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At least 1,423 records · Page 79Linked to original sources
PubMed1998

Exaggerated natriuresis as a candidate intermediate phenotype in spontaneously hypertensive rats.

OBJECTIVE: To determine whether exaggerated natriuresis and exaggerated renal sympathoinhibition during volume loading constitute an intermediate phenotype in spontaneously hypertensive rats. DESIGN: The borderline hypertensive rat, the F1 of a cross between a spontaneously hypertensive rat and a normotensive Wistar-Kyoto rat, is a NaCl-sensitive model of genetic hypertension. In addition to hypertension, borderline hypertensive rats fed 8% NaCl food develop characteristic alterations in regulation of renal sympathetic nerve activity and neural regulation of renal function similar to those in the spontaneously hypertensive rat parent. Like the Wistar-Kyoto rat parent, borderline hypertensive rats fed 1% NaCl food remain normotensive and do not exhibit these alterations in renal sympathetic neural mechanisms. These renal sympathetic neural mechanisms constitute a complex quantitative trait that could represent an intermediate phenotype. METHODS: A backcross population, developed by mating borderline hypertensive rats with Wistar-Kyoto rats, was fed 8% NaCl food for 12 weeks from age 4 to 16 weeks. Responses to intravenous isotonic saline volume loading (10% body weight/30 min) in 81 backcross rats chronically instrumented for measurement of mean arterial pressure, renal sympathetic nerve activity, and urinary sodium excretion were determined. RESULTS: Mean arterial pressure was 105-180 mmHg and was not correlated to the magnitude either of the decrease in renal sympathetic nerve activity or of the increase in urinary sodium excretion during volume loading. CONCLUSIONS: These two aspects of the complex quantitative trait, exaggerated natriuresis and exaggerated renal sympathoinhibition during volume loading, are not part of an intermediate phenotype in spontaneously hypertensive rats.

Animals↗
PubMed2002

Loss of chromosome 16 from renal epithelial cells in humans.

This work explores the notion that low-frequency, acquired aneuploidy may play a role in complex genetic traits such as essential hypertension. To this end, renal epithelial cells in urinary sediments and in renal cysts were examined by fluorescent in situ hybridization with DNA probes specific for the heterochromatic and centromere regions of chromosomes 16 and 1. Chromosome 16 was probed because it harbors variant genes causing monogenic hypertension. These genes have also been investigated for their role in essential hypertension. Chromosome 1 was also probed as an internal control. Higher proportions of renal epithelial cells in the urinary sediments showed monosomy of chromosome 16 than monosomy of chromosome 1 (P<0.001). We also observed in epithelial cells of renal cysts a preponderance of monosomy for chromosome 16 over monosomy for chromosome 1 (P<0.024). Low-frequency loss of heterozygosity that results from acquired monosomy of chromosome 16 and perhaps other chromosomes may contribute to expression of complex genetic traits such as essential hypertension, in which the diverse phenotypic manifestations are poorly understood.

Adolescent↗
PubMed1999

Evolution and clonal traits of Mycobacterium tuberculosis complex in Guinea-Bissau.

