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Evolution of HLA genes: population differentiation and signatures of recent selection in native and admixed populations from Brazil

Grant number: 12/09950-9
Support Opportunities:Scholarships in Brazil - Post-Doctorate
Effective date (Start): September 01, 2012
Effective date (End): August 31, 2016
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Principal Investigator:Regina Célia Mingroni Netto
Grantee:Kelly Nunes
Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center, AP.CEPID


There is consensus that the HLA genes (Human Leucocyte Antigen), which encode proteins essential for adaptive immune response, evolve under balancing selection regime - which increases the genetic diversity compared to the expected under neutrality. However, questions concerning the time scale of the action of natural selection and its effects on population differentiation remain controversial, and are the subject of this project. The first question to discuss is how does balancing selection modulate population differentiation in the HLA genes. Although theoretical models suggest that the balancing selection reduces differentiation between populations, a recent study by our group showed that differentiation is greater in the MHC region (Major Histocompatibility Complex), where HLA genes are located, than in the rest of the genome. One interpretation for this result is that balancing selection favors different sets of alleles in distinct populations, resulting in a pattern of high diversity within and population differentiation between populations. However, our previous study used a reduced number of microsatellites, and had to deal with uncertainties about the mutational model of this marker. In this project we propose to analyze 700,000 SNPs (7,000 in the MHC region) in 100 individuals from five Native American populations, to test the hypothesis that differences between populations in HLA genes differs from the genomic average. The second question we will address concerns the time scale on which natural selection acts: we will test for signs of recent selection (in the order of hundreds of years) working in the HLA genes. Although several methods have detected selection in HLA genes, most are only sensitive to ancient selective (on the order of thousands of years). To test for recent selection we will use the admixture mapping approach, which searches genomic regions with atypical admixture proportions, suggesting a selective advantage of one of the ancestral components in recent evolutionary history. We propose to genotype 700,000 SNPs in 150 individuals of admixed quilombolas communities, which have tri-hybrid ancestry, so as to test if the South American environment imposes some kind of recent selective pressure in HLA genes. The two analyzes are complementary in terms of theoretical and operational. First, they try to characterize more precisely - temporal and geographically - the system of natural selection acting on HLA genes. Secondly, the data generated for Native America will be used to estimate the ancestry of the admixed population. A study using large-scale genotyping of native and admixed populations have great statistical power to test hypotheses open on the action of natural selection in HLA genes, and bring original responses on the evolution of these genes.

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Scientific publications (10)
(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)
CANTOR, MAURICIO; PIRES, MATHIAS M.; MARQUITTI, FLAVIA M. D.; RAIMUNDO, RAFAEL L. G.; SEBASTIAN-GONZALEZ, ESTHER; COLTRI, PATRICIA P.; PEREZ, S. IVAN; BARNECHE, DIEGO R.; BRANDT, DEBORA Y. C.; NUNES, KELLY; et al. Nestedness across biological scales. PLoS One, v. 12, n. 2, . (15/11985-3, 14/21106-4, 11/11346-0, 11/13054-6, 13/02738-7, 13/22016-6, 09/54422-8, 12/09950-9)
KIMURA, LILIAN; NUNES, KELLY; INES MACEDO-SOUZA, LUCIA; ROCHA, JORGE; MEYER, DIOGO; MINGRONI-NETTO, REGINA CELIA. Inferring paternal history of rural African-derived Brazilian populations from Y chromosomes. AMERICAN JOURNAL OF HUMAN BIOLOGY, v. 29, n. 2, SI, . (98/14254-2, 12/18010-0, 12/09950-9, 13/08028-1)
NUNES, KELLY; ZHENG, XIUWEN; TORRES, MARGARETH; MORAES, MARIA ELISA; PIOVEZAN, BRUNO Z.; PONTES, GERLANDIA N.; KIMURA, LILIAN; CARNAVALLI, JULIANA E. P.; MINGRONI NETTO, REGINA C.; MEYER, DIOGO. HLA imputation in an admixed population: An assessment of the 1000 Genomes data as a training set. HUMAN IMMUNOLOGY, v. 77, n. 3, p. 307-312, . (12/09950-9, 12/18010-0, 13/08028-1)
LEMES, RENAN B.; NUNES, KELLY; CARNAVALLI, JULIANA E. P.; KIMURA, LILIAN; MINGRONI-NETTO, REGINA C.; MEYER, DIOGO; OTTO, PAULO A.. Inbreeding estimates in human populations: Applying new approaches to an admixed Brazilian isolate. PLoS One, v. 13, n. 4, . (12/18010-0, 12/09950-9)
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, . (12/18010-0, 11/12500-2, 14/12123-2, 12/22796-9, 12/09950-9)
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, . (12/18010-0, 11/12500-2, 13/12162-5, 14/12123-2, 12/22796-9, 12/09950-9)
NUNES, KELLY; AGUIAR, VITOR R. C.; SILVA, MARCIO; SENA, ALEXANDRE C.; DE OLIVEIRA, DANIELLI C. M.; DINARDO, CARLA L.; KEHDY, FERNANDA S. G.; TARAZONA-SANTOS, EDUARDO; ROCHA, VANDERSON G.; CARNEIRO-PROIETTI, ANNA BARBARA F.; et al. How Ancestry Influences the Chances of Finding Unrelated Donors: An Investigation in Admixed Brazilians. FRONTIERS IN IMMUNOLOGY, v. 11, . (12/18010-0, 12/09950-9)
AMORIM, CARLOS EDUARDO G.; NUNES, KELLY; MEYER, DIOGO; COMAS, DAVID; BORTOLINI, MARIA CATIRA; SALZANO, FRANCISCO MAURO; HUNEMEIER, TABITA. Genetic signature of natural selection in first Americans. Proceedings of the National Academy of Sciences of the United States of America, v. 114, n. 9, p. 2195-2199, . (12/09950-9)
NUNES, KELLY; PIOVEZAN, BRUNO; TORRES, MARGARETH A.; PONTES, GERLANDIA N.; KIMURA, LILIAN; CARNAVALLI, JULIANA E. P.; MINGRONI NETTO, REGINA CELIA; MORAES, MARIA ELISA; MEYER, DIOGO. Population variation of HLA genes in rural communities in Brazil, the Quilombos from the Vale do Ribeira, Sao Paulo - Brazil. HUMAN IMMUNOLOGY, v. 77, n. 6, p. 447-448, . (12/09950-9, 12/18010-0, 13/08028-1)
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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