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PubMedDate not supplied

The application of molecular phylogenetics to the analysis of viral genome diversity and evolution.

DNA sequencing and molecular phylogenetics are increasingly being used in virology laboratories to study the transmission of viruses. By reconstructing the evolutionary history of viral genomes the behaviour of viral populations can be modelled, and the future of epidemics may be forecast. The manner in which such viral DNA sequences are analysed is the focus of this review. Many researchers resort to the often-quoted 'black box' approach because phylogenetics theory can be daunting, and phylogenetics software packages can appear to be difficult to use. However, because phylogenetic analyses are often used in important and sensitive arenas, for example to provide evidence indicating transmission between persons, it is vital that appropriate care is taken to estimate reliably true relationships. In this review, we discuss how a molecular phylogenetics study should be approached, give an overview of the methods and programs for analysing DNA sequence data, and point readers to appropriate texts for further details. The aim of this review, therefore, is to provide researchers with an easy to understand guide to molecular phylogenetics, with special reference to viral genomes.

Amino Acid Sequence↗
PubMed2005

Association of a haplotype block spanning SDAD1 gene and CXC chemokine genes with allergic rhinitis.

BACKGROUND: Seasonal allergic rhinitis (SAR) is a common allergic disorder characterized by episodes of sneezing, rhinorrhea, and swelling of the nasal mucosa. Although the pathogenesis of SAR remains unclear, there does appear to be a genetic predisposition to development of SAR. We previously identified regions of chromosomes 1p, 4q, and 9q linked to SAR in 48 families (188 members) identified through children with SAR against orchard grass pollens. OBJECTIVE: The aim of the current study was to identify susceptibility genes for SAR on 4q. METHODS: We screened for markers associated with SAR on 4q with 17 microsatellite markers and then for mutations in 11 genes. We genotyped 44 single nucleotide polymorphisms (SNPs) in 48 SAR families and performed haplotype-based haplotype relative risk statistics implemented in the UNPHASED program. We also examined expression of genes with human multiple tissue and immune system cDNA panels. RESULTS: We found that 1 microsatellite marker, D4S3042, was associated with SAR (P = .034). The haplotype-based haplotype relative risk approach revealed that SNPs in SDA1 domain containing 1; chemokine, CXC motif, ligand (CXCL)-9; CXCL10; and CXCL11 were associated with SAR (P = .001-.04). These SNPs made up a haplotype block, and the most common haplotype of this block was transmitted preferentially to affected offspring (P = .002). CONCLUSION: Our results suggests that genetic variations in a haplotype block spanning the SDA1 domain containing 1 and CXC chemokine genes on 4q21 may contribute to development of SAR in the Japanese population.

Adolescent↗
PubMed2005

Combining inter- and intrapopulation information with the Weitzman approach to diversity conservation.

This article introduces a new perspective on Weitzman's methodology for assessing the distribution of resources in genetic diversity conservation programs. Intrapopulation information is added to the procedure by diffusion process formulas to calculate genetic extinction probabilities, and therefore the marginal diversities and elasticities of diversity. The method was tested with a set of European cattle breeds from Spain and France and provided satisfactory results.

Algorithms↗
PubMed2000

Use of rep-PCR to define genetic relatedness among Bacteroides fragilis strains.

Bacteroides fragilis, a component of the normal flora and an important anaerobic pathogen in non-intestinal endogenous infections, has recently been associated with enteric diseases. In this study, 41 B. fragilis strains were analysed in relation to their genetic diversity. This collection included two reference strains (ATCC 23745 and 25285), 20 isolates from non-intestinal infections, six from intestinal infections, five from intestinal microflora and eight from an aquatic environment. The fingerprints were generated by using two repetitive sequences (REP and ERIC) as primers to PCR (rep-PCR). A dendrogram was obtained with the Taxotron Program. Three clusters (threshold genotypes I, II and III) were observed when the genetic distance was 0.30. These results confirm previous data found regarding the genotypical diversity of B. fragilis.

Bacteroides Infections↗
PubMed1979

Pharmacogenetics of tolbutamide metabolism in humans.

