GATTACA · Genetics of Alternative Transcript Abundance upon immune Cellular Activation

The human body is constantly exposed to infectious agents. Efficient immune response is therefore fundamental to protect the cells from infection and keep individuals healthy. Still, extreme variations are observed in the efficiency of immune response among individuals and populations. Recently, the dissection of the genetic bases of the host immune response to infection has fostered a large interest in the scientific community. As a result, there is now a growing understanding of the influence of genetic variation on the transcriptional reprogramming of immune cells during infection. However, it is now widely accepted that the underlying ‘one gene–one protein’ paradigm is overly simplistic and cannot account for the full complexity of the transcriptome. Here, we propose to study how genetic variants affect transcript diversity to modulate the response to pathogens at the individual and population levels. To do so, we will seek to identify genetic variants that have conferred a selective advantage to human populations through modulation of isoforms usage in response to infection. This work will rely on an innovative strategy that combines coexpression-based studies of the isoform regulatory networks with analysis of the genetic determinants of splicing in response to infection. In doing so, this study should improve our understanding of isoform regulation and identify novel regulatory elements and splicing factor-target relationships in the specific context of infection.