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Success in elucidating neural and genetic mechanisms for a female-typical sociosexual behavior have encouraged new work on mechanisms for the underlying concepts, motivation and arousal. Evidence for global arousal is adduced, and brainstem pathways contributing to global arousal are under investigation.
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Several lines of evidence point to the involvement of recessive mutations in the predisposition to, and hence initiation of, cancer in vivo. Analyses of the genetic behavior of transformed cells suggest that at least one way to explain these events is to invoke loci which suppress the tumorous phenotype and which are inactivated by mutation. These suppressors are the subject of much speculation, but whether or not they are ultimately determined to be the regulators of differentiation antigens, growth factors, or proto-oncogenes, it is certain that the investigation of such loci will allow yet another glimpse at the inner mysteries of organismal development.
Two rhesus (Macaca mulatta) monkey lymphocyte-defined (LD) antigens have been identified using two typing cells as stiumlators in a one-way mixed leukocyte culture (MLC) assay. An analysis of the genetic behavior of these LD antigens in six rhesus monkey families revealed that both antigens were linked with RhLA. One probable recombinant indicated that the LD locus lies outside the two known RhLA-SD loci and the locus which controls the serum protein, properdin B(Bf). These two antigens, LD1 and LD2, had observed gene frequencies of 0.07 and 0.25, respectively. Neither of these two new LD antigens was significantly associated with any serologically defined (SD) antigen.
In Drosophila melanogaster, a specific PGAL4 transposon induces the Voila1 genetic variant and produces multiple phenotypes. Homozygous Voila1/1 flies rarely reach adulthood, whereas heterozygous Voila1/+ adult males show strong bisexual behavior. Males with a single copy of Voila1 driving the feminizing transgene UAS-transformer show very reduced sexual activity but no overall effect on their behavior. Voila1 is specifically expressed in the nervous system. In the CNS, it is expressed mainly in the mushroom bodies and, to a lesser extent, in the antennal lobes. In the peripheral nervous system, GAL4 expression is almost entirely restricted to the gustatory sensilla. Using chromosomal deficiencies, the behavioral alteration was genetically mapped to the same location as the PGAL4 element (86E1-2). The multiple behavioral effects of the Voila genetic variant are discussed in light of its expression in the nervous system and its genetic basis.
The transmission disequilibrium test (TDT), designed as a test of linkage in the presence of association (i.e. linkage disequilibrium), has received considerable attention in the recent statistical genetics literature due to its advantages over other within-family analytic methods. One limitation of the conventional TDT is its application solely to linkage disequilibrium between a genetic marker and a single categorical trait (e.g. presence or absence of a disease). In this paper, we present an extension of the TDT using logistic regression to examine the relation between a candidate gene or genetic marker and one or more continuous or categorical explanatory variables. This logistic regression extension of the TDT possesses all of the desirable features of the conventional TDT, as well as many advantages associated with traditional regression analysis. We describe the model and its properties, as well as a number of its possible applications, and apply it to examine linkage disequilibrium between the dopamine receptor D2 gene (DRD2) and symptoms of childhood attention deficit hyperactivity disorder (ADHD). We also briefly compare the logistic regression TDT to other quantitative TDTs that have been proposed in the literature, and highlight the advantages of a regression-based approach for examining the relation between a candidate gene and one or more continuous or categorical traits. Given its features, we regard the logistic regression extension of the TDT as a flexible new data analytic method with extensive potential applications to problems in medical, psychiatric, and behavioral genetics.
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Behavioral genetic studies indicate that nongenetic factors play a role in the development of bipolar and major depressive disorders. The trait of neuroticism is common among individuals with major affective disorders. We hypothesized that high neuroticism among parents affects the family environment and parenting practices and thereby increases the risk of psychosocial problems among offspring. This hypothesis is tested in a sample of participants at high and low risk for major affective disorders, which contained parents with bipolar disorder (55), major depression (21), or no mental disorder (148) and their 146 children between 4 and 14 years of age. Parents with high neuroticism scores were characterized by low psychosocial functioning, poor parenting, more dependent stressful life events, and the use of more emotion-focused and less task-oriented coping skills. High neuroticism in parents was associated with internalizing and externalizing problems among the children, as assessed by parent and teacher ratings on the Child Behavior Checklist and clinician ratings. The results suggest that high neuroticism in parents with major affective disorders is associated with inadequate parenting practices and the creation of a stressful family environment, which are subsequently related to psychosocial problems among the offspring.
