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PubMed1982

Pleiotropic and other genetic effects influencing the activities of brain and liver enzymes in congenic lines of C57BL/6J mice with defined electrophoretic variant markers.

A single genetic factor may affect the realization of several enzymes. To investigate the extent of pattern pleiotropy in the mouse, the activities of 28 enzymes in livers and brains from an inbred stock of C57BL/6JNctr and five F1 stocks heterozygous for known electrophoretic variants were measured. Five congenic backcross stocks of C57BL/6J, each homozygous for one or more electrophoretic markers, were mated with C57BL/6JNctr to construct the heterozygous variant F1 stocks. One of the five F1 stocks had no enzyme activities significantly different from those of C57BL/6JNctr, while two had one enzyme, one had four enzymes, and another had six enzymes with activities that were significantly different from those of C57BL/6JNctr. The latter two F1 stocks with multiple activity differences were those having the largest proportion of their genome of donor origin. Two of the F1 stocks were different from each other for one enzyme, and two were different for another enzyme. These differences and the relationship of these enzyme activities to the variant genes suggest that several genetic factors may affect an enzyme's realization.

Animals↗

PubMed1986

Genetic determination of striatal tyrosine hydroxylase activity in mice.

An additive major gene effect is described for tyrosine hydroxylase activity in mouse corpus striatum (CS). Quantitative genetic analysis indicated the presence of a segregating Mendelian factor with robust additive effect in F2 generations derived from crossing two highly inbred mouse strains, C57BL/6ByJ and BALB/cJ, with intermediate (INT) and high (HI) TH activity in CS. Significant positive correlation was found between striatal and mesencephalic TH activity in the segregating generations, raising the possibility that a common single gene may express its effect through pleiotropy or linkage. Genetic preparations taking advantage of the major gene effect should serve well as animal models of DA-mediated neuropsychiatric disorders.

Animals↗

PubMed1993

Evolutionary mechanisms of senescence.

This paper reviews theories of the evolution of senescence. The population genetic basis for the decline with age in sensitivity of fitness to changes in survival and fecundity is discussed. It is shown that this creates a pressure of selection that disproportionately favors performance early in life. The extent of this bias is greater when there is a high level of extrinsic mortality; this accounts for much the diversity in life-history patterns among different taxa. The implications of quantitative genetic theory for experimental tests of alternative population genetic models of senescence are discussed. In particular, the negative genetic correlations between traits predicted by the antagonistic pleiotropy model may be obscured by positive correlations that are inevitable in a multivariate system, or by the effects of variation due to deleterious mutations. The status of the genetic evidence relevant to these theories is discussed.

Age Factors↗

PubMed1993

Genetic influences on glucose neurotoxicity, aging, and diabetes: a possible role for glucose hysteresis.

Glucose may drive some age-correlated impairments and may mediate some effects of dietary restriction on senescence. The hypothesis that cumulative deleterious effects of glucose may impair hypothalamic neurons during aging, leading to hyperinsulinemia and other age-correlated pathologies, is examined in the context of genetic influences. Susceptibility to toxic effects of gold-thio-glucose (GTG) is correlated with longevity across several mouse strains. GTG and chronic hyperglycemia induce specific impairments in the ventromedial hypothalamus similar to impairments which occur during aging. GTG and a high-calorie diet both induce chronic hyperinsulinemia, leading initially to hypoglycemia, followed by the development of insulin resistance and hyperglycemia. Aging in humans and rodents appears to entail a similar pattern of hyperinsulinemia followed by insulin resistance. In humans, genetic susceptibility to high-calorie diet-induced impairments in glucose metabolism is extremely common in many indigenous populations, possibly due to the selection of the 'thrifty genotype'. It is suggested that the 'thrifty genotype' may entail enhanced sensitivity to the neurotoxic effects of glucose, and may represent an example of antagonistic pleiotropy in human evolution. These data are consistent with the hypothesis that genetic susceptibility of hypothalamic neurons to the cumulative toxic effects of glucose (glucose neurohumoral hysteresis) may correlate with genetic influences on longevity.