Two hundred twenty-nine consecutive isolates of Mycobacterium tuberculosis complex from patients with pulmonary tuberculosis in Guinea-Bissau, which is located in West Africa, were analyzed for clonal origin by biochemical typing and DNA fingerprinting. By using four biochemical tests (resistance to thiophene-2-carboxylic acid hydrazide, niacin production, nitrate reductase test, and pyrazinamidase test), the isolates could be assigned to five different biovars. The characteristics of four strains conformed fully with the biochemical criteria for M. bovis, while those of 85 isolates agreed with the biochemical criteria for M. tuberculosis. The remaining 140 isolates could be allocated into one of three biovars (biovars 2 to 4) representing a spectrum between the classical bovine (biovar 1) and human (biovar 5) tubercle bacilli. By using two genotyping methods, restriction fragment length polymorphism analysis with IS6110 (IS6110 RFLP analysis) and spoligotyping, the isolates could be separated into three groups (groups A to C) of the M. tuberculosis complex. Group A (n = 95), which contained the majority of classical human M. tuberculosis isolates, had large numbers of copies of IS6110 elements (mean number of copies, 9) and a distinctive spoligotyping pattern that lacked spacers 33 to 36. Isolates of the major group, group B (n = 119), had fewer IS6110 copies (mean copy number, 5) and a spoligotyping pattern that lacked spacers 7 to 9 and 39 and mainly comprised isolates of biovars 1 to 4. Group C isolates (n = 15) had one to three IS6110 copies, had a spoligotyping pattern that lacked spacers 29 to 34, and represented biovar 3 to 5 isolates. Four isolates whose biochemical characteristics conformed with those of M. bovis clustered with the group B isolates and had spoligotype patterns that differed from those previously reported for M. bovis, in that they possessed spacers 40 to 43. Interestingly, isolates of group B and, to a certain extent, also isolates of group C showed a high degree of variability in biochemical traits, despite genotypic identity in terms of IS6110 RFLP and spoligotype patterns. We hypothesize that isolates of groups B and C have their evolutionary origin in West Africa, while group A isolates are of European descent.

Adult↗
PubMed2006

Evolution of proteinase inhibitor defenses in North American allopolyploid species of Nicotiana.

We studied the jasmonate (JA)-elicited trypsin-proteinase inhibitor (TPI) anti-herbivore defense system in North American Nicotiana to understand how complex polygenetic traits evolve after allopolyploidy speciation. N. quadrivalvis (Nq) and N. clevelandii (Nc) are allotetraploid descendant species of the ancestors of the diploid species N. attenuata (Na) and N. obtusifolia (No). From cDNA, intron and promoter sequence analyses, and Southern blotting, we deduced that only the maternally derived No TPI genes were retained in the tetraploid genomes (Nq, Nc), whereas the sequences of the paternal Na ancestor were deleted. The number of TPI repeats in different Nicotiana taxa was independent of phylogenetic associations. In Na, TPI activity and mRNA transcript accumulation as well as JA levels increased dramatically above wound-induced levels when the oral secretions (OS) from Manduca sexta larvae were introduced into wounds. This OS-mediated amplification of defense signaling and downstream response was also found in the tetraploid genomes but was absent from No; in No, OS treatment suppresses TPI mRNA accumulation and activity and does not increase JA accumulation. Hence, the tetraploids retained components of Na's signaling system, but lost Na's TPI genes and used No's TPI genes to retain a functional TPI defense system, underscoring the genomic flexibility that enables complex polygenic traits to be retained in allopolyploid species.

Amino Acid Sequence↗
PubMed2005

Towards compendia of negative genetic association studies: an example for Alzheimer disease.

Most genetic sequence variants that contribute to variability in complex human traits will have small effects that are not readily detectable with population samples typically used in genetic association studies. A potentially valuable tool in the gene discovery process is meta-analysis of the accumulated published data, but in order to be valid these require a sample of studies representative of the true genetic effect and thus hypothetically should include some positive and an abundance of negative reports. A survey of the literature on association studies for Alzheimer disease (AD) from January 2004-April 2005, identified 138 studies, 86 of which reported positive findings other than for apolipoprotein E (APOE), strongly indicative of publication bias. We report here an analysis of 62 genetic markers, tested for association with AD risk as well as for possible effects upon quantitative indices of AD severity (mini-mental state examination scores, age-at-onset, and cerebrospinal fluid (CSF) beta-amyloid (Abeta) and CSF tau proteins). Within this set, only modest signals were present that, with the exception of APOE are easily lost when corrections for multiple hypotheses are applied. In isolation, results are thus broadly negative. Genes studied encompass both novel candidates as well as several recently claimed to be associated with AD (e.g. urokinase plasminogen activator (PLAU) and acetyl-coenzyme A acetyltransferase 1 (ACAT1)). By reporting these data we hope to encourage the publication of gene compendia to guide further studies and aid future meta-analyses aimed at resolving the involvement of genes in complex human traits.