Microprojectile bombardment to deliver DNA into plant cells represents a major breakthrough in the development of plant transformation technologies and accordingly has resulted in transformation of numerous species considered recalcitrant to Agrobacterium- or protoplast-mediated transformation methods. This article attempts to review the current understanding of the molecular and genetic behavior of transgenes introduced by microprojectile bombardment. The characteristic features of the transgene integration pattern resulting from DNA delivery via microprojectile bombardment include integration of the full length transgene as well as rearranged copies of the introduced DNA. Copy number of both the transgene and rearranged fragments is often highly variable. Most frequently the multiple transgene copies and rearranged fragments are inherited as a single locus. However, a variable proportion of transgenic events produced by microprojectile bombardment exhibit Mendelian ratios for monogenic and digenic segregation vs events exhibiting segregation distortion. The potential mechanisms underlying these observations are discussed.
Myotonic dystrophy type 2 (DM2) is caused by the extreme expansion of the repeating tetranucleotide CCTG*CAGG sequence from <30 repeats in normal individuals to approximately 11,000 for the full mutation in certain patients. This repeat is in intron 1 of the zinc finger protein 9 gene on chromosome 3q21. Since prior work demonstrated that CTG*CAG and GAA*TTC triplet repeats (responsible for DM1 and Friedreich's ataxia, respectively) can expand by genetic recombination, we investigated the capacity of the DM2 tetranucleotide repeats to also expand during this process. Both gene conversion and unequal crossing over are attractive mechanisms to effect these very large expansions. (CCTG*CAGG)n (where n=30, 75, 114 or 160) repeats showed high recombination crossover frequencies (up to 27-fold higher than the non-repeating control) in an intramolecular plasmid system in Escherichia coli. Furthermore, a distinct orientation effect was observed where orientation II (CAGG on the leading strand template) was more prone to recombine. Expansions of up to double the length of the tetranucleotide repeats were found. Also, the repeating tetranucleotide sequence was more prone to expansions (to give lengths longer than a single repeating tract) than deletions as observed for the CTG*CAG and GAA*TTC repeats. We determined that the DM2 tetranucleotide repeats showed a lower thermodynamic stability when compared to the DM1 trinucleotide repeats, which could make them better targets for DNA repair events, thus explaining their expansion-prone behavior. Genetic studies in SOS-repair mutants revealed high frequencies of recombination crossovers although the SOS-response itself was not induced. Thus, the genetic instabilities of the CCTG*CAGG repeats may be mediated by a recombination-repair mechanism that is influenced by DNA structure.
Ionizing radiation is expected to produce mutants with deletions or other chromosomal rearrangements. These mutants are useful for a variety of purposes, such as creating null alleles and cloning genes whose existence is known only from their mutant phenotype; however, only a few mutations generated by ionizing radiation have been characterized at the molecular level in Arabidopsis thaliana. Twenty fast neutron-generated alleles of the Arabidopsis HY4 locus, which encodes a blue light receptor, CRY1, were isolated and characterized. Nine of the mutant alleles displayed normal genetic behavior. The other 11 mutant alleles were poorly transmitted through the male gametophyte and were lethal in homozygous plants. Southern blot analysis demonstrated that alleles of the first group generally contain small or moderate-sized deletions at HY4, while alleles of the second group contain large deletions at this locus. These results demonstrate that fast neutrons can produce a range of deletions at a single locus in Arabidopsis. Many of these deletions would be suitable for cloning by genomic subtraction or representational difference analysis. The results also suggest the presence of an essential locus adjacent to HY4.
