of exon identity is a common mechanism of human inherited disease." Genome Research 21(10):1563-71.