Aging↗

PubMed1980

Immunogenetics of response to a purified antigen from group A streptococci. II. Linkage of response to HLA.

Employing an in vitro blastogenesis model, evidence has been set forth for a major gene locus which controls response to a purified, extracellular antigen from group A streptococci. Response to this antigen is inherited in an autosomal dominant manner. Analysis of the data for linkage to HLA was done with the computer program LINKAS which can resolve pleiotropy from linkage and can detect and estimate recombination in the presence of etiological heterogeneity. Maximum likelihood estimation and likelihood ratio tests were used to assess the relative support for competing hypotheses. The results of this analysis indicate that at least two loci are involved in one of two ways: one locus that is closely linked to HLA and one locus that is unlinked; or a two-locus system of complementary alleles which are both tightly linked to HLA.

Adolescent↗

PubMed2001

Pleiotropic morphological and abiotic stress resistance phenotypes of the hyper-abscisic acid producing Abo- mutant in the periwinkle Catharanthus roseus.

The pleiotropic properties of a abo abo (Abo-) gamma-ray induced mutant of Catharanthus roseus cv. Nirmal, selected among the M2 generation seeds for ability to germinate at 45 degrees C, are described. The mutant produced seeds possessing tricotyledonous embryos, unlike the typically dicotyledonous embryos present in the wild type Abo+ seeds. In comparison to Abo+ adults, the mutant plants had short stature and lanceolate leaves. The vascular bundles in the leaves and stem were poorly developed. Leaf surfaces were highly trichomatous, epidermal, cortex and mesophyll cells were small sized and a large majority of stomata were closed. Besides high temperature, the mutant was salinity and water-stress tolerant. The abscisic acid (ABA) content in the leaves was about 500-fold higher. The genetic lesion abo responsible for the above pleiotropy was recessive and inherited in Mendelian fashion. The seedlings and adult plants of the mutant accumulated higher proline than Abo+ plants. The phenotypes of abo abo mutants permitted the conclusions that (i) the mutant synthesizes ABA constitutively, (ii) both ABA-dependent and ABA independent pathways for proline and betaine accumulation are functional in the mutant, and (iii) cell division, elongation and differentiation processes in embryo and adult plant stages are affected in the mutant

Abscisic Acid↗

PubMed1997

The genetic basis of atherosclerosis.

Atherogenesis is a complex process that involves the contributions of several pathophysiological sub-systems. The dissection of the genetic component of atherosclerosis has become possible using current molecular technologies and analytical methods. Genetic factors are considered to determine the limits under which atherosclerosis develops and environmental factors are considered to position an individual's risk within these limits. Atherosclerosis proceeds through a well-characterized series of pathological stages that involve key cell types and the expression of particular gene products. Reductionist experimental models have helped to produce a list of several hundred candidate genes for the study of the genetic component of atherosclerosis. Within certain families and isolated communities the effect of a single candidate gene upon atherosclerosis susceptibility may be profound, as in the case of mutations in the gene encoding the low-density lipoprotein receptor, which produce familial hypercholesterolemia and premature atherosclerosis. However, particular candidate genes have small effects on atherosclerosis or to one of its intermediate phenotypes, in whole populations. In addition, pleiotropy and epistasis can confound the identification of the genetic component of atherosclerosis. Despite these limitations, it might still be possible to use genetic information clinically in order to classify individuals who are susceptible to atherosclerosis, especially if as yet undiscovered candidate genes are found to be important determinants of disease. However, it will be impossible to predict the onset of a clinical manifestation of atherosclerosis in a particular person. This is due to the confounding influence of other forces, such as variations in interindividual environmental landscape, non-linear interactions between genes and environment, and even the possible influence of biological chaos.

Arteriosclerosis↗

PubMed1988

Cellular and molecular aspects of myelin protein gene expression.

