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PubMed1989

Molecular mechanics studies on poly(purine).poly(pyrimidine) sequences in DNA: polymorphism and local variability.

Energy minimization has been carried out on three poly(purine).poly(pyrimidine) sequences--d(G)10.d(C)10, d(A)10.d(T)10, and d(AG)5.d(CT)5--using the molecular mechanics program AMBER (Assisted Model Building and Energy Refinement). In order to extensively scan the conformational space available, five different helical models were studied, three of them being right-handed helices while the other two were left helical. For all three sequences the right-handed A- and B-type helices are energetically slightly preferred over the left helices, but the energy difference between the various right-handed helices is only marginal. A detailed analysis has been carried out to characterize the local structural variability in the refined structures, both in terms of torsion angles as well as other parameters such as base-pair tilt, wedge roll, and wedge tilt, etc. All three sequences exhibit similar structural features for a particular form, but both the forms A and B show significant deviations from fiber models. In particular, the A-form structures have higher unit rise (2.7 A), and lower unit twist (31 degrees) and base-pair tilt (12 degrees), compared to the fiber model, which has corresponding values of 2.56 A, 32.7 degrees, and 20 degrees, respectively. All these changes indicate that the refined models are closer to the A-form structure observed in crystals of oligonucleotides. In the refined B-for models, the helical parameters are close to the fiber B-form, although the torsion angles show considerable variations. None of the three sequences examined, including the d(A)n.d(T)n sequence, show any pronounced curvature for the B-form structure.

Base Sequence↗
PubMed2002

Re-annotation of genome microbial coding-sequences: finding new genes and inaccurately annotated genes.

BACKGROUND: Analysis of any newly sequenced bacterial genome starts with the identification of protein-coding genes. Despite the accumulation of multiple complete genome sequences, which provide useful comparisons with close relatives among other organisms during the annotation process, accurate gene prediction remains quite difficult. A major reason for this situation is that genes are tightly packed in prokaryotes, resulting in frequent overlap. Thus, detection of translation initiation sites and/or selection of the correct coding regions remain difficult unless appropriate biological knowledge (about the structure of a gene) is imbedded in the approach. RESULTS: We have developed a new program that automatically identifies biologically significant candidate genes in a bacterial genome. Twenty-six complete prokaryotic genomes were analyzed using this tool, and the accuracy of gene finding was assessed by comparison with existing annotations. This analysis revealed that, despite the enormous effort of genome program annotators, a small but not negligible number of genes annotated within the framework of sequencing projects are likely to be partially inaccurate or plainly wrong. Moreover, the analysis of several putative new genes shows that, as expected, many short genes have escaped annotation. In most cases, these new genes revealed frameshifts that could be either artifacts or genuine frameshifts. Some entirely unexpected new genes have also been identified. This allowed us to get a more complete picture of prokaryotic genomes. The results of this procedure are progressively integrated into the SWISS-PROT reference databank. CONCLUSIONS: The results described in the present study show that our procedure is very satisfactory in terms of gene finding accuracy. Except in few cases, discrepancies between our results and annotations provided by individual authors can be accounted for by the nature of each annotation process or by specific characteristics of some genomes. This stresses that close cooperation between scientists, regular update and curation of the findings in databases are clearly required to reduce the level of errors in genome annotation (and hence in reducing the unfortunate spreading of errors through centralized data libraries).

Computational Biology↗
PubMedDate not supplied

Evolution of consanguinity in the Bishopric of Lugo (Spain) from 1900 to 1979.

