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PubMed2006

Factor correction as a tool to eliminate between-session variation in replicate experiments: application to molecular biology and retrovirology.

BACKGROUND: In experimental biology, including retrovirology and molecular biology, replicate measurement sessions very often show similar proportional differences between experimental conditions, but different absolute values, even though the measurements were presumably carried out under identical circumstances. Although statistical programs enable the analysis of condition effects despite this replication error, this approach is hardly ever used for this purpose. On the contrary, most researchers deal with such between-session variation by normalisation or standardisation of the data. In normalisation all values in a session are divided by the observed value of the 'control' condition, whereas in standardisation, the sessions' means and standard deviations are used to correct the data. Normalisation, however, adds variation because the control value is not without error, while standardisation is biased if the data set is incomplete. RESULTS: In most cases, between-session variation is multiplicative and can, therefore, be removed by division of the data in each session with a session-specific correction factor. Assuming one level of multiplicative between-session error, unbiased session factors can be calculated from all available data through the generation of a between-session ratio matrix. Alternatively, these factors can be estimated with a maximum likelihood approach. The effectiveness of this correction method, dubbed "factor correction", is demonstrated with examples from the field of molecular biology and retrovirology. Especially when not all conditions are included in every measurement session, factor correction results in smaller residual error than normalisation and standardisation and therefore allows the detection of smaller treatment differences. Factor correction was implemented into an easy-to-use computer program that is available on request at: biolab-services@amc.uva.nl?subject=factor. CONCLUSION: Factor correction is an effective and efficient way to deal with between-session variation in multi-session experiments.

Female↗
PubMed1990

Quality control in the flow cytometric measurement of T-lymphocyte subsets: the multicenter AIDS cohort study experience. The Multicenter AIDS Cohort Study Group.

Since 1984, the Multicenter AIDS Cohort Study (MACS) has utilized four flow cytometry laboratories to measure T-lymphocyte subset levels semiannually in a large cohort of homosexual men. This report summarizes the steps taken in the MACS laboratories to attain comparability of lymphocyte subset determinations across the centers and over time. Identical flow cytometers, monoclonal antibodies, and analytic procedures have been used, and over a period of time, the procedure for sample preparation was also standardized. Interlaboratory proficiency testing utilizing identical specimens analyzed in the four laboratories was performed to evaluate the comparability of the data among the laboratories. Our results verify that such testing can identify technical bias in flow cytometric evaluations performed at different laboratories. Temporal laboratory consistency in flow cytometric measurements was evaluated using data from each site's HIV-seronegative homosexual reference group. Both sequential 95% confidence intervals (mean +/- 2 x SEM) and the within-person standard deviations of the immune measurements were considered. Significant variation in CD3, CD4, and CD8 lymphocyte subset percentages over time in the seronegative reference population was observed. Our observations indicate that the lymphocyte subset values of this seronegative group should be used to adjust those obtained on the seropositive study participants during a particular time period, thereby allowing improved discrimination of the effects of HIV on T cells in infected individuals. The data presented are of use for designing epidemiologic and intervention studies in HIV-1-infected individuals, especially for calculating sample sizes. The methods we have used to assess the quality of data in the MACS have general application to quality control programs in flow cytometry laboratories. In particular, comparison of sequential confidence intervals and within-person standard deviations for lymphocyte subset determinations on control populations are essential to a comprehensive proficiency testing program because they permit assessment of consistency within a laboratory over time.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Did natural selection or genetic drift produce the cranial diversification of neotropical monkeys?

A central controversy among biologists is the relative importance of natural selection and genetic drift as creative forces shaping biological diversification (Fisher 1930; Wright 1931). Historically, this controversy has been an effective engine powering several evolutionary research programs during the last century (Provine 1989). While all biologists agree that both processes operate in nature to produce evolutionary change, there is a diversity of opinion about which process dominates at any particular organizational level (from DNA and proteins to complex morphologies). To address this last level, we did a broadscale analysis of cranial diversification among all living New World monkeys. Quantitative genetic models yield specific predictions about the relationship between variation patterns within and between populations that may be used to test the hypothesis that genetic drift is a sufficient explanation for morphological diversification. Diversity at several levels in a hierarchy of taxonomic/phylogenetics relationship was examined from species within genera to families within superfamilies. The major conclusion is that genetic drift can be ruled out as the primary source of evolutionary diversification in cranial morphology among taxa at the level of the genus and above as well as for diversification of most genera. However, drift may account for diversification among species within some Neotropical primate genera, implying that morphological diversification associated with speciation need not be adaptive in some radiations.

