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PubMed1999

Viral load and a locus on chromosome 11 affect the late clinical disease caused by Theiler's virus.

Theiler's virus causes a persistent infection and a demyelinating disease of mice which is a model for multiple sclerosis. Susceptibility to viral persistence maps to several loci, including the interferon gamma locus. Inactivating the gene coding for the interferon gamma receptor makes 129/Sv mice susceptible to persistent infection and clinical disease, whereas inactivating the interferon gamma gene makes C57BL/6 mice susceptible to persistent infection but not to clinical disease. This difference in phenotype is due to the difference in genetic background. Clinical disease depends on high viral load and Tmevd5, a locus on chromosome 11. These results have consequences for the identification of viruses which might be implicated in multiple sclerosis.

Animals↗

PubMed2003

Early onset albuminuria in Dahl rats is a polygenetic trait that is independent from salt loading.

The aim of the study was to characterize the genetic basis for the early onset of increased urinary albumin excretion (UAE) observed in the salt-sensitive Dahl rat (SS). We first characterized blood pressures and UAE values in adult SS compared with the spontaneously hypertensive rat (SHR) strain. Blood pressure measurements by radiotelemetry at 14 wk demonstrated similar spontaneous hypertension in both strains on a low-sodium diet containing 0.2% NaCl by weight, whereas UAE was markedly increased in SS compared with SHR (253.07 +/- 68.39 vs. 1.65 +/- 1.09 mg/24 h, P < 0.0001). Analysis of UAE in young animals of both strains fed a low-sodium diet demonstrated that UAE is elevated in SS as early as 4 wk of age (P < 0.0001), when ultrastructural evaluation of glomeruli by electron microscopy appears still normal. At 8 wk SS demonstrated a 280-fold elevated UAE compared with SHR (P < 0.0001). Consequently, to identify quantitative trait loci (QTLs) contributing to salt-independent early manifestation of increased UAE in the SS rat, we performed genome-wide linkage and QTL mapping analysis in a young F(2) population derived from the two contrasting strains. UAE was determined in 539 F(2) animals at 8 wk. We identified seven suggestive or significant UAE QTLs on rat chromosomes (RNO) RNO2, RNO6, RNO8, RNO9, RNO10, RNO11, and RNO19, accounting together for 34% of the overall variance of UAE in this F(2) population. Thus early onset albuminuria in the SS rat is under polygenetic influence and independent from salt loading.

Albuminuria↗

PubMed1994

Mutation load depending on variance in reproductive success and mating system.

Equalization of reproductive success of individuals, although it results in an increase of effective population size, leads also to an increase of the mutation load. The magnitude of this increase depends highly on the mode of fitness interactions between deleterious mutations, and is higher in the case of inbreeding. Recommended practices in conservation genetics must be evaluated in regards to these differing consequences of an increase of effective population size. To keep a balance between retaining genetic variability and minimizing the increase of the mutation load, equalization of reproductive success of a set of individuals rather than of every individual might be more advantageous.

Animals↗

PubMed2005

Genetic polymorphisms in CX3CR1 predict HIV-1 disease progression in children independently of CD4+ lymphocyte count and HIV-1 RNA load.

BACKGROUND: The impact of CX3CR1 polymorphisms on human immunodeficiency virus type 1 (HIV-1) pathogenesis is controversial, with conflicting reports of their role in disease progression in HIV-1-infected adults. METHODS: A cohort of 1055 HIV-1-infected children were genotyped for 2 CX3CR1 polymorphisms, V/I249 and T/M280, and their impact on HIV-1-related disease progression, including central nervous system (CNS) impairment, was evaluated. RESULTS: Children with the CX3CR1 I/I249 genotype experienced more-rapid disease progression (I/I249 vs. V/V249: relative hazard [RH], 2.19 [95% confidence interval {CI}, 1.30-3.68], P=.003; I/I249 vs. V/I249: RH, 1.77 [95% CI, 1.00-3.14], P=.05) and a trend toward more CNS impairment (I/I249 vs. V/V249: RH, 2.19 [95% CI, 1.00-4.78], P=.049; I/I249 vs. V/I249: RH, 2.02 [95% CI, 0.85-4.83], P=.11). Children with the V249-T280 haplotype experienced significantly less disease progression (RH, 0.42 [95% CI, 0.24-0.73]; P=.002) and CNS impairment (RH, 0.39 [95% CI, 0.39-0.22]; P=.001). Of note, these effects remained significant after CD4+ lymphocyte count and plasma HIV-1 RNA load at baseline were adjusted for and in a longitudinal, multivariate analysis. CONCLUSIONS: CX3CR1 genotypes and haplotypes impact HIV-1 disease progression independently of CD4+ lymphocyte count and plasma HIV-1 RNA load, suggesting that the fundamental role of CX3CR1 in the alteration of disease progression might be the recruitment of immunomodulatory cells responsible for the control of HIV-1.

