Diversidade do gene KIR3DL3 em populações mundiais e aspectos evolutivos
Carregando...
Data
2020-04-27
Autores
Andrade, Heloísa de Souza
Título da Revista
ISSN da Revista
Título de Volume
Editor
Universidade Estadual Paulista (Unesp)
Resumo
Os receptores killer semelhantes à imunoglobulina (KIRs) são moléculas receptoras transmembranares expressas em células natural killer e T citotóxicas. Esses receptores reconhecem moléculas do sistema imunológico, principalmente moléculas do complexo principal de histocompatibilidade (HLA) de classe I na superfície de células somáticas. Os genes KIR são altamente polimórficos tanto do ponto de vista de número de cópias de cada gene quanto do conteúdo de sequência. KIR3DL3 é um gene KIR considerado framework, pois está presente em todos os indivíduos em duas cópias. Aqui, abordamos a diversidade genética e os aspectos evolutivos do gene KIR3DL3 em populações humanas de todo o mundo, usando uma abordagem de bioinformática desenvolvida para este estudo e que minimiza viés de mapeamento e erros de genotipagem. O conjunto de amostras compreende 2504 indivíduos de 26 populações distintas, provenientes do consórcio 1000 Genomes Project, além de 216 amostras brasileiras do estado de São Paulo que foram sequenciadas utilizando sequenciamento de segunda geração. Marcadores informativos de ancestralidade foram utilizados na população brasileira para determinar o perfil de ancestralidade genômica de cada indivíduo e para se obter uma média da população total. A variabilidade genética do KIR3DL3 é muito maior do que conhecemos atualmente, especialmente quando consideramos íntrons e sequências regulatórias. A diversidade de proteínas de KIR3DL3 é fortemente influenciada pelo perfil de ancestralidade do indivíduo, com proteínas completas e resíduos de aminoácidos apresentando diferentes frequências entre africanos, europeus e outras populações. Nesse caso, as populações do leste da Ásia apresentam um padrão diferente das demais considerando frequências de alelos, proteínas, sequências regulatórias e perfil de seleção natural. Por esse motivo, qualquer estudo de associação com doenças envolvendo KIR3DL3 deve ser realizado considerando a estratificação populacional. Alguns segmentos de KIR3DL3 são altamente conservados, como os éxons que codificam o peptídeo líder e o domínio extracelular D2, importantes para a interação com HLA, enquanto outros segmentos, como a região promotora e o éxon 6 (domínio transmembranar) são bastante variáveis. Encontramos evidências de seleção balanceadora na região promotora, provavelmente mantendo sequências com diferentes ações regulatórias. Essa evidência é mais forte entre europeus e no leste asiático. Também encontramos evidências de seleção balanceadora em íntrons, que devem ser considerados como possíveis portadores de elementos regulatórios.
Killer-cell Immunoglobulin-like Receptors (KIRs) are transmembrane receptors expressed in Natural Killer cells and cytotoxic T cells. These receptors recognize molecules from the immune system, mainly molecules from the major class I histocompatibility complex on somatic cells' surface. KIR genes are highly polymorphic regarding the number of copies of each locus and their sequence content. KIR3DL3 is a framework KIR gene present in every individual. Here we addressed KIR3DL3 genetic diversity and evolutionary aspects in worldwide human populations, using a bioinformatics pipeline created for this study, minimizing mapping bias and genotyping errors. The samples included 2504 individuals from 26 populations (1000 Genomes Project consortium), and 216 Brazilians samples sequenced using second-generation sequencing. Ancestry informative markers were used in the Brazilian population to access the contribution of the different ancestry profiles of each individual and to obtain an average of the whole population. KIR3DL3 genetic variability is far more significant than we currently acknowledge, especially when considering intronic segments and regulatory sequences. KIR3DL3 protein diversity is strongly influenced by the ancestry background, with different frequencies of protein versions and amino acid residues among Africans, Europeans, and other populations. In this matter, populations from East Asia present an unusual pattern considering protein frequencies, regulatory sequences diversity, and how natural selection has shaped KIR3DL3 diversity and haplotype frequencies. Because of that, any association study involving KIR3DL3 should be performed concerning for population stratification. Some KIR3DL3 segments are highly conserved, such as the exons encoding the leader peptide and the extracellular domain D2, important for HLA interaction, while other segments, such as the promoter region and exon 6 (the transmembrane domain) are highly variable. We found evidence of balancing selection in the promoter region, probably maintaining sequences with different promotion capabilities, and it is evident among Europeans and East Asians. We also find evidence of balancing selection in some large intronic segments, and they must be considered as possibly carrying regulatory elements.
Killer-cell Immunoglobulin-like Receptors (KIRs) are transmembrane receptors expressed in Natural Killer cells and cytotoxic T cells. These receptors recognize molecules from the immune system, mainly molecules from the major class I histocompatibility complex on somatic cells' surface. KIR genes are highly polymorphic regarding the number of copies of each locus and their sequence content. KIR3DL3 is a framework KIR gene present in every individual. Here we addressed KIR3DL3 genetic diversity and evolutionary aspects in worldwide human populations, using a bioinformatics pipeline created for this study, minimizing mapping bias and genotyping errors. The samples included 2504 individuals from 26 populations (1000 Genomes Project consortium), and 216 Brazilians samples sequenced using second-generation sequencing. Ancestry informative markers were used in the Brazilian population to access the contribution of the different ancestry profiles of each individual and to obtain an average of the whole population. KIR3DL3 genetic variability is far more significant than we currently acknowledge, especially when considering intronic segments and regulatory sequences. KIR3DL3 protein diversity is strongly influenced by the ancestry background, with different frequencies of protein versions and amino acid residues among Africans, Europeans, and other populations. In this matter, populations from East Asia present an unusual pattern considering protein frequencies, regulatory sequences diversity, and how natural selection has shaped KIR3DL3 diversity and haplotype frequencies. Because of that, any association study involving KIR3DL3 should be performed concerning for population stratification. Some KIR3DL3 segments are highly conserved, such as the exons encoding the leader peptide and the extracellular domain D2, important for HLA interaction, while other segments, such as the promoter region and exon 6 (the transmembrane domain) are highly variable. We found evidence of balancing selection in the promoter region, probably maintaining sequences with different promotion capabilities, and it is evident among Europeans and East Asians. We also find evidence of balancing selection in some large intronic segments, and they must be considered as possibly carrying regulatory elements.
Descrição
Palavras-chave
KIR3DL3, Polimorfismo, Haplótipo, NGS, Ancestralidade, Seleção natural, Evolução, Polymorphism, Haplotype, Ancestry, Natural selection, Evolution