Adaptation, Physiological↗
PubMed1999

Density and molecular epidemiology of Aspergillus in air and relationship to outbreaks of Aspergillus infection.

After five patients were diagnosed with nosocomial invasive aspergillosis caused by Aspergillus fumigatus and A. flavus, a 14-month surveillance program for pathogenic and nonpathogenic fungal conidia in the air within and outside the University Hospital in Rotterdam (The Netherlands) was begun. A. fumigatus isolates obtained from the Department of Hematology were studied for genetic relatedness by randomly amplified polymorphic DNA (RAPD) analysis. This was repeated with A. fumigatus isolates contaminating culture media in the microbiology laboratory. The density of the conidia of nonpathogenic fungi in the outside air showed a seasonal variation: higher densities were measured during the summer, while lower densities were determined during the fall and winter. Hardly any variation was found in the numbers of Aspergillus conidia. We found decreasing numbers of conidia when comparing air from outside the hospital to that inside the hospital and when comparing open areas within the hospital to the closed department of hematology. The increase in the number of patients with invasive aspergillosis could not be explained by an increase in the number of Aspergillus conidia in the outside air. The short-term presence of A. flavus can only be explained by the presence of a point source, which was probably patient related. Genotyping A. fumigatus isolates from the department of hematology showed that clonally related isolates were persistently present for more than 1 year. Clinical isolates of A. fumigatus obtained during the outbreak period were different from these persistent clones. A. fumigatus isolates contaminating culture media were all genotypically identical, indicating a causative point source. Knowledge of the epidemiology of Aspergillus species is necessary for the development of strategies to prevent invasive aspergillosis. RAPD fingerprinting of Aspergillus isolates can help to determine the cause of an outbreak of invasive aspergillosis.

Air Microbiology↗
PubMed2006

Characteristics of hepatitis B virus in Ghana: full length genome sequences indicate the endemicity of genotype E in West Africa.

Hepatitis B virus (HBV) genotypes from A to H have distinct geographical distributions and have been shown to affect the clinical features as well as the course of the HBV infection. HBV genotype E has been found only in Africa. However, the complete genomes of this genotype, which were isolated mainly from West Africa, were available only for a few samples. In this study, five full-length genomes and seven other small S genes of HBV strains from Ghanaian blood donors were sequenced and investigated. Following phylogenetic analysis, all of the Ghanaian HBV strains were clustered closely in genotype E. All of the 12 small S genes showed the same characteristic of subtype ayw4. The complete genomes of the five Ghanaian strains showed marked similarity with each other and with the reported genotype E strains (96.7%-99.1%). Genotype E strains showed low intra-genotypic diversity (1.8%) and carried the conserved signature pattern in pre-S1 as well as in the full genome sequence. Of note, the finding of the G145R escape mutant in an unvaccinated Ghanaian blood donor might raise concern as to the ongoing nation-wide hepatitis B vaccination program in Ghana.

Amino Acid Sequence↗
PubMed1998

Subtle involuntary movements are not reliable indicators of incipient Huntington's disease.

In the past, Huntington's disease was diagnosed when movement disturbances were present in concordance with a positive family history. Early motor signs, however, are often not found in a standard neurologic examination, and their expression is variable. Not until later stages of the disease could one be sure about the diagnosis. Since genetic diagnosis became available, the onset of symptoms and signs could be studied in the earliest phase. The aim of the study was to evaluate observer agreement of the assessment of early motor signs in Huntington's disease. A total of 17 gene carriers, 22 noncarriers, and eight partners were recorded on video performing several facial movements after instruction and engaging in a 5-minute conversation. Three experienced neurologists, unaware of the genetic status of the participants, judged and classified the video recordings independently. The cases with disagreement were judged a second time after the neurologists discussed these cases. The observer agreement after the first judgment is poor (kappas 0.09, 0.24, 0.45) and after the second judgment satisfactory (kappas 0.79, 0.90, 0.78). Consequences for clinical practice and research programs into early symptoms and signs are discussed.