CD4 Lymphocyte Count↗

PubMed2006

How gene-stress-behavior interactions can promote adolescent alcohol use: the roles of predrinking allostatic load and childhood behavior disorders.

A variety of environmental and genetic factors modulating the risk for alcoholism have been described, which predominantly act by interacting with each other. For example, the family, peers and society determine the level of exposure to stress and alcohol, while genes modulate how sensitive an individual responds to both. The resulting behaviors feed back to the social environment, modulating and in the worst case increasing further stress exposure. We here review neurobiological evidence how such a process of mutual interaction can involve and affect drinking. In at-risk adolescents it may have been in force for many years before they have their first alcoholic drink, increasing their risk for addiction by generating allostatic load. As an example, psychiatric disorders involving attention deficit, hyperactivity, or disruptive behaviors first evolve during childhood and are influenced by all the above factors. They are also strongly associated with harmful adolescent drinking and later alcohol use disorders. One important implication of this concept is that issues such as family adversity, adolescent psychiatric disorders, or adolescent drinking might not only be associated with, but causally related to, the risk for later addiction. They are targets for preventive interventions, which should start as early as possible in subjects at-risk.

Adolescent↗

PubMedDate not supplied

[Genetic variability of hepatitis C virus in the health area of Elche (Spain). Correlation between core antigen and viral load].

We investigated the prevalence of the various genotypes of hepatitis C virus (HCV) in 281 patients evaluated between March, 2000 and March, 2002 in the health area of Elche. Of these patients, 55 were coinfected with human immunodeficiency virus (HIV). The genotype was related to viral load and the co-existence of HIV infection. Likewise, the relationship between these parameters and the presence of the HCV core antigen was established. The results indicate that genotype 1b was the most prevalent (38.4%) followed by genotype 3a (23.1%). Patients coinfected with HIV presented fewer infections due to group 1 genotypes (p < 0.05).Patients with HIV presented a greater viral load in all the genotypes, with genotype 3 presenting a high viral load. Detection of the HCV core antigen showed a close correlation with viral load determinations. Although not yet sufficiently assessed, determination of the HCV core antigen constitutes a simple technique that could eventually contribute to improving the management of patients with chronic HCV hepatitis.

AIDS-Related Opportunistic Infections↗

PubMed1999

Fasting, postprandial, and post-methionine-load homocysteinaemia and methylenetetrahydrofolate reductase polymorphism in vascular disease.

Hyperhomocysteinaemia is an independent risk factor for cardiovascular disease. The C677T mutation of the methylenetetrahydrofolate reductase (MTHFR) is a common genetic cause of increased homocysteine (HCY) levels. Post-methionine-load HCY concentrations allow identification of certain cases of hyperhomocysteinaemia not demonstrated by fasting levels. This study investigated the relationship between MTHFR polymorphism and (1) fasting HCY levels (77 patients); (2) post-methionine HCY levels (54 patients); and (3) postprandial HCY concentrations (36 patients) in cardiovascular disease. As expected, mean fasting HCY value was higher in the +/+ patients. Moreover, patients who were homozygous for the mutation exhibited significantly increased mean post-methionine-load HCY; in contrast, literature results are conflicting. Mean postprandial HCY, which is not known to be increased in controls, was also increased in the (+/+) patients, although the difference did not reach statistical significance, probably owing to the small size of the sample. MTFHR polymorphism is known to be aggravated by a drop in circulating folate. Additional risk factors may be more prevalent in patients with cardiovascular disease.

Adolescent↗

PubMed1986

Central alpha-adrenoceptors during the development of hypertension in rats on high and low salt intake.

