Evolution of the common VWF haplotype associated with type 1 VWD. This schematic illustrates the proposed evolution of the common VWF haplotype. The original VWF DNA had a common core haplotype (H1) of GATGACGCT6 (haplotype includes 2 promoter polymorphisms at nucleotides –1185 [G+/A–, Bst UI] and –1051 [A+/G–, NlaIII]; exon 8, aa 318 [T+/A–, Msl I]; exon 12, aa 471 [G+/A–, Aat II]; exon 18, aa 789 [A+/G–, RsaI]; exon 28, aa 1547 [C+/T–, Bst EII]; exon 28, aa 1584 [A+/G–, KpnI] intron 30, nt –19 [A–/C+, Bsp1286I]; exon 42, aa 2413 [C+/T–, Aci I]; and STR 2 in intron 40. The site of the Tyr1584Cys mutation is indicated with an asterisk. At some point in history, a spontaneous mutation of G>A occurred at the CpG dinucleotide in exon 13. This was followed later by 2 crossing-over events in the VWF gene—one at the 5′ end of the gene (H2, AGTGACGCT6) and the other between exon 28 and intron 30 (H3, GATGACGAC3). Black bars indicate the affected chromosome and white bars indicate the unaffected chromosome. In H2 and H3, the wild-type chromosome has crossed onto the affected chromosome.