Gene conversion and evolution of Xq28 duplicons involved in recurring inversions causing severe hemophilia A.
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.
Bagnall
Richard D
RD
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.
Ayres
Karen L
KL
Green
Peter M
PM
Giannelli
Francesco
F
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