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PubMed2025

α1-Antitrypsin Gene Variation Associates With Asthma Exacerbations and Related Health Care Utilization.

BACKGROUND: α1-Antitrypsin deficiency is caused by rare pathogenic variants in SERPINA1, the strongest genetic risk factor for chronic obstructive pulmonary disease. Few studies have evaluated the effects of SERPINA1 variation on asthma severity accounting for critical gene-by-environment interactions with smoking. OBJECTIVE: To characterize the influence of SERPINA1 variation on asthma severity. METHODS: DNA samples from 847 non-Hispanic White and 446 African American participants from the Severe Asthma Research Program underwent SERPINA1 resequencing to identify rare variants. An independent population of 1955 individuals with asthma and α1-antitrypsin concentrations from a Cleveland Clinic Health System (CCHS) database were evaluated for severity measures. RESULTS: In White participants, a history of minimum smoking significantly interacted with SERPINA1 low-to-rare frequency variation to determine risk for asthma-related health care utilization. This was attributed to protease inhibitor type Z heterozygotes (MZ, N = 11), who had a higher frequency of emergency department (ED) visits (6 [54.5%] MZ heterozygotes, odds ratio [OR] = 7.60, 95% confidence interval [CI] = 1.71-39.7, P = .010), hospitalization (5 [45.5%], OR = 16.1, 95% CI = 2.64-150.4, P = .0050) in the past year, and lifetime intensive care unit (ICU) admissions (6 [54.5%], OR = 12.5, 95% CI = 2.44-75.6, P = .0032) compared with 146 individuals without SERPINA1 variants (30 [20.5%] reporting ED visits, 17 [11.6%] hospitalization, and 15 [10.3%] ICU admission). SERPINA1 variant-by-ever smoking interactions in African American participants for ED visits (P = .069) were related to 4 of 6 compound heterozygotes reporting an ED visit. In CCHS, α1-antitrypsin concentrations were inversely associated with moderate-to-severe asthma risk (OR = 0.97 per 10 mg/dL increase in α1-antitrypsin, 95% CI = 0.94-0.99, P = .010) and exacerbations (OR = 0.84 per 10 mg/dL, 95% CI = 0.76-0.94, P = .002). CONCLUSIONS: SERPINA1 variation and α1-antitrypsin concentrations impact asthma severity through gene-environment interactions with minimum smoking.

Adult↗
PubMed1994

Response to environmental change: genetic variation and fitness in Drosophila buzzatii following temperature stress.

Drosophila buzzatii typically may encounter high temperatures in nature, and this species is genetically variable for resistance to stress, both within and among populations. Fitness of survivors to stress, however, was reduced, and observed as a reduction in male fertility and female fecundity. With time following exposure to severe stress, reproductive capacity improved, but lifetime offspring production still was reduced significantly. This effect would greatly reduce a population's recovery from small size, which could occur following exposure to some man-made or environmental extreme. Although the results presented here were obtained for effects of heat stress, such consequences likely apply to a wide range of natural and man-made environmental stresses, including heavy metal toxicity or other pollutants. Low levels of these pollutants may not cause an observable effect on populations, even if some individuals are killed or offspring production is decreased. If genetic variation for resistance is present, higher tolerance may evolve. However, if concentrations are permitted to rise too far, some stress threshold may be reached, as observed for thermal stress, causing mass die-off or sterility and, possibly, local extinction. Understanding the effects of stress is important when preparing programs for the conservation of species. Organisms generally do not become extinct when resources are abundant and the climate benign, but unfortunately, no guarantee can be made that environmental conditions in any locality will remain stable over a long time. Consequently, a high possibility of exposure to an extreme stress in an area would greatly reduce its usefulness as a reserve. Likewise, when choosing organisms for reintroduction, stress resistance of the chosen individuals and high levels of genetic variation within a population would be valuable. The organisms placed there must be able to change. Analysis of stress resistance (at non-lethal levels) among either family groups or for different populations would be very useful when deciding which individuals to reintroduce to an area or place in a reserve. Additionally, analysis may suggest that stress resistance is very low in a population or species. If identified, particular care may be taken to monitor the occurrence of that stress in the environment, and to take action to protect the population from that stress. Preservation of species should be designed for the future, with the goal to preserve, not simply to postpone extinction.