The cellular and molecular aspects of myelin protein metabolism have recently been among the most intensively studied in neurobiology. Myelination is a developmentally regulated process involving the coordination of expression of genes encoding both myelin proteins and the enzymes involved in myelin lipid metabolism. In the central nervous system, the oligodendrocyte plasma membrane elaborates prodigious amounts of myelin over a relatively short developmental period. During development, myelin undergoes characteristic biochemical changes, presumably correlated with the morphological changes during its maturation from loosely-whorled bilayers to the thick multilamellar structure typical of the adult membrane. Genes encoding four myelin proteins have been isolated, and each of these specifies families of polypeptide isoforms synthesized from mRNAs derived through alternative splicing of the primary gene transcripts. In most cases, the production of the alternatively spliced transcripts is developmentally regulated, leading to the observed protein compositional changes in myelin. The chromosomal localizations of several of the myelin protein genes have been mapped in mice and humans, and abnormalities in two separate genes appear to be the genetic defects in the murine dysmyelinating mutants, shiverer and jimpy. Insertion of a normal myelin basic protein gene into the shiverer genome appears to correct many of the clinical and cell biological abnormalities associated with the defect. Most of the dysmyelinating mutants, including those in which the genetic defect is established, appear to exhibit pleiotropy with respect to the expression of other myelin genes. Post-translational events also appear to be important in myelin assembly and metabolism. The major myelin proteins are synthesized at different subcellular locations and follow different routes of assembly into the membrane. Prevention of certain post-translational modifications of some myelin proteins can result in the disruption of myelin structure, reminiscent of naturally occurring myelin disorders. Studies on the expression of myelin genes in tissue culture have shown the importance of epigenetic factors (e.g., hormones, growth factors, and cell-cell interactions) in modulating myelin protein gene expression. Thus, myelinogenesis has proven to be very useful system in which to examine cellular and molecular mechanisms regulating the activity of a nervous system-specific process.

Animals↗

PubMed2003

Relaxin: a pregnancy hormone as central player of body fluid and circulation homeostasis.

The peptide relaxin has long been regarded as an important hormone of pregnancy, contributing to changes in connective tissue composition as well as to regulation of implantation, myometrial activity and labor. On the other hand, the astonishing pleiotropy of this hormone escaped scientific awareness. This review focuses on new facets of relaxin, including its antifibrotic effects, its role in the control of pituitary hormone release, its vasodilator and pro-angiogenic properties and its versatile myocardial actions. Recent progress in understanding relaxin's receptor and signaling mechanisms is also highlighted. The peptide will be characterized as potential regulator of body fluid and circulation homeostasis.

Blood Circulation↗

PubMed2003

The free-radical hypothesis of aging goes prokaryotic.

With respect to oxidative damage and its targets, growth-arrested bacterial cells show some of the same signs of senescence as aging insects, worms and mammals. In addition, the fact that the life span of growth-arrested Escherichia coli cells is greatly extended by limiting oxygen availability suggests that free radicals may be one causal factor behind bacterial senescence. Recent analysis reveals a novel culprit in this oxidation, namely the production of aberrant proteins, which are especially susceptible to oxidative attack. This route of oxidation appears to elude the classical oxidative defense proteins. In addition, the failure of growth-arrested cells to fully combat oxidative damage may be linked to a trade-off between proliferation activities and stress management. Even during stasis, E. coli cells maintain a basal transcription of reproduction-related genes, and resources are thus partly diverted from maintenance and stress defences to activities relating to proliferation. Thus, some aspects of bacterial senescence may lend support to contemporary theories of aging, including the free radical, antagonistic pleiotropy, and disposable soma theories.

Animals↗

PubMed2002

QTL clusters reflect character associations in wild and cultivated rice.