BACKGROUND: The levels of consanguinity in human populations are known to be influenced by demographic and geographical factors, and by socio-cultural customs that govern spouse choice. Within the general model applicable to the populations of Western Europe, Galicia (north-west Spain) is a region that is especially interesting, due to its geographical and historical peculiarities that could have conditioned its behaviour pattern with respect to consanguinity. PRIMARY OBJECTIVE: The object of this paper is to analyse the evolution of the consanguinity structure levels in the rural population of the Bishopric of Lugo (Galicia) during the period 1900-1979. SUBJECTS AND METHODS: The study covers a total of 752 parishes included in 52 municipalities of the rural area of the Bishopric of Lugo. Of a total of 117,583 marriages in the period studied, 6701 were between biologically related individuals up to the level of second cousins. The percentage of the different types of consanguineous marriages, the consanguinity rates, and the average coefficient of inbreeding of the population was calculated. Also, for the analysis of the temporal variation of consanguinity, version 3.01 of Jandel Scientific's Table Curve program was used. MAIN OUTCOMES AND RESULTS: The consanguinity rate for the whole of the period is 5.70% and the average coefficient of inbreeding is 2.2477 x 10(-3), values which fall within the observed range for Spanish populations. As for the consanguinity structure, the most frequent types of consanguineous marriages are between second cousins (2.65% of all marriages), but the high proportion of marriages between uncles/nieces or aunts/nephews (0.16%) and first cousins (2.12%) with regard to the total number of marriages should be emphasized. The average value of the M22/M33 ratio is 0.80, and throughout the study period it was above the 0.25 expected in conditions of panmixia. Regarding the evolution of the average coefficient of inbreeding, its annual values fit a polynomial regression curve with one ascending and one descending branch and an inflection point in the year 1919. CONCLUSIONS: As in other rural areas of Galicia, the structure of consanguinity in the Bishopric of Lugo is characterized by the high proportion of marriages between uncles/nieces or aunts/nephews and first cousins, a phenomenon which appears to be generalized in the rural populations of northern Spain. It is suggested that the high proportion of uncle/niece marriages that have been found in the population studied are very probably due to the important migratory phenomenon which took place in this region at the end of the 19th century and in the first third of the 20th century.

Consanguinity↗
PubMed2004

A phylogenetic reconstruction of the epidemiological history of canine rabies virus variants in Colombia.

Historically, canine rabies in Colombia has been caused by two geographically distinct canine variants of rabies virus (RV) which between 1992 and 2002 accounted for approximately 95% of Colombian rabies cases. Genetic variant 1 (GV1) has been isolated up until 1997 in the Central Region and the Department of Arauca, and is now considered extinct through a successful vaccination program. Genetic variant 2 (GV2) has been isolated from the northern Caribbean Region and continues to circulate at present. Here we have analyzed two sets of sequence data based upon either a 147 nucleotide region of the glycoprotein (G) gene or a 258 nucleotide region that combines a fragment of the non-coding intergenic region and a fragment of the polymerase gene. Using both maximum likelihood (ML) and Markov chain Monte Carlo (MCMC) methods we have estimated the time of the most recent common ancestor (MRCA) of the two variants to be between 1983 and 1988. Reconstructions of the population history suggest that GV2 has been circulating in Colombia since the 1960s and that GV1 evolved as a separate lineage from GV2. Estimations of the effective population size at present show the GV2 outbreak to be approximately 20 times greater than that of GV1. Demographic reconstructions were unable to detect a decrease in population size concurrent with the elimination of GV1. We find a raised rate of nucleotide substitution for GV1 gene sequences when compared to that of GV2, although all estimates have wide confidence limits. We demonstrate that phylogenetic reconstructions and sequence analysis can be used to support incidence data from the field in the assessment of RV epidemiology.

Amino Acid Sequence↗
PubMed2006

HIV global surveillance: foundation for retroviral discovery and assay development.

The high level of HIV genetic diversity has important implications for screening, diagnostic testing and patient monitoring. Continued diversification and global redistribution of HIV groups, subtypes and recombinants make it imperative that serological and molecular assays be designed and evaluated to ensure reliable performance on all HIV infections. Recognizing the importance of this issue, we initiated a comprehensive program to monitor global diversification of HIV, search for newly emerging variants, assemble large-volume panels of genetically and geographically diverse strains, and develop strategies to determine the impact of HIV diversity on assays used for detecting and monitoring HIV infection. Efforts to identify and characterize rare and emerging HIV strains have lead to the identification of HIV-1 group O, group N, and dual infections of groups M and O. A panel of plasma specimens was established that includes specimens collected from 12 countries in Africa, Asia, Europe, and South America; the panel comprises infections due to HIV-1 group M subtypes A, B, C, D, F, and G, as well as CRF01, CRF02, and unique recombinant forms, group N, and group O. Serological and molecular characterization of this unique panel has provided vital sequence data to support assay development and an invaluable source of well-defined specimens to evaluate and compare assay performance. The ability to address the challenge posed by ongoing evolution of HIV and the emergence of new variants requires continued surveillance of global HIV strain diversity, a sound scientific foundation for assay development, and suitable panels to evaluate and validate assay performance.

Africa↗
PubMed2002

Possible migration routes into South America deduced from mitochondrial DNA studies in Colombian Amerindian populations.

