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

Nat Commun. 2019 Apr 11;10(1):1671. doi: 10.1038/s41467-019-09689-7.

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 monocytes 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • African Continental Ancestry Group / genetics
  • Alternative Splicing / immunology*
  • Animals
  • Biological Evolution
  • European Continental Ancestry Group / genetics
  • Genetic Variation / immunology
  • Healthy Volunteers
  • Humans
  • Immunity / genetics*
  • Infections / immunology*
  • Male
  • Neanderthals / genetics
  • Polymorphism, Single Nucleotide
  • Protein Isoforms / genetics
  • Protein Isoforms / immunology
  • Quantitative Trait Loci / immunology
  • Selection, Genetic / immunology*
  • Sequence Analysis, RNA
  • Transcriptome / immunology*
  • Whole Exome Sequencing

Substances

  • Protein Isoforms