The genetic basis of character association related to differentiation found in the primary gene pool of rice was investigated based on the genomic distribution of quantitative trait loci (QTLs). Major evolutionary trends in cultivated rice of Asiatic origin ( Oryza sativa) and its wild progenitor ( O. rufipogon) are: (1) differentiation from wild to domesticated types (domestication), (2) ecotype differentiation between the perennial and annual types in wild races, and (3) the Indica versus Japonica type differentiation in cultivated races. Using 125 recombinant inbred lines (RILs) derived from a cross between an Indica cultivar of O. sativa and a strain of O. rufipogon carrying some Japonica-like characteristics, we mapped 147 markers, mostly RFLPs, on 12 chromosomes. Thirty-seven morphological and physiological quantitative traits were evaluated, and QTLs for 24 traits were detected. The mapped loci showed a tendency to form clusters that are composed of QTLs of the domestication-related traits as well as Indica/Japonica diagnostic traits. QTLs for perennial/annual type differences did not cluster. This cluster phenomenon could be considered "multifactorial linkages" followed by natural selection favoring co-adapted traits. Further, it is possible that the clustering phenomenon is partly due to pleiotropy of some unknown key factor(s) controlling various traits through diverse metabolic pathways. Chromosomal regions where QTL clusters were found coincided with the regions harboring genes or gene blocks where the frequency of cultivar-derived alleles in RILs is higher than expected. This distortion may be partly due to unconscious selection favoring cultivated plant type during the establishment of RILs.

Journal Article↗

PubMed2002

Molecular dissection of the genetic relationships of source, sink and transport tissue with yield traits in rice.

Source, sink, and translocation capacity of assimilates play important roles during the formation of grain yield. The present study was conducted to characterize the genetic bases of traits representing source, sink and transport tissue, and their relationships with yield traits in rice, by analyzing QTLs for these traits and various ratios among them. The genetic materials were a recombinant inbred population derived from a cross between two indica cultivars Zhenshan 97 and Minghui 63, the parents of the most-widely grown hybrid rice in China. Using a linkage map that covers a total of 1,796 cM based on 221 molecular marker loci, a total of 81 QTLs were identified for the 15 traits studied (three leaf areas as the source, total spikelets per panicle as the sink, the number of large vascular bundles in the stem as transport tissue, three source to sink ratios, three transport tissue to source ratios, one transport tissue to sink ratio and three yield traits). The amount of variation explained by individual QTLs ranged from 1.12% to 24.14%. Five QTLs were identified to show interaction effects with the environment, which explained from 3.19% to 9.15% of the variation. The results showed that close linkage or pleiotropy is the genetic basis for the correlations of grain yield traits with source, sink, transport tissue and the various ratios among them. Of the 25 QTLs identified for source-sink-transport tissue trait, and 43 for various ratios, 8 and 22 QTLs, respectively, were mapped to the similar genomic blocks harboring QTLs for yield traits, especially for grain weight. Co-location of QTLs for yield traits with those for ratios among source, sink and transport tissue may provide a genetic explanation for the physiological expression of yield traits, and also suggest that improvement in ratios among source, sink and transport tissue may result in improvement in yield potential.

Chimera↗

PubMed2003

Identification of putative QTL that underlie yield in interspecific soybean backcross populations.

Glycine soja, the wild progenitor of soybean, is a potential source of useful genetic variation in soybean improvement. The objective of our study was to map quantitative trait loci (QTL) from G. soja that could improve the crop. Five populations of BC(2)F(4)-derived lines were developed using the Glycine max cultivar IA2008 as a recurrent parent and the G. soja plant introduction (PI) 468916 as a donor parent. There were between 57 and 112 BC(2)F(4)-derived lines in each population and a total of 468 lines for the five populations. The lines were evaluated with simple sequence repeat markers and in field tests for yield, maturity, plant height, and lodging. The field testing was done over 2 years and at two locations each year. Marker data were analyzed for linkage and combined with field data to identify QTL. Using an experimentwise significance threshold of P=0.05, four yield QTL were identified across environments on linkage groups C2, E, K, and M. For these yield QTL, the IA2008 marker allele was associated with significantly greater yield than the marker allele from G. soja. In addition, one lodging QTL, four maturity QTL, and five QTL for plant height were identified across environments. Of the 14 QTL identified, eight mapped to regions where QTL with similar effects were previously mapped. Many regions carrying the yield QTL were also significant for other traits, such as plant height and lodging. When the significance threshold was reduced and the data were analyzed with simple linear regression, four QTL with a positive allele for yield from G. soja were mapped. One epistatic interaction between two genetic regions was identified for yield using an experimentwise significance threshold of P=0.05. Additional research is needed to establish whether multiple trait associations are the result of pleiotropy or genetic linkage and to retest QTL with a positive effect from G. soja.