Mitochondrial DNA haplotype studies have been useful in unraveling the origins of Native Americans. Such studies are based on restriction site and intergenic deletion/insertion polymorphisms, which define four main haplotype groups common to Asian and American populations. Several studies have characterized these lineages in North, Central, and South American Amerindian, as well as Na Dene and Aleutian populations. Siberian, Central Asian, and Southeast Asian populations have also been analyzed, in the hope of fully depicting the route(s) of migration between Asia and America. Colombia, a key route of migration between North and South America, has until now not been studied. To resolve the current lack of information about Colombian Amerindian populations, we have investigated the presence of the founder haplogroups in 25 different ethnic groups from all over the country. The present research is part of an interdisciplinary program, Expedición Humana, fostered by the Universidad Javeriana and Dr. J. E. Bernal V. The results show the presence of the four founder A-D Amerindian lineages, with varied distributions in the different populations, as well as the presence of other haplotypes in frequencies ranging from 3% to 26%. These include some unique or private polymorphisms, and also indicate the probable presence of other Asian and a few non-Amerindian lineages. A spatial structure is apparent for haplogroups A and D, and to a lesser extent for haplogroup C. While haplogroup A and D frequencies in Colombian populations from the northwestern side of the Andes resemble those seen in Central American Amerindians more than those seen in South American populations, their frequencies on the southeastern side more closely resemble the bulk of South American frequencies so far reported, raising the question as to whether they reflect more than one migration route into South America. High frequencies of the B lineage are also characteristic of some populations. Our observations may be explained by historical events during the pre-Columbian dispersion of the first settlers and, later, by disruptions caused by the European colonization.

Colombia↗
PubMed1995

Effect of accounting for different phenotypic variances by sire breed and sex on selection of sires based on expected progeny differences for 200- and 365-day weights.

The effects of accounting for different phenotypic variances according to sire breed and sex subclasses on estimation of sire breed effects and prediction of expected progeny differences of sires mated to Hereford and Angus cows were investigated. Data consisted of 6,977 and 6,530 records of 200-d (weaning) and 365-d (yearling) weights, respectively, of F1 calves sired by bulls (662 and 661, respectively) of 23 breeds that have been evaluated in the Germ Plasm Evaluation Program at the U.S. Meat Animal Research Center, Clay Center, NE. Models compared included fixed effects of genetic group of sire (samples of sires evaluated at different times), dam breed, sex, birth year of calf and age of dam, plus sire within genetic group and dam within dam breed as random effects. Variance structures were different: Model I assumed homogeneous variances across sire breed-sex subclasses; Model II accounted for differences in phenotypic variance by sire breed and sex subclasses. Differences between estimates of sire group effects obtained with the two models were not significant for either trait. Product-moment and rank correlations between expected progeny differences obtained with Model I and Model II were greater than .93 when computed within each group and .99 or larger when computed across breeds. There were slight changes in the numbers of sires contributed by different breeds to the proportions selected across breeds under different selection intensities when sires were ranked with the two models. However, differences between means predicted under Model II were small when sires were ranked and selected based on the two models. Changes in standard errors of prediction for expected progeny differences and standard errors for estimates of breed effects obtained when adjusting for differences of phenotypic variances, compared to not adjusting, were proportional to the ratios of the phenotypic standard deviations of the sire breeds to the common phenotypic standard deviation.

Animals↗
PubMed2005

Risks and benefits of phase 1 oncology trials, 1991 through 2002.

BACKGROUND: Previous reviews of phase 1 oncology trials reported a rate of response to treatment of 4 to 6 percent and a toxicity-related death rate of 0.5 percent. These results may not reflect the rates in current phase 1 oncology trials. METHODS: We reviewed all nonpediatric phase 1 oncology trials sponsored by the Cancer Therapy Evaluation Program at the National Cancer Institute between 1991 and 2002. We report the rates of response to treatment, of stable disease, of grade 4 toxic events, and of treatment-related deaths. RESULTS: We analyzed 460 trials involving 11,935 participants, all of whom were assessed for toxicity and 10,402 of whom were assessed for a response to therapy. The overall response rate (i.e., for both complete and partial responses) was 10.6 percent, with considerable variation among trials. "Classic" phase 1 trials of single investigational chemotherapeutic agents represented only 20 percent of the trials and had a response rate of 4.4 percent. Studies that included at least one anticancer agent approved by the Food and Drug Administration constituted 46.3 percent of the trials and had a response rate of 17.8. An additional 34.1 percent of participants had stable disease or a less-than-partial response. The overall rate of death due to toxic events was 0.49 percent. Of 3465 participants for whom data on patient-specific grade 4 toxic events were available, 14.3 percent had had at least one episode of grade 4 toxic events. CONCLUSIONS: Overall response rates among phase 1 oncology trials are higher than previously reported, although they have not changed for classic phase 1 trials, and toxicity-related death rates have remained stable. Rates of response and toxicity vary, however, among the various types of phase 1 oncology trials.

