Paralogous X-Y mismatching explains acute GVHD risk in male recipients with female donors. (A) Six missense variants on the Y chromosome are exclusive to sex-mismatched male patients with acute GVHD. These variants correspond to 9 variant peptides, which are restricted to 4 genes. Genomic positions for PCDH11Y, USP9Y, UTY, and NLGN4Y are shown with dotted lines to paralogous genes on the X chromosome. Protein coding sequence alignments indicating identity matches (bars) and mismatches (dots) are shown for regions that contain individual variant residues (red) and peptides with high-affinity prediction (bold). Ending amino acid coordinates are given to the right of each sequence alignment. Two male-specific variants are named biallelic polymorphisms rs2524543 and rs2563389 with minor allele frequencies 46% and 45%, respectively (red). Note the predicted cleavage sites (black triangles) created by coding variants in PCDH11Y and USP9Y. *For clarity, other alternative cleavage sites are not shown (see Figure 4 for details), and chromosome X is shown in reverse (3′) orientation. (B) The number of predicted high-affinity binding peptides per patient in male-to-male allogeneic HCT recipients with and without acute GVHD.