Analysis of Variance↗

PubMed2005

The Vrn-H2 locus is a major determinant of flowering time in a facultative x winter growth habit barley (Hordeum vulgare L.) mapping population.

With the aim of dissecting the genetic determinants of flowering time, vernalization response, and photoperiod sensitivity, we mapped the candidate genes for Vrn-H2 and Vrn-H1 in a facultative x winter barley mapping population and determined their relationships with flowering time and vernalization via QTL analysis. The Vrn-H2 candidate ZCCT-H genes were completely missing from the facultative parent and present in the winter barley parent. This gene was the major determinant of flowering time under long photoperiods in controlled environment experiments, irrespective of vernalization, and under spring-sown field experiments. It was the sole determinant of vernalization response, but the effect of the deletion was modulated by photoperiods when the vernalization requirement was fulfilled. There was no effect under short photoperiods. The Vrn-H1 candidate gene (HvBM5A) was mapped based on a microsatellite polymorphism we identified in the promoter of this gene. Otherwise, the HvBM5A alleles for the two parents were identical. Therefore, the significant flowering time QTL effect associated with this locus suggests tight linkage rather than pleiotropy. This QTL effect was smaller in magnitude than those associated with the Vrn-H2 locus and was significant in two-way interactions with Vrn-H2. The Vrn-H1 locus had no effect on vernalization response. Our results support the Vrn-H2/Vrn-H1 repressor/structural gene model for vernalization response in barley and suggest that photoperiod may also affect the Vrn genes or tightly linked loci.

Chromosome Mapping↗

PubMed2005

QTLs mapping for fruit size and shape in chromosomes 2 and 4 in pepper and a comparison of the pepper QTL map with that of tomato.

Quantitative trait locus (QTL) mapping for fruit weight and shape in pepper (Capsicum spp.) was performed using C. chinense and C. frutescens introgression lines of chromosomes 2 and 4. In chromosome 2, a single major fruit-weight QTL, fw2.1, was detected in both populations that explained 62% of the trait variation. This QTL, as well as a fruit-shape QTL, fs2.1, which had a more minor effect, were localized to the tomato fruit-shape gene ovate. The cloned tomato fruit-weight QTL, fw2.2, did not play a major role in controlling fruit size variations in pepper. In chromosome 4, two fruit-weight QTLs, fw4.1 and fw4.2, were detected in the same genomic regions in both mapping populations. In addition, a single fruit-shape QTL was detected in each of the mapping populations that co-localized with one of the fruit-weight QTLs, suggesting pleiotropy or close linkage of the genes controlling size and shape. fw2.1 and fw4.2 represent major fruit-weight QTLs that are conserved in the three Capsicum species analyzed to date for fruit-size variations. Co-localization of the pepper QTLs with QTLs identified for similar traits in tomato suggests that the pepper and tomato QTLs are orthologous. Compared to fruit-shape QTLs, fruit-weight QTLs were more often conserved between pepper and tomato. This implies that different modes of selection were employed for these traits during domestication of the two Solanaceae species.

Capsicum↗

PubMed2005

Genetic determination and correlation of body mass index and bone mineral density at the spine and hip in Chinese Han ethnicity.