Adult↗
PubMed1995

Involvement of p53 expression in cAMP-mediated apoptosis in immortalized granulosa cells.

In the accompanying paper we described the induction of apoptosis by extended cyclic AMP (cAMP)-mediated signals in primary granulosa cells and the reduction in this process in transformed cells expressing SV40 T antigen. In the present work, we examined the effect of overexpression of either wild-type or mutant p53 on cAMP-mediated apoptosis in steroidogenic granulosa cell lines transfected with SV40 DNA together with the Ha-ras oncogene and a temperature-sensitive variant of p53, p53val135. In cell lines expressing low amounts of T antigen and high amounts of p53val135, growth arrest was induced by transferring the cells from 37.5 degrees to 32 degrees C, a temperature which allows the manifestation of the wild-type phenotype of p53 and the induction of the WAF1 gene. While nonstimulated cells showed only a very modest apoptotic process, rapid and massive apoptosis was evident in cells stimulated by forskolin at 32 degrees C. The presence of serum could delay, but not abolish, this phenomenon. Progesterone production in such cells treated with cAMP was significantly higher at 32 degrees C than at 37.5 degrees C, suggesting that wild-type p53 can also enhance granulosa cell differentiation. Furthermore, at least at early stages, apoptosis is correlated with increased cell differentiation. On the other hand, in lines expressing high amounts of T antigen and low amounts of p53, neither an increase in cAMP-induced differentiation nor massive apoptosis was seen at 32 degrees C. These findings demonstrate that wild-type p53 can cooperate with cAMP-generated signals in the induction of steroidogenesis and of programmed cell death in granulosa cells.

Animals↗
PubMed2006

Measuring covariation in RNA alignments: physical realism improves information measures.

MOTIVATION: The importance of non-coding RNAs is becoming increasingly evident, and often the function of these molecules depends on the structure. It is common to use alignments of related RNA sequences to deduce the consensus secondary structure by detecting patterns of co-evolution. A central part of such an analysis is to measure covariation between two positions in an alignment. Here, we rank various measures ranging from simple mutual information to more advanced covariation measures. RESULTS: Mutual information is still used for secondary structure prediction, but the results of this study indicate which measures are useful. Incorporating more structural information by considering e.g. indels and stacking improves accuracy, suggesting that physically realistic measures yield improved predictions. This can be used to improve both current and future programs for secondary structure prediction. The best measure tested is the RNAalifold covariation measure modified to include stacking. AVAILABILITY: Scripts, data and supplementary material can be found at http://www.binf.ku.dk/Stinus_covariation

Algorithms↗
PubMed2005

Detection of a novel familial catalase mutation (Hungarian type D) and the possible risk of inherited catalase deficiency for diabetes mellitus.

The enzyme catalase is the main regulator of hydrogen peroxide metabolism. Recent findings suggest that a low concentration of hydrogen peroxide may act as a messenger in some signalling pathways whereas high concentrations are toxic for many cells and cell components. Acatalasemia is a genetically heterogeneous condition with a worldwide distribution. Yet only two Japanese and three Hungarian syndrome-causing mutations have been reported. A large-scale (23 130 subjects) catalase screening program in Hungary yielded 12 hypocatalasemic families. The V family with four hypocatalasemics (60.6 +/- 7.6 MU/L) and six normocatalasemic (103.6 +/- 23.5 MU/L) members was examined to define the mutation causing the syndrome. Mutation screening yielded four novel polymorphisms. Of these, three intron sequence variations, namely G-->A at the nucleotide 60 position in intron 1, T-->A at position 11 in intron 2, and G-->T at position 31 in intron 12, are unlikely to be responsible for the decreased blood catalase activity. However, the novel G-->A mutation in exon 9 changes the essential amino acid Arg 354 to Cys 354 and may indeed be responsible for the decreased catalase activity. This inherited catalase deficiency, by inducing an increased hydrogen peroxide steady-state concentration in vivo, may be involved in the early manifestation of type 2 diabetes mellitus for the 35-year old proband.

