Saccharomyces cerevisiae cells are exquisitely sensitive to altered dosage of the spindle pole body duplication gene, NDC1. We show that the NDC1 locus is haploinsufficient because diploid yeast cells cannot survive with a single chromosomal copy of the NDC1 gene. Diploid cells with a single copy of NDC1 can survive by gaining an extra copy of the NDC1-containing chromosome. NDC1 haploinsufficiency is a dominant loss-of-function phenotype that leads to aneuploidy. Furthermore, we report that overexpression of NDC1 leads to spindle pole body duplication defects indistinguishable from those observed in ndc1-1 mutant cells. Cells overexpressing NDC1 arrest with monopolar spindles and exhibit increase-in-ploidy phenotypes. Thus, both increased and decreased NDC1 dosage can lead to aneuploidy. The striking sensitivity of yeast cells to changes in NDC1 gene dosage suggests a model for the behavior of some tumor suppressor genes and oncogenes in which loss-of-function mutations and overexpression, respectively, lead to increased genetic instability.

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W e investigated the etiology of six problem behaviors that might facilitate an understanding of behavioral pathways to substance use and abuse in adolescents. These behavioral measures, classified as Conduct Problems, Hyperactivity, School Problems, Low Self-esteem, Neuroticism, and Social Withdrawal were the result of a previously reported (Siewert et al., 2003) modification of the Drug Use Screening Inventory (DUSI; Tarter, 1990;Tarter & Hegedus, 1991). We developed these measures as interpretable components of risk for substance use and abuse in a community based sample of 633 twin pairs, who were under the legal drinking age of 21 (mean age = 15.0 years). Using multivariate analyses, model comparisons indicated that these six behavioral measures could be thought of as two heritable, and genetically distinct, dimensions of problem behavior. Two closely competing models resulted from our analyses. The best fitting model hypothesized a general genetic factor loading on all 6 behavioral measures with a second genetic factor loading on only the three internalizing behavioral measures with loadings of 0.25-0.59 and 0.26-0.44, respectively. A second model, which fit the data almost as well, hypothesized one genetic factor loading only on the externalizing behavioral measures, and a second genetic factor loading only on the internalizing behavioral measures, with a correlation between the two latent factors of 0.75. Because our analyses show that there are two genetically distinct factors influencing these six problem behaviors, we anticipate that there may be different patterns of relationship of these factors to risk for substance use, abuse, and dependence.In a previous paper (Siewert et al., 2003) we reported on the psychometric and predictive properties of subscales derived from the Drug Use Screening Inventory (DUSI; Tarter, 1990;Tarter & Hegedus, 1991). We found that these subscales may contribute to a description of behavioral components of risk for substance use and abuse in nonclinical samples of adolescents, even though the DUSI was developed for use in clinical settings. Our goal in exploring the behaviors assessed by the DUSI was to understand the behavioral pathways to substance use and abuse in adolescence. By choosing to assess behaviors that show good discriminant validity between clinical and nonclinical samples (Kirisci et al., 1995), and which have been nominated by clinicians as of particular importance in describing the syndrome of behavioral problems often comorbid with substance use disorders, we hope to focus our study of adolescent problem behaviors on those that show an especially close relationship to the risk for substance use and abuse.To develop behavioral measures that might be used as predictors of substance use and abuse within an adolescent community sample, we modified the Drug Use Screening Inventory resulting in six subscales that characterize the common behavioral problems of adolescence: Conduct Problems, Hyperactivity, Low Self-esteem, Neuroticism, Social Withdrawal, and Sch...

W e investigated the etiology of six problem behaviors that might facilitate an understanding of behavioral pathways to substance use and abuse in adolescents. These behavioral measures, classified as Conduct Problems, Hyperactivity, School Problems, Low Self-esteem, Neuroticism, and Social Withdrawal were the result of a previously reported (Siewert et al., 2003) modification of the Drug Use Screening Inventory (DUSI; Tarter, 1990;Tarter & Hegedus, 1991). We developed these measures as interpretable components of risk for substance use and abuse in a community based sample of 633 twin pairs, who were under the legal drinking age of 21 (mean age = 15.0 years). Using multivariate analyses, model comparisons indicated that these six behavioral measures could be thought of as two heritable, and genetically distinct, dimensions of problem behavior. Two closely competing models resulted from our analyses. The best fitting model hypothesized a general genetic factor loading on all 6 behavioral measures with a second genetic factor loading on only the three internalizing behavioral measures with loadings of 0.25-0.59 and 0.26-0.44, respectively. A second model, which fit the data almost as well, hypothesized one genetic factor loading only on the externalizing behavioral measures, and a second genetic factor loading only on the internalizing behavioral measures, with a correlation between the two latent factors of 0.75. Because our analyses show that there are two genetically distinct factors influencing these six problem behaviors, we anticipate that there may be different patterns of relationship of these factors to risk for substance use, abuse, and dependence.In a previous paper (Siewert et al., 2003) we reported on the psychometric and predictive properties of subscales derived from the Drug Use Screening Inventory (DUSI; Tarter, 1990;Tarter & Hegedus, 1991). We found that these subscales may contribute to a description of behavioral components of risk for substance use and abuse in nonclinical samples of adolescents, even though the DUSI was developed for use in clinical settings. Our goal in exploring the behaviors assessed by the DUSI was to understand the behavioral pathways to substance use and abuse in adolescence. By choosing to assess behaviors that show good discriminant validity between clinical and nonclinical samples (Kirisci et al., 1995), and which have been nominated by clinicians as of particular importance in describing the syndrome of behavioral problems often comorbid with substance use disorders, we hope to focus our study of adolescent problem behaviors on those that show an especially close relationship to the risk for substance use and abuse.To develop behavioral measures that might be used as predictors of substance use and abuse within an adolescent community sample, we modified the Drug Use Screening Inventory resulting in six subscales that characterize the common behavioral problems of adolescence: Conduct Problems, Hyperactivity, Low Self-esteem, Neuroticism, Social Withdrawal, and Sch...