Aged↗
PubMed1995

Genetic linkage of the ACE gene to plasma angiotensin-converting enzyme activity but not to blood pressure. A quantitative trait locus confers identical complex phenotypes in human and rat hypertension.

BACKGROUND: An allelic variant of the ACE gene has been found to be linked to plasma angiotensin-converting enzyme (ACE) activity in humans and has been implicated in the etiology of some common cardiovascular disorders. Previously, we have shown significant genetic linkage of blood pressure to a region on rat chromosome 10 that contains ACE in an experimental F2-intercross between the stroke-prone spontaneously hypertensive rat (SHRSPHD) and the normotensive Wistar-Kyoto (WKYHD-0) reference strain. Subsequent investigations revealed marked differences in plasma ACE activity among the SHRSPHD and WKYHD-0 strains. Nonetheless, the physiological relevance of these findings remained obscure. We therefore investigated the genetic determination of plasma ACE activity and its relation to blood pressure and dietary NaCl exposure in a model of experimental genetic hypertension, the SHRSPHD. METHODS AND RESULTS: We conducted a further crossbreeding experiment between SHRSPHD and a congenic reference strain, WKYHD-1, that carries a 6-centimorgan (cM) long, SHRSP-homologous segment introgressed in chromosome 10, 26 cM remote from ACE. This allowed us to contrast effects on blood pressure and ACE activity conferred by the ACE locus with other more remote loci within the congenic chromosomal region. Genetic analysis in this F2 (WKYHD-1 x SHRSPHD) cross revealed that plasma ACE activity was determined almost entirely by genetic effects of the ACE gene locus (lod score = 43). However, neither plasma ACE nor the ACE locus showed any cosegregation with blood pressure before or after dietary NaCl exposure. CONCLUSIONS: These results demonstrate that a molecular variant of the ACE gene determines plasma ACE activity but exhibits no direct effect on blood pressure. Moreover, the findings also exclude the possibility that plasma ACE is secondarily affected by blood pressure or excess dietary NaCl exposure. Our results reconcile the previous discrepancy between findings in human and experimental hypertension.

Animals↗
PubMed2004

Improving crop salt tolerance.

Salinity is an ever-present threat to crop yields, especially in countries where irrigation is an essential aid to agriculture. Although the tolerance of saline conditions by plants is variable, crop species are generally intolerant of one-third of the concentration of salts found in seawater. Attempts to improve the salt tolerance of crops through conventional breeding programmes have met with very limited success, due to the complexity of the trait: salt tolerance is complex genetically and physiologically. Tolerance often shows the characteristics of a multigenic trait, with quantitative trait loci (QTLs) associated with tolerance identified in barley, citrus, rice, and tomato and with ion transport under saline conditions in barley, citrus and rice. Physiologically salt tolerance is also complex, with halophytes and less tolerant plants showing a wide range of adaptations. Attempts to enhance tolerance have involved conventional breeding programmes, the use of in vitro selection, pooling physiological traits, interspecific hybridization, using halophytes as alternative crops, the use of marker-aided selection, and the use of transgenic plants. It is surprising that, in spite of the complexity of salt tolerance, there are commonly claims in the literature that the transfer of a single or a few genes can increase the tolerance of plants to saline conditions. Evaluation of such claims reveals that, of the 68 papers produced between 1993 and early 2003, only 19 report quantitative estimates of plant growth. Of these, four papers contain quantitative data on the response of transformants and wild-type of six species without and with salinity applied in an appropriate manner. About half of all the papers report data on experiments conducted under conditions where there is little or no transpiration: such experiments may provide insights into components of tolerance, but are not grounds for claims of enhanced tolerance at the whole plant level. Whether enhanced tolerance, where properly established, is due to the chance alteration of a factor that is limiting in a complex chain or an effect on signalling remains to be elucidated. After ten years of research using transgenic plants to alter salt tolerance, the value of this approach has yet to be established in the field.

