Model for the evolutionary origin of the human HBA locus. Based on the results reported in this article, our previous model for the evolutionary origin of the human HBA locus23 has been revised. Genes are color-coded and indicated by gene symbols or names at first appearance. Shaded gray bars indicate when Agnathans (invertebrate chordates) and Gnathostomes (fish, mammals) first appeared in geologic time. Extant representative species are indicated on the right (human, platypus, pufferfish, lamprey, and sea squirt). Loci from these species are shown on a cyan background; inferred loci are shown on a gray background. Green lines indicate the trajectory of evolution of the human HBA locus. Distal erythroid enhancers in introns of the NPRL3 gene are indicated by a red circle. Gene symbols: HB hemoglobin (encoding a globin with oxygen transport function); MPG, N-methylpurine DNA glycosylase; NPRL3, nitrogen permease regulator-like 3 (GATOR1 complex subunit); RHBDF1, rhomboid 5 homolog 1. The evolutionary time scale is based on Burmester et al.45