Gene conversion and evolution of Xq28 duplicons involved in recurring inversions causing severe hemophilia A

Inversions breaking the 1041 bp intlh-I or the 9.5-kb int22h-I 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, intlh-2 and int22h-2 or int22h-3. We find that (1) intlh 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; (S) sequence variations in a sample of human X chromosomes defined eight haplotypes of int22h-I and 27 of int22h-2 plus int22h-3; (6) the latter two sequences, which lie, respectively, 500 and 600 kb telomeric to int22h-I are five-fold more identical when in cis than when in trans, thus Suggesting that gene conversion may be predominantly intrachromosomal; (7) intlh, 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 intlh 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 ail explanation, that intrachromosomal gene conversion and cosegregation of the duplicated regions favors retention of the ancestral sequence and thus reduces the evolution rate.