Mathematical Genomics of Mutation Hotspots in Human Hemoglobin Beta

Source abstract

Hemoglobin subunit beta (HBB) is essential for balanced hemoglobin assembly, and mutations in its short coding sequence cause severe hemoglobinopathies such as β-thalassemia. Pathogenic variants are not randomly distributed but cluster into mutation regions, forming hotspots that influence structural stability and disease progression. To characterize mutation regions, this study shifts focus from isolated point mutations to contiguous hotspot neighborhoods, defining 26 regions from 109 pathogenic mutation sites in the HBB human protein. Quantitative analyses of amino acid frequencies, polarity distributions, hydropathy n-grams, and intrinsic disorder profiles reveal that hotspots are compositionally robust yet unique: they preserve local stability through overlapping subsequences, while also exhibiting recurrence of signatures in distant non-overlapping fragments. Importantly, sequence homology analysis confirmed no relationship among hotspots, underscoring their uniqueness as ordered arrangements rather than simple sequence similarities. These findings highlight the power of quantitative hotspot analysis in uncovering hidden organizational principles of the HBB human sequence, with implications for predictive diagnostics and future comparative studies across globin families and clinical mutational spectra.