Quantitative trait loci associated with susceptibility to therapy-related acute murine promyelocytic leukemia in hCG-PML/RARA transgenic mice.

Therapy-related acute myelogenous leukemia (t-AML) is an important late adverse effect of alkylator chemotherapy. Susceptibility to t-AML has a genetic component, yet specific genetic variants that influence susceptibility are poorly understood. We analyzed an F(2) intercross (n = 282 mice) between mouse strains resistant or susceptible to t-AML induced by the alkylator ethyl-N-nitrosourea (ENU) to identify genes that regulate t-AML susceptibility. Each mouse carried the hCG-PML/RARA transgene, a well-characterized initiator of myeloid leukemia. In the absence of ENU treatment, transgenic F(2) mice developed leukemia with higher incidence (79.4% vs 12.5%) and at earlier time points (108 days vs 234 days) than mice in the resistant background. ENU treatment of F(2) mice further increased incidence (90.4%) and shortened median survival (171 vs 254 days). We genotyped F(2) mice at 384 informative single nucleotide polymorphisms across the genome and performed quantitative trait locus (QTL) analysis. Thirteen QTLs significantly associated with leukemia-free survival, spleen weight, or white blood cell count were identified on 8 chromosomes. These results suggest that susceptibility to ENU-induced leukemia in mice is a complex trait governed by genes at multiple loci. Improved understanding of genetic risk factors should lead to tailored treatment regimens that reduce risk for patients predisposed to t-AML.

A high-resolution map of segmental DNA copy number variation in the mouse genome.

Submicroscopic (less than 2 Mb) segmental DNA copy number changes are a recently recognized source of genetic variability between individuals. The biological consequences of copy number variants (CNVs) are largely undefined. In some cases, CNVs that cause gene dosage effects have been implicated in phenotypic variation. CNVs have been detected in diverse species, including mice and humans. Published studies in mice have been limited by resolution and strain selection. We chose to study 21 well-characterized inbred mouse strains that are the focus of an international effort to measure, catalog, and disseminate phenotype data. We performed comparative genomic hybridization using long oligomer arrays to characterize CNVs in these strains. This technique increased the resolution of CNV detection by more than an order of magnitude over previous methodologies. The CNVs range in size from 21 to 2,002 kb. Clustering strains by CNV profile recapitulates aspects of the known ancestry of these strains. Most of the CNVs (77.5%) contain annotated genes, and many (47.5%) colocalize with previously mapped segmental duplications in the mouse genome. We demonstrate that this technique can identify copy number differences associated with known polymorphic traits. The phenotype of previously uncharacterized strains can be predicted based on their copy number at these loci. Annotation of CNVs in the mouse genome combined with sequence-based analysis provides an important resource that will help define the genetic basis of complex traits.

Identification of candidate alkylator-induced cancer susceptibility genes by whole genome scanning in mice.

Secondary malignancies are a serious adverse consequence of alkylator chemotherapy. The risk of developing an alkylator-associated malignancy is influenced by genetic background, although the relevant genetic factors are poorly understood. To screen for novel susceptibility factors, we established a mouse model of alkylator-induced malignancy. We exposed mice from 20 inbred strains to the prototypical alkylating agent, N-nitroso-N-ethylurea (ENU). ENU was a potent carcinogen in many of the strains tested, inducing 140 tumors in 240 ENU-treated mice (66% incidence of at least one tumor in evaluable mice), compared with a background incidence of 8% spontaneous tumors in 240 strain-, age-, and sex-matched control mice (relative risk, 8.4; P < 0.0001). A wide variety of tumor histologies were noted, including epithelial carcinomas, soft tissue sarcomas, and hematopoietic tumors. Cancer susceptibility was a heritable trait for the most common tumor types, lung adenocarcinoma (H(2) = 0.25), T cell lymphoma (H(2) = 0.19), and myeloid malignancies (H(2) = 0.10). Quantitative trait locus mapping identified regions on chromosomes 3, 6, 9, and 15 containing candidate genes associated with lung adenoma, lung carcinoma, and lymphoma susceptibility. This novel mouse model recapitulates many features of human alkylator-associated cancer and supports the hypothesis that susceptibility to this syndrome is influenced by inherited polymorphisms that could be used to make informed clinical treatment decisions.

Insertion/deletion polymorphisms in tribal populations of southern India and their possible evolutionary implications.

India has the unique distinction of having perhaps the largest diversities, both biological and cultural. The Nilgiri Hills of southern India, a home for several tribal pockets representing different genetic isolates, provides a genetic wealth to understand human evolution. We have analyzed eight widely distributed polymorphic insertion/deletion loci (AluAPO, AluACE, AluDI, AluPLAT, AluPV92, AluFXIIIB, CD4 del and mtNUC) in 250 unrelated individuals from five tribal populations (Badaga, Irula, Kota, Kurumba, and Toda). All loci were highly polymorphic except the CD4 del locus, at which the deletion allele was fixed in Kotas and Kurumbas. The levels of average heterozygosities were found to be high in all the populations. In most populations, they were also higher than those predicted by the island model of population structure. The gene diversity (GST = 8.3%) was found to be higher than that in populations of most global regions with the exception of Africa. It is clear from the present study that drift effects could have accentuated the process of genetic differentiation of the tribal populations. The possibility of an early demographic expansion of modern humans within south India also cannot be ruled out.

Trace metal concentration in scalp hair of occupationally exposed autodrivers.

The concentrations of Cr, Pb, Zn, Cu, Ni and Cd were analyzed by Atomic Absorption Spectrophotometer in the scalp hair of professional male autodrivers who are occupationally exposed to the vehicular/industrial pollutants in the industrial city of Coimbatore, Tamil Nadu. The unwashed hair samples when compared with the washed hair showed a significantly higher levels of Cr, Zn and Pb. The correlation coefficient showed a strong mutual dependence on the scalp hair of the exposed individuals and no correlation was found among the trace metals except for Ni-Pb and Ni-Cd. The results in general showed a positive exogenous contribution of all the analyzed industrial trace metals. The drivers who are occupationally exposed to vehicular/industrial pollution are at risk.

An anticlastogenic in vivo micronucleus assay for tea.

Common use of antimutagens and anticarcinogens in everyday life is an effective measure for preventing human cancer and genetic diseases. Antioxidant properties of tea have vast potential as protective agents against diverse toxic effects. The present study was aimed to evaluate the role of aqueous clonal tea extracts (green tea, oolong tea and black tea) in modulating the genotoxic damage induced by cyclophosphamide (CP), a commonly used chemotherapeutic drug and a well-known mutagen and clastogen. All the three tea extracts at 1 and 2% concentration did not increase the frequency of micronucleated polychromatic erythrocytes (MPE) in bone marrow cells of mice when administered individually. The tea extracts decreased the micronuclei (MN) induced by CP. Therefore, regular intake of tea may improve the antioxidant status in in vivo and thereby reduce the risk of cancer and coronary heart disease.