This study was designed to focus on the genetic control of tolbutamide dispositon in humans and to provide insight into the potential for high accrued blood levels in individuals receiving fixed dosage regimens. Tolbutamide was administered intravenously to 42 nondiabetic subjects, eight of their relatives, and to five sets of twins. A ninefold variation in the rate of tolbutamide disappearance from plasms (Kd) was found. This variation was characterized by a trimodal frequency distribution, suggestive of monogenic inheritance and consistent with pedigree analysis, indicating autosomal transmission of rapid and slow inactivation of tolbutamide. A heritability value of 0.995 for Kd indicated little influence of environmental factors on variation of this rate. Interindividual differences in the binding of 35S-tolbutamide to serum proteins were also assessed. No correlation was found between tolbutamide serum protein binding affinity and Kd. Analysis of the metabolites of tolbutamide in urine samples provided evidence for the microsomal oxidation of the drug to hydroxytolbutamide as the primary site of genetic control. In conclusion, this study provides evidence for monogenic control of tolbutamide metabolism in man. The results suggest that fixed dosage regimens of this drug, as were prescribed in the controversial University Group Diabetes Program study, might lead to higher accrued blood levels in slow inactivators.

Adolescent↗
PubMedDate not supplied

The computer-assisted differentiation of hemoglobin variants.

Using a TRS-80 Radio Shack microcomputer system, we have computerized the differentiation of hemoglobin variants according to their mobilities in four methods of zone electrophoresis, each measuring a somewhat different aspect of molecular structure. In the identification routine of the program, the electrophoretic mobilities of an unknown variant are compared mathematically to the mobilities of previously analyzed variants; the computer prints out those known variants whose mobilities are within a specifiable interval on either side of the mobilities of the unknown variant. Properly specifying this interval is essential to the effectiveness of the identification. Another routine in the program classifies the variants according to any of ten molecular variables. Computerizing the identification and the information output provides a way to differentiate many variants, allows convenient handling of a large number of data on them, and facilitates their structural analysis.

Blood Protein Electrophoresis↗
PubMed1983

Tumor-specific tRNA modifications in mouse plasmacytomas and other tumors.

RPC-5 chromatography has been used to analyze the aa-tRNA populations found in normal organs and in various tumors in experimental animals. The most extensively studied animal systems have been mineral-oil-induced mouse plasmacytomas and carcinogen-induced rat hepatomas. Certain aa-tRNA species appear to be tumor-specific, e.g., rat hepatoma phenylalanyl-tRNA1 and plasmacytoma asparaginyl-tRNAs2-4. In addition, one of the tumor-specific peaks of asparaginyl-tRNA can be found in normal livers of animals bearing plasmacytomas at a distant site. Many other significant quantitative and qualitative differences among histologically similar plasmacytomas and between normal tissues and plasmacytomas were observed in the chromatographic patterns of isoaccepting aa-tRNAs for 11 of 20 amino acids. Some of the qualitative differences in chromatographic patterns could be correlated with the tumorous nature of the tissue using computer analysis. The program utilized cluster analysis to compare the RPC-5 patterns of aa-tRNAs from 11 plasmacytomas and two normal tissues for each of the 20 amino acids. The variations in these chromatographic profiles are though to be caused by varying degrees of incomplete synthesis of some of the normally modified nucleosides in tRNAs.

Amino Acid Sequence↗
PubMed2005

[Analysis of genetic diversity of spring durum wheat (Triticum durum Desf.) cultivars released in Russia in 1929-2004].

Based on genealogical analysis, the genetic diversity of 78 spring durum wheat cultivars released in Russia in 1929-2004 have been examined. The temporal trends of change in diversity were studied using series of n x m matrices (where n is the number of the cultivars and m is the number of original ancestors) and calculating coefficients of parentage in sets of cultivars released in particular years. The pool of original ancestors of spring durum wheat cultivars includes 90 landraces and old varieties, more than a half (57%) of which originate from European countries, including Russia and Ukraine (45%). The original ancestors strongly differ in the frequency of presence in the cultivar pedigrees. Landraces Beloturka, Sivouska, Kubanka (T. durum Desf.), Transbaikalian emmer, Yaroslav emmer (T. dicoccum Schuebl.), Poltavka (T. aestivum L.), and the original ancestors of cultivars Kharkov 46, Narodnaya, and Melanopus 1932 enter in the pedigrees of more than half of cultivars created within the framework of various breeding programs. At that, their distribution by cultivars from different breeding centers strongly varies. Analysis of temporal dynamics of genetic diversity, based on genetic profiles and coefficients of parentage, has shown that the genetic diversity of Russian durum wheats increased during the period examined. Nevertheless, genetic erosion of the local material-a loss of approximately 20% of the pool of Russian original ancestors-has been found. The contribution of the original ancestors to the pedigrees of different cultivars, constructed in different breeding centers and recommended for cultivation in different regions, has been estimated. The variation of the released cultivars was highest in the Lower Volga region and lowest in the Ural region. In all, the lower threshold of genetic diversity in all regions does not reach the critical level, corresponding to the similarity of half-sibs. The set of modern cultivars included in the Russian Official List 2004 has a cluster structure.