Crops, Agricultural↗
PubMed2003

FXR and ABCG5/ABCG8 as determinants of cholesterol gallstone formation from quantitative trait locus mapping in mice.

BACKGROUND & AIMS: Cholesterol gallstone formation is a complex genetic trait. To identify additional cholesterol gallstone susceptibility loci, we performed a quantitative trait locus analysis using an intercross of PERA/Ei and I/LnJ inbred strains of mice. METHODS: Mice of both sexes were examined for gallstone weight and evaluated according to a scoring system for the physical chemistry of cholelithiasis during feeding of a lithogenic diet. Intercross offspring were genotyped, and linkage analysis was performed by interval mapping. Differences in messenger RNA expression of positional candidate genes were determined using reverse-transcription and real-time polymerase chain reaction. RESULTS: We identified significant loci associated with gallstone weight on chromosomes 10 and 4, named Lith7 and Lith8, respectively (both susceptibility alleles conferred by strain I/LnJ). Positional candidate genes with higher expression in I/LnJ mice are Fxr (official symbol, Nr1h4), encoding the nuclear bile salt receptor, on chromosome 10 and Shp1 (official symbol, Nr0b2), encoding the small heterodimer partner 1, on chromosome 4. A significant locus associated with gallstone score on chromosome 17, named Lith9 (susceptibility allele conferred by strain PERA/Ei), colocalizes with the genes Abcg5 and Abcg8 that encode the canalicular cholesterol transporter. Higher hepatic messenger RNA expression of Abcg5 and Abcg8 in strain PERA/Ei correlates positively with higher biliary cholesterol levels. CONCLUSIONS: Our findings suggest a primary role of the nuclear bile salt receptor FXR and the canalicular cholesterol transporter ABCG5/ABCG8 in the genetic susceptibility and pathogenesis of cholesterol cholelithiasis in these strains of inbred mice.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed1996

A genetic linkage map of mouse chromosome 2 extending from thrombospondin to paired box gene 1, including the H3 minor histocompatibility complex.

The classical minor histocompatibility 3 (H3) locus was originally defined by the phenotype of skin graft rejection, which is a complex genetic trait. H3 is now known to be a gene complex comprised of a minimum of two functionally interdependent alloantigen-encoding loci, H3a and H3b. H3a encodes a peptide recognized by cytotoxic T cells, and H3b encodes a peptide that stimulates helper T cells. The H3 complex also contains the beta2-microglobulin gene (B2m), and polymorphisms in B2m contribute to the tissue rejection phenotype. We describe a high-density genetic linkage map of a 16-cM region of mouse Chromosome 2 from thrombospondin (Thbs1) to paired box gene 1 (Pax1). This genetic map includes H3a, H3b, and B2m. Other genes and anonymous loci have also been placed on the map. H3a maps between D2Mit444 and B2m in close vicinity to several known genes. H3b maps 12 cM distal to H3a, and the proprotein convertase subtilisin/kexin type 2 gene (Pcsk2; formerly Nec2) cosegregates with H3b in a high-resolution backcross panel. The H3 complex spans a region that shows conserved synteny to human chromosomes 15q, 2q, and 20p.

Animals↗
PubMed2003

QTLs for Na+ and K+ uptake of the shoots and roots controlling rice salt tolerance.

An F2 and an equivalent F3 population derived from a cross between a high salt-tolerance indica variety, Nona Bokra, and a susceptible elite japonica variety, Koshihikari, were produced. We performed QTL mapping for physiological traits related to rice salt-tolerance. Three QTLs for survival days of seedlings (SDSs) under salt stress were detected on chromosomes 1, 6 and 7, respectively, and explained 13.9% to 18.0% of the total phenotypic variance. Based on the correlations between SDSs and other physiological traits, it was considered that damage of leaves was attributed to accumulation of Na+ in the shoot by transport of Na+ from the root to the shoot in external high concentration. We found eight QTLs including three for three traits of the shoots, and five for four traits of the roots at five chromosomal regions, controlled complex physiological traits related to rice salt-tolerance under salt stress. Of these QTLs, the two major QTLs with the very large effect, qSNC-7 for shoot Na+ concentration and qSKC-1 for shoot K+ concentration, explained 48.5% and 40.1% of the total phenotypic variance, respectively. The QTLs detected between the shoots and the roots almost did not share the same map locations, suggesting that the genes controlling the transport of Na+ and K+ between the shoots and the roots may be different.

