KIR2DL4 genetic diversity in a Brazilian population sample: implications for transcription regulation and protein diversity in samples with different ancestry backgrounds

Abstract

KIR2DL4 is an important immune modulator expressed in natural killer cells; HLA-G is its main ligand. We have characterized the KIR2DL4 genetic diversity by considering the promoter, all exons, and all introns in a highly admixed Brazilian population sample and by using massively parallel sequencing. We introduce a molecular method to amplify and to sequence the complete KIR2DL4 gene. To avoid the mapping bias and genotype errors commonly observed in gene families, we have developed and validated a bioinformatic pipeline designed to minimize these errors and applied it to survey the variability of 220 individuals from the State of São Paulo, southeastern Brazil. We have also compared the KIR2DL4 genetic diversity in the Brazilian cohort with the diversity previously reported by the 1000Genomes consortium. KIR2DL4 presents high linkage disequilibrium throughout the gene, with coding sequences associated with specific promoters. There are few but divergent promoter haplotypes. We have also detected many new KIR2DL4 sequences, all bearing nucleotide exchanges in introns and encoding previously described proteins. Exons 3 and 4, which encode the external domains, are the most variable. The ancestry background influences the KIR2DL4 allele frequencies and must be considered for association studies regarding KIR2DL4.

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Fig. 1

Data availability

The VCF file with phased genotypes is available upon request.

Code availability

(Software application or custom code): hla-mapper (www.castelli-lab.net/apps/hla-mapper/), vcfx (www.castelli-lab.net/apps/vcfx), phasex (available upon request); the GATK package is provided by the Broad Institute (https://gatk.broadinstitute.org).

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Acknowledgements

We also thank Dra. Cynthia Maria de Campos Prado Manso for language editing.

Funding

This work was supported by Fundação de Amparo à Pesquisa do Estado de São—FAPESP/Brazil (Grants 2017/19223-0 and 2017/05042-4). This study was partially funded by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)—Finance Code 001.

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Correspondence to Erick C. Castelli.

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Ethics approval and consent to participate

The Human Research Ethics Committee of the School of Medicine/Unesp has approved the study protocol (Protocol 24157413.7.0000.5411). All participants signed an informed consent before blood collection.

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The authors declare that they have no conflict of interest.

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Weiss, E., Andrade, H.S., Lara, J.R. et al. KIR2DL4 genetic diversity in a Brazilian population sample: implications for transcription regulation and protein diversity in samples with different ancestry backgrounds. Immunogenetics 73, 227–241 (2021). https://doi.org/10.1007/s00251-021-01206-9

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Keywords

  • Polymorphisms
  • Natural killer cells
  • KIR genes
  • Haplotypes
  • HLA
  • Second-generation sequencing
  • KIR2DL4