GENOMIC SEQUENCE COMPARISON OF THE HUMAN AND MOUSE XRCC1 DNA-REPAIR GENE REGIONS

The XRCC1 (X-ray repair cross complementing) gene is involved in the efficient repair of DNA single-strand breaks formed by exposure to ionizing radiation and alkylating agents. The human gene maps to chromosome 19q13.2, and the mouse homologue maps to the syntenic region on chromosome 7. Two cosmids (approximately 38 kb each) containing the human and mouse genes were sequenced to an average 8-fold clonal redundancy. The XRCC1 gene spans a genomic distance of 26 kb in mouse and 31.9 kb in human. Both genes contain 17 exons, are 84% identical within the coding regions, and are 86% identical at the amino acid sequence level. Intron and exon lengths are highly conserved. For the human cosmid, a total of 43 Alu repetitive elements are present, a density of 1.1 Alu/kb, but due to clustering, the local density is as high as 1.8 Alu/kb. In addition, we observed a statistically significant bias for insertion of these elements in the 3'-5' orientation relative to the direction of XRCC1 transcription, predominantly in the second and third introns. This bias may indicate that XRCC1 is more accessible to Alu retroposition events during transcription than genes not expressed during spermatogenesis. The density of B1 and B2 elements in the mouse is 0.4/kb, integrated primarily in the 5'-3' orientation. The human chromosome 19-specific minisatellite PE670 was present in the same orientation in 3 introns in the human gene, and a similar repeat was found at 3 different locations in the mouse cosmid. Five simple sequence repeats were found in the human cosmid, and 16 different repeats were observed in the mouse cosmid. The coding region prediction algorithm XGRAIL 1.1 identified 15 of 17 exons in the human gene and 14 of 17 in the mouse, In addition to the coding regions, 9 conserved elements were identified between mouse and human, with sequence identities ranging from 65 to 78%. Several of these elements correspond to introns that are conserved across their entire length and may be important for proper splicing of the transcript to maintain regions of the XRCC1 protein required for proper folding. (C) 1995 Academic Press, Inc