Gene Frequency↗
PubMed2006

Associations between DNA markers and resistance to diseases in sugarcane and effects of population substructure.

Association between markers and sugarcane diseases were investigated in a collection of 154 sugarcane clones, consisting of important ancestors or parents, and cultivars. 1,068 polymorphic AFLP and 141 SRR markers were scored across all clones. Data on the four most important diseases in the Australian sugarcane industry were obtained; these diseases being pachymetra root rot (Pachymetra chaunorhiza B.J. Croft & M.W. Dick), leaf scald (Xanthomonas albilineans Dowson), Fiji leaf gall (Fiji disease virus), and smut (Ustilago scitaminea H. & P. Sydow). By a simple regression analysis, association between markers and diseases could be readily detected. However, many of these associations were due to the effects of embedded population structure and random effects. After taking population structure into account, we found that 59% of the phenotypic variation in smut resistance ratings could be accounted for by 11 markers, 32% of variation for leaf scald and pachymetra root rot rating by 4 markers, and 26% of Fiji leaf gall by 5 markers. The results suggest that marker-trait associations can be readily detected in populations generated from modern sugarcane breeding programs. This may be due to special features of past sugarcane breeding programs leading to persistent linkage disequilibrium in modern parental populations.

Genetic Linkage↗
PubMed2003

Is there a role for genetic testing in patients with melanoma?

Autosomal dominant inheritance of mutations in the locus or the gene may confer a high risk of cutaneous melanoma development. The penetrance of mutations is influenced by UV exposure. Inherited variants in the melanocortin-1 receptor also confer increased risk of cutaneous melanoma. Features associated with increased genetic susceptibility to cutaneous melanoma include the presence of multiple affected first-degree relatives on one side of the family, multiple primary melanomas in the same individual, earlier age of onset, and the presence of multiple atypical nevi, but none of these factors reliably predicts for the presence of mutations. It is currently premature to offer predictive DNA testing for melanoma outside of defined research protocols. This is because of (1). the low likelihood of finding mutations in known melanoma susceptibility genes, even in more than 60% of melanoma-prone kindreds; (2). the broad confidence limits on current estimates of lifetime penetrance of mutations and the wide variation in this penetrance with locality; (3). a high "background" incidence of melanoma in non-mutation carriers in melanoma-prone families; (4). current uncertainties about the factors determining the functionality and phenotypic expression of the trait among carriers of these mutations (penetrance), even if found; and (5). the lack of proved efficacy of melanoma prevention and surveillance strategies, even for mutation carriers. Rather than singling out those deemed to be at high risk because of family history, all patients carrying risk factors for cutaneous melanoma should be subject to stringent programs of sun protection and skin surveillance.

ADP-Ribosylation Factors↗
PubMed2005

Mtreemix: a software package for learning and using mixture models of mutagenetic trees.

SUMMARY: Mixture models of mutagenetic trees constitute a class of probabilistic models for describing evolutionary processes that are characterized by the accumulation of permanent genetic changes. They have been applied to model the accumulation of chromosomal gains and losses in tumor development and the development of drug resistance-associated mutations in the HIV genome.Mtreemix is a software package for estimating mutagenetic trees mixture models from observed cross-sectional data and for using these models for predictions. We provide programs for model fitting, model selection, simulation, likelihood computation and waiting time estimation. AVAILABILITY: Mtreemix, including source code, documentation, sample data files and precompiled Solaris and Linux binaries, is freely available for non-commercial users at http://mtreemix.bioinf.mpi-sb.mpg.de/

Algorithms↗
PubMed1995

Identification of hepatitis C virus genotypes among hospitalized patients in British Columbia, Canada.