The purpose of the present study was to evaluate the magnitude of genetic determination of spine and hip bone mineral density (BMD) and body mass index (BMI), and to explore the genetic, environmental, and phenotypic correlations among the above phenotypes in Chinese Han ethnicity. The sample was composed of at least 217 complete nuclear families in Chinese Han ethnicity. BMD at the spine and hip was measured using a dual-energy X-ray absorptiometry scanner. The heritability (h2) of BMI and BMD at the spine and hip, the genetic correlation (rhoG) and environmental correlation (rhoE) among the three phenotypes were evaluated via variance analysis, with age, sex, and age-by-sex interaction as covariates. The phenotypic correlation (rhoP) and the bivariate heritability rhoG2 were also calculated. The heritability for BMD and BMI was approximately 0.70 and approximately 0.50, respectively (p<0.0001). The common environment shared by household members (household effect) is significant for BMI variation (p=0.0004). Significant genetic, environmental, and phenotypic correlation was observed. The rhoG2 values were 0.13 for BMI/spine BMD, 0.18 for BMI/hip BMD, and 0.58 for the spine BMD/hip BMD. While BMD at the spine and hip have significant genetic determination, BMI is more likely to be affected by environmental factors than BMD. In addition, BMD at the spine and hip shares more genetic effect (pleiotropy) than BMI and BMD do in Chinese Han ethnicity, though the effects are significant for both.

Adult↗

PubMed2006

Unique and common genetic effects between bone mineral density and calcaneal quantitative ultrasound measures: the Fels Longitudinal Study.

INTRODUCTION: Areal bone mineral density (BMD) and calcaneal quantitative ultrasound (QUS) measures are correlated, and both traits predict osteoporotic fracture risk independently. However, few studies have examined whether common genetic effects (i.e., pleiotropy) exist between these traits in extended families. In this study, we estimated the additive genetic correlation and random environmental correlation between BMD measured at various skeletal sites and calcaneal QUS measures. METHODS: Our sample included 537 adults (251 men and 286 women) from 110 families participating in the Fels Longitudinal Study. Total hip, femoral neck, lumbar spine, and total body BMD were measured using dual energy X-ray absorptiometry. Three measures of calcaneal structure--broadband ultrasound attenuation (BUA), speed of sound (SOS), and quantitative ultrasound index (QUI)--were collected from the non-dominant heel using the Sahara sonometer. Applying a variance components-based maximum likelihood method, we estimated the heritability of each trait and estimated the genetic and environmental correlations between the different BMD and QUS measures. RESULTS: Heritability estimates were significant for all measures of BMD and QUS ranging from 0.55 to 0.78. Significant non-zero genetic correlations were found between the different BMD and QUS measures. All genetic correlations were also significantly different from 1. Genetic correlations between total hip BMD and each of the QUS measures were 0.63 with BUA, 0.50 with SOS, and 0.56 with QUI. For femoral neck BMD, genetic correlations were similar to those between total hip BMD and QUS measures. Genetic correlations between BMD of the lumbar spine and QUS measures ranged from 0.34 to 0.38, and those between total body BMD and QUS measures, from 0.51 to 0.54. In contrast, all random environmental correlations were not significantly different from zero. CONCLUSION: This study demonstrates that BMD and calcaneal QUS measures among healthy men and women are significantly heritable and are, in part, jointly influenced by a common set of underlying genes. Additionally, this study also provides evidence for a unique set of genes that independently influences each individual trait.

Absorptiometry, Photon↗

PubMed2004

Physiological and pathological roles of alpha3beta1 integrin.

Alpha3beta1 integrin has been considered to be a mysterious adhesion molecule due to the pleiotropy in its ligand-binding specificity. However, recent studies have identified laminin isoforms as high-affinity ligands for this integrin, and demonstrated that alpha3beta1 integrin plays a number of essential roles in development and differentiation, mainly by mediating the establishment and maintenance of epithelial tissues. Furthermore, alpha3beta1 integrin is also implicated in many other biological phenomena, including cell growth and apoptosis, angiogenesis and neural functions. This integrin receptor forms complexes with various other membrane proteins, such as the transmembrane-4 superfamily proteins (tetraspanins), cytoskeletal proteins and signaling molecules. Recently, lines of evidence have been reported showing that complex formation regulates integrin functions in cell adhesion and migration, signal transduction across cell membranes, and cytoskeletal organization. In addition to these roles in physiological processes, alpha3beta1 integrin performs crucial functions in various pathological processes, especially in wound healing, tumor invasion and metastasis, and infection by pathogenic microorganisms.

Animals↗