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 e fficient repair of DNA single-strand breaks formed by exposure to ioni zing radiation and alkylating agents. The human gene maps to chromosom e 19q13.2, and the mouse homologue maps to the syntenic region on chro mosome 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 c oding 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 insert ion of these elements in the 3'-5' orientation relative to the directi on of XRCC1 transcription, predominantly in the second and third intro ns. This bias may indicate that XRCC1 is more accessible to Alu retrop osition events during transcription than genes not expressed during sp ermatogenesis. The density of B1 and B2 elements in the mouse is 0.4/k b, integrated primarily in the 5'-3' orientation. The human chromosome 19-specific minisatellite PE670 was present in the same orientation i n 3 introns in the human gene, and a similar repeat was found at 3 dif ferent locations in the mouse cosmid. Five simple sequence repeats wer e found in the human cosmid, and 16 different repeats were observed in the mouse cosmid. The coding region prediction algorithm XGRAIL 1.1 i dentified 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 identifie d between mouse and human, with sequence identities ranging from 65 to 78%. Several of these elements correspond to introns that are conserv ed across their entire length and may be important for proper splicing of the transcript to maintain regions of the XRCC1 protein required f or proper folding. (C) 1995 Academic Press, Inc