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

Abstract

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.

Biased pathogenic assertions of loss of function variants challenge molecular diagnosis of admixed individuals

“…These observations confirmed that indeed, the proportion of variants absent from large datasets may reflect the underrepresentation of Brazilian parental populations, and Brazilian themselves, among international studies. In accordance with other studies on Brazilians (Kehdy et al, 2015), SABE individuals were shown to be highly admixed, with average proportions of 0.73 European, 0.18 African, 0.07 Native American, and 0.03 Eastern Asian ancestries (Naslavsky et al, 2020), the latter representing nonadmixed Japanese individuals of first and second generations.…”

“…Recently, an expansion of ABraOM was published with a new dataset generated by WGS of 1,171 individuals of SABE cohorts adding over 76 million SNVs and indels, in addition to accurate HLA allele calls and mobile element insertions. Nearly 2 million highconfidence variants were identified and annotated as absent from large public databases (Naslavsky et al, 2020). Also, over 22 thousand potential loss of function variants (pLOFs) were detected using LOFTEE (Karczewski et al, 2020), an annotation tool that identify pLOF variants using transcript features to improve its accuracy.…”

Expanding the phenotype of E318K (c.952G > A) MITF germline mutation carriers: case series and review of the literature

“…medcalc.org/calc/odds_ratio.php). Median allele frequency of MITF in our findings was compared to the MAF in an Online Archive of Brazilian Mutations (http://abraom.ib.usp.br), which contains genomic variants obtained with whole-exome and whole-genome sequencing from SABE, a census-based sample of elderly individuals from São Paulo, Brazil's largest city (http:// abraom.ib.usp.br) [12]. Patient data are presented in an aggregated or non-identifiable manner and no informed consent was deemed necessary by the institutional ethics committee board.…”

An immunogenetic view of COVID-19

“…Lower right panel : The frequency of the Asian-restricted B*46:01 allele. Frequency data were obtained from the Brazilian and 1000 Genomes high-coverage sequencing data processed with specific HLA bioinformatics workflow ( Naslavsky et al, 2020 ), and from the allelefrequencies.net website ( Gonzalez-Galarza et al, 2020 ). …”

“…In addition, a major challenge to imputation is the informativeness of the reference panel (i.e., a large subset of samples with both the SNP microarray data and also HLA and KIR alleles genotyped by other methods) for the target sample. Despite efforts ( Levin et al, 2014 ; Okada et al, 2015 ; Tian et al, 2016 ; Naslavsky et al, 2020 ), most reference panels are underrepresented for non-European and/or populations of mixed ancestry ( Zheng et al, 2014 ; Neville et al, 2017 ), compromising the accuracy of HLA allele imputation for these groups (reviewed in Meyer and Nunes, 2017 ). For these reasons, there are worldwide initiatives to build better reference panels that include samples of under-represented populations, such as the Brazilian ( Naslavsky et al, 2020 ; Vince et al, 2020 ).…”