The distribution pattern of hepatitis C virus (HCV) genotypes among patients from British Columbia has been investigated by reverse transcription polymerase chain reaction (PCR) amplification of the 5' noncoding region (NCR) and direct DNA sequencing of the PCR product. The sequence data obtained from the British Columbia isolates were compared with HCV sequences for the NCR obtained from GenBank for the construction of a phylogenetic tree using the GDE program, version 2.2. The data show that in British Columbia there are 7 subtypes distributed among major genotypes 1, 2, and 3. The study also shows a new subtype of genotype 1 that represents 29% of the analyzed cases.

Base Sequence↗
PubMed2005

Estimating pollen flow using SSR markers and paternity exclusion: accounting for mistyping.

Highly informative genetic markers, such as simple sequence repeats (SSRs), can be used to directly measure pollen flow by parentage analysis. However, mistyping (i.e. false inference of genotypes caused by the occurrence of null alleles, mutations, and detection errors) can lead to substantial biases in the estimates obtained. Using computer simulations, we evaluated a direct method for estimating pollen immigration using SSR markers and a paternity exclusion approach. This method accounts for mistyping and does not rely on assumptions about the distribution of male reproductive success. If ignored, even minor rates of mistyping (1.5%) resulted in overestimating pollen immigration by up to 150%. When we required at least two mismatching loci before excluding candidate fathers from paternity, the resulting pollen immigration estimates had small biases for rates of mistyping up to 4.5%. Requiring at least three mismatches for exclusion was needed to minimize the upward biases of pollen immigration caused by rates of mistyping up to 10.5%. The minimum number of highly variable SSR loci needed to minimize cryptic gene flow and obtain reliable estimates of pollen immigration varied from five to seven for a sampling scheme applicable to most conifers (i.e. when paternal haplotypes can be unambiguously determined). Between five and nine highly variable SSR loci were needed for a more general sampling scheme that is applicable to all diploid seed plants. With moderately variable SSR markers, consistently accurate estimates of pollen immigration could be obtained only for rates of mistyping up to 4.5%. We developed the POLLEN FLOW (PFL) computer program which can be used to obtain unbiased and precise estimates of pollen immigration under a wide range of conditions, including population sizes as large as 600 parents and mistyping rates as high as 10.5%.

Alleles↗
PubMed2005

Association of defensin beta-1 gene polymorphisms with asthma.

BACKGROUND: Defensins are antimicrobial peptides that may take part in airway inflammation and hyperresponsiveness. OBJECTIVE: We characterized the genetic diversity in the defensin beta-1 (DEFB1) locus and tested for an association between common genetic variants and asthma diagnosis. METHODS: To identify single nucleotide polymorphisms (SNPs), we resequenced this gene in 23 self-defined European Americans and 24 African Americans. To test whether DEFB1 genetic variants are associated with asthma, we genotyped 4 haplotype-tag SNPs in 517 asthmatic and 519 control samples from the Nurses' Health Study (NHS) and performed a case-control association analysis. To replicate these findings, we evaluated the DEFB1 polymorphisms in a second cohort from the Childhood Asthma Management Program. RESULTS: Within the NHS, single SNP testing suggested an association between asthma diagnosis and a 5' genomic SNP (g.-1816 T>C; P = .025) and intronic SNP (IVS+692 G>A; P = .054). A significant association between haplotype (Adenine, Cytosine, Thymine, Adenine [ACTA]) and asthma ( P = .024) was also identified. Associations between asthma diagnosis and both DEFB1 polymorphisms were observed in Childhood Asthma Management Program, a second cohort: g.-1816 T>C and IVS+692 G>A demonstrated significant transmission distortion ( P = .05 and .007, respectively). Transmission distortion was not observed in male subjects. The rare alleles (-1816C and +692A) were undertransmitted to offspring with asthma, suggesting a protective effect, contrary to the findings in the NHS cohort. Similar effects were evident at the haplotype level: ACTA was undertransmitted ( P = .04) and was more prominent in female subjects ( P = .007). CONCLUSION: Variation in DEFB1 contributes to asthma diagnosis, with apparent gender-specific effects.

Asthma↗
PubMed1990

Variations of cervical vertebrae after expression of a Hox-1.1 transgene in mice.

To understand the function of murine homeobox genes, a genetic analysis is mandatory. We generated gain-of-function mutants by introducing genomic sequences of the Hox-1.1 gene under the control of a chicken beta-actin promoter into mice. Our previous data had shown that these transgenic mice are nonviable after birth and are born with craniofacial abnormalities. In a subsequent detailed analysis of severely affected animals, malformations of the basioccipital bone, the atlas, and the axis were observed. Manifestation of an additional vertebra, a proatlas, occurred at the craniocervical transition. The dominant interference of the Hox-1.1 transgene with developmental programs seems to occur around day 9 of gestation, the time of neural crest migration and somite differentiation. We discuss the resulting phenotype with respect to a developmental control function of Hox-1.1.