The current understanding of suicidal behaviors is that such behaviors are multidetermined and mental state and trait related. Genetic factors appear to be of great importance, as suggested by the findings of family, twin, and adoption studies. Whether these genetic factors are similar to those involved in the susceptibility to psychiatric disorders closely related to suicidal behavior (eg, manic depressive illness, schizophrenia or substance use disorders) is yet unknown. However, a genetic factor of susceptibility to suicide, independent or additive to the genetic transmission of the psychiatric disorders that are related to suicidal behavior, is strongly suggested by the data of the Copenhagen adoption study and a study of Amish families. Recently, new approaches have been proposed to identify the genetic component of such complex traits. Association studies between genetic markers and a disease phenotype has been successfully applied to several complex disease such as essential hypertension. One candidate gene for suicidal behaviors is the tryptophane hydroxylase (TPH) gene which is the first and possibly rate-limiting enzyme of the metabolic pathway for serotonin. Indeed, altered serotoninergic function in both completed suicide and suicide attempt has been one of the most replicated findings in modern biological psychiatry. In our knowledge, only two studies have tested the association between suicide attempt and the TPH gene and their authors found negative results. Despite these negative results, association studies that use candidate gene remain one of the methods of choice for studying the genetic component of suicidal behaviors.
We trained BALB/c Byllco (C), CD-1, SV 129/SvPasCr1 (129 SV), C57BL/6 (B6) and DBA/2J (D2) mice using the olfactory tubing maze with the hope of gaining insight into behavioral genetics related to learning and memory processes. All strains of mice acquired the odor-reward associations using this new task except the D2 strain. The C, CD-1, and 129 SV consistently remembered the associations from the sixth 20-trial training session, reaching 80% +/- 5 correct responses in session seven. The B6 mice required one more session to reach 76%, while the D2 mice never learned the correct odor-reward associations. All mice learned the paradigm and the timing of the task, although the 129 SV mice decreased slower the inter-trial intervals across sessions. With this new task, D2 mice, with a deficit totally devoted to an impairment on learning and memory, can be used as a model of hippocampal dysfunction, in some respects like that observed in human amnesic patients whose selective hippocampal-dependent memory is deeply impaired. The high-scoring strains (C, CD-1, and 129 SV) seem to be ideal in this task to study a gene-targeting mutation postulated to reduce behavioral performance, and inversely, for D2 mice. The moderate-scoring strain, B6, should be ideal for allowing gene-targeting to go either way. In addition, this new task, which enables automated training of odor associations, could be used for studying the phenomenon of transitivity in mice, as described in rats.
PURPOSE: The neurobiological basis of alcohol dependence, established pharmacotherapies for alcohol dependence, pharmacotherapies under investigation, and obstacles to treatment are discussed. SUMMARY: Alcohol binds to hydrophobic pockets of proteins, changing their three-dimensional structure and their function. Proteins that are particularly sensitive to alcohol include ion channels, neurotransmitter receptors, and enzymes involved in signal transduction. Established pharmacologic treatments, notably disulfiram and naltrexone, combined with behavioral therapies, may reduce the amount of drinking, the risk of relapse, the number of days of drinking, and craving in some alcohol-dependent individuals. For many patients, however, these treatments are not effective. Recent advances in molecular and behavior genetics are guiding the development of new drugs; these efforts seek to identify pharmacologic pathways relevant to alcohol dependence and to more effectively match treatments to individuals according to their genetic characteristics. Efficacy and safety concerns for acamprosate have been satisfied; the drug was recently released for marketing in the United States. Medications such as sertraline, ondansetron, topiramate, and aripiprazole represent novel lines of research and are currently being tested for use in the treatment of alcoholism. Even with more efficacious medications, however, a transformation must occur in how alcoholism treatment is viewed, not only by the public but also by clinicians. CONCLUSION: In addition to existing drug treatments for alcohol dependence, many other medications are under investigation, particularly for specific types of alcoholism. Pharmacogenomics is expected to play an important role in this research effort.
