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Defining the genetic and evolutionary architecture of alternative splicing in response to infection

Abstract : Host and environmental factors contribute to variation in human immune responses, yet the genetic and evolutionary drivers of alternative splicing in response to infection remain largely uncharacterised. Leveraging 970 RNA-sequencing profiles of resting and stimulated mono-cytes from 200 individuals of African-and European-descent, we show that immune activation elicits a marked remodelling of the isoform repertoire, while increasing the levels of erroneous splicing. We identify 1,464 loci associated with variation in isoform usage (sQTLs), 9% of them being stimulation-specific, which are enriched in disease-related loci. Furthermore , we detect a longstanding increased plasticity of immune gene splicing, and show that positive selection and Neanderthal introgression have both contributed to diversify the splicing landscape of human populations. Together, these findings suggest that differential isoform usage has been an important substrate of innovation in the long-term evolution of immune responses and a more recent vehicle of population local adaptation.
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Submitted on : Tuesday, April 21, 2020 - 10:55:12 AM
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Maxime Rotival, Hélène Quach, Lluis Quintana-Murci. Defining the genetic and evolutionary architecture of alternative splicing in response to infection. Nature Communications, 2019, 10 (1), pp.1671. ⟨10.1038/s41467-019-09689-7⟩. ⟨pasteur-02549071⟩



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