Should we undertake genetic research on intelligence?

Although the concept of intelligence is difficult to define, research has provided evidence for a significant genetic component. Attempts are now being made to use molecular genetic approaches to identify genes contributing to intelligence, and to determine the ways in which they interact with environmental variables. This research is then likely to determine the developmental pathways of intelligence, in an effort to understand mental handicap and learning disorders and develop new treatment strategies. This paper reviews research on the genetic basis of intelligence, and discusses the ethical concerns, including the role of genetic information, the value we place on intelligence and the allocation of resources. It will be argued that the objections raised are problematic, and that because of the value of this knowledge and the prospect of improving lives, this research is morally required. We will then provide a brief analysis of the issues raised by enhancement of intelligence using genetic technology, and will argue that there is no intrinsic difference between this and other means of optimising intelligence.     

Expression and characterization of GSK-3 mutants and their effect on beta-catenin phosphorylation in intact cells

Glycogen synthase kinase-3 (GSK-3) is a serine-threonine kinase that is involved in multiple cellular signaling pathways, including the Wnt signaling cascade where it phosphorylates beta-catenin, thus targeting it for proteasome-mediated degradation. Unlike phosphorylation of glycogen synthase, phosphorylation of beta-catenin by GSK-3 does not require priming in vitro, i.e. it is not dependent on the presence of a phosphoserine, four residues C-terminal to the GSK-3 phosphorylation site. Recently, a means of dissecting GSK-3 activity toward primed and non-primed substrates has been made possible by identification of the R96A mutant of GSK-3beta. This mutant is unable to phosphorylate primed but can still phosphorylate unprimed substrates (Frame, S., Cohen, P., and Biondi R. M. (2001) Mol. Cell 7, 1321-1327). Here we have investigated whether phosphorylation of Ser(33), Ser(37), and Thr(41) in beta-catenin requires priming through prior phosphorylation at Ser(45) in intact cells. We have shown that the Arg(96) mutant does not induce beta-catenin degradation but instead stabilizes beta-catenin, indicating that it is unable to phosphorylate beta-catenin in intact cells. Furthermore, if Ser(45) in beta-catenin is mutated to Ala, beta-catenin is markedly stabilized, and phosphorylation of Ser(33), Ser(37), and Thr(41) in beta-catenin by wild type GSK-3beta is prevented in intact cells. In addition, we have shown that the L128A mutant, which is deficient in phosphorylating Axin in vitro, is still able to phosphorylate beta-catenin in intact cells although it has reduced activity. Mutation of Tyr(216) to Phe markedly reduces the ability of GSK-3beta to phosphorylate and down-regulate beta-catenin. In conclusion, we have found that the Arg(96) mutant has a dominant-negative effect on GSK-3beta-dependent phosphorylation of beta-catenin and that targeting of beta-catenin for degradation requires prior priming through phosphorylation of Ser(45).     

Regeneration of almond from immature seed cotyledons

Adventitious shoots were regenerated from immature cotyledons of four almond cultivars (`Ne Plus Ultra', `Nonpareil', `Carmel' and `Parkinson'). Open-pollinated fruit were collected from orchard-grown trees 100–115 days after full bloom. The proximal ends of the cotyledons were excised and the embryonic axes discarded. The effects of different concentrations of thidiazuron (TDZ) and indole-3-butyric acid (IBA) and the presence or absence of light for the first 7 days of culture were determined. Shoot regeneration rates were highest for cotyledons cultured for 8 weeks on Murashige and Skoog (MS) basal medium containing TDZ (10.0 M), followed by 4 weeks on medium without plant growth regulators. Regeneration levels were further improved if cotyledons were maintained in darkness for the first 7 days. IBA (0.5 M) significantly reduced the development of adventitious shoots. The frequency of cotyledons that developed adventitious shoots under the optimum tested conditions for `Ne Plus Ultra', `Nonpareil', `Carmel', and `Parkinson' were 80.0%, 73.3%, 100.0% and 86.7%, respectively.     

Isolation and characterization of microsatellite loci in Santalum lanceolatum and Santalum leptocladum (Santalaceae)

? Premise of the study: Microsatellite primers were developed for the first time in the native Australian sandalwood species Santalum lanceolatum. ? Methods and Results: Using an enrichment cloning protocol, five novel polymorphic codominant loci were developed and characterized in S. lanceolatum and S. leptocladum. In addition to these, three existing microsatellite loci from other sandalwood species were successfully amplified and characterized for S. lanceolatum and S. leptocladum. Among the eight loci, allelic diversity ranged from 4 to 29. ? Conclusions: Primers will be useful for studies of clonality, genetic diversity and spatial genetic structure in wild populations. When coupled with other molecular techniques will help investigate the relationship between S. lanceolatum and S. leptocladum, species of commercial and conservation interest.     