Antineoplastic Agents↗
PubMed2006

AmpliChip CYP450 GeneChip: a new gene chip that allows rapid and accurate CYP2D6 genotyping.

Methods for Cytochrome P450-2D6 (CYP2D6) genotyping are often time-consuming and laborious, which can restrict their use in pretherapeutic screening programs. Gene chip technology could overcome this problem. The aim of this study was to evaluate CYP2D6 genotyping by a new improved gene chip compared to a PCR-RFLP method. AmpliChip CYP450 GeneChip(R) (AmpliChip) is a microarray hybridization method for genotyping CYP2D6 and CYP2C19. One hundred fifty-nine DNA samples were genotyped both by AmpliChip as well as by PCR-RFLP and, where applicable, by a SNaPshot technique which detects single nucleotide polymorphisms based on the single base extension principle. In 152 of the 159 samples, CYP2D6 genotypes determined with the AmpliChip were in accordance with the results of PCR-RFLP. All seven discrepant samples had gene duplications and were subjected to SNaPshot analysis. SNaPshot results concurred with those of the AmpliChip for six out of seven samples. In the one divergent result, DNA sequencing confirmed that the AmpliChip had assigned the correct genotype. In conclusion, AmpliChip is a highly reliable method for CYP2D6 genotyping that allows the correct determination of all relevant CYP2D6 alleles in one single run. It therefore represents a very efficient and fast method, offering new perspectives for the application of pharmacogenetics in clinical medicine.

Cytochrome P-450 CYP2D6↗
PubMed2002

Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program.

BACKGROUND: Increasing numbers of BRCA1 mutation carriers are being identified in cancer risk evaluation programs. However, no estimates of cancer risk specific to a clinic-based population of mutation carriers are available. These data are clinically relevant, because estimates based on families ascertained for linkage studies may overestimate cancer risk in mutation carriers, and population-based series may underestimate it. Wide variation in risk estimates from these disparate ascertainment groups makes counseling in risk evaluation programs difficult. The purpose of this study was to estimate BRCA1-related cancer risks for individuals ascertained in a breast cancer risk evaluation clinic. METHODS: Cumulative observed and age-adjusted cancer risk estimates were determined by analyzing 483 BRCA1 mutation carriers in 147 families identified in two academic breast and ovarian cancer risk evaluation clinics. Cancer risks were computed from the proportion of individuals diagnosed with cancer during a 10-year age interval from among the total number of individuals alive and cancer-free at the beginning of that interval. Age-of-diagnosis comparisons were made using two-sided Student's t tests. RESULTS: By age 70, female breast cancer risk was 72.8% (95% confidence interval [CI] = 67.9% to 77.7%) and ovarian cancer risk was 40.7% (95% CI = 35.7% to 45.6%). The risk for a second primary breast cancer by age 70 was 40.5% (95% CI = 34.1% to 47.0%). We also identified an increased risk of cancer of the colon (twofold), pancreas (threefold), stomach (fourfold), and fallopian tube (120-fold) in BRCA1 mutation carriers as compared with Surveillance, Epidemiology, and End Results (SEER) Program population-based estimates. CONCLUSION: The estimates for breast and ovarian cancer risk in BRCA1 mutation carriers is higher than population-based estimates but lower than estimates based on families ascertained for linkage studies. These cancer risk estimates may most closely approximate those faced by BRCA1 mutation carriers identified in risk evaluation clinics.

Adult↗
PubMed2005

Trichoderma biodiversity in China: evidence for a North to South distribution of species in East Asia.

