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PubMed1996

The detection and evaluation of aneugenic chemicals.

Although aneuploidy makes a significant contribution to both somatic and inherited disease the mechanisms by which environmental chemicals may induce numerical chromosome aberrations are only poorly defined. The European Union Project was aimed to further our understanding of those chemical interactions with the components of the mitotic and meiotic cell division cycle which may lead to aneuploidy and to characterise the parameters such as cellular metabolism which may influence the activity of aneugenic chemicals. C-mitosis can be induced by the highly lipophilic polychlorinated biphenyl and the completion of mitosis and cleavage can be modified by agents which deplete cellular levels of reduced glutathione. Modifications of the fidelity of chromosome segregation were produced by inhibiting the functioning of topoisomerase II during chromatid separation. In contrast, the modification of centromere integrity resulted in chromosome breakage as opposed to disturbance of segregation. Modifiers of tubulin assembly and centriolar functioning in somatic cells such as acrylamide, vinblastine and diazepam reproduced their activity in rodent bone marrow and male germ cells. The analysis of chromosome malsegregation in Aspergillus nidulans by a structurally related series of halogenated hydrocarbons was used to develop a QSAR model which had high predictive value for the results of fungal tests for previously untested related chemicals. Metabolic studies of potential aneugens in genetically engineered human lymphoblastoid cells demonstrated the detoxification of the aneugenic activity of chloral hydrate and the activation of 2,3-dichlorobutane, 1,1,2-trichloroethane and trichloroethylene by Phase I biotransforming enzymes. Cell transformation studies in Syrian hamster dermal cultures using a panel of 22 reference and or potential aneugens indicated that 15 of the 22 produced positive results following single exposures. Five of the aneugens which were negative following single exposures produced positive results where cultures were continuously exposed for up to 6 weeks to low concentrations following a single non-transforming exposure to the mutagen dimethyl sulphate. The transformation studies indicate that a significant proportion of chemical aneugens are potential complete carcinogens and/or co-carcinogens. To optimise the enumeration of chromosomes following exposure to potential chemical aneugens whole chromosome paints and centromere specific probes suitable for use in fluorescence in situ hybridisation (FISH) were developed for the rat, mouse and Chinese hamster and selected human probes evaluated for their suitability for routine use. Molecular chromosome probes were used to develop protocols for enumerating chromosomes in metaphase cells and centromeres and micronuclei in interphase cells. The analysis of segregation of specific centromeres in binucleate cells following cytochalasin B treatment was shown to be a potentially valuable system for characterising non-disjunction following chemical exposure. Whole chromosome paints and centromere specific probes were used to demonstrate the presence of dose-response thresholds following treatment with a reference panel of spindle inhibiting chemicals. These data indicate that the FISH technology is suitable for evaluating the relative hazards of low-dose exposures to aneugenic chemicals.

Aneuploidy↗

PubMed1990

Randomized comparison of doxorubicin and vindesine to doxorubicin for patients with metastatic soft-tissue sarcomas.

Two treatment regimens for metastatic soft-tissue sarcomas were compared in a randomized trial in the cooperative group setting. Histopathologic diagnosis was affirmed by pathology reference panel review in 72% of the 347 patients. In 21% of patients, the reference panel affirmed the diagnosis of soft-tissue sarcoma but disagreed as to type; 7% of patients were ineligible based upon cell type. Of 298 patients evaluable, measurable tumor regression (partial or complete response) occurred in 17% of patients to doxorubicin (70 mg/m2 intravenously) and 18% of patients to doxorubicin (70 mg/m2 intravenously) and vindesine (3 mg/m2 intravenously), each given every 3 weeks. No difference existed in complete response (4% for doxorubicin, 6% for doxorubicin and vindesine) or median survival (9.4 months for doxorubicin, 9.9 months for doxorubicin and vindesine). Overall, 60% of those patients on doxorubicin and vindesine and 46% on doxorubicin experienced a severe or worse toxicity of treatment (P = 0.01). With greater toxicity and lack of any gains in efficacy, the results do not support use of the combination of doxorubicin and vindesine for metastatic soft-tissue sarcomas.

Adult↗

PubMed2006

Development and evaluation of HIV-1 subtype RNA panels for the standardization of HIV-1 NAT assays.