Analysis of Variance↗
PubMed2003

The karyotypic structure of cell populations in vitro as an integral system.

This review describes regularities of karyotypic variability maintaining karyotypic stabilization of continuous cell lines. Statistical analysis of individual karyotypes of "marker" and "markerless" cell lines show that survival of cell population in vitro is maintained by a certain ratio of cells with different structural variants of karyotype (SVK). Characteristic feature of karyotypic variability in the "markerless" cell lines during long-term cultivation under various conditions is dicentric formation due to telomeric associations. These dicentrics seem to form genetical structures providing adaptation to conditions in vitro of the cell population as an autonomous system. Correlations between the numerical variability reflecting in SVK, and structural variability (dicentric formation) are manifestations of an integral cell-populational function. Experimental data allow to suggest that integrity of the karyotypic structure of cell populations is maintained not only by selection of random variations, but also by programmed (adaptive) changes of karyotype. As a whole, in the cell population the state is realized that can be called karyotypic homeostasis; the observed phenomena characterize processes maintaining such homeostasis.

Adaptation, Physiological↗
PubMed1991

Usher syndrome: results of a screening program in Colombia.

Otological, ophthalmological and genetic studies were performed in 46 patients with Usher syndrome, identified through a screening program in Colombia. Of them, 69.6% had Usher syndrome type I, 26.1% type II, and 4.3% type III. Thirty-three patients showed profound deafness (71.7%), while 13 (28.3%) had moderate to severe hearing loss. The ophthalmologic manifestations showed marked variability. Although the majority of the patients had serious ocular impairment before age 20, 32.6% had good central visual acuity. The prevalence of Usher syndrome in Colombia, estimated at 3.2/100,000, warrants the implementation of screening programs in schools for the deaf and for the blind. Our study confirms that Usher syndrome shows no geographic or racial variation and that the disorder has a wide variability of expression and genetic heterogeneity. The large size of the families we have detected may provide important opportunities for further genetic studies, particularly in terms of the assignment of the locus and gene mapping.

Colombia↗
PubMed2004

Genetic analysis of Indian aromatic and quality rice (Oryza sativa L.) germplasm using panels of fluorescently-labeled microsatellite markers.

Genetic relationships among Indian aromatic and quality rice (Oryza sativa) germplasm were assessed using 30 fluorescently labeled rice microsatellite markers. The 69 rice genotypes used in this study included 52 Basmati and other scented/quality rice varieties from different parts of India and 17 indica and japonica varieties that served as controls. A total of 235 alleles were detected at the 30 simple sequence repeat (SSR) loci, 62 (26.4%) of which were present only in Basmati and other scented/quality rice germplasm accessions. The number of alleles per locus ranged from 3 to 22, with an average of 7.8, polymorphism information content (PIC) values ranged from 0.2 to 0.9, with an average of 0.6, and the size range between the smallest and the largest allele for a given microsatellite locus varied between 3 bp and 68 bp. Of the 30 SSR markers, 20 could distinguish traditional Basmati rice varieties, and a single panel of eight markers could be used to differentiate the premium traditional Basmati, cross-bred Basmati, and non-Basmati rice varieties having different commercial value in the market-place. When estimates of inferred ancestry or similarity coefficients were used to cluster varieties, the high-quality Indian aromatic and quality rice genotypes could be distinguished from both indica and japonica cultivars, and crossbred varieties could be distinguished from traditional Basmati rices. The results indicate that Indian aromatic and quality germplasm is genetically distinct from other groups within O. sativa and is the product of a long independent pattern of evolution. The data also suggest that there is scope for exploiting the genetic diversity of aromatic/quality rice germplasm available in India for national Basmati rice breeding programs.