Immunogenetic factors in beryllium sensitization and chronic beryllium disease

Exposure to beryllium in the workplace can cause beryllium sensitization and chronic beryllium disease. Sensitization to beryllium can be detected in the laboratory using the beryllium lymphocyte proliferation test. It was shown that anti-HLA antibodies could block the beryllium-specific response in the beryllium lymphocyte proliferation test, thereby implicating HLA genes in chronic beryllium disease. A supratypic genetic marker, HLA-DPB1*E69, was found to be strongly associated with immunologic sensitization to beryllium and chronic beryllium disease in beryllium workers. However, there are 40 HLA-DPB1 gene variants that have E69 but that also have other DNA sequence variations. The purpose of the study was to evaluate the evidence for potential differential susceptibility that may be associated with the physical characteristics of HLA protein molecules for which different HLA-DPB1*E69 variants code; that is, do some HLA-DPB1*E69 variants convey higher risk of beryllium sensitization and chronic beryllium disease than others. To do this, two approaches were pursued: first, detailed analysis of the findings from the published literature was performed, and second, computational chemistry was used to seek clues concerning the physical properties of the HLA protein molecules for which these alleles code. Among the 40 HLA-DPB1 gene variants that code for E69, molecular epidemiological studies have suggested a risk hierarchy, where some variants appear to convey low to moderate risk of chronic beryllium disease (e.g., HLA-DPB1*0201, approximately 3-fold increased risk), some convey an intermediate risk (e.g., HLA-DPB1*1901, approximately 5-fold) and others convey high risk (e.g., HLA-DPB1*1701, >10-fold). Molecular modeling has been used to further investigate a potential mechanistic basis for these observations. We found a strong correlation between the hierarchical order of risk of chronic beryllium disease associated with specific alleles and the predicted surface electrostatic potential and charge of the corresponding isotypes. Therefore, when alleles were grouped by the relative negative charge on the molecules for which they code, the data suggest that those alleles associated with the most negatively charged proteins carry the greatest risk of beryllium sensitization and disease.     

Transcriptional signatures of normal human mammary epithelial cells in response to benzo[a]pyrene exposure: a comparison of three microarray platforms

Microarrays are used to study gene expression in a variety of biological systems. A number of different platforms have been developed, but few studies exist that have directly compared the performance of one platform with another. The goal of this study was to determine array variation by analyzing the same RNA samples with three different array platforms. Using gene expression responses to benzo[a]pyrene exposure in normal human mammary epithelial cells (NHMECs), we compared the results of gene expression profiling using three microarray platforms: photolithographic oligonucleotide arrays (Affymetrix), spotted oligonucleotide arrays (Amersham), and spotted cDNA arrays (NCI). While most previous reports comparing microarrays have analyzed pre-existing data from different platforms, this comparison study used the same sample assayed on all three platforms, allowing for analysis of variation from each array platform. In general, poor correlation was found with corresponding measurements from each platform. Each platform yielded different gene expression profiles, suggesting that while microarray analysis is a useful discovery tool, further validation is needed to extrapolate results for broad use of the data. Also, microarray variability needs to be taken into consideration, not only in the data analysis but also in specific probe selection for each array type.     

Site Specific Cleavage Mediated by MMPs Regulates Function of Agrin

Background

Agrin is the key inducer of postsynaptic differentiations at the neuromuscular junction. The multidomain heparan sulfate proteoglycan is mediating via its N-terminal segment the interaction with laminin, whereas the C-terminal portion is responsible for Dystroglycan binding and clustering of the Acetylcholine receptor. Matrix metalloproteinases (MMP) are known to play essential roles in matrix remodeling, degradation and regulation of extracellular signaling networks.

Principal Findings

Site-specific processing of Agrin provides key insight into regulatory effects of Matrix metalloproteinases (MMPs). Here, we present a detailed study of agrin processing by different MMPs together with a molecular understanding of binding and cleavage at both terminal fragments. The data suggest for a regulatory effect of MMP cleavage at particularly important functional sites of agrin. Cleave of agrin abolishes the agrin-laminin complex formation and the Acetylcholine receptor clustering at the neuromuscular junction.

Conclusion/Significance

Agrin is a target of specific MMP processing resulting in agrin subfragments with different regulatory activities. MMP processing is a powerful tool to regulate extracellular signaling networks.