Statistical Bioinformatics Seminar: Dr Angli Xue (Garvan Institute)

Title: TenK10K multiome initiative : Genetic regulation of cell-type–specific
chromatin accessibility shapes immune function and disease risk 

Speaker: Dr Angli Xue, Garvan Institute of Medical Research 

Abstract: Understanding how genetic variation influences gene regulation at the
single-cell level is crucial for elucidating the mechanisms underlying complex
diseases.  However, limited large-scale single-cell multi-omics data have constrained
our understanding of the regulatory pathways that link variants to gene expression.
Here, we present the TenK10K multiome initiative as part of the TenK10K phase 1
projects: chromatin accessibility profiles from 3.5 million peripheral blood mononuclear
cells (PBMCs) across 1,013 donors, generated using single-cell ATAC-seq and multiome
(RNA+ATAC) sequencing, with matched whole-genome sequencing.  We characterised ~441,000
chromatin peaks across 28 immune cell types and mapped ~243,000 chromatin accessibility
QTLs (caQTLs), 60% of which are cell-type-specific.  Integration with TenK10K scRNA-seq
(5.4 million PBMCs) identified 31,688 candidate cis-regulatory elements colocalised with
eQTLs; over half (52.5%) show evidence of causal effects mediated via chromatin
accessibility.  Combining caQTLs with GWAS loci for 17 diseases and 44 blood traits
uncovered 10–41% more colocalised signals compared to eQTLs alone.  For example,
incorporating caQTLs increased the number of candidate inflammatory bowel disease (IBD)
genes in CD8 effector memory T cells from 39 to 55.  We demonstrate cell-type-specific
mechanisms, such as a regulatory effect on IRGM acting through altered chromatin
accessibility in CD8 effector memory T cells but not in naïve cells.  Using a graphical
neural network, we link peaks to genes in unpaired multiome data with up to 80% higher
accuracy than with paired data lacking QTLs, improving gene regulatory network inference
by identifying 128 additional TF–target pairs (a 22% increase).  These findings
provide an unprecedented single-cell map of chromatin accessibility and genetic
variation in human circulating immune cells, establishing a powerful resource for
dissecting cell-type-specific regulation and advancing our understanding of genetic risk
for complex diseases.  

About the speaker: Dr Angli Xue is an NHMRC Investigator Fellow (EL1) and a postdoctoral
researcher with Prof Joseph Powell at the Garvan Institute of Medical Research.  He
currently leads the multiome stream of the TenK10K project — a population cohort study
aiming to map 50 million human cells from 10,000 individuals.  His research focuses on
leveraging large-scale multi-omics data to uncover cell type–specific genetic
regulatory mechanisms and identify novel drug targets.  Dr Xue earned his BSc from
Zhejiang University and completed a PhD in Statistical Genetics at The University of
Queensland under the supervision of Prof Jian Yang.  He is the recipient of an NHMRC
Investigator Grant (2025–2029) and a Ramaciotti Health Investment Grant as Chief
Investigator.  

This event will be held online.  

Zoom: https://uni-sydney.zoom.us/j/85114748391