Alleles↗
PubMed1988

Early events in murine erythroleukemia cells induced to differentiate. Accumulation and gene expression of the transformation-associated cellular protein p53.

Oncogenes may play a crucial role in the genetic program of cellular differentiation; even, probably, at a very early stage in this program, which can be described as pre-commitment. We have investigated the variation in, and the control level of, the accumulation of the transformation-associated cellular protein p53 in murine erythroleukemia cells induced to differentiate by hexamethylene bisacetamide. Using flow cytofluorimetry after double staining of the cells, we have found that p53 decreased from two hours after the input of the inducer, to reach a basal level of about 30% of the starting value. The stability of the protein was found to be affected neither by the inducer nor by the position of the cells in the cell cycle. Looking for the regulation mechanism of the p53 decay, we found that the mRNA started to decrease as early as half an hour after the hexamethylene bisacetamide was put in the culture medium, and that the transcription rate of the gene itself could not account for the observed down-regulation of the mRNA, suggesting a post-transcriptional control for the mRNA accumulation. This control did not require the de-novo synthesis of a protein component, as shown by cycloheximide experiments, but seemed to be governed by the induced synthesis of an RNA molecule. Hypothetical models for such a regulation process are discussed in the light of recent reports on the metabolism of mRNA.

Acetamides↗
PubMedDate not supplied

Racial inequity in America's ESRD program.

The end-stage renal disease (ESRD) program has a significant overrepresentation of racial and ethnic minority groups. The increased susceptibility of nonwhite populations to ESRD has not been fully explained and probably represents a complex interplay of genetic, cultural, and environmental influences. Because the program delivers care under a uniform health care payment system, it represents a unique environment in which to explore variation in health care delivery. A number of disparities in outcomes and delivery of ESRD care have been noted for racial minority participants. These include possible overdiagnosis of hypertensive nephrosclerosis, decreased provision of renal replacement therapy, limited referral for home dialysis modalities, underprescription of dialysis, increased use of synthetic grafts rather than fistulas as permanent angioaccess, and delayed wait-listing for renal transplantation. Transplantation inequities mean that black patients are likely to remain on dialysis relatively longer, so that their susceptibility to less than optimal processes of care increases disproportionately. Improved survival and quality of life (QOL) for blacks with ESRD may have encouraged provider complacency about racial disparities in the ESRD program and in particular about referral for transplantation. It is also apparent that minority ESRD patients may, similar to their non-ESRD counterparts, be referred less frequently for invasive cardiovascular (CV) procedures. Despite these observations of inequality in ESRD care, the adjusted mortality for minority participants in the ESRD program are better than for the majority population. This seeming paradox may define an opportunity to improve outcomes for minorities with ESRD even more.

Black or African American↗
PubMed2005

Comparing host and parasite phylogenies: gyrodactylus flatworms jumping from goby to goby.

The combination of exceptionally high species diversity, high host specificity, and a complex reproduction system raises many questions about the underlying mechanisms triggering speciation in the flatworm genus Gyrodactylus. The coevolutionary history with their goby hosts was investigated using both topology- and distance-based approaches; phylogenies were constructed of the V4 region of the 18S rRNA and the complete ITS rDNA region for the parasites, and 12S and 16S mtDNA fragments for the hosts. The overall fit between both trees was significant according to the topology-based programs (TreeMap 1.0, 2.0 beta and TreeFitter), but not according to the timed analysis in TreeMap 2.0 beta and the distance-based method (ParaFit). An absolute timing of speciation events in host and parasite ruled out the possibility of synchronous speciation for the gill parasites, favouring the distance-based result. Based on this information together with the biological background of host and parasite, the following TreeMap solution was selected. The group of gill parasites evolved from a host switch from G. arcuatus, parasitizing the three-spined stickleback onto the gobies, followed by several host-switching events among the respective goby hosts. The timing of these events is estimated to date back to the Late Pleistocene, suggesting a role for refugia-mediated mixing of parasite species. In contrast, it is suggested that co-speciation in the fin-parasites resulted in several host-associated species complexes. This illustrates that phylogenetically conserved host-switching mimics the phylogenetic signature of co-speciation, confounding topology-based programs.

