Castelli, E. C. | bioRxiv Science

bioRxiv2020

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

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

genetics↗

bioRxiv2020

Whole-genome sequencing of 1,171 elderly admixed individuals from the largest Latin American metropolis (Sao Paulo, Brazil)

As whole-genome sequencing (WGS) becomes the gold standard tool for studying population genomics and medical applications, data on diverse non-European and admixed individuals are still scarce. Here, we present a high-coverage WGS dataset of 1,171 highly admixed elderly Brazilians from a census-based cohort, providing over 76 million variants, of which ~2 million are absent from large public databases. WGS enabled identifying ~2,000 novel mobile element insertions, nearly 5Mb of genomic segments absent from human genome reference, and over 140 novel alleles from HLA genes. We reclassified and curated nearly four hundred variant's pathogenicity assertions in genes associated with dominantly inherited Mendelian disorders and calculated the incidence for selected recessive disorders, demonstrating the clinical usefulness of the present study. Finally, we observed that whole-genome and HLA imputation could be significantly improved compared to available datasets since rare variation represents the largest proportion of input from WGS. These results demonstrate that even smaller sample sizes of underrepresented populations bring relevant data for genomic studies, especially when exploring analyses allowed only by WGS.

genomics↗