Srb/mediator proteins that are associated with RNA polymerase II holoenzyme have been implicated in transcriptional repression in Saccharomyces cerevisiae. We show here that the defect in repression of SUC2 caused by mutation of SRB8, SRB9, SRB11, SIN4 or ROX3 is suppressed by increased dosage of the SFL1 gene, and the genetic behavior of the sfl1Delta mutation provides further evidence for a functional relationship. Sfl1 acts on SUC2 through a repression site located immediately 5' to the TATA box, and Sfl1 binds this DNA sequence in vitro. Moreover, LexA-Sfl1 represses transcription of a reporter, and repression is reduced in an srb9 mutant. Finally, we show that Sfl1 co-immunoprecipitates from cell extracts with Srb9, Srb11, Sin4 and Rox3. We propose that Sfl1, when bound to its site, interacts with Srb/mediator proteins to inhibit transcription by RNA polymerase II holoenzyme.
The erythrocyte osmotic fragility was evaluated on 19 unmedicated subjects with Huntington's disease and 42 individuals at 50% risk, 27 children at 25% risk, and a group of 60 hematologically normal control persons. Five older subjects at 50% risk for Huntington's disease as well as 6 Alzheimer's disease individuals were also evaluated for comparison. The osmotic fragility of fresh and 24-hour incubated red cells was analyzed and a fragility index calculated for each individual. The fragility index for the Huntington's disease group was statistically lower than that of the control group (P less than .001) suggesting that the Huntington's disease erythrocytes had a reduced osmotic fragility. In the 50% risk group, 45% of the subjects demonstrated decreased osmotic fragility and 55% had normal fragility. For those subjects in the 25% risk group, 22.2% had decreased fragility and 77.8% had normal fragility. Twenty-seven offspring were evaluated of the 14 persons at 50% risk for Huntington's disease with children; eight of the 14 individuals at 50% risk showed normal fragility and all 16 of their children showed fragility indices with the normal range. The remaining six persons at 50% risk for Huntington's disease had increased erythrocyte fragility and out of their 11 children, five showed normal fragility and six had decreased fragility. These data support the hypothesis of reduced erythrocyte osmotic fragility in individuals affected with and at risk for Huntington disease, and demonstrate the need of further study of the erythrocyte in this complex behavioral genetic disease.
Behavior genetics studies in mice demand efficient training protocols for rapid phenotypic screening. However, the capacity of neonatal mice to form and retain associative memories has been difficult to study due to their limited sensorimotor capacities. The present study describes a method for robust, naturalistic associative learning in neonatal mice as young as 3 days old. After removal of the dam from the home cage for 2 h, preweanling CD-1 mice of ages 3, 5, and 10 days postnatal were conditioned to associate an arbitrary odorant with the suckling and milk delivery that ensued upon her return to the home cage. After a second maternal deprivation, neonates were tested on their acquired preference for that odorant. Neonates exhibited a learned preference for the conditioned odorant over a novel control odorant. No learning was observed without deprivation, that is, when the dam was removed only briefly for scenting. One-trial learning sufficed to show clear preferences for the conditioned odorant, although repeated training (three sessions over 8 days) significantly increased the expression of preference. The development of neonatal associative learning protocols requiring minimal human intervention is important for the behavioral phenotyping of mutant and transgenic strains, particularly those modeling developmental disorders.
A-type potassium currents are important determinants of neuronal excitability. In spinal cord dorsal horn neurons, A-type currents are modulated by extracellular signal-regulated kinases (ERKs), which mediate central sensitization during inflammatory pain. Here, we report that Kv4.2 mediates the majority of A-type current in dorsal horn neurons and is a critical site for modulation of neuronal excitability and nociceptive behaviors. Genetic elimination of Kv4.2 reduces A-type currents and increases excitability of dorsal horn neurons, resulting in enhanced sensitivity to tactile and thermal stimuli. Furthermore, ERK-mediated modulation of excitability in dorsal horn neurons and ERK-dependent forms of pain hypersensitivity are absent in Kv4.2(-/-) mice compared to wild-type littermates. Finally, mutational analysis of Kv4.2 indicates that S616 is the functionally relevant ERK phosphorylation site for modulation of Kv4.2-mediated currents in neurons. These results show that Kv4.2 is a downstream target of ERK in spinal cord and plays a crucial role in pain plasticity.