Wellcome Sanger Institute and PacBio to explore how gene activity shapes immune system

A major new initiative was launched on Tuesday (15 April) by the Wellcome Sanger Institute in collaboration with Pacific Biosciences to map how gene activity shapes the immune system.

The work could help identify new therapeutic targets for conditions such as inflammatory bowel disease (IBD).

Scientists will use advanced long-read sequencing technology to profile gene expression at single-cell resolution, applying the technology to nearly 1,500 blood and gut tissue samples from three major ongoing studies.

This will capture not only the extent to which genes are expressed but also which versions - known as isoforms - of each gene are used.

It will create high-resolution maps of RNA expression and splicing across different cell types, tissues and individuals that could be key to understanding some conditions and reveal why some treatments work better for certain people.

It is the first time that the Hinxton-based institute will use long-read single-cell RNA sequencing at scale.

Samples will be used from three of its studies, including IBDverse and IBD-Response1, which aim to uncover new ways to treat IBD, a chronic inflammatory condition of the gastrointestinal tract that is estimated to affect up to 10 million people worldwide.

The third study, Project JAGUAR, is a collaboration across seven Latin American countries that explores how genetic diversity shapes immune responses.

Dr Gosia Trynka, group leader at the Wellcome Sanger Institute and science director at Open Targets, said: “Project JAGUAR represents a transformative step toward globally inclusive research, bringing much-needed diversity to our understanding of immune regulation. I’m particularly excited that this new initiative will place samples from underrepresented populations, specifically from Peru and Mexico, at the forefront of this uniquely ambitious study. By exploring how ancestry shapes transcriptional complexity at single-cell resolution, we are taking an important leap forward in ensuring that insights from genomic research truly reflect the diversity of human biology.”

The single-cell transcriptomics revolution has enabled us to understand how gene activity varies across individual cells, tissues and health conditions. While DNA sequencing reveals changes in the genetic code itself, RNA sequencing offers a dynamic snapshot of which genes are active and the level of activity in any given tissue sample or cell.

Most large-scale efforts have so far relied on short-read sequencing, helping to build detailed maps of gene expression across many thousands of samples and showing which genes are switched on or off in different tissues and health conditions.

But short reads cannot fully capture the diversity of RNA isoforms - the different versions of RNA that can come from a single gene, due to alternative splicing.

The datasets from the project will made openly available to further global research.

Christian Henry, president and CEO of PacBio, said: “At PacBio, we believe the most meaningful science happens when technology serves a clear purpose. This collaboration with the Sanger Institute brings that vision to life, using HiFi long-read sequencing to uniquely capture the full isoform landscape at single-cell resolution and at scale.

“It is a powerful example of how accuracy and completeness can reveal new insights into immune function, IBD progression, and treatment response. Through Project JAGUAR, we’re proud to support greater representation in genomic research so that these insights translate into real benefits for communities around the world.”

Dr Carl Anderson, interim head of human genetics at the Wellcome Sanger Institute, said: “Long-read sequencing gives us the chance to look at gene activity in much greater detail than before. By applying this technology at scale, we hope to uncover biological differences that could explain why some people respond better to treatments for conditions like inflammatory bowel disease than others.

“IBD affects many lives, and current therapies don’t work for everyone. This project could help us understand why and open new directions for more effective, personalised treatment. If successful, it could also establish a powerful approach for studying the molecular basis of many other human health conditions.”