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Expression and eQTL mapping of HLA genes: analyses based on large-scale RNAseq assays

Grant number: 14/12123-2
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): September 01, 2014
Effective date (End): August 31, 2018
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Principal researcher:Diogo Meyer
Grantee:Vitor Rezende da Costa Aguiar
Home Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated scholarship(s):16/24734-1 - A bioinformatic tool to reliably estimate expression and map eQTLs of HLA genes in multiple datasets, BE.EP.PD


The MHC (Major Histocompatibility Complex) class I and II genes, also known as HLA genes in humans (Human Leukocyte Antigens), are highly polymorphic and there is a substancial body of evidence showing that they have been a target of balancing selection. In addition, these loci have also been associated with more diseases than any other region in the genome. While diversity and differentiation at HLA coding variants have been extensively studied, less is known about their regulatory variation and population-level expression patterns. This is partly because high-throughput technologies of gene expression analysis have serious limitations when applied to HLA genes, e.g. the mapping of transcripts to a reference genome is problematic, since the high degree of polymorphism results in a great divergence between an individual's alleles and the reference sequence, resulting in a high degree of bias and/or inaccuracy when estimating expression patterns for these genes. Here we propose specific approaches to overcome these difficulties, allowing an unbiased quantification of expression levels of HLA genes from generic RNAseq assays. This information on expression levels will allow us to 1) draw a comprehensive multi-population map of HLA gene expression; 2) identify genetic variants which regulate HLA expression levels (i.e., expression QTLs or eQTLs); 3) investigate if HLA loci show patterns of allelic-specific expression (i.e., unequal expression levels between two alleles of a gene). These results will allow us to test the evolutionary hypotheses that HLA balancing selection results from the coexpression of the two alleles of a heterozygote, which maximizes the response to pathogens. Additionally, we will use the eQTLs to test whether the regulatory variants at HLA loci are also targets of strong balancing selection, as are the coding variants. We aim to release our methods as a bioinformatic package to be used by the scientific research community.

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
AGUIAR, VITOR R. C.; CESAR, JONATAS; DELANEAU, OLIVIER; DERMITZAKIS, EMMANOUIL T.; MEYER, DIOGO. Expression estimation and eQTL mapping for HLA genes with a personalized pipeline. PLOS GENETICS, v. 15, n. 4, . (15/19990-6, 13/22007-7, 16/24734-1, 12/18010-0, 14/12123-2)
MEYER, DIOGO; AGUIAR, VITOR R. C.; BITARELLO, BARBARA D.; BRANDT, DEBORA Y. C.; NUNES, KELLY. A genomic perspective on HLA evolution. IMMUNOGENETICS, v. 70, n. 1, p. 5-27, . (11/12500-2, 12/09950-9, 12/18010-0, 14/12123-2, 12/22796-9)
BRANDT, DEBORA Y. C.; AGUIAR, VITOR R. C.; BITARELLO, BARBARA D.; NUNES, KELLY; GOUDET, JEROME; MEYER, DIOGO. Mapping Bias Overestimates Reference Allele Frequencies at the HLA Genes in the 1000 Genomes Project Phase I Data. G3-GENES, GENOMES, GENETICS, v. 5, n. 5, p. 931-941, . (11/12500-2, 12/09950-9, 12/18010-0, 13/12162-5, 14/12123-2, 12/22796-9)

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