Multiple nucleic acid-based techniques (NAT) have been implemented for testing blood and plasma donors for HIV-1 RNA which may be detected at an earlier stage of infection when HIV antigen or antibody is absent or below the limit of detection of current assays. The available NAT assays are based on different technologies. In order to evaluate the performance of nucleic acid-based techniques (NAT assays) and to allow accurate comparisons of results from different assays, it is essential to have well characterized specimens with known copy numbers as a standard. For this purpose, a comprehensive study was conducted to develop two HIV-1 RNA reference panels. The first (Panel 1) was prepared using a single specimen from the HIV-1 group M subtype B and consists of panel members with a wide range of HIV-1 RNA copy numbers. Panel 2 consists of 26 members representing HIV-1 group M subtypes A, C, D, E, F, G and groups O and N. For accurate determination of HIV-1 RNA copy numbers of each member of Panel 2, they were analyzed using various testing platforms/technologies available through the cooperation of five independent laboratories participating in the study. A consensus value for HIV RNA copy number was assigned to each member of Panel 2 based on statistical analysis of the data provided by the participants. Both panels could serve as reference panels to be used by manufacturers of HIV NAT tests to evaluate the sensitivity limits of their assays.

Genetic Techniques↗

PubMed2001

Combined PCR-heteroduplex mobility assay for detection and differentiation of influenza A viruses from different animal species.

Transfer of influenza A viruses from animal hosts to man may lead to the emergence of new human pandemic strains. The early detection and identification of such events are therefore paramount in the surveillance of influenza viruses. To detect and partially characterize influenza A viruses from different animal species, a combined reverse transcription (RT)-PCR heteroduplex mobility assay (HMA) was designed. This M gene RT-PCR was shown to be sensitive and specific for the detection of human, avian, and swine influenza A viruses. PCR amplicons from human, avian, and swine viruses of 15 different subtypes, with between 1.9 and 21.4% nucleotide divergence, were differentiated by HMA. Sequencing of the amplicons showed that the heteroduplex mobility patterns correlated with the sequence divergence between test and reference DNA. The application of the RT-PCR HMA method for rapid screening of samples was assessed with a reference panel of viruses of human, avian, and swine origin. The avian H9N2 virus A/HongKong/1073/99, which crossed the species barrier to humans, was screened against the reference panel. It was found to be most closely related to the avian A/Quail/HongKong/G1/97 H9N2 reference PCR product. Sequence analysis showed a nucleotide divergence of 1.1% between the A/Quail/HongKong/G1/97 and A/HongKong/1073/99 amplicons. From the results of our work, we consider the RT-PCR HMA method described to offer a rapid and sensitive means for screening for novel or unusual influenza viruses.

Animals↗

PubMed1993

Highly informative typing of the human TNF locus using six adjacent polymorphic markers.

The human tumor necrosis factor locus (TNF locus) is located within the major histocompatibility complex between the class III genes and HLA-B. We recently characterized and studied two closely linked highly informative dinucleotide repeats (AC/GT)n (designated TNFa) and (TC/GA)k (designated TNFb) in the upstream region of the human TNF-beta (lymphotoxin) gene. We also characterized two linked (TC/GA) and (TC/GA)-like repeats located downstream of the TNF-alpha gene, designated TNFe and TNFd, respectively. Here, we combine these four markers together with a biallelic TC/GA repeat in the first intron of the TNF-beta gene (TNFc) and a biallelic NcoI RFLP (TNFn) to type 105 cell lines from the American Society of Histocompatibility and Immunogenetics Workshop and the Center for Human Polymorphism Studies reference panels of HLA typing cell lines. These 6 polymorphic markers define 35 distinct TNF haplotypes and together with the reference panel can be used for disease association and population genetics studies.

Alleles↗

PubMed2007

Assessing immunophenotyping performance: proficiency-validation for adopting improved flow cytometry methods.

BACKGROUND: The continuous improvement and evolution of immune cell phenotyping requires periodic upgrading of laboratory methods and technology. Flow cytometry laboratories that are participating in research protocols sponsored by the NIAID are required to perform "switch" studies to validate performance before methods for T-cell subset analysis can be changed. METHODS: Switch studies were conducted among the four flow cytometry laboratories of the Multicenter AIDS Cohort Study (MACS), comparing a 2-color, lyse-wash method and a newer, 3-color, lyse no-wash method. Two of the laboratories twice failed to satisfy the criteria for acceptable differences from the previous method. Rather than repeating more switch studies, these laboratories were allowed to adopt the 3-color, lyse no-wash method. To evaluate the impact of the switch to the new method at these two sites, their results with the new method were evaluated within the context of all laboratories participating in the NIH-NIAID-Division of AIDS Immunology Quality Assurance (IQA) proficiency-testing program. RESULTS: Laboratory performance at these two sites substantially improved relative to the IQA standard test results. Variation across the four MACS sites and across replicate samples was also reduced. CONCLUSIONS: Although switch studies are the conventional method for assessing comparability of laboratory methods, two alternatives to the requirement of repeating failed switch studies should be considered: (1) test the new method and assess performance on the proficiency testing reference panel, and (2) prior to adoption of the new methods, use both the old and the new method on the reference panel samples and demonstrate that performance with the new method is better according to standard statistical procedures. These alternatives may help some laboratories' transition to a new and superior methodology more quickly than if they are required to attempt multiple, serial switch studies.

