From Antigens to Alleles: Evolving Strategies in Blood Group Typing

Abstract

Blood group typing has changed more in the past three decades than in the preceding hundred years. What began as an exercise in observing agglutination reactions has become, increasingly, an exercise in reading DNA: a shift from describing antigens as they appear on the red cell surface to interpreting the alleles that put them there. Serological methods remain fast, cheap, and well understood, but they falter in predictable ways — when a patient has been recently transfused, when an antigen is weakly expressed, when a needed antiserum is no longer manufactured, or when a therapeutic monoclonal antibody swamps the test with false reactivity. Molecular genotyping has closed these gaps gradually rather than all at once, moving from single-locus PCR assays to dense microarrays, then to targeted next-generation sequencing, and now to long-read whole-genome approaches capable of resolving structurally complex loci such as Rh and ABO at the level of individual alleles. This review traces that progression and weighs the comparative strengths and limitations of each generation of technology, with particular attention to transfusion support in sickle cell disease and thalassaemia, the classification of weak and partial D phenotypes, noninvasive fetal blood group prediction from maternal plasma, large-scale donor genotyping, and the recent entry of machine learning into antigen prediction from genome-wide data. It also considers the problems that remain unresolved: incomplete genotype-to-phenotype concordance for structurally variable genes, the cost and infrastructure required to run sequencing-based assays routinely, and the continuing under-representation of non-European ancestries in the reference panels on which much of this technology was built. The overall picture is one in which genotyping has become indispensable alongside serology rather than a replacement for it, and in which the technology's remaining promise depends as much on equitable access and standardisation as on further refinement of the assays themselves.