Evaluation of MHC Class I genes variability, regulation and evolutive history

Abstract

The Major Histocompatibility Complex (MHC) is the most variable region of the human genome. The classical class I genes within the human MHC (HLA-A, HLA-B and HLA-C) are associated with antigen presentation to T CD8+ cells. These genes are quite variable, allowing the presentation of many different peptides. However, such degree of polymorphisms is challenging when tissue transplantation is required, because HLA compatibility between donor and recipient is mandatory for a good graft acceptance and survival. The non-classical class I genes (HLA-G, HLA-E and HLA-F) encode for immune suppressor molecules that are key features when immune-modulation is necessary, such as during pregnancy. Many polymorphisms at the classical and non-classical class I genes were previously associated with autoimmune and degenerative diseases, as well as with certain tumors. The aim of the present research project is the evaluation of the HLA class I genes variability in a Brazilian sample by using next generation sequencing, including the coding, 5' promoter and 3' untranslated regions of such genes. In this context, Brazil is considered one of the most admixed populations in the world and a great repository of genetic variability. The Brazilian HLA haplotypes will be compared with data obtained by commercial kits (that usually detect variability in only few exons) evaluating the ability of such kits to appropriately determine the HLA haplotypes found in the Brazilian sample. The Brazilian variability will be compared and concatenated with data from the 1000Genome Project. This database will be used to infer signatures of natural selection acting on the coding and regulatory sequence of the class I genes. In addition, the project aim to infer a panel of microRNAs and transcription factors that may influence the expression of such genes, as well as to detect functional polymorphic sites in the regulatory regions. This data will lead to a better understanding of the expression regulation of class I genes and will allow a future development of expression manipulation strategies for therapeutic use. (AU)