Category Archives: Uncategorized

Friday, December 8th, 2023

10:00 am PST

Location: Y2E2 111

Deep learning on local sites for protein structure and function analysis

Understanding how the three-dimensional structure of a protein leads to its function is important for determining disease mechanisms, developing targeted therapeutics, and engineering new proteins with desired functional characteristics. The expansion of protein structure databases due to experimental and computational advances provides an unprecedented opportunity to learn structure-function relationships in a data-driven manner. Deep learning methods that operate on protein structures have shown promise for specific tasks, but their utility for functional analysis has been limited due to inconsistencies in model training and evaluation, lack of labeled proteinfunction data, and an inability to reconcile global predictions with local biochemical mechanisms. In this dissertation, I explore these challenges and propose a framework for protein analysis based on learning on local sites rather than the entire protein structure. First, to establish standards for model development and evaluation, I present work on (1) developing a suite of benchmark datasets, processing tools, and baseline models, and (2) quantifying the effect of differing structure compositions in the training data. I then describe a self-supervised learning method that leverages evolutionary relationships to learn general-purpose representations of local structural sites and show how these representations enable improved performance on downstream tasks involving classification, search, and annotation of functional sites. By clustering millions of sites, I propose a framework for protein analysis based on conserved structural motifs which enables the discovery of functional relationships across protein classes. Finally, I present a method for explainable function annotation that predicts the overall function of a protein as well as the individual residues which are responsible.

Zoom: https://stanford.zoom.us/j/95316385692

(PW: 271506)

12/7/23

Speaker: Kyle Daniels, Assistant Professor of Genetics, Stanford University

Title: Decoding the language of signaling domains to control cell function

Abstract: Cell therapies are powerful technologies in which human cells are reprogrammed for therapeutic applications such as killing cancer cells or replacing defective cells. The technologies underlying cell therapies are increasingly complexity, making rational engineering of cell therapies more difficult. Creating the next generation of cell therapies will require improved experimental approaches and predictive models. Artificial intelligence (AI) and machine learning (ML) methods have revolutionized several fields in biology including genome annotation, protein structure prediction, and enzyme design. Combining experimental library screens and AI to build create predictive models, design rules, and improved designs could accelerate the development of cell therapies. Chimeric antigen receptor (CAR) costimulatory domains derived from native immune receptors steer the phenotypic output of therapeutic T cells. We constructed a library of CARs containing ~2,300 synthetic costimulatory domains, built from combinations of 13 signaling motifs. These CARs promoted diverse cell fates, which were sensitive to motif combinations and configurations. Neural networks trained to decode the combinatorial grammar of CAR signaling motifs allowed extraction of key design rules. For example, non-native combinations of motifs which bind tumor necrosis factor receptor-associated factors (TRAFs) and phospholipase C gamma 1 (PLCg1) enhanced cytotoxicity and stemness associated with effective tumor killing. Thus, libraries built from minimal building blocks of signaling, combined with machine learning, can efficiently guide engineering of receptors with desired phenotypes.

Suggested readings:

Daniels_DecodingCARTPhenotype_primary[4]

OConnell_CLASSIC_primary[87]

Prediction and inference from population scale datasets

Thursdays 11/16 1:30-3:00 pm in MSOB x303

Population biobanks are a valuable resource for identifying genetic and environmental factors that contribute to disease. Recent advances in statistical methods and computational power have enabled the analysis of large-scale datasets from these biobanks, leading to the discovery of novel therapeutic targets and pathways. This seminar will present on the use of population biobank scale datasets for the analysis of renal, liver, and sex hormone biomarkers. In addition, I will discuss the path from statistical methodological development to target identification for glaucoma to therapeutic development using monoclonal antibodies to mimic effects of protective mutations in humans. Finally, I will present on approaches for disease risk prediction using genetics, metabolomics, and proteomics data. Together, the methods and applications presented in this talk demonstrate the value of population-scale cohorts to advance our understanding of disease and development of new treatments.

Suggested reading:

Rare protein-altering variants in ANGPTL7 lower intraocular pressure and protect against glaucoma, https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1008682

Genetics of 35 blood and urine biomarkers, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867639/

Tanigawa Y, Qian J, Venkataraman G, Justesen JM, Li R, Tibshirani R, et al. (2022) Significant sparse polygenic risk scores across 813 traits in UK Biobank. PLoS Genet 18(3): e1010105. https://doi.org/10.1371/journal.pgen.1010105

Bayesian model comparison for rare-variant association studies
GR Venkataraman, C DeBoever, Y Tanigawa… – The American Journal of Human Genetics, 2021. Julia Carrasco-Zanini,et al.
MedRxiv 2023.07.18.23292811; doi:https://doi.org/10.1101/2023.07.18.23292811

This weekly seminar (running during Fall, Winter and Spring quarters) doubles as a class “Workshops in Biostatistics (BIODS/STATS 260).”