Towards assessing the biodiversity and biogeography of Trichoderma, we have analyzed the occurrence of Trichoderma species in soil and litter from four areas in China: North (Hebei province), South-East (Zhejiang province), West (Himalayan, Tibet) and South-West (Yunnan province). One hundred and thirty five isolates were grouped according to tentative morphological identification. A representative 64 isolates were verified at the species level by the oligonucleotide barcode program TrichO Key v.1.0 and the custom BLAST server TrichoBLAST, using sequences of the ITS1 and 2 region of the rRNA cluster and from the longest intron of the tef1 (translation elongation factor 1-alpha) gene. Eleven known species (Trichoderma asperellum, T. koningii, T. atroviride, T. viride, T. velutinum, T. cerinum, T. virens, T. harzianum, T. sinensis, T. citrinoviride, T. longibrachiatum) and two putative new species (T. sp. C1, and T. sp. C2), distinguished from known species both by morphological characters and phylogenetic analysis, were identified. A significant difference in the occurrence of these species was found between the North (Hebei) and South-West (Yunnan) areas, which correlates with previously reported species distributions in Siberia and South-East Asia, respectively. As in previous studies, T. harzianum accounted for almost half of the biodiversity; although, in this study, it was exclusively found in the North, and was predominantly represented by an ITS1 and 2 haplotype, which has so far been rarely found elsewhere. This study therefore reveals a North-South gradient in species distribution in East Asia, and identifies Northern China as a potential center of origin of a unique haplotype of T. harzianum.

China↗
PubMed2006

Maternal care associated with methylation of the estrogen receptor-alpha1b promoter and estrogen receptor-alpha expression in the medial preoptic area of female offspring.

Variations in maternal behavior are associated with differences in estrogen receptor (ER)-alpha expression in the medial preoptic area (MPOA) and are transmitted across generations such that, as adults, the female offspring of mothers that exhibit increased pup licking/grooming (LG) over the first week postpartum (i.e. high LG mothers) show increased ERalpha expression in the MPOA and are themselves high LG mothers. In the present studies, cross-fostering confirmed an association between maternal care and ERalpha expression in the MPOA; the biological offspring of low LG mothers fostered at birth to high LG dams show increased ERalpha expression in the MPOA. Cross-fostering the biological offspring of high LG mothers to low LG dams produces the opposite effect. We examined whether the maternal programing of ERalpha expression is associated with differences in methylation of the relevant ERalpha promoter. Levels of cytosine methylation across the ERalpha1b promoter were significantly elevated in the adult offspring of low, compared with high, LG mothers. Differentially methylated regions included a signal transducer and activator of transcription (Stat)5 binding site and the results of chromatin immunoprecipitation assays revealed decreased Stat5b binding to the ERalpha1b promoter in the adult offspring of low, compared with high, LG mothers. Finally, we found increased Stat5b levels in the MPOA of neonates reared by high, compared with low, LG mothers. These findings suggest that maternal care is associated with cytosine methylation of the ERalpha1b promoter, providing a potential mechanism for the programming of individual differences in ERalpha expression and maternal behavior in the female offspring.

Animals↗
PubMed2005

The risk of developing second cancers among survivors of childhood soft tissue sarcoma.

BACKGROUND: Previous studies have shown that children who are treated for soft tissue sarcoma (STS) are at increased risk for developing second cancers. However, the risk for specific cancer sites and variations in risk by treatment and STS histology remain unclear. METHODS: The study evaluated 1499 children (age < 18 years) who survived for > or = 1 year after they were diagnosed with STS and who were reported to the Surveillance, Epidemiology, and End Results (SEER) population-based cancer registries from 1973 to 2000. RESULTS: Twenty-seven children developed 28 subsequent primary malignancies, compared with 4.5 expected malignancies based on general population rates (observed-to-expected [O/E] ratio = 6.3 (95% confidence interval [95% CI], 4.2-9.1). The risk of developing a subsequent malignancy was increased among children with rhabdomyosarcoma (observed = 11 malignancies; O/E ratio = 7.7), fibromatous neoplasms (observed = 9 malignancies; O/E ratio = 5.8), and other specified STS (observed = 7 malignancies; O/E ratio = 6.5). Initial therapy with radiation and chemotherapeutic agents was associated with a significantly higher risk of second malignancies compared with surgery alone (O/E ratio = 15.2 vs. 1.4; P < 0.0001). Elevated risks were observed for acute myeloid leukemia, cutaneous melanoma, female breast cancer, and sarcomas of the bone and soft tissue, with generally higher risks among patients who initially received combined modality therapy. Excess cancers of the oral cavity were prominent among long-term survivors. For several children, the pattern of multiple malignancies was consistent with a genetic syndrome, particularly neurofibromatosis type 1 and Li-Fraumeni syndrome. CONCLUSIONS: The risk of second malignancies was increased for all histologic types of childhood STS and was particularly high among patients who received combined modality therapy.