Animals↗
PubMed2004

Molecular evolution of the phytochrome gene family in sorghum: changing rates of synonymous and replacement evolution.

The photoreceptor phytochromes, encoded by a small gene family, are responsible for controlling the expression of a number of light-responsive genes and photomorphogenic events, including agronomically important phenotypes such as flowering time and shade-avoidance behavior. The understanding and control of flowering time are particularly important goals in sorghum cultivar development for diverse environments, and naturally occurring variation in the phytochrome genes might prove useful in breeding programs. Also of interest is whether variation observed at the phytochrome loci in domesticated sorghum, or in particular races, is a result of human selection. Population genetic studies can reveal evidence of such selection in patterns of polymorphism and divergence. In this study we report a population genetic analysis of the PHY gene family in Sorghum bicolor (L.) Moench in a diverse panel including both cultivated and wild accessions. We show that the level of nucleotide variation in all gene family members is about half the average for this species, consistent with purifying selection acting on these loci. However, the rate of amino acid substitution is accelerated at PHYC compared to the other two loci. In comparisons to a closely related sorghum species, PHYC shows a pattern of intermediate frequency amino acid changes that differ from the patterns observed in comparisons across longer evolutionary distances. There is also a departure from expected patterns of polymorphism and divergence at synonymous sites in PHYC, although the data do not fit a simple model of directional or diversifying selection. Cultivated sorghum has a level of variation similar to that of wild relatives (ssp. verticilliflorum), but many polymorphisms are subspecies-specific, including several amino acid variants.

Amino Acid Sequence↗
PubMed2004

Centralized immunogens as a vaccine strategy to overcome HIV-1 diversity.

Genetic variation of HIV-1 represents a major obstacle for AIDS vaccine development. With the amino acid sequence divergence as high as 30% in envelopes between different subtypes among HIV-1 group M viruses, it is unlikely that cross-subtype protection will occur equally well among all subtypes. Computer programs have been used to generate 'centralized' HIV gene sequences: consensus, ancestor or center of the tree. These sequences can decrease the genetic distances between the 'centralized' and wild-type gene immunogens to half of those between any wild-type immuongens to each other. Recent studies demonstrated that an artificial group M consensus env gene is equidistant from any subtype and recombinants. It is biologically functional and preserves antigenicity similar to contemporary Env proteins. Most importantly, the group M consensus Env immunogen can elicit both T- and B-cell responses to wild-type HIV-1 isolates.

AIDS Vaccines↗
PubMed2006

A global view of genetic diversity in cultivated sorghums using a core collection.

We report here an analysis of the structure of genetic diversity in cultivated sorghums. A core collection of 210 landraces representative of race, latitude of origin, response to day length, and production system was analysed with 74 RFLP probes dispersed throughout the genome. Multivariate analyses showed the specificity of the subrace guinea margaritiferum, as well as the geographical and racial pattern of genetic diversity. Neighbour-joining analysis revealed a clear differentiation between northern and southern equatorial African accessions. The presence of Asian accessions in these 2 major geographical poles for sorghum evolution indicated two introductions of sorghum into Asia. Morphological race also influenced the pattern of sorghum genetic diversity. A single predominant race was identified in 8 of 10 clusters of accessions, i.e., 1 kafir, 1 durra, 4 guinea, and 2 caudatum clusters. Guinea sorghums, with the exception of accessions in the margaritiferum subrace, clustered in 3 geographical groups, i.e., western African, southern African, and Asian guinea clusters; the latter two appeared more closely related. Caudatum were mainly distributed in 2 clusters, the African Great Lakes caudatum cluster and those African caudatum originating from other African regions. This last differentiation appears related to contrasting photoperiod responses. These results aid in the optimization of sampling accessions for introgression in breeding programs.

