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Molecular evolution and population genetics of HLA genes

Grant number: 09/09127-8
Support type:Regular Research Grants
Duration: October 01, 2009 - March 31, 2012
Field of knowledge:Biological Sciences - Genetics
Principal researcher:Diogo Meyer
Grantee:Diogo Meyer
Home Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil


Immune system genes comprise the class with the strongest evidence for evolving under natural selection. This results from the coevolution of the immune system and pathogens, where changes in one component result in selective pressure on the other. Natural selection on the coding region of one of the classes of immune genes, the HLA loci, is particularly well documented. However, important questions remain unanswered. (a) Is there selection on the regulatory regions of HLA genes? (b) Are alleles which present similar peptides (i.e., those that are in the same "supertype") selectively equivalent to each other? (c) How does selection on HLA genes affect differentiation among populations? (d) How does positive selection, acting on HLA genes influence the evolutionary dynamics of closely linked genes? In order to address these issues, we propose the generation of new HLA data for human populations, in combination with computational analyses of data which is already available. Four main lines of research will be developed. (a) We propose a population study of regulatory and coding regions of classical class I HLA (HLA-A, B, and C) and class II loci (DPB1, DQB1, DRB1) in Amerindian (N=300) as well as African, Asian and European populations (N=230). This dataset will be used to test the hypothesis that regulatory regions are also under selection. (b) Using population genetic approaches, we will test the hypothesis that selection on HLA loci specifically maximizes supertype diversity. (c) We will genotype 50 microsatellite loci spread throughout the genome (N=14), and 20 in the MHC region (N=300). Together with data already available or being generated by our group, we will have a total of 300 individuals with data on microsatellites and HLA loci. These will be used to investigate the effects of natural selection on population differentiation. (d) Using the human and chimpanzee genomes, and the large number of SNPs catalogued in the HAPMAP, we will investigate how positive selection, by favoring specific variants, affects variability and differentiation of closely linked regions of the genome. All these subprojects converge on a common theme, which is the understanding of how natural selection acts on HLA genes, and its evolutionary consequences. (AU)

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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)
BITARELLO, BARBARA DOMINGUES; FRANCISCO, RODRIGO DOS SANTOS; MEYER, DIOGO. Heterogeneity of Ratios at the Classical HLA Class I Genes over Divergence Time and Across the Allelic Phylogeny. Journal of Molecular Evolution, v. 82, n. 1, p. 38-50, . (09/09127-8, 11/12500-2)
RAMALHO, RODRIGO F.; GELFMAN, SAHAR; DE SOUZA, JORGE E.; AST, GIL; DE SOUZA, SANDRO J.; MEYER, DIOGO. Testing for Natural Selection in Human Exonic Splicing Regulators Associated with Evolutionary Rate Shifts. Journal of Molecular Evolution, v. 76, n. 4, p. 228-239, . (09/09127-8)
NUNES, KELLY; MAIA, MARIA HELENA THOMAZ; DOS SANTOS, EDUARDO JOSE MELO; DOS SANTOS, SIDNEY EMANUEL BATISTA; GUERREIRO, JOAO FARIAS; PETZL-ERLER, MARIA LUIZA; BEDOYA, GABRIEL; GALLO, CARLA; POLETTI, GIOVANNI; LLOP, ELENA; et al. How natural selection shapes genetic differentiation in the MHC region: A case study with Native Americans. HUMAN IMMUNOLOGY, v. 82, n. 7, p. 523-531, . (09/09127-8, 12/09950-9)

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