Genomic coordinates and continental distribution of 120 blood group variants reported by the 1000 Genomes Project

Abstract

BACKGROUND The 1000 Genomes Project provides a database of genomic variants from whole genome sequencing of 2504 individuals across five continental superpopulations. This database can enrich our background knowledge of worldwide blood group variant geographic distribution and identify novel variants of potential clinical significance. STUDY DESIGN AND METHODS The 1000 Genomes database was analyzed to 1) expand knowledge about continental distributions of known blood group variants, 2) identify novel variants with antigenic potential and their geographic association, and 3) establish a baseline scaffold of chromosomal coordinates to translate next‐generation sequencing output files into a predicted red blood cell (RBC) phenotype. RESULTS Forty‐two genes were investigated. A total of 604 known variants were mapped to the GRCh37 assembly; 120 of these were reported by 1000 Genomes in at least one superpopulation. All queried variants, including the ACKR1 promoter silencing mutation, are located within exon pull‐down boundaries. The analysis yielded 41 novel population distributions for 34 known variants, as well as 12 novel blood group variants that warrant further validation and study. Four prediction algorithms collectively flagged 79 of 109 (72%) known antigenic or enzymatically detrimental blood group variants, while 4 of 12 variants that do not result in an altered RBC phenotype were flagged as deleterious. CONCLUSION Next‐generation sequencing has known potential for high‐throughput and extended RBC phenotype prediction; a database of GRCh37 and GRCh38 chromosomal coordinates for 120 worldwide blood group variants is provided as a basis for this clinical application.

Automated typing of red blood cell and platelet antigens from whole exome sequences

“…Our study is not the first to evaluate large‐scale targeted NGS or WES for RBC antigen typing . However, ours is the first to automate the analysis and to evaluate its use for extended antigen typing.…”

“…RBC genotyping has also increased the availability of RBC units for routine extended antigen matching in chronically transfused patients and has enabled selection of antigen‐matched units when compatibility cannot be demonstrated due to warm autoantibodies or drug interference in pretransfusion testing. Although single‐nucleotide polymorphism (SNP)‐based assays currently dominate the RBC and PLT genotyping market, next generation sequencing (NGS) approaches including targeted NGS, whole exome sequencing (WES), and whole genome sequencing (WGS) are being actively pursued by several groups …”

<p>Potential of next-generation sequencing to match blood group antigens for transfusion</p>

“…60 Montemayor-Garcia et al presented a new geographical distribution of allelic blood group variants, the description of which was based on genomic sequences from the same project. 61 The report presented a novel distribution of known variants and 12 novel variants, probably antigenic…”

Developments beyond blood group serology in the genomics era

“…This report presents the continental distribution for 120 blood group SNVs and short insertion/deletion variants and describes novel variants likely to impact on antigen expression. Again, the need for experimental and serological confirmation is stressed (Montemayor‐Garcia et al , ).…”