DNA, Plant↗
PubMed2000

Transgenic approaches to crop improvement.

Transgenic crops are now grown commercially on several million hectares, principally in North America. To date, the predominant crops are maize (corn), soybean, cotton, and potatoes. In addition, there have been field trials of transgenics from at least 52 species including all the major field crops, vegetables, and several herbaceous and woody species. This review summarizes recent data relating to such trials, particularly in terms of the trends away from simple, single gene traits such as herbicide and insect resistance towards more complex agronomic traits such as growth rate and increased photosynthetic efficiency. Much of the recent information is derived from inspection of patent databases, a useful source of information on commercial priorities. The review also discusses the time scale for the introduction of these transgenes into breeding populations and their eventual release as new varieties.

Breeding↗
PubMed1996

A quantitative trait locus in major histocompatibility complex determining latent period of mouse lymphomas.

The effects of two host genes on retrovirus-induced murine lymphoma were evaluated by studying 114 F2 intercross mice between SL/Kh and AKR/Ms mice. Out of 47 T-lymphoma-bearing F2 mice, 45 had the AKR-derived dominant allele at Tism-1. The length of the lymphoma latent period was not related to type of tumor. Instead, it was significantly shortened by a recessive SL/Kh-derived allele at a major histocompatibility complex (MHC)-linked locus on Chr. 17. A quantitative trait analysis of the latent period yielded a maximal logarithm of likelihood ratio for linkage (LOD) score of 7.06 at a class II gene within MHC. The SL/Kh-derived recessive gene was named lla (lymphoma latency acceleration).

Alleles↗
PubMed2026

Application of Omics Technologies for Cowpea Improvement.

Cowpea (Vigna unguiculata) is a vital crop for food security, nutrition, and climate resilience in sub-Saharan African and other semi-arid regions. However, its improvement is constrained by the complexity of polygenic traits such as drought tolerance, pest resistance, and seed quality. Conventional breeding, while foundational, remains insufficient to address these challenges at the required pace. Recent advances in multi-omics technologies, including genomics, transcriptomics, proteomics, and metabolomics, provide new opportunities to dissect complex traits, identify candidate genes, and accelerate the development of resilient, high-yielding cultivars. This review presents a critical synthesis of current applications of omics technologies in cowpea improvement, highlighting their contributions to stress adaptation, nutritional enhancement, and precision breeding. The review also examines key technical and institutional constraints limiting the adoption of omics-assisted breeding in cowpea, including inadequate research infrastructure, challenges in multi-omics data integration, and limited technical capacity across breeding programs in sub-Saharan Africa. It discusses strategies to address these barriers through regional collaboration, investment in bioinformatics capacity, and the integration of computational approaches into breeding pipelines. Overall, the review concludes that combining multi-omics technologies with artificial intelligence and machine learning has strong potential to improve genotype-phenotype prediction, accelerate breeding decisions, and support the development of climate-resilient and nutritionally enhanced cowpea cultivars.

cowpea↗
PubMed2002

Organisation of the human genome and our tools for identifying disease genes.

Determination of the sequence of the human genome has been a major undertaking. It provided powerful tools to explore the genetic component in complex diseases. To fully understand the genetic pathways contributing to complex disease traits, we must not only reveal the genomic locus of all genes involved, but also delineate the functionally relevant allelic variation in such genes and understand the patterns of gene expression leading up to the actual disease trait. Insight in the genetic contribution to clinical endpoints of complex disease and their biological risk factors, therefore, requires an understanding of both the structure and the biology of the genome. This paper constitutes a tutorial overview of the organisation of the human genome, the tools it provides for molecular genetic studies, and the genomic background of the current strategies for gene identification.

