Multiple genetic loci modify susceptibility to plasmacytoma-related morbidity in Eμ-v-abltransgenic mice

Abstract

There is a great difference in susceptibility to v-abl transgene-induced plasmacytoma between the BALB͞cAn and the relatively resistant C57BL͞6J mouse strains. We have used the Mapmaker͞SURVIVOR algorithm to analyze genome-wide scans on over 800 transgenic F2 hybrid mice, and have mapped at least six loci on chromosomes 2, 4, 11, 17, and 18 that modify tumor-related morbidity. As in human multiple myeloma, males were found to be more prone to plasmacytomagenesis. Different loci influence tumor susceptibility in male and female mice. Survival in females may be largely controlled by a pair of interacting loci on chromosomes 2 and 17.

Genetic architecture of tuberculosis resistance in a mouse model of infection

“…Linkage to chromosomes 7, 12, 15 and 17 exceeded the LanderKruglyak dense map thresholds for significance (logarithm of odds (LOD)44.2) ( Table 3) when linkage was evaluated either with a robust nonparametric statistics 16 or with a newly introduced LOD score based on the Cox proportional-hazards model. 17 Chromosome 12 locus Interestingly, but not unusual given the apparent polygenic architecture described here, it was the susceptible parental strain C3H that contributed the MTB-resistance allele of the chromosome 12 locus. As shown in Figure 2a, mice homozygous for the C3H-derived allele had significant advantage in survival as compared to the B6-allele homozygous and heterozygous animals (Po0.0001).…”

“…Analysis of linkage of survival phenotypes to autosomal loci was performed by using the Mapmaker/SURVIVOR extension of MAPMAKER as described in Symons et al 17 This software computes LOD scores under the Cox proportional hazards model by using a variant of the expectation maximization algorithm using Monte Carlo simulation. Mapmaker/SURVIVOR is available from MJD at mjdaly@genome.wi.mit.edu.…”

A note on QTL detecting for censored traits

“…Then we develop a procedure based on partial likelihood for detecting QTL and show how to assess genome-wide statistical significance. In comparison to Symons et al [17], Broman [2] and Diao et al [4], our approach has some advantages. First, we used the Cox semiparametric PH model which is most popular for survival analysis.…”

“…The incompleteness of the trait values presents a major challenge in the application of the interval-mapping approach [11]. Symons et al [17] computed LOD scores under the Cox proportional hazards (PH) model using a variant of the EM algorithm using Monte Carlo simulation to make the computations tractable as described by Lipsitz and Ibrahim [13]. The EM algorithm incorporates all possible values of missing covariates according to the appropriate probability distributions.…”

Microarray Data Analysis

“…There we were able to utilize binary tree partitioning techniques to discover epistatic genes without prominent independent (marginal) effect, while at the same time illuminating an underlying interaction structure. The results summarizing the application of our approach are described in Symons et al [8]; however, the methodological paper was never written. Nevertheless, this is our joint work for which I am most grateful to Terry, and that ultimately motivated me to start and finish my PhD dissertation.…”