THE RATES AND PATTERNS OF DELETIONS IN THE HUMAN FACTOR-IX GENE

Deletions are commonly observed in genes with either segments of highl y homologous sequences or excessive gene length. However, in the facto r IX gene and in most genes, deletions (of greater than or equal to 21 bp) are uncommon. We have analyzed DNA from 290 families with hemophi lia B (203 independent mutations) and have found 12 deletions >20 bp. Eleven of these are >2 kb (range >3-163 kb), and one is 1.1 kb. The ju nctions of the four deletions that are completely contained within the factor IX gene have been determined. A novel mutation occurred in pat ient HB128: the data suggest that a 26.8-kb deletion occurred between two segments of alternating purines and pyrimidines and that a 2.3-kb sense strand segment derived from the deleted region was inserted. For our sample of 203 independent mutations, we estimate the ''baseline'' rates of deletional mutation per base pair per generation as a functi on of size. The rate for large (>2 kb) deletions is exceedingly low. F or every mutational event in which a given base is at the junction of a large deletion, there are an estimated 58 microdeletions (<20 bp) an d 985 single-base substitutions at that base. Analysis of the nine rep orted deletion junctions in the factor IX gene literature reveals that (i) five are associated with inversions, orphan sequences, or sense s trand insertions; (ii) four are simple deletions that display an exces s of short direct repeats at their junctions; (iii) there is no dramat ic clustering of junctions within the gene; and (iv) with the exceptio n of alternating purines and pyrimidines, deletion junctions are not p referentially associated with repetitive DNA.