Acquired Immunodeficiency Syndrome↗

PubMed1993

Pathology review in cancer research.

Pathology observer agreement studies are clearly important in the development of new pathology assessments and in the quality control of those assessments in common use. Setting up such studies, and reporting and interpreting their results requires careful thought and statistical expertise. Investigators are advised to seek collaboration with a statistician before embarking on these studies. Pathology reference panel reviews in multicentre studies are useful for checking eligibility when there is a high level of disagreement on the eligibility criterion between local pathologists and the reference panel members, but good agreement between members of the panel. However, such situations are uncommon.

Animals↗

PubMed2003

Sequence characterization of the protease and partial reverse transcriptase proteins of the NED panel, an international HIV type 1 subtype reference and standards panel.

The NED panel (NIH-ENVA-DOD) was assembled by the Virology Quality Assurance Laboratory for use as an international HIV-1 subtype reference and standards panel. The panel contains 44 minimally cultured strains from diverse geographic areas donated by the Walter Reed Army Institute of Research and F. Brun-Vezinet (Hôpital Bichat-Claude Bernard, Paris, France). The contributors assigned the strains to group M subtypes A (5), B (10), C (6), D (3), E (10), F (5), G (2), H (1), and O (2) before donation. Phylogenetic and recombination analyses of the protease gene and a partial sequence of the reverse transcriptase gene of each seed pool indicated potentially three more recombinants in the panel in addition to the two previously recognized recombinants. Alignments of the amino acids to corresponding regions of pNL4-3 showed protease amino acid sequence identity ranged from 68.5 % (group O) to 95.2 % (subtype B). Reverse transcriptase amino acid identity ranged from 84.5% (group O) to 96.8% (clade B). Codons associated with antiretroviral resistance were primarily wild type and highly conserved among all the clades.

Drug Resistance, Viral↗

PubMed1995

The concept of individualized hypertension care in general practice and outpatient clinics. The general practitioner hypertension practice study (III).

OBJECTIVE: To examine test ordering practice among general practitioners and hospital medical specialists according to the concept of individualized hypertension care. DESIGN: Mailed hypothetical case histories, with reference panels to categorize tests. SETTING: Uppsala-Orebro region in mid-Sweden. SUBJECTS: General practitioners (N = 90) and hospital medical specialists (N = 69) in randomly sampled primary health care centres and hospitals. MAIN OUTCOME MEASURES: Test ordering scores. RESULTS: 84% of invited GPs and 72% of specialists participated. According to reference panel standards, primary care physicians performed 75% of obligatory tests and specialists 88%. Superfluous tests constituted a larger proportion of the practice of hospital specialists (11-28%) than GPs (2-12%) in the six cases. Summarized examination scores revealed a wide practice variation within and between the two physician categories, specialists scoring significantly higher in three cases. Standardization of practice was more common among specialists, and differed significantly regarding serum potassium test, chest X-ray and ECG. Both groups deviated from current guidelines by omitting metabolic parameters. CONCLUSION: There is considerable practice variation in individualized hypertension care, which might influence treatment outcome. Practice audit and continuing medical education could contribute to care standardization according to guidelines.

Adult↗

PubMed2003

Low microsatellite instability and high loss of heterozygosity rates indicate dominant role of the suppressor pathway in squamous cell carcinoma of head and neck and loss of heterozygosity of 11q14.3 correlates with tumor grade.

