Nonhomologous recombination in the human genome: deletions in the human factor VIII gene.
Four deletions in the human factor VIII gene have been characterized at the sequence level in patients with hemophilia A. Deletion JH 1 extends 57 kb from IVS 10 to IVS 18. Intron 13 and exon 14 are partially deleted in patients JH 7 and JH 37, with a loss of 3.2 and 2.4 kb of DNA, respectively. The 3' deletion breakpoint of the JH 21 event resides in intron 3 and extends 5' into intron 1, resulting in the loss of exons 2 and 3. Seven of the eight breakpoints sequenced (5' and 3' for each of the four deletions) occur in nonrepetitive sequence, while the 3' breakpoint of the JH 1 resides in an Alu repetitive element. All of the deletions are the result of nonhomologous recombination. The 5' and 3' breakpoints of JH 1, JH 7, and JH 37 share 2- to 3-bp homologies at the deletion junctions. In contrast, two nucleotides have been inserted at the JH 21 deletion junction. Short sequence homologies may facilitate end-joining reactions in nonhomologous recombination events.
Woods-Samuels
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Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, Maryland 21205.
Kazazian
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Antonarakis
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D001483:Base Sequence; D002872:Chromosome Deletion; D004247:DNA; D005091:Exons; D005169:Factor VIII / Q000235:genetics*; D015894:Genome, Human; D006467:Hemophilia A / Q000235:genetics*; D006801:Humans; D007438:Introns; D008969:Molecular Sequence Data; D011995:Recombination, Genetic; D015183:Restriction Mapping
D005169:Factor VIII; D004247:DNA