Yeong-Gwan Park

Frequent loss of heterozygosity on chromosomes 4, 12 and 19 in radiation-induced lymphomas in mice.

We found frequent loss of heterozygosity (LOH) on chromosomes 4, 12 and 19 in radiation-induced lymphomas from (BALB/cHeA x STS/A) F1 hybrid mice by allelotype analysis at polymorphic microsatellite loci. The incidences of LOH were 27% (20 of 74 lymphomas), 57% (42 of 74 lymphomas) and 50% (37 of 74 lymphomas) on chromosomes 4 (at D4Mit31), 12 (at D12Mit17) and 19 (at D19Mit11), respectively. These frequent LOH regions are homologous to human chromosomes 9p and 1p, chromosome 12q32.1 and chromosome 10q, respectively. Strain-specific preferential allele loss was observed only on chromosome 4. However, no bias in the frequency of loss between alleles of maternal and paternal origin was observed, indicating that genomic imprinting may not be predominantly involved in these lymphomas. The results suggest that these three regions might harbor tumor suppressor genes responsible for this lymphomagenesis.

Putative tumor suppressor gene region within 0.85 cM on chromosome 12 in radiation-induced murine lymphomas.

Analyses of genetic alterations in tumors from F1 hybrid mice produced by inter‐subspecific crosses between genetically well‐characterized inbred strains provide precise and comprehensive evidence for genetic abnormalities such as allelic loss. We performed loss of heterozygosity (LOH) analyses of 125 radiation‐induced lymphomas of (BALB/cHeA × MSM/Ms)F1 hybrid mice by polymerase chain reaction (PCR) analysis of microsatellite DNA polymorphic markers. Very frequent LOH was found at a distal region on chromosome 12. To precisely define the most common region of LOH, we first determined the order of and distances between the available microsatellite loci around the region by using 586 (CXSD × MSM/Ms)F2 hybrid mice (1172 meiosis). The locus order and distances were [centromere]—D12Mit132—(0.34 cM)—D12Mit50—(2.05 cM)—[D12Mit122, D12Mit53]—(0.85 cM)—D12Mit233—(0.43 cM)—D12Mit279—(0.17 cM)—D12Mit181—[telomere]. We then investigated the features of LOH at these loci. The highest frequency of LOH (83 of 125, 66%) was found at D12Mit233. The LOH patterns of individual lymphomas indicated that the most common region of LOH was within the 0.85 cM between D12Mit53 and D12Mit233, a region homologous to human chromosome 14q32.1. These results suggest that a putative novel tumor suppressor gene exists within this region. Mol. Carcinog. 22:175–181, 1998.

Analysis of highly frequent allelic loss region on distal chromosome 12 in murine radiation-induced lymphomas.

Recent genetic studies of tumorigenesis have strongly suggested an existence of tumor suppressor gene(s) on murine chromosome 12 and human chromosome 14q32. We previously described that putative tumor suppressor gene(s) might reside between D12Mit53 and D12Mit233. We analyzed three genes, Tcl1, Yy1 and Tnfalphaip2, which had been mapped around the region, as the candidates in radiation lymphomagenesis of (BALB/c x MSM/Ms)F1 hybrid mice. The locus order and distances of the three genes and microsatellite loci were estimated as follows: [centromere] - Tcl1-(> or =0.085 cM)-D12Mit50-(0.085 cM)D12Mit132-(1.96 cM)D12Mit122-(0.085 cM)D12Mit53-(1.37 cM)-[D12Mit233,D12Mit279,Yy1]-(0.085 cM)-D12Mit181-(> or =0.17 cM)-Tnfalphaip2 - [telomere]. Allele losses at Tcl1, Yy1 genes and D12Mit233 were observed in 94(45%), 143(68%) and 147(70%) of 210 lymphomas, respectively. In semi-quantitative analysis of Yy1 mRNA levels by RT-PCR, kinetics of the yield of the Yy1-cDNA-specific PCR products showed almost the same profiles among thymic lymphomas with allelic loss at Yy1, lymphomas with both alleles retained and normal thymus. These results suggest that Tcl1, Yy1 and Tnfalphaip2 genes are not predominantly involved in radiation lymphomagenesis of mice. In further analysis of the common allelic loss region, we found new loci, Y152pR1 and Y184pR2, from YACs which located in the hot region between D12Mit53 and D12Mit233, and the highest frequency of allelic loss (71%) was observed at the Y184pR2 locus. The LOH patterns of individual lymphomas suggest that putative tumor suppressor gene(s) lies between Y152pR1 and Y184pR2.

Mapping of putative ether-anesthesia resistance gene using C57BL/6J and MSM/Ms mouse strains

PurposeWe attempted to identify the locations of major mouse genes responsible for sensitivity to diethylether (ether) anesthesia, using microsatellite linkage analyses including Quantitative Trait Locus (QTL) analysis.MethodsTo determine the locations of ether anesthesia resistance genes on chromosomes, an ether anesthesia-resistant mouse strain, C57BL/6J (C57BL), and an ether anesthesia-sensitive mouse strain, MSM/Ms (MSM), were used. The sensitivity of mice to ether anesthesia was determined from the latency time required to lose the righting reflex during exposure to 4% ether vapor in air. The (C57BL × MSM) F1 mice were found to be resistant to ether, showing that the resistant phenotype is genetically dominant. Twelve resistant and 12 sensitive mice were then selected from the 196 backcrossed F2 mice (F1 × MSM) at 11–16 weeks of age. Genomic DNA samples were extracted from the tails for mapping ether anesthesia-related genes using microsatellite linkage analyses.ResultsOne major putative gene related to resistance to ether anesthesia was restricted in the region 23 to 37 cM from the centromere in chromosome 7 by primary and secondary linkage analyses. The QTL analysis narrowed the position of the gene to 29.0 cM, with a maximum logarithm of odds (LOD) score of 3.03, and it was termed Etan1 (ether-anesthesia 1).ConclusionMicrosatellite linkage analyses, including QTL analysis, determined the location of the ether-resistance gene, Etan1, within a narrow range. Our findings should be helpful for further experiments, such as cloning of the gene governing the sensitivity to ether anesthesia in mice.