Loss of heterozygosity (LOH) and microsatellite instability (MSI) have been recognized as important events in squamous cell carcinoma of the head and neck (HNSCC), suggesting involvement of both suppressor and mutator pathways. We analyzed 153 HNSCC with 8 Bethesda reference panel markers and 14 microsatellite markers selected from chromosomal regions known to harbor either tumor-suppressor genes or oncogenes. A combination of multiplex fluorescence-based polymerase chain reaction and automatic fragment analysis was performed. LOH was observed in 78% of all tumors. 2% to 17% LOH frequency was observed with Bethesda reference panel markers comparing to higher 8% to 48% LOH in chromosomal areas 3p, 9p, 11q, and 17p. LOH of 11q14.3 correlated with tumor grade. The proportions of high- and low-MSI tumors were 3% and 10%, respectively, but no mutation was identified in MLH1 and MSH2 mismatch repair genes. These results indicate the dominant role of the suppressor in comparison with the mutator pathway in HNSCC carcinogenesis.

Adaptor Proteins, Signal Transducing↗

PubMed1995

Predicting ligand binding to proteins by affinity fingerprinting.

BACKGROUND: There are many ways to represent a molecule's properties, including atomic-connectivity drawings, NMR spectra, and molecular orbital models. Prior methods for predicting the biological activity of compounds have largely depended on these physical representations. Measuring a compound's binding potency against a small reference panel of diverse proteins defines a very different representation of the molecule, which we call an affinity fingerprint. Statistical analysis of such fingerprints provides new insights into aspects of binding interactions that are shared among a wide variety of proteins. These analyses facilitate prediction of the binding properties of these compounds assayed against new proteins. RESULTS: Affinity fingerprints are reported for 122 structurally-diverse compounds using a reference panel of eight proteins that collectively are able to generate unique fingerprints for about 75% of the small organic compounds tested. Application of multivariate regression techniques to this database enables the creation of computational surrogates to represent new proteins that are surprisingly effective at predicting binding potencies. We illustrate this for two enzymes with no previously recognizable similarity to each other or to any of the reference proteins. Fitting of analogous computational surrogates to four other proteins confirms the generality of the method; when applied to a fingerprinted library of 5000 compounds, several sub-micromolar hits were correctly predicted. CONCLUSIONS: An affinity fingerprint database, which provides a rich source of data defining operational similarities among proteins, can be used to test theories of cryptic homology unexpected from current understanding of protein structure. Practical applications to drug design include efficient pre-screening of large numbers of compounds against target proteins using fingerprint similarities, supplemented by a small number of empirical measurements, to select promising compounds for further study.

Chromatography, Affinity↗

PubMed1984

Strategies for multilocus linkage analysis in humans.

The increasing number of DNA polymorphisms characterized in humans will soon allow the construction of fine genetic maps of human chromosomes. This advance calls for a reexamination of current methodologies for linkage analysis by the family method. We have investigated the relative efficiency of two-point and three-point linkage tests for the detection of linkage and the estimation of recombination in a variety of situations. This led us to develop the computer program LINKAGE to perform multilocus linkage analysis. The investigation also enables us to propose a method of location scores for the efficient detection of linkage between a disease locus, or a new genetic marker, and a linkage group previously established from a reference panel of families. The method is illustrated by an application to simulated pedigree data in a situation akin to Duchenne muscular dystrophy. These results show that considerable economy and efficiency can be brought to the mapping endeavor by resorting to appropriate strategies of detecting linkage and by constructing the human genetic map on a common reference panel of families.

Chromosome Mapping↗

PubMed2004

Polymorphisms of the equine major histocompatibility complex class II DRA locus.

The full extent of the polymorphism of ELA-DRA in Equidae is not yet known. Given the apparent differences in DRA polymorphisms between Equidae and other species, the aims of this study were to more fully characterize ELA-DRA, determine the extent of gene polymorphism and establish the allele-frequency distribution. An allele reference panel for the second exon of ELA-DRA was established by sequence-based typing of 69 equine DNA samples consisting of various breeds of domestic horse (Equus caballus), together with donkeys (Equus asinus), Grant's zebras (Equus boehmi) and one onager (Equus hemionus). Five of the six previously reported alleles detected using single-strand conformation polymorphism were found: ELA-DRA*0101, ELA-DRA*0201, ELA-DRA*0301, ELA-DRA*0501 (Albright-Fraser DG et al. Polymorphism of DRA among equids. Immunogenetics 1996: 43: 315-7) and ELA-DRA*0601 (GenBank accession number AF5419361). In addition to the previously reported alleles, five novel ELA-DRA alleles were detected within the ELA-DRA allele reference panel. One of these was identified in E. caballus (ELA-DRA*JBH11), one in E. boehmi and E. hemionus (ELA-DRA*JBZ185) and three in E. asinus (ELA-DRA*JBD3, ELA-DRA*JBD17 and ELA-DRA*JBH45). A total of 565 equine DNA samples were screened using reference-strand-mediated conformation analysis, a double-stranded conformation-based mutation detection system that can be used to type existing ELA-DRA alleles and identify new variants. Based on our findings, at least 11 ELA-DRA alleles are now known to exist, and this level of polymorphism at the DRA locus appears to be unique to the genus Equus. Both the previously reported alleles and the new alleles displayed a species-specific distribution.