Alleles↗
PubMed2007

Bias in association studies of systemic lupus erythematosus susceptibility due to geographical variation in the frequency of a programmed cell death 1 polymorphism across Europe.

We obtained eight collections of DNA samples from ethnically matched systemic lupus erythematosus (SLE) patients and controls from five European countries totaling 783 patients and 1210 controls. A highly significant cline in the frequency of the PD1.3 A allele was found among controls but not among SLE patients. The frequency of the PD1.3 A allele increased from the Northeast to the Southwest of Europe. The cline was clearly apparent (P=1.2 x 10(-6)) when data from controls of other five SLE susceptibility studies were included in the analysis. This variation has severely biased SLE association studies owing to the lack of parallel changes in SLE patients. As a consequence, the PD1.3 A allele was more common in SLE patients than in controls in the Northeast and Center of Europe, similar to controls in Southeast Europe, and less frequent than in the controls in the Southwest of the Continent. This dissociation in allele frequencies between SLE patients and controls in different subpopulations indicated that programmed cell death 1 variation and disease susceptibility are not independent but the type of relationship is currently unclear. As allele frequency clines are common in other polymorphisms their impact in genetic epidemiology studies should be carefully considered.

Antigens, CD↗
PubMed2006

Endothelial nitric oxide synthase haplotypes are associated with features of metabolic syndrome.

BACKGROUND: The metabolic syndrome, a cluster of several metabolic disorders, is increasingly being recognized as a risk factor for cardiovascular disease. Endothelium-derived nitric oxide facilitates skeletal muscle glucose uptake, and data from animal models indicate that endothelial nitric oxide synthase (eNOS) gene-null mice present with a phenotype of insulin resistance, hypertension, and hypertriglyceridemia, much like that observed in humans with metabolic syndrome. We used haplotype tagging single nucleotide polymorphisms (htSNPs) to investigate the role of genetic variation in the eNOS gene (NOS3) in metabolic syndrome in humans. METHODS: We recruited 738 unrelated persons from a cross-sectional population-based epidemiological survey in the province of Segovia in Central Spain (Castille). Metabolic syndrome was defined according to the recently modified National Cholesterol Education Program Adult Treatment Panel III guidelines. RESULTS: Haplotype analysis showed a statistically significant association between some NOS3 gene variants and features of metabolic syndrome. Relative to the most common haplotype, 121, the haplotype 212 was associated with an increased odds ratio (OR) for metabolic syndrome [OR = 1.81, 95% confidence interval (CI) 1.15-2.84], and for decreased HDL-cholesterol concentrations (OR 1.52, 95% CI 1.01-2.29), and with increased mean values for the homeostasis model assessment of insulin resistance (P = 0.043), and triglycerides (P = 0.026). CONCLUSIONS: Our results suggest that genetic variation at the eNOS locus is associated with features of metabolic syndrome, and might represent a new genetic susceptibility component for insulin resistance, hypertriglyceridemia, and low HDL-cholesterol concentrations.

Adult↗
PubMed2006

Benefits of cooperation between breeding programs in the presence of genotype by environment interaction.