Adolescent↗
PubMed2003

Complex haplotypes of IRS2 gene are associated with severe obesity and reveal heterogeneity in the effect of Gly1057Asp mutation.

In order to understand the role of the insulin receptor substrate-2 (IRS2) gene (chromosome region: 13q34) in obesity, a complex disorder associated with insulin resistance and glucose intolerance, we determined single nucleotide polymorphims (SNPs) and complex haplotypes in women with morbid obesity and a body mass index (BMI) of 41+/-0.8 kg/m2 ( n=99) compared with controls having a BMI of 23.8+/-0.1 kg/m2 ( n=92). Sequencing of unphased DNA or digestion of polymerase chain reaction fragments revealed seven SNPs, including a new C/T(-769) replacement at the 5' untranslated region. Considering four or seven SNPs, we reconstructed with the PHASE program nine or 24 haplotypes, respectively, that were well correlated into the cladogram. Logistic regression analysis with nine haplotypes in the whole sample revealed that obesity was associated with haplotype H3, with P<0.025, an odds ratio (OR) of 1.9 and a 95% confidence interval (CI) of 1.1-3.4, or pairs 3/3 ( P<0.005, OR=8.7, CI=1.9-40.1) and 3/4 ( P<0.023, OR=2.5, CI=1.1-5.6), all containing the the Gly1057Asp allelic variant of IRS2, whereas controls were associated with H5 and H6 ( P<0.02, OR=0.2, CI=0.01-0.81). Although obese H5 carriers (also containing Gly1057Asp mutation) were the most insulin resistant, haplotypes of IRS2 were poorly correlated (analysis of variance) with insulin resistance. By contrast, haplotypes H3, H4 and pairs 3/3 were consistently associated with increased 2-h glucose levels during an oral glucose tolerance test in obese individuals ( P<0.0005, 0.025 and 0.027, respectively). These data indicate that IRS2 is an influential gene in severe obesity and glucose intolerance in this population, whereas gene-based haplotypes of IRS2 have revealed heterogeneity in the behaviour of the Gly1057Asp mutation in relation to insulin resistance.

Adult↗
PubMed2000

Emerging genetic diversity of HIV-1 in South America.

OBJECTIVE: Genotype determination and risk group analysis of HIV-1 infected individuals in selected regions of South America. DESIGN: Cross-sectional convenience sampling of HIV-1-positive individuals in Peru, Ecuador, Uruguay and Paraguay from March, 1994 through September, 1998. METHODS: HIV-1-positive subjects were identified through the national AIDS surveillance program in each country. A standardized questionnaire was used to obtain demographic, clinical and risk factor data on each study subject. Viral DNA was extracted from participants' peripheral blood mononuclear cells either directly or after co-cultivation. A nested PCR was used to obtain selected fragments of the envelope genes for genotyping by the heteroduplex mobility assay (HMA). A 600 bp sequence encompassing the V3 loop was sequenced from a selection of 23 of these samples for phylogenetic analysis and confirmation of HMA genotype. RESULTS: Among the 257 successfully genotyped HIV-1-positive samples, genotype B was found in 98.3% (228/232) of those obtained from subjects in Peru, Ecuador, and Paraguay. In contrast, 56% (14/25) of the samples from Uruguay were genotype F, and the remainder were genotype B. Genotype F was detected for the first time in Peru (2/224) and Paraguay (1/4), and genotype A for the first time in Peru (1/224). Phylogenetic analysis confirmed the genotype identified by HMA in the 23 samples sequenced. There was no detectable genetic clustering of HIV-1 within the different high-risk groups or geographic locations. CONCLUSIONS: These findings verify and extend the presence of several different HIV-1 genotypes in South America.

Amino Acid Sequence↗
PubMed2000

The extent of HLA class II allele level disparity in unrelated bone marrow transplantation: analysis of 1259 National Marrow Donor Program donor-recipient pairs.