Amino Acid Sequence↗

PubMed2006

On line clinical reasoning assessment with Script Concordance test in urology: results of a French pilot study.

BACKGROUND: The Script Concordance test (SC) test is an assessment tool that measures the capacity to solve ill-defined problems, that is, reasoning in a context of uncertainty. This study assesses the feasibility, reliability and validity of the SC test made available on the Web to French urologists. METHODS: A 97 items SC test was developed based on major educational objectives of French urology training programmes. A secure Web site was created with two sequential modules: a) The first one for the reference panel to elaborate the scoring system; b) The second for candidates with different levels of experience in urology: Board certified urologists, chief-residents, residents, medical students. All participants were recruited on a voluntary basis. Statistical analysis included descriptive statistics of the participants' scores and factorial analysis of variance (ANOVA) to study differences between groups' means. Reliability was evaluated with Cronbach's alpha coefficient. RESULTS: The on line SC test has been operational since June 2004. Twenty-six faculty members constituted the reference panel. During the following 10 months, 207 participants took the test online (124 urologists, 29 chief-residents, 38 residents, 16 students). No technical problem was encountered. Forty-five percent of the participants completed the test partially only. Differences between the means scores for the 4 groups were statistically significant (P = 0.0123). The Bonferroni post-hoc correction indicated that significant differences were present between students and chief-residents, between students and urologists. There were no differences between chief-residents and urologists. Reliability coefficient was 0.734 for the total group of participants. CONCLUSION: Feasibility of Web-based SC test was proved successful by the large number of participants who participated in a few months. This Web site has permitted to quickly confirm reliability of the SC test and develop strategy to improve construct validity of the test when applied in the field of urology. Nevertheless, optimisation of the SC test content, with a smaller number of items will be necessary. Virtual medical education initiative such as this SC test delivered on the Internet warrants consideration in the current context of national pre-residency certification examination in France.

Academic Medical Centers↗

PubMed2003

HLA-DR typing by polymerase chain reaction amplification with sequence-specific primers in paternity disputes.

BACKGROUND: HLA-DR typing was generally performed by serology before. HLA-DRB1 typing can be achieved by polymerase chain reaction amplification with sequence specific primers (PCR-SSP). METHODS: In this study, primers for "low-resolution" HLA-DR typing by PCR-SSP were synthesized upon our request by a company in Taiwan. Twenty-eight DNA samples from international standardized DNA Reference Panel and 20 DNA samples with known serological typing were used as control. We conducted HLA-DR PCR-SSP typing on 18 samples from 6 true paternity trios, 16 samples from 8 true duos, 27 from 9 false trios, and 8 from 4 false duos. These DNAs from disputed paternity families had been previously tested for the parentage using polymerase chain reaction (PCR)-amplified short tandem repeat (STR) analysis. RESULTS: No false positive nor false negative results were obtained in typing 28 positive control DNA samples from international standardized DNA Reference Panel for HLA Class II. Among the 20 DNA samples typed by microlymphocytotoxicity technique, the discordant typing results between HLA-DR PCR-SSP typing and serological typing were found in 3 (15%). In the family of true paternity, HLA-DR typing could not exclude any of alleged fathers and the pattern of inheritance was consistent with autosomal codominant. By HLA-DR typing alone, paternity in 2 alleged fathers out of 9 false trios and 2 alleged fathers out of 4 false duos could not be excluded. CONCLUSIONS: Precise HLA-DR typing can be achieved by PCR-SSP analysis. Economic considerations preclude HLA-DR typing in routine parentage tests where STR typing is performed first.

Alleles↗

PubMed2005

Online clinical reasoning assessment with the Script Concordance test: a feasibility study.