Acatalasia↗
PubMed2026

Genetic structure and selection signatures of Beijing-You chicken populations provide insight into breed conservation.

Preserving genetic diversity and maintaining population viability are critical yet challenging goals that demand rigorous evaluation of conservation strategies. Beijing-You chicken, as the sole indigenous chicken breed originating from Beijing, China, is currently maintained as four independent populations under distinct conservation programs. How different conservation regimes have shaped its genomic architecture remains largely unknown, limiting evidence-based evaluation. Here, we generated whole-genome resequencing data from 240 individuals representing four Beijing-You chicken populations to assess population structure, genetic diversity, and signatures of selection over decades of conservation. All four populations formed distinct clusters, reflecting measurable differentiation after decades of separate conservation. The differences in genetic diversity were broadly consistent with the variation in effective population size estimates. Runs of homozygosity and linkage disequilibrium decay patterns further characterized each population, with extended values indicating reduced effective population size and increased inbreeding under long-term conservation. We applied the fixation index (FST) and pairwise diversity ratio (θπ) methods to identify selection signatures. A total of 171 genes were identified as candidates. These genes were enriched in pathways related to reproduction, growth regulation, and environmental adaptation. These findings highlight patterns of reduced diversity and skewed relatedness, which could arise from management-related factors such as breeding preferences or mating strategies. Still, they are also compatible with neutral processes, including drift and founder effects. Regardless of the underlying cause, integrating scientifically informed conservation strategies with routine genomic monitoring across generations is essential for sustaining genetic diversity in Beijing-You chicken and other indigenous breeds.

Beijing-You chicken↗
PubMed2000

A novel HLA-B*40 allele and novel exon 1 sequences of two B*40 alleles identified in potential marrow donors.

Sequence-specific oligonucleotide probe hybridization and sequence-specific primer polymerase chain reaction (PCR) typing suggested the presence of variants of HLA-B*40 in three individuals. Two were part of 3,500 potential marrow donors being screened for the National Marrow Donor Program, while the third was a clinical specimen. PCR products encompassing HLA-B locus exons 1 through 3 were prepared and subcloned. In one individual, a native of the Pacific Islands, sequencing revealed a novel HLA-B*40 allele (B*4023). In two other individuals, a previously unknown exon 1 sequence was determined for HLA-B*4016 (ethnicity unknown) and B*4020 (Hispanic). These findings further illustrate the substantial genetic variation present at the HLA-B locus within human populations.

Alleles↗
PubMed1997

Nested DNA inversion as a paradigm of programmed gene rearrangement.

Programmed gene rearrangements are employed by a variety of microorganisms, including viruses, prokaryotes, and simple eukaryotes, to control gene expression. In most instances in which organisms mediate host evasion by large families of homologous gene cassettes, the mechanism of variation is not thought to involve DNA inversion. Here we report that Campylobacter fetus, a pathogenic Gram-negative bacterium, reassorts a single promoter, controlling surface-layer protein expression, and one or more complete ORFs strictly by DNA inversion. Rearrangements were independent of the distance between sites of inversion. These rearrangements permit variation in protein expression from the large surface-layer protein gene family and suggest an expanding paradigm of programmed DNA rearrangements among microorganisms.

Bacterial Outer Membrane Proteins↗
PubMed1996

Genetic Modulation of Plasma Fibrinogen Concentrations: Possible Importance of Interleukin-6.

Current knowledge indicates that high plasma levels of fibrinogen, a key protein in the hemostatic system, help predict the major ischemic complications of atherosclerosis, that is, stroke and myocardial infarction. Molecular variations at the fibrinogen genes loci have been shown to regulate fibrinogen concentrations in plasma. However, it is also known that fibrinogen is an acute phase reactant and that its plasma levels are increased by the inflammatory mediator interleukin-6 (IL-6) as a consequence of stimulated gene expression. Certain risk factors for atherosclerosis are known to cause inflammatory and proliferative events within the vessel wall, especially when combined. This raises the question of whether and to what extent high plasma fibrinogen levels in patients with major thrombotic complications of atherosclerosis could be the epiphenomena of as yet poorly elucidated issues in vascular medicine (i.e., severity of vascular damage). Screening of the fibrinogen genes loci in both young patients with established risk factors and in patients evaluated for regression of atherosclerosis who have participated in risk factor reduction programs may provide further insight into the role of genetic factors in the development of atherosclerosis and in the regulation of plasma fibrinogen levels.

