title: Gene conversion and evolution of Xq28 duplicons involved in recurring inversions causing severe hemophilia A.
abstract: Inversions breaking the 1041 bp int1h-1 or the 9.5-kb int22h-1 sequence of the F8 gene cause hemophilia A in 1/30,000 males. These inversions are due to homologous recombination between the above sequences and their inverted copies on the same DNA molecule, respectively, int1h-2 and int22h-2 or int22h-3. We find that (1) int1h and int22h duplicated more than 25 million years ago; (2) the identity of the copies (>99%) of these sequences in humans and other primates is due to gene conversion; (3) gene conversion is most frequent in the internal regions of int22h; (4) breakpoints of int22h-related inversions also tend to involve the internal regions of int22h; (5) sequence variations in a sample of human X chromosomes defined eight haplotypes of int22h-1 and 27 of int22h-2 plus int22h-3; (6) the latter two sequences, which lie, respectively, 500 and 600 kb telomeric to int22h-1 are five-fold more identical when in cis than when in trans, thus suggesting that gene conversion may be predominantly intrachromosomal; (7) int1h, int22h, and flanking sequences evolved at a rate of about 0.1% substitutions per million years during the divergence between humans and other primates, except for int1h during the human-chimpanzee divergence, when its rate of evolution was significantly lower. This is reminiscent of the slower evolution of palindrome arms in the male specific regions of the Y chromosome and we propose, as an explanation, that intrachromosomal gene conversion and cosegregation of the duplicated regions favors retention of the ancestral sequence and thus reduces the evolution rate.
authors.affiliation: Department of Medical and Molecular Genetics, Guy's, King's College and St. Thomas' Hospitals Medical College, King's College, London SE1 9RT, United Kingdom.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Bagnall
authors.forename: Karen L
authors.initials: KL
authors.lastname: Ayres
authors.forename: Peter M
authors.initials: PM
authors.lastname: Green
authors.forename: Francesco
authors.initials: F
authors.lastname: Giannelli
mesh_terms: D000818:Animals; D002522:Chlorocebus aethiops / Q000235:genetics; D019457:Chromosome Breakage / Q000235:genetics; D007446:Chromosome Inversion / Q000235:genetics*; D041321:Chromosomes, Human, X / Q000235:genetics*; D019143:Evolution, Molecular; D005785:Gene Conversion / Q000235:genetics*; D020440:Gene Duplication; D006467:Hemophilia A / Q000235:genetics*; D006801:Humans; D008253:Macaca mulatta / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D002679:Pan troglodytes / Q000235:genetics; D014960:X Chromosome / Q000235:genetics