Animals↗
PubMed2006

Inbreeding and endangered species management: is New Zealand out of step with the rest of the world?

There is growing evidence that inbreeding can negatively affect small, isolated populations. This contrasts with the perception in New Zealand, where it has been claimed that native birds are less affected by inbreeding depression than threatened species from continental regions. It has been argued that New Zealand's terrestrial birds have had a long history of small population size with frequent inbreeding and that this has 'purged" deleterious alleles. The rapid recovery of many tiny and inbred populations after introduced predators have been controlled, and without input from more genetically diverse populations, has further supported the view that inbreeding is not a problem. This has led to a general neglect of inbreeding as a factor in recovery programs for highly endangered species such as the Black Robin (Petroica traversi) and Kakapo (Strigops habroptilis). We examined the reasons for this situation and review the New Zealand evidence for genetic purging. Complete purging of the genetic load and elimination of inbreeding depression are unlikely to occur in natural populations, although partial purging may be more likely where small populations have become inbred over an extended period of time, such as on small isolated islands. Recent molecular data are consistent with the view that island endemics, including New Zealand's threatened birds, have low genetic variation and hence have possibly gone through longer periods of inbreeding than threatened species from continental regions. Nevertheless, results from recent field studies in New Zealand indicate that, despite the opportunity for purging, inbreeding depression is evident in many threatened species. Although inbreeding depression has not prevented some populations from recovering from severe bottlenecks, the long-term consequences of inbreeding and small population size--the loss of genetic variation--are potentially much more insidious. The degrees to which genetic factors reduce population viability generally remain unquantified in New Zealand. Although minimizing ecological risks (e.g., preventing reinvasion of islands by mammalian predators) will continue to receive high priority in New Zealand because of their much larger impacts, we advocate that genetic considerations be better integrated into recovery plans.

Animals↗
PubMed2006

Building a European biomedical grid on cancer: the ACGT Integrated Project.

This paper presents the needs and requirements that led to the formation of the ACGT (Advancing Clinico Genomic Trials) integrated project, its vision and methodological approaches of the project. The ultimate objective of the ACGT project is the development of a European biomedical grid for cancer research, based on the principles of open access and open source, enhanced by a set of interoperable tools and services which will facilitate the seamless and secure access to and analysis of multi-level clinico-genomic data, enriched with high-performing knowledge discovery operations and services. By doing so, it is expected that the influence of genetic variation in oncogenesis will be revealed, the molecular classification of cancer and the development of individualised therapies will be promoted, and finally the in-silico tumour growth and therapy response will be realistically and reliably modelled. Its main design decisions and results at its current stage of development are presented.

Biomedical Research↗
PubMed2005

Genetic diversity among alfalfa (Medicago sativa) cultivars coming from a breeding program, using SSR markers.

Alfalfa (Medicago sativa) is an autotetraploid, allogamous and heterozygous species whose cultivars are synthetic populations. The breeders apply selection pressure for some agronomic traits within a breeding pool to increase the frequency of favorable individuals. The objective of this study was to investigate the differentiation level among seven cultivars originating from one breeding program, and between these cultivars and the breeding pool, with eight SSR markers. These highly polymorphic and codominant markers, together with recent population genetic statistics extended to autotetraploids, offer tools to analyse genetic diversity in alfalfa. The number of alleles per locus varied between 3 and 24. All loci were at a panmictic equilibrium in the cultivars, except one, probably because of null alleles. With seven SSR loci, each cultivar was at panmictic equilibrium. The mean gene diversity was high, ranging from 0.665 to 0.717 in the cultivars. The parameter F(ST) indicated a low but significant diversity among cultivars. Among 21 pairs of cultivars, 15 were significantly different. The breeding pool also had a high diversity, and was significantly different from each cultivar except the most recent one. Considering the characteristics of the breeding program and the mode of cultivar elaboration, we found that they were unable to generate a large variety differentiation. Estimation of population genetics parameters at SSR loci can be applied for assessing the differences between cultivars or populations, either for variety distinction or the management of genetic resources.

Breeding↗