Journal Article↗
PubMedDate not supplied

Prospects and perspectives in mutation breeding.

Induction of mutations, primarily a method of generating variation, can contribute to plant improvement when combined with selection, or recombination and selection, or with other methods of manipulating genetic variation. As a source of variability, induced mutations supplement naturally occurring variation. When specific mutants are selected following mutagenic treatments it is highly likely that a number of mutational changes will have occurred in the selected genotype. Hence, although most of the mutant varieties released so far have resulted from mutation and direct selection, the future trend will be for increasing use of mutants in association with recombination. Whereas induced mutations are generally regarded as random events, there are suggestions of some mutational specificity in response to different mutagenic agents and treatments. The best immediate prospects for increasing specificity lie in the manipulation of the selection environment. Biochemical selection applied to large number of plant cells in culture to locate mutations in specific biosynthetic pathways and the subsequent regeneration of whole plants offers great prospect for reducing the cost of breeding programs and altering the amount or composition of a desired end or intermediate product. Mutations in conbination with other techniques of genetic engineering will constitute the tools of the plant breeders of the future. Their present role in plant breeding has been established. They have advantages in certain situations, disadvantages in others. Greater understanding will lead to their more widespread use.

Cells, Cultured↗
PubMed2004

Determination of genetic status in a closed colony of rhesus monkeys (Macaca mulatta).

The long-term management of breeding colonies requires some measure of genetic diversity in the animal population. For the maintenance of breeding colonies of monkeys used for biomedical research, known pedigrees supply precise data to determine the genetic status of colonies. We present data of genetic analyses in an old closed colony of rhesus macaques (Macaca mulatta) that was established in 1932 with 100 animals. For more than 40 years, the animals were kept on an isolated island and, in 1980, single-male breeding groups were established. A total of 333 DNA samples of these animals were typed to 20 microsatellite markers using multiplex PCR in order to verify inbreeding coefficient (alpha) and level of heterozygosity. We found an average heterozygosity of 64% and obtained alpha=-0.03293 (+/-0.00573). Our results indicate that the reproductive strategy used was effective because consanguineous breeding was avoided. A continuous genetic program must be carried out in order to obtain better quality primates for biomedical research.

Animals↗
PubMed1976

Difficulties and pitfalls in the interpretation of screening tests for the detection of inborn errors of metabolism.

A review of factors which may be responsible for false positive and false negative results in a screening program for the detection of inborn errors of metabolism is presented. Administration of medication, dietary therapy, chemical treatment of specimens, delay in analysis, hypersensitivity of procedures utilized, interfering metabolites and inadequate metabolic development or enzymatic maturation in the patient may all produce results resembling an actual inborn error of metabolism. Inadequate nutritional intake prior to procurement of specimen and loss of material during analytical procedures may produce false negative results. As well, certain less severe variants of inborn errors may present in an unusual manner or may only present during periods of stress to the patient. These factors are discussed in relation to the performance of a metabolic screening program. It is suggested that these progrms should be performed by specialized, central laboratories experienced in the complexities of detection of inborn errors of metabolism.

Anticonvulsants↗
PubMed1993

A computer program for the design of PCR primers for diagnosis of highly variable genomes.

PCRDiag (Diagnosis by PCR) is a computer program which allows the localization of pairs of oligonucleotides with optimal thermodynamic requirements for use in a PCR assay. The program is designed for the selection of pairs of primers complementary to sequences present in a group, whose identification is intended, but are absent in other non-specific sequences. The program constitutes a powerful tool, specially in systems which display a high degree of sequence heterogeneity, as is the case of RNA viruses. The program runs on IBM-PC and compatible computers and has no special software requirements. It does not need the previous alignment of the sequences analyzed.

Algorithms↗