Fig. 1.

Human-specific changes in CD33 are primarily present in the Sia-binding V-set domain. (A) Comparison of amino acid sequences of CD33 from humans and “great apes” was performed using Conformational Analysis Tools software. The Great ape genomes included in the analysis are gorilla, chimpanzee, and bonobo and were compared against the human protein as the template. The conservation of the sequence is indicated with yellow being the most and red being the least conserved regions. Amino acids that are different from huCD33 are highlighted in pink. Amino acids encoding the different CD33 domains are indicated above the sequence with different colors corresponding to schematic in inset, namely, V-set domain in green, C2 domain in light blue, transmembrane domain in gray, and cytoplasmic end in light pink. The flexible C–C′ loop is indicated in orange. Amino acids that are in contact with Neu5Ac in huCD33 are highlighted in magenta and N-glycosylation sites in blue. (B) Phylogenetic analysis of the evolution of the extracellular domains of CD33 proteins from human, Great apes, and archaic genomes. The number of genomes (n) for each group included in the analysis is indicated. Human and great ape CD33 sequences were compared with six Neanderthal and two Denisovan genomes. Amino acid changes present in huCD33 were also present in the ancient genomes. The positions of the amino acids that are different between human and the apes are mentioned, and the identity of the amino acid present in the corresponding positions for each group is indicated by the single letter abbreviations along the branch. Amino acids at positions 152 and 154 are within the C2 domain of CD33 protein and italicized. Polymorphisms within the human population at positions 22, 65, and 69 of CD33 protein are indicated. Amino acids in gorilla CD33 at positions 66 and 148 are different from other apes and are bold. Possible timeline for the diversion of the hominin lineage is indicated in the tree. Length of the branches in the tree is not to scale.