Alleles↗
PubMed2005

Quantitative trait loci mapped to single-nucleotide resolution in yeast.

Identifying the genetic variation underlying quantitative trait loci remains problematic. Consequently, our molecular understanding of genetically complex, quantitative traits is limited. To address this issue directly, we mapped three quantitative trait loci that control yeast sporulation efficiency to single-nucleotide resolution in a noncoding regulatory region (RME1) and to two missense mutations (TAO3 and MKT1). For each quantitative trait locus, the responsible polymorphism is rare among a diverse set of 13 yeast strains, suggestive of genetic heterogeneity in the control of yeast sporulation. Additionally, under optimal conditions, we reconstituted approximately 92% of the sporulation efficiency difference between the two genetically distinct parents by engineering three nucleotide changes in the appropriate yeast genome. Our results provide the highest resolution to date of the molecular basis of a quantitative trait, showing that the interaction of a few genetic variants can have a profound phenotypic effect.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Epistatic and environmental control of genome-wide gene expression.

All etiological studies of complex human traits focus on analyzing the causes of variation. Given this complexity, there is a premium on studying those processes that mediate between gene products and cellular or organismal phenotypes. Studies of levels of gene expression could offer insight into these processes and are likely to be especially useful to the extent that the major sources of their variation are known in normal tissues. The classical study of monozygotic (MZ) and dizygotic (DZ) twins was employed to partition the genetic and environmental influences in gene expression for over 6500 human genes measured using microarrays from lymphoblastoid cell lines. Our results indicate that mean expression levels are correlated about .3 in monozygotic (MZ) and .0 in dizygotic (DZ) twins suggesting an overall epistatic regulation of gene expression. Furthermore, the functions of several of the genes whose expression was most affected by environmental effects, after correction for measurement error, were consistent with their known role in mediating sensitivity to environmental influences.

Adolescent↗
PubMed2002

Naturally occurring variation in cardiovascular traits among inbred mouse strains.

The objective of this study was to characterize genetic variation in complex cardiovascular traits in two commonly used inbred mouse strains. We performed echocardiography, graded treadmill exercise, tail cuff plethysmography, and telemetry (heart rate, activity, temperature) in age- ( approximately 9 weeks) and sex-matched A/J and C57BL/6J (B6) inbred mice. B6 mice had significantly larger end-diastolic dimension (3.31+/-0.42 mm versus 2.83+/-0.31 mm) and left ventricle mass (46.2+/-14.1 versus 32.7+/-11.5 g) than A/J mice. This relative hypertrophy was eccentric (relative wall thickness ratios: 0.30+/-0.01 versus 0.32+/-0.01) and was not associated with a difference in systolic blood pressure (122.0+/-13.2 versus 123.1+/-20.8 mmHg). Left ventricle fractional shortening (39.1+/-6.2 versus 47.1+/-6.9%) and heart rate (433+/-55 versus 524+/-45 beats per minute) were significantly lower in B6 versus A/J, respectively, resulting in similar resting echocardiographic cardiac indices (0.58+/-0.19 versus 0.50+/-0.17 ml/min/g). Maximum exercise time on a treadmill was significantly greater in B6 than in A/J mice (9.6+/-3.4 versus 4.4+/-1.9 minutes). Telemetry showed that body temperature was generally greater and heart rate lower in B6 than A/J; the relation with activity was more complex. These data suggest that relative to A/J, B6 mice have a phenotype characteristic of the "athlete's heart," that is, eccentric, physiologic hypertrophy, slower heart rates, and increased exercise endurance. This systematic characterization of functionally related cardiovascular traits in A/J and C57BL/6J mice revealed numerous differences whose genetic bases can be dissected with recombinant inbred, recombinant congenic, and chromosome substitution strains.

Animals↗