Biology subjects

Booth, J.

Publications and source records attributed to Booth, J..

3 recordsLinked to original sources

bioRxiv2023

A multiscale functional map of somatic mutations in cancer integrating protein structure and network topology

A major goal of cancer biology is to understand the mechanisms underlying tumorigenesis driven by somatically acquired mutations. Two distinct types of computational methodologies have emerged: one focuses on analyzing clustering of mutations within protein sequences and 3D structures, while the other characterizes mutations by leveraging the topology of protein-protein interaction network. Their insights are largely non-overlapping, offering complementary strengths. Here, we established a unified, end-to-end 3D structurally-informed protein interaction network propagation framework, NetFlow3D, that systematically maps the multiscale mechanistic effects of somatic mutations in cancer. The establishment of NetFlow3D hinges upon the Human Protein Structurome, a comprehensive repository we compiled that incorporates the 3D structures of every single protein as well as the binding interfaces of all known protein interactions in humans. NetFlow3D leverages the Structurome to integrate information across atomic, residue, protein and network levels: It conducts 3D clustering of mutations across atomic and residue levels on protein structures to identify potential driver mutations. It then anisotropically propagates their impacts across the protein interaction network, with propagation guided by the specific 3D structural interfaces involved, to identify significantly interconnected network "modules", thereby uncovering key biological processes underlying disease etiology. Applied to 1,038,899 somatic protein-altering mutations in 9,946 TCGA tumors across 33 cancer types, NetFlow3D identified 1,4444 significant 3D clusters throughout the Human Protein Structurome, of which ~55% would not have been found if using only experimentally-determined structures. It then identified 26 significantly interconnected modules that encompass ~8-fold more proteins than applying standard network analyses. NetFlow3D and our pan-cancer results can be accessed from http://netflow3d.yulab.org.

systems biology↗

bioRxiv2022

Dietary Lipid Oxidization Products Alter Growth, Adiposity and Gut Microbial Ecology in Prepubertal Porcine Model

Elevated levels of dietary fats in westernized diets, associated with increased risk of obesity and other chronic diseases, are increasingly consumed by children in the United States. Cooking practices such as high heat frying and increased use of oxidizable sources of fats have introduced high levels of lipid oxidation products (LOPs) into these diets. The effects of these highly reactive dietary compounds on human biology are largely unstudied, especially in the gut where these compounds are likely present at higher concentrations. Given that the gut microbiome can be influenced by dietary components and then in turn have a systemic impact, we investigated the effects of consuming LOPs on gut bacterial and fungal communities and on growth and body composition during the prepubertal period in a porcine model. The presence of LOPs in the high fat diet reduced growth and body fat gain in the model. The gut microbiome was uniquely altered by both high fat and the presence of LOPs, with notable changes in the abundances of Turicibacterales, Spriochaetales, RF39, Lactobacillales and Erysipelotrichales. The mycobiome was dominated by Kazachstania, a porcine specific yeast, which was only minimally influenced by the dietary regimen. Application of machine learning identified dietary fat and LOPs as strong predictors of body fat. The genus Methanobrevibacter was the key microbial predictor of body fat. This study highlights the need for further studies on the biological effects of LOPs which have become ubiquitous in human, livestock and pet diets in developed countries.

physiology↗

bioRxiv2021

Characterizing the genetic basis of trait evolution in the Mexican cavefish

Evolution in response to a change in ecology often coincides with various morphological, physiological, and behavioral traits. For most organisms little is known about the genetic and functional relationship between evolutionarily derived traits, representing a critical gap in our understanding of adaptation The Mexican tetra, Astyanax mexicanus, consists of largely independent populations of fish that inhabit at least 30 caves in Northeast Mexico, and a surface fish population, that inhabits the rivers of Mexico and Southern Texas. The recent application of molecular genetic approaches combined with behavioral phenotyping have established A. mexicanus as a model for studying the evolution of complex traits. Cave populations of A. mexicanus are interfertile with surface populations and have evolved numerous traits including eye degeneration, insomnia, albinism and enhanced mechanosensory function. The interfertility of different populations from the same species provides a unique opportunity to define the genetic relationship between evolved traits and assess the co-evolution of behavioral and morphological traits with one another. To define the relationships between morphological and behavioral traits, we developed a pipeline to test individual fish for multiple traits. This pipeline confirmed differences in locomotor activity, prey capture, and startle reflex between surface and cavefish populations. To measure the relationship between traits, individual F2 hybrid fish were characterized for locomotor behavior, prey-capture behavior, startle reflex and morphological attributes. Analysis revealed an association between body length and slower escape reflex, suggesting a trade-off between increased size and predator avoidance in cavefish. Overall, there were few associations between individual behavioral traits, or behavioral and morphological traits, suggesting independent genetic changes underlie the evolution of behavioral and morphological traits. Taken together, this approach provides a novel system to identify genes that underlie naturally occurring genetic variation in morphological and behavioral traits.

evolutionary biology↗