Our purpose was to investigate the binding characteristics of central alpha-adrenoceptors during the early stages of the development of hypertension in rats on high and low salt (NaCl) intake. We measured alpha 1-[( 3H]prazosin) and alpha 2-[( 3H]rauwolscine) binding in membranes of the hypothalamus and medulla oblongata of six groups of young Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHR) and subtotally nephrectomized WKY (SN) rats with mean arterial blood pressure (MAP) ranging from normotensive to hypertensive levels after 1 week of salt restriction or loading. In the hypothalamus the SN-high salt rats and both SHR groups had elevated alpha 1-number but there was no change in alpha 2-number. Moreover, MAP was positively correlated with mean hypothalamic alpha 1-number in the six groups. In the medulla oblongata alpha 1-number was unaffected. However, high salt diet influenced medullary alpha 2-binding in the opposite manner in WKY rats versus SN rats and SHR. In these latter groups the affinity was increased and the number decreased in response to high salt intake. Furthermore, a positive correlation between MAP and mean alpha 1:alpha 2 ratio existed in both the hypothalamus and the medulla of the six groups. The data suggest that hypothalamic alpha 1-binding capacity was increased in SHR due principally to a genetic condition which is mimicked by salt loading in the SN rats. Medullary alpha 2-adrenoceptors of WKY, which remained normotensive despite salt loading, responded differently to high salt intake than those of the SN and SHR, whose blood pressure rose significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2005

A novel expression system for genomic DNA loci using a human artificial chromosome vector with transformation-associated recombination cloning.

Following the recent completion of the human genome sequence, genomics research has shifted its focus to understanding gene complexity, expression, and regulation. However, in order to investigate such issues, there is a need to develop a practical system for genomic DNA expression. Transformation-associated recombination (TAR) cloning has proven to be a convenient tool for selective isolation of a genetic locus from a complex genome as a circular YAC using recombination in yeast. The human artificial chromosome (HAC) vector containing an acceptor loxP site has served as a platform for the reproducible expression of transgenes. In this study, we describe a system that efficiently expresses a genetic locus in mammalian cells by retrofitting a TAR-YAC with the donor loxP site and loading it onto the HAC vector by the Cre/loxP system. In order to demonstrate functional expression of genomic loci, the entire human hypoxanthine phosphoribosyl transferase (HPRT) locus contained in a 100 kb YAC was loaded onto the HAC vector and was shown to complement the genetic defect in Hprt-deficient CHO cells. Thus, the combination of TAR cloning and the HAC vector may serve as a powerful tool for functional genomic studies.

Animals↗

PubMed1987

Functional strain in bone tissue as an objective, and controlling stimulus for adaptive bone remodelling.

The skeleton consists of a series of elements with a variety of functions. In locations where shape or protection are of prime importance the bone's architecture is achieved during growth under direct genetic control. In locations where resistance to repetitive loading is important only the general form of the bone will be achieved as a result of growth alone, the remaining characteristics result from functional adaptation. This mechanism ensures that bone architecture is modelled and remodelled until prevailing strains match those genetically prescribed for that location. For this match to be established, and subsequently maintained, bone cells must be able to 'assess' feedback derived directly or indirectly from the functional strains produced within the tissue. These strains are therefore the objective of functionally adaptive remodelling, and the stimulus for its control. Evans was the first person to refer to the recording of functional strains from gauges attached to bone in vivo. This technique has allowed quantitative investigations on bone's normal functional strain environment, and its adaptive response to changes in its state of strain. Recent investigations have extended to the immediate effects of dynamic strains on the structure of the bone matrix, and the biochemical behaviour of the resident bone cells. Such studies should reveal the mechanism by which strains within the matrix are transduced into the biochemical signals by which adaptive remodelling is controlled.

Animals↗

PubMed2006

Viral load, organ distribution, histopathological lesions, and cytokine mRNA expression in goats infected with a molecular clone of the caprine arthritis encephalitis virus.

Caprine arthritis encephalitis virus (CAEV) is a lentivirus of goats that causes persistent infection characterized by the appearance of inflammatory lesions in various organs. To define the sites of persistence, 5 goats were infected with a molecular clone of CAEV, and the viral load was monitored by real-time-PCR and RT-PCR in different sites 8 years after infection. The lymph nodes proved to be an important virus reservoir, with moderate virus replication relative to what is reported for lentiviruses of primates. Mammary gland and milk cells were preferred sites of viral replication. The viral load varied significantly between animals, which points to an important role of the genetic background. We found a clear association between occurrence of histopathological lesions and viral load in specific sites. The mRNA expression analysis of several cytokines did not reveal differences between animals that could explain the considerable individual variations in viral load observed.

Animals↗

PubMed1998

Allelic variation in the vitamin D receptor, lifestyle factors and lumbar spinal degenerative disease.

