Study reveals how gene activity shapes immunity across species

More than 250,000 single cells studied to chart evolution of antiviral and antibacterial immunity

By sequencing genes from over a quarter of a million cells across six mammalian species, researchers at the Wellcome Sanger Institute, EMBL’s European Bioinformatics Institute and collaborators, have shown how genes in the immune response have varied activity between cells and species.

The study, published today (24 October) in Nature, looked in unprecedented detail at the genes that are activated in a cell’s initial response to a pathogen invasion – the innate immune response. They measured the activity of thousands of genes in over 250,000 individual cells using single cell genomics technology to chart the evolution of antiviral and antibacterial immunity.

Previous work has shown that many genes in the innate immune response have rapidly evolved in vertebrates. This is thought to be caused by the relentless pressure of attack from pathogens like bacteria and viruses. These include genes that make cytokine and chemokine molecules, which act in a variety of ways – some are inflammatory molecules that alert the body to danger; others restrict a pathogen’s ability to multiply and others induce cell death. They represent a successful host strategy to counteract rapidly evolving pathogens.

The team showed that these genes which have evolved rapidly across species, also have highly variable activity in different cells within an individual’s tissue.

In contrast, they found that genes which are conserved between species, and regulate the immune response, are more consistently activated across cells within a tissue. These genes may be under tighter constraints because they are involved in many different functions within cells. But, they are also targeted by viruses. These constrained genes represent an Achilles’ heel, used by pathogens to subvert the immune system.

“We think that this pattern of activation – where some genes are under tight control, and others have more variable activity – has evolved as a way to fine-tune the immune response. It is effective, but balanced. Genes can evolve to help a cell control an attacker, and the use of those genes can vary between cells, so surrounding tissues are not affected by a massive fall-out.”

Dr Tzachi Hagai Lead author of the research at the Wellcome Sanger Institute

“The power of DNA sequencing at the resolution of single cells means this kind of study is now possible. There are an estimated 37 trillion cells in the human body, each with the same genetic code. But individual cells behave differently, they use that genetic code in a different way. By studying individual cells we can understand these fundamental building blocks of life and how they work together – including how they resist pathogens.”

Dr Sarah Teichmann Head of Cellular Genetics at the Wellcome Sanger Institute and senior author of the research

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Notes to Editor

Publication:

Tzachi Hagai et al. (2018) Gene expression variability across cells and species shapes innate immunity. Nature. DOI: 10.1038/s41586-018-0657-2

Funding:

This project was supported by ERC grants (ThDEFINE, ThSWITCH) and an EU FET-OPEN grant (MRG-GRAMMAR No 664918), Wellcome Sanger core funding (Grant No WT206194), a HFSP Long-Term Fellowship, EMBO Long-Term and Advanced fellowships and Fondazione Umberto Veronesi.

Selected websites

  • European Bioinformatics Institute (EMBL-EBI)

    The European Bioinformatics Institute (EMBL-EBI) is a global leader in the storage, analysis and dissemination of large biological datasets. We help scientists realise the potential of ‘big data’ by enhancing their ability to exploit complex information to make discoveries that benefit humankind. We are at the forefront of computational biology research, with work spanning sequence analysis methods, multi-dimensional statistical analysis and data-driven biological discovery, from plant biology to mammalian development and disease. We are part of EMBL and are located on the Wellcome Genome Campus, one of the world’s largest concentrations of scientific and technical expertise in genomics.

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