Selected Publications

ℹ️ The full list of publications is available on Google Scholar or here.

High order expression dependencies finely resolve cryptic states and subtypes in single cell data

Published in bioRxiv, 2023

Single cells are typically typed by clustering in reduced dimensional transcriptome space. Here we introduce Stator, a novel method, workflow and app that reveals cell types, subtypes and states without relying on local proximity of cells in gene expression space. Rather, Stator derives higher-order gene expression dependencies from a sparse gene-by-cell expression matrix. From these dependencies the method multiply labels the same single cell according to type, sub-type and state (activation, differentiation or cell cycle sub-phase). By applying the method to data from mouse embryonic brain, and human healthy or diseased liver, we show how Stator first recapitulates other methods’ cell type labels, and then reveals combinatorial gene expression markers of cell type, state, and disease at higher resolution. By allowing multiple state labels for single cells we reveal cell type fates of embryonic progenitor cells and liver cancer states associated with patient survival.

Recommended citation: Abel Jansma*, Yuelin Yao*, Jareth Wolfe, Luigi Del Debbio, Sjoerd Viktor Beentjes, Chris P. Ponting, and Ava Khamseh. "High order expression dependencies finely resolve cryptic states and subtypes in single cell data." bioRxiv (2023): 2023-12.

A TGFβ-ECM-integrin signaling axis drives structural reconfiguration of the bile duct to promote polycystic liver disease

Published in Science Translational Medicine, 2023

Pathological liver cysts are an important comorbidity in multiple diseases and syndromes driven by dysfunction of the primary cilium (PC), a complex sensory organelle that protrudes from the apical surface of biliary epithelial cells (BECs). The essential nature of PC in liver development makes understanding the molecular role of this organelle in the structural maintenance of the adult bile duct challenging. Here, we show that PC loss deletion of Wdr35 in adult mouse BECs is sufficient to cause bile duct expansion, driving cyst formation through the de novo production of a fibronectin-rich pro-cystic microenvironment. This newly formed niche promotes both cell-autonomous changes in cell shape and duct-level mechanical rearrangements that converge to drive cyst-fission, a novel process whereby single, large cysts undergo morphological splitting. This process gives rise to many, smaller polycystic progeny and can be halted by pharmacological inhibition of a specific pro-cystic integrin receptor

Recommended citation: Scott Waddell*, Yuelin Yao*, Paula Olaizola, Edward J. Jarman, Konstantinos Gournopanos, Ersi Christodoulou, Philippe Gautier et al. "A TGFβ-ECM-integrin signaling axis drives structural reconfiguration of the bile duct to promote polycystic liver disease." Science Translational Medicine 15, no.713 (2023): 10.1126/scitranslmed.abq5930

Comparative transcriptome in large-scale human and cattle populations

Published in Genome Biology, 2022

Cross-species comparison of transcriptomes is important for elucidating evolutionary molecular mechanisms underpinning phenotypic variation between and within species, yet to date it has been essentially limited to model organisms with relatively small sample sizes. Here, we systematically analyze and compare 10,830 and 4866 publicly available RNA-seq samples in humans and cattle, respectively, representing 20 common tissues. Focusing on 17,315 orthologous genes, we demonstrate that mean/median gene expression, inter-individual variation of expression, expression quantitative trait loci, and gene co-expression networks are generally conserved between humans and cattle. By examining large-scale genome-wide association studies for 46 human traits (average n = 327,973) and 45 cattle traits (average n = 24,635), we reveal that the heritability of complex traits in both species is significantly more enriched in transcriptionally conserved than diverged genes across tissues.

Recommended citation: Yuelin Yao*, Shuli Liu*, Charley Xia*, Yahui Gao*, Zhangyuan Pan*, Oriol Canela-Xandri, Ava Khamseh et al. "Comparative transcriptome in large-scale human and cattle populations." Genome Biology 23, no. 1 (2022): 1-24.

Pig genome functional annotation enhances the biological interpretation of complex traits and human disease

Published in Nature Communications, 2021

The functional annotation of livestock genomes is crucial for understanding the molecular mechanisms that underpin complex traits of economic importance, adaptive evolution and comparative genomics. Here, we provide the most comprehensive catalogue to date of regulatory elements in the pig (Sus scrofa) by integrating 223 epigenomic and transcriptomic data sets, representing 14 biologically important tissues. We systematically describe the dynamic epigenetic landscape across tissues by functionally annotating 15 different chromatin states and defining their tissue-specific regulatory activities. We demonstrate that genomic variants associated with complex traits and adaptive evolution in pig are significantly enriched in active promoters and enhancers. Furthermore, we reveal distinct tissue-specific regulatory selection between Asian and European pig domestication processes. Compared with human and mouse epigenomes, we show that porcine regulatory elements are more conserved in DNA sequence, under both rapid and slow evolution, than those under neutral evolution across pig, mouse, and human. Finally, we provide biological insights on tissue-specific regulatory conservation, and by integrating 47 human genome-wide association studies, we demonstrate that, depending on the traits, mouse or pig might be more appropriate biomedical models for different complex traits and diseases.

Recommended citation: Zhangyuan Pan*, Yuelin Yao*, Hongwei Yin, Zexi Cai, Ying Wang, Lijing Bai, Colin Kern et al. "Pig genome functional annotation enhances the biological interpretation of complex traits and human disease." Nature communications 12, no. 1 (2021): 5848.