A new polymorphism in the human factor VIII gene : implications for linkage analysis in haemophilia A and for the evolution of int22h sequences

• Published in: British journal of haematology 2000-11, Vol.111 (2), p.544-548
• Main Authors: BOWEN, Derrick J, DE BRASI, Carlos D, LARRIPA, Irene B, COLLINS, Peter W
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Chromosome Mapping; Evolution, Molecular; Factor VIII - genetics; Gene Frequency; Genetic Carrier Screening; Genotype; Hematologic and hematopoietic diseases; Hematology; Hemophilia A - diagnosis; Hemophilia A - genetics; Humans; Introns; Male; Medical sciences; Platelet diseases and coagulopathies; Polymorphism, Single Nucleotide; Wales
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1046/j.1365-2141.2000.02373.x

A new polymorphism in the human factor VIII gene has been localized and characterized. It is a biallelic, single nucleotide polymorphism located in intron 22 of the gene, within the 9.5 kb int22h-1 segment. The allelic forms are G (frequency 0.65) and A (frequency 0.35), giving a predicted rate of heterozygosity of 0.46. The polymorphism occurs within a CG dinucleotide and affects an MspI site (CCGG). Int22h-1 is duplicated twice extragenically at Xq28; both extragenic copies (int22h-2 and -3) are also polymorphic with respect to MspI. Investigation of 156 MspI [-] alleles, comprising 30 intragenic and 126 extragenic sites, indicated that all were due to A alleles and none had arisen by C to T transition within the CG dinucleotide. The intragenic MspI site (designated MspI A) is located 737 bases downstream of a previously described XbaI restriction fragment length polymorphism. Despite their close proximity, the polymorphisms are not in complete linkage disequilibrium; haplotype analysis in 85 factor VIII genes from a Caucasian population predicts an informativity of approximately 60% in linkage studies using both, compared with an informativity of approximately 47% in studies using either on its own.