Dr. Antonio Rausell, Imagine Institute, France
Tuesday 14th March, 1.00 p.m., Stacey Lecture Theatre 1
The human immune response to pathogens is highly heterogeneous across individuals. The genetic component of a number of primary immunodeficiencies highlights the importance of variants in immune genes. Protein truncating variants (PTVs; including premature stop-gains, frameshifts and splice-disrupting variants) are a major source of human variation with the potential to cause gene loss of function. Though individually rare, PTVs are collectively prevalent, and represent a genomic substrate for occasional homozygous loss of function that could lead to recessive immune disorders. Less explored, the high amount of heterozygous rare PTVs could be an unexpected source of disease-causing variants through a dominant-negative effect or through haploinsufficiency. In addition to inter-individual differences, a heterogeneous immune response may also be found across the individual cells from the same subject, despite sharing the same genetic background. Single-cell heterogeneity can be partly explained by stochastic expression of innate immunity genes, the different composition of subpopulations of immune cells and/or the continuum of intermediate cell-states transited by an activation/differentiation process. In the first part of the talk I will present our recently developed bioinformatics methods for the assessment of genetic variants, both in coding and non-coding regions, and their application to the study of rare immune diseases. In the second part, I will present our ongoing single-cell transcriptome analyses of immune cells aiming at understanding cell heterogeneity and its phenotypic consequences associated to susceptibility to HIV infection and rare autoimmune proliferative disorders.