Experiment
Linkage analysis was performed on a population of (NZB/BlNJ x DBA/2J)F1 x NZB/BlNJ backcross animals to identify genetic loci associated with susceptibility to B-cell lymphoproliferative disease. Out of 202 backcross animals approximately 37% (n=74) displayed histological evidence of lymphoproliferative disease. Of this subset, 67 animals were genotyped for 75 polymorphic markers spaced 15.8 cM apart. Linkage to lymphoproliferative disease mapped to mouse Chromosome 14 near D14Mit160 (40 cM), mouse Chromosome 18 near D18Mit4 (57 cM), and to mouse Chromosome 19 near D19Mit6 (55 cM). Homozygosity for NZB/BlNJ-derived alleles at these loci is associated with disease susceptibility. Authors state loci at chromosomes 18 and 19 warrant further investigation.
The chromosome 14 locus is designated Slpd1 (susceptibility to lymphoproliferative disease 1). An 11 Mb segment surrounding Slpd1 was sequenced and a point mutation was detected in the NZB/BlNJ strain in the 3' flanking region of Mirn16-1. This nucleotide change was not present in DBA/2J, SJL/J, BALB/c, NOD/SCID, or NZW. RNA analysis showed decreased expression of Mirn16-1 in the NZB/BlNJ strain compared to C57BL/6J. This decrease in gene expression was even more pronounced in a malignant B-cell line derived from diseased NZB/BlNJ animals. Therefore, Mirn16-1 is an attractive candidate gene. The Slpd1 locus is syntenic to human Chromosome 13q14.3, which has been linked to chronic lymphocytic leukemia in humans. Two highly conserved genes in this region, and possible candidates for Slpd1, are Dleu2 (27.6 cM) and Trim13 (formerly Rfp2).
Analysis Tools