A comprehensive analysis of the HLA-D region loci, DRB1, DRB3, DRB5, DQA1, DQB1, DPA1 and DPB1, was performed to determine allelic diversity and underlying HLA disparity in 1259 bone marrow recipients and their unrelated donors transplanted through the National Marrow Donor Program. Although 43.0% of DRB1 alleles known to exist at the beginning of the study were found in this predominantly Caucasian transplant population, a few alleles predominated at each locus. In recipients, 67.1% of DRB1 alleles identified were one or two of six common DRB1 alleles. Only 118 (9.4%) donor-recipient pairs were matched for all alleles of DRB1, DQA1, DQB1, DPA1 and DPB1. While 79.4% of the pairs were matched for DRB1, only 13.2% were matched for DPB1 alleles. Almost 66% of pairs differed by more than one allele mismatch and 59.0% differed at more than one HLA-D locus. DQB1 was matched in 85.9% of DRB1-matched pairs. In contrast, only 13.9% of the pairs matched for DRB1, DQA1 and DQB1 were also matched for DPA1 and DPB1. This database, highlighting the underlying HLA disparity within the pairs, forms the foundation of an ongoing study to establish the relationship between HLA matching and successful outcome in unrelated allogeneic stem cell transplant.

Alleles↗
PubMed1999

Centric fusion differences among Oryx dammah, O. gazella, and O. leucoryx (Artiodactyla, Bovidae)

G- and C-banded karyotypes of the genus Oryx were compared using the standard karyotype of Bos taurus. Chromosomal complements were 2n = 56 in O. gazella gazella, 2n = 58 in O. g. beisa and O. g. callotis, 2n = 56-58 in O. dammah, and 2n = 57-58 in O. leucoryx. The number of autosomal arms in all karyotypes was 58. Nearly all variation in diploid number was the result of three independent centric fusions, but one 2n = 57 specimen of O. g. gazella deviated from the normal complement of 2n = 56 due to XXY aneuploidy. A 2;17 centric fusion was fixed in O. g. gazella, whereas O. g. beisa and O. g. callotis lacked this fusion and had indistinguishable karyotypes. Oryx dammah was polymorphic for a 2;15 centric fusion, and O. leucoryx was polymorphic for an 18;19 centric fusion. The five Oryx taxa shared a fixed 1;25 centric fusion; the small acrocentric element involved in the 1;25 fusion was identified by fluorescence in situ hybridization using a cosmid specific to Bos chromosome 25. The X and Y chromosomes were also conserved among the five taxa. Oryx g. gazella differed from the other Oryx species because of the fixed 2;17 centric fusion. This difference reflects an apparently longer period of geographic isolation between O. g. gazella and other populations of Oryx, and it is consistent with the classification of O. gazella and O. beisa as distinct species (see Kingdon, 1997). The lack of monobrachial relationships among the Oryx taxa indicates that sterility barriers between species have not developed. Viability of hybrid offspring constitutes a threat to captive breeding programs designed for endangered species conservation; in the case of Oryx, the 2;15, 2;17, and 18;19 metacentrics could serve as marker chromosomes for assessing hybridization between certain Oryx taxa.

Aneuploidy↗
PubMed2003

Evaluation of candidate control genes for diagnosis and residual disease detection in leukemic patients using 'real-time' quantitative reverse-transcriptase polymerase chain reaction (RQ-PCR) - a Europe against cancer program.

Real-time quantitative RT-PCR (RQ-PCR) is a sensitive tool to monitor minimal residual disease (MRD) in leukemic patients through the amplification of a fusion gene (FG) transcript. In order to correct variations in RNA quality and quantity and to calculate the sensitivity of each measurement, a control gene (CG) transcript should be amplified in parallel to the FG transcript. To identify suitable CGs, a study group within the Europe Against Cancer (EAC) program initially focused on 14 potential CGs using a standardized RQ-PCR protocol. Based on the absence of pseudogenes and the level and stability of the CG expression, three genes were finally selected: Abelson (ABL), beta-2-microglobulin (B2M), and beta-glucuronidase (GUS). A multicenter prospective study on normal (n=126) and diagnostic leukemic (n=184) samples processed the same day has established reference values for the CG expression. A multicenter retrospective study on over 250 acute and chronic leukemia samples obtained at diagnosis and with an identified FG transcript confirmed that the three CGs had a stable expression in the different types of samples. However, only ABL gene transcript expression did not differ significantly between normal and leukemic samples at diagnosis. We therefore propose to use the ABL gene as CG for RQ-PCR-based diagnosis and MRD detection in leukemic patients. Overall, these data are not only eligible for quantification of fusion gene transcripts, but also for the quantification of aberrantly expressed genes.

Archives↗