Dairy cattle breeding programs and dairy farmers are selecting sires and dams across environments. Genotype x environment interaction (G x E) limits the possibilities for cooperation between breeding programs operating in different environments. The objectives of this study were 2-fold: 1) to investigate the effects of heritability, selection intensity, number of progeny per bull, and size of breeding programs on possibilities for cooperation between dairy cattle breeding programs in the short and long term in the presence of G x E, and 2) to quantify the effect of such cooperation on genetic gain. A dairy cattle situation with 2 breeding programs operating in 2 environments was simulated using a deterministic pseudo-BLUP selection index model. Long-term cooperation between the 2 breeding programs was possible in the presence of G x E, when the genetic correlation was higher than 0.80 to 0.90, resulting in up to 15% extra genetic gain. In addition, in the initial generations of selection, the breeding programs could benefit from mutually selecting sires and dams from each other when the genetic correlation was as low as 0.40 to 0.60. With more intense selection, breeding programs were less likely to benefit from cooperation with breeding programs in other environments. Heritability and number of progeny per bull had little effect on possibilities for cooperation, unless the heritabilities and the number of progeny per bull were extremely different in the 2 environments. Small breeding programs benefited more from cooperation than did large breeding programs, and benefits were possible even at lower values (i.e., <0.80) of the genetic correlation. Possibilities for cooperation across environments would affect the optimal design of dairy cattle breeding programs considering genetic gain, inbreeding, and costs.

Animals↗
PubMed1979

Flagellar-phase variation: isolation of the rh1 gene.

In Salmonella, expression of flagellar antigen alternates between two serotypes (phases) encoded by two genes, H1 and H2. The mechanism which controls the alternative expression of the H1 and H2 genes was examined by cloning these genes and the genetic elements which control their activity on hybrid vehicles in Escherichia coli. H2 gene activity was shown to be controlled by a recombinational switch located adjacent to the H2 gene. Activity of the H1 gene is thought to be repressed, when the H2 gene is expressed, by the product of another gene, rh1 (repressor of H1), which is controlled coordinately with the H2 gene. In this report, we describe the construction of hybrid lambda vehicles which contain, in addition to the H2 gene, a genetic activity corresponding to rh1. Variation of flagellar antigens analogous to that observed in Salmonella was observed when E. Coli strains were transduced with the hybrid lambda. By using the lambdaH2rh1 hybrid to program protein synthesis in UV-irradiated cells, the synthesis of a polypeptide was correlated with rh1 gene product activity. We conclude that the H2 region consists of two cotranscribed genes, H2 and rh1. The expression of both gene products is regulated by the same recombinational event.

Bacterial Proteins↗
PubMedDate not supplied

Insights into X chromosome inactivation from studies of species variation, DNA methylation and replication, and vice versa.

I am indebted to Mary Lyon as her X-inactivation hypothesis stimulated my mentor, Barton Childs, and in turn, myself, to think about the consequences of X-inactivation in heterozygous females. I often reread her original papers setting forth the single active X hypothesis, and still marvel at the concise and compelling exposition of the hypothesis and the logical predictions which seemed prophetic at my first reading, and have survived the test of time. My contribution to this Festschrift reviews evidence derived from studies of DNA methylation, species variation and DNA replication that reveals an important role for methylated CpG islands and suggests a role for late DNA replication in propagating X inactivation from one cell to its progeny. These studies also show that X inactivation is a powerful research tool for identifying the factors which program and maintain developmental processes.

Animals↗
PubMed1997

[Genetic effects of destabilizing selection for adaptively important traits in Drosophila melanogaster lines].

Related lines of Drosophila melanogaster selected for reproductive activity for more than 750 generations were studied. Results of the long-term selection experiment support D.K. Belyaev's concept of destabilizing selection. Selection for a behavioral trait (male mating activity) affected the intrinsic structure of the organism. Flies of the low-activity line (LA) exhibited numerous morphological, biochemical, and physiological alterations. Variation rate in the selected lines was accelerated; appearing mutations were often allelic and nonrandomly distributed over chromosomes. Selection was shown to mediate novel sources of variability, e.g., induction and repression of the hobo hybrid dysgenesis. In the process of selection, a genetically determined program of hobo transpositions in the genome was formed.

Adaptation, Physiological↗