BACKGROUND: The script concordance (SC) test is an assessment tool that measures capacity to solve ill-defined problems, that is, reasoning in context of uncertainty. This tool has been used up to now mainly in medicine. The purpose of this pilot study is to assess the feasibility of the test delivered on the Web to French urologists. METHODS: The principle of SC test construction and the development of the Web site are described. A secure Web site was created with two sequential modules: (a) The first one for the reference panel (n = 26) with two sub-tasks: to validate the content of the test and to elaborate the scoring system; (b) The second for candidates with different levels of experience in Urology: Board certified urologists, residents, medical students (5 or 6th year). Minimum expected number of participants is 150 for urologists, 100 for residents and 50 for medical students. Each candidate is provided with an individual access code to this Web site. He/she may complete the Script Concordance test several times during his/her curriculum. RESULTS: The Web site has been operational since April 2004. The reference panel validated the test in June of the same year during the annual seminar of the French Society of Urology. The Web site is available for the candidates since September 2004. In six months, 80% of the target figure for the urologists, 68% of the target figure for the residents and 20% of the target figure for the student passed the test online. During these six months, no technical problem was encountered. CONCLUSION: The feasibility of the web-based SC test is successful as two-thirds of the expected number of participants was included within six months. Psychometric properties (validity, reliability) of the test will be evaluated on a large scale (N = 300). If positive, educational impact of this assessment tool will be useful to help urologists during their curriculum for the acquisition of clinical reasoning skills, which is crucial for professional competence.

Clinical Competence↗

PubMed2003

Hepatitis C virus subtyping by a core-envelope 1-based reverse transcriptase PCR assay with sequencing and its use in determining subtype distribution among Danish patients.

A reverse transcriptase PCR (RT-PCR) assay using conserved primers deduced from the core-envelope 1 (C-E1) region of the hepatitis C virus (HCV) genome was developed for subtyping purposes. The sensitivity and specificity of this assay tested against two HCV reference panels containing genotype 1 through 5 subtypes were similar to those of an RT-PCR assay from the 5'-untranslated region (5'-UTR). The sensitivity of the RT-PCR typing assay in the more variable C-E1 region was, however, lower than that of the RT-PCR in the highly conserved 5'-UTR when testing multiple clinical samples. Thus, 71 (88%) of 81 consecutive samples from hospitalized Danish patients positive for HCV antibodies and RNA (5'-UTR) were positive also in the C-E1 RT-PCR assay. Phylogenetic analysis of the E1 sequences obtained by direct sequencing of HCV from two reference panels and 71 Danish patients allowed us to readily distinguish the subtypes. In contrast, phylogenetic analysis of their corresponding 5'-UTR sequences was able to predict only major genotypes. Three different genotypes and four subtypes were identified among Danish samples: 1a (43%), 1b (11%), 2b (6%), and 3a (39%). An isolate from a Somalian refugee was identified as a new HCV type related to Somalian isolates described as subtype 3h. The most common genotype in Denmark is genotype 1 (53%), which is the most difficult to treat. However, Denmark had the highest prevalence in Europe of subtype 3a, which responds more favorably to treatment. The described C-E1 RT-PCR with sequencing is suggested as an easy routine assay for definitive genotyping and subtyping of HCV.

5' Untranslated Regions↗

PubMed2006

Natural variation and genetic covariance in adult hippocampal neurogenesis.

Adult hippocampal neurogenesis is highly variable and heritable among laboratory strains of mice. Adult neurogenesis is also remarkably plastic and can be modulated by environment and activity. Here, we provide a systematic quantitative analysis of adult hippocampal neurogenesis in two large genetic reference panels of recombinant inbred strains (BXD and AXB/BXA, n = 52 strains). We combined data on variation in neurogenesis with a new transcriptome database to extract a set of 190 genes with expression patterns that are also highly variable and that covary with rates of (i) cell proliferation, (ii) cell survival, or the numbers of surviving (iii) new neurons, and (iv) astrocytes. Expression of a subset of these neurogenesis-associated transcripts was controlled in cis across the BXD set. These self-modulating genes are particularly interesting candidates to control neurogenesis. Among these were musashi (Msi1h) and prominin1/CD133 (Prom1), both of which are linked to stem-cell maintenance and division. Twelve neurogenesis-associated transcripts had significant cis-acting quantitative trait loci, and, of these, six had plausible biological association with adult neurogenesis (Prom1, Ssbp2, Kcnq2, Ndufs2, Camk4, and Kcnj9). Only one cis-acting candidate was linked to both neurogenesis and gliogenesis, Rapgef6, a downstream target of ras signaling. The use of genetic reference panels coupled with phenotyping and global transcriptome profiling thus allowed insight into the complexity of the genetic control of adult neurogenesis.

Animals↗