Our paper on single-cell splicing QTL is now published as a cover article in Nature Genetics. www.nature.com/articles/s41... Congratulations to co-first authors Chi Tian, Yihan Tong, and Yuntian Zhang! Huge thanks to AIDA leaders Shyam Prabhakar, @jayshin.bsky.social, Woong-Yang, and Kian Hong! - ThreadSky

boxiangliu.bsky.social • 196 days ago

Our paper on single-cell splicing QTL is now published as a cover article in Nature Genetics. https://www.nature.com/articles/s41588-024-02019-8

Congratulations to co-first authors Chi Tian, Yihan Tong, and Yuntian Zhang! Huge thanks to AIDA leaders Shyam Prabhakar, @jayshin.bsky.social, Woong-Yang, and Kian Hong!

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boxiangliu.bsky.social•196 days ago

We established a robust pipeline to analyze alternative splicing using 10x 5' single-cell data. Because of "exon painting" effect, ~90% of exons are covered by 5' short-read, despite 5' bias. ~86% of short-read ss are replicated by long-read, likely more with more long-read samples.

boxiangliu.bsky.social•196 days ago

We observed significant improvement in exon coverage compared to 3' short-read data (4-6 fold!).

boxiangliu.bsky.social•196 days ago

Dynamic AS and dynamic sQTLs are widespread along the B-cell development trajectory, some of which may be implicated in disease. For example, PAX5 dynamic isoforms are key determinants of B cell differentiation, and CLEC2D dynamic sQTL is colocalized with autoimmune disease.

boxiangliu.bsky.social•196 days ago

We identified a pathway from genetic variants -> cis-eQTL (of a splicing factor) -> trans-sQTL (of a key T-cell differentiation marker) -> T-cell proportions (of naive vs. memory T cells). All of these are inferred using a single population-scale single-cell dataset.

boxiangliu.bsky.social•196 days ago

We also identified and validated a putative causal mechanism.

A genetic variant influencing the TCHP exon 4 inclusion, which putatively affects Graves' disease risk. We validated the variant-to-splicing relationship using a minigene assay.

boxiangliu.bsky.social•196 days ago

In summary, we established a robust single-cell splicing analysis pipeline and uncovered functional regulatory pathways and novel disease mechanisms.

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