Biology subjects

Laman Trip, D. S.

Publications and source records attributed to Laman Trip, D. S..

5 recordsLinked to original sources

bioRxiv2026

Unifying the genetic landscape of common and rare diseases via latent neighborhoods

Resolving disease mechanisms and identifying safer drug targets remains challenging due to difficulties in integrating inconsistent sources of genetic evidence. Here, we developed a deep-learning (DL) method for obtaining latent representations of human diseases and other terms by coupling a variational autoencoder (VAE) to network embeddings from graph representation learning on a protein interaction network. We apply this approach to map the landscape of human disease, by systematically integrating evidence for [~]42,000 traits and terms from sources such as clinical reports (ClinVar), genome-wide association studies (GWAS), mouse phenotypes and gene ontology. Similar diseases share their latent neighborhoods with the sources of evidence highlighting different aspects of the same cell biology for its role in disease. By decoding latent neighborhoods, we unify the sources of evidence and integrate across diseases to prioritize genes for common and rare diseases. Through examples for diabetes, hearing loss, and familial long QT syndrome, we illustrate how the methodology can be applied to develop hypotheses for disease mechanisms and to propose experimental models, measurements, targets and potential drugs that may improve diagnosis and treatments.

genetics↗

bioRxiv2025

Network-based framework for studying etiology and phenotype diversity in primary ciliopathies

Recent advances in sequencing technologies have increasingly enabled the identification of genetic causes for human monogenic diseases. However, systematic understanding remains limited due to the rarity, genetic heterogeneity, and complex genotype-phenotype relationships of these diseases. Primary ciliopathies are a diverse group of rare disorders caused by variants in genes associated with the cilium, a cellular organelle involved in signaling during development and cell homeostasis. These genetic variants result in a wide spectrum of clinical phenotypes involving the brain, eye, kidney and skeleton. It remains unclear to what extent this phenotypic diversity can be attributed to the disease-causing genes and their specific roles in ciliary function. Here, we systematically compared human primary ciliopathies with each other and with mouse phenotypes by propagating known disease genes through a network of protein interactions. Network propagation improved the clustering of primary ciliopathies with shared clinical phenotypes and facilitated the identification of mouse phenotypes closely related to primary ciliopathies due to shared groups of proteins in the interaction network. By leveraging this phenotype-specific approach, we prioritized candidate genes for ciliopathies and identified likely pathogenic variants in CEP43, a novel candidate gene for human primary ciliopathies in three previously unsolved cases. This study demonstrates that network propagation enhances the genetic and phenotypic understanding of primary ciliopathies, aiding in the prioritization of candidate genes and identification of relevant mouse models for these rare disorders, and providing a framework for unraveling shared underlying mechanisms for other rare genetic diseases.

genetics↗

bioRxiv2024

An atlas of protein-protein associations of human tissues prioritizes candidate disease genes

Proteins that interact together participate in the same cellular process and influence the same organismal traits. Despite the progress in mapping protein-protein interactions we lack knowledge of how they differ between tissues. Due to coordinated (post)transcriptional control, protein complex members have highly correlated abundances that are predictive of functional association. Here, we have compiled 7873 proteomic samples measuring protein levels in 11 human tissues and use these to define an atlas with tissue-specific protein associations. This method recapitulates known protein complexes and the larger structural organization of the cell. Interactions of stable protein complexes are well preserved across tissues, while signaling and metabolic interactions show larger variation. Further, we find that less than 18% of differences between tissues are estimated to be due to differences in gene expression while cell-type specific cellular structures, such as synaptic components, represent a significant driver of differences between tissues. We further supported the brain protein association network through co-fractionation experiments in synaptosomes, curation of brain derived pull-down data and AlphaFold2 models. Together these results illustrate how this brain specific protein interaction network can functionally prioritize candidate genes within loci linked to brain disorders.

systems biology↗

bioRxiv2022

Fundamental limits to progression of cellular life in frigid environments

Life on Earth, including for microbes and cold-blooded animals, often occurs in frigid environments. At frigid temperatures, nearly all intracellular processes slow down which is colloquially said to decelerate lifes pace and, potentially, aging. But even for one cell, an outstanding conceptual challenge is rigorously explaining how the slowed-down intracellular processes collectively sustain a cells life and set its pace. Here, by monitoring individual yeast cells for months at near-freezing temperatures, we show how global gene-expression dynamics and Reactive Oxygen Species (ROS) act together as the primary factors that dictate and constrain the pace at which a budding yeasts life can progresses in frigid environments. We discovered that yeast cells help each other in surviving and dividing at frigid temperatures. By investigating the underlying mechanism, involving glutathione secretion, we discovered that ROS is the primary determinant of yeasts ability to survive and divide at near-freezing temperatures. Observing days-to-months-long cell-cycle progression in individual cells revealed that ROS inhibits S-G2-M (replicative) phase while elongating G1 (growth) phase up to a temperature-dependent threshold duration, beyond which yeast cannot divide and bursts as an unsustainably large cell. We discovered that an interplay between global gene-expression speed and ROS sets the threshold G1-duration by measuring rates of genome-wide transcription and protein synthesis at frigid temperatures and then incorporating them into a mathematical model. The same interplay yields unbeatable "speed limits" for cell cycling - shortest and longest allowed doubling times - at each temperature. These results establish quantitative principles for engineering cold-tolerant microbes and reveal how frigid temperatures can fundamentally constrain microbial life and cell cycle at the systems-level.

systems biology↗

bioRxiv2019

Cells reshape habitability of temperature by secreting antioxidants to help each other replicate and avoid population extinction

How the rising global temperatures affect organisms is a timely question. The conventional view is that high temperatures cause microbes to replicate slowly or die, both autonomously. Yet, microbes co-exist as a population, raising the underexplored question of whether they can cooperatively combat rising temperatures. Here we show that, at high temperatures, budding yeasts help each other and future generations of cells replicate by secreting and extracellularly accumulating glutathione - a ubiquitous heat-damage-reducing antioxidant. Yeasts thereby collectively delay and can halt population extinctions at high temperatures. As a surprising consequence, even for the same temperature, a yeast population can either exponentially grow, never grow, or grow after unpredictable durations (hours-to-days) of stasis, depending on its population density. Despite the conventional theory stating that heat-shocked cells autonomously die and cannot stop population extinctions, we found that non-growing yeast-populations at high temperatures - due to cells cooperatively accumulating extracellular glutathione - continuously decelerate and can eventually stop their approach to extinction, with higher population-densities stopping faster. We show that exporting glutathione, but not importing, is required for yeasts to survive high temperatures. Thus, cooperatively eliminating harmful extracellular agents - not glutathiones actions inside individual cells - is both necessary and sufficient for surviving high temperatures. We developed a mathematical model - which is generally applicable to any cells that cooperatively replicate by secreting molecules - that recapitulates all these features. These results show how cells can cooperatively extend boundaries of life-permitting temperatures.

systems biology↗