OBJECTIVE: To describe the relation between spinal degenerative disease, allelic variation in the vitamin D receptor gene, and lifestyle factors in a population-based association study. METHODS: Random population-based sample of 110 men and 172 women over 60 years of age participating in the Dubbo Osteoporosis Epidemiology Study who had spinal radiographs (performed according to a standardised approach), assessment of lifestyle factors, bone densitometry as well as blood taken for genotyping. RESULTS: Spinal degenerative disease of varying severity was common in this sample. Multivariate analysis of genetic and lifestyle factors simultaneously strengthened the statistical significance of each indicating the presence of additive gene environment interaction. Allelic variation in the vitamin D receptor gene was associated with severity of osteophytosis (adjusted OR "TT" v "tt" 0.41, 95% CI 0.17, 0.97), presence of disc narrowing (adjusted OR "TT" v "tt" 0.45, 95% CI 0.20, 0.99) and weakly with presence of osteophytosis (adjusted OR "TT" v "tt" 0.47, 95% CI 0.19, 1.16) but not with severity of disc narrowing (OR "TT" v "tt" 1.05, 95% CI 0.40, 2.72) or apophyseal arthritis (OR "TT" v "tt" 0.63, 95% CI 0.24, 1.59). Adjustment for femoral neck bone density did not change these findings suggesting that the association is not mediated through bone density. Presence and severity of spinal degenerative disease increased with age at all sites. Current smoking increased both the presence (adjusted OR 9.70, 95% CI 2.08, 45.1) and severity (adjusted OR 2.91, 95% CI 1.16, 9.03) of spinal osteophytosis with intermediate values for past smokers. Severity of osteophytosis was also independently associated with body mass index and quadriceps strength consistent with a contributory effect of physical loading. CONCLUSIONS: In this elderly sample, both genetic and lifestyle factors were associated with the presence and severity of spinal degenerative disease. There were site specific differences in associations at the spine, which may be because of misclassification of disease status or may indicate possible environmental and genetic differences in the pathophysiology of spinal degenerative disease. Further studies are required to confirm these findings in different population samples and to further explore potential aetiological mechanisms particularly gene environment interaction.

Aged↗

PubMed2025

Common gardens reveal genomic susceptibility and vulnerability to climate change in Eucalyptus.

Accelerated global climate change and increased species introduction across international scales have raised concerns about the potential for trees to experience maladaptation or lagging adaptation in response to these environmental shifts. However, our knowledge regarding the relationship between the genomic metrics used to predict maladaptation and actual fitness proxies in trees remains limited. Here, we present a population genomic analysis of 295 families from 28 provenances of Eucalyptus pellita, a widely cultivated fast-growing tree species, and conducted two common garden experiments. Genomic susceptibility encompassing individual heterozygosity (H), genomic inbreeding (FROH), and genomic load (inferred from deleterious mutations) exhibited distinct geographic patterns, shedding light on the origin and evolutionary history of E. pellita. The genetic basis of local adaptation was elucidated through genotype-environment associations and genome-wide association studies, including 198 loci associated with climate and 2388 loci regulating different traits. Furthermore, Australian provenances have higher genomic vulnerability under prospective climate alterations than Papua New Guinea and Indonesia provenances. By integrating phenotypic data across two common gardens, the relationship between leaf functional traits and predicted metrics of maladaptation was closer than growth attributes. Notably, pronounced natural selection signals linked to leaf morphogenesis have been identified by comparing two lineages spanning the oceans. This study underscores the immense potential of leveraging genomic susceptibility and genomic vulnerability to decipher the local (mal)adaptation of forest trees.

Eucalyptus↗

PubMed2002

Host genetic profiles predict virological and immunological control of HIV-1 infection in adolescents.

OBJECTIVE: To evaluate the correlation between host genetic profiles and virological and immunological outcomes among HIV-1-seropositive participants from the Reaching for Excellence in Adolescent Care and Health (REACH) cohort. METHODS: HLA class I and chemokine coreceptor (CCR) alleles and haplotypes were resolved in 227 HIV-1-seropositive adolescents (ages 13-18 years; 75% females; 71% African-Americans) and 183 HIV-seronegative individuals, with quarterly follow-up visits between 1996 and 2000. Each HLA and CCR variant with consistent risk and protective effect on HIV-1 pathogenesis was assigned a score of -1 and +1, respectively. All individual markers and genetic scores were analyzed in relation to plasma viral load (VL) and CD4 T lymphocytes during a 6-12-month interval when no antiretroviral therapy was taken. RESULTS: HLA-B*57 alone was a strong predictor of VL (P < 0.0001), but composite genetic profiles found in over 50% of patients consistently outperformed the individual component markers in multivariable analyses with or without adjustment for gender, race, age, and membership of clinical patient groups. Adolescents (n = 37) with a favorable combination of VL (< 1000 copies/ml) and CD4 T cell counts (> 450 x 10(6) cells/l) consistently had more positive (+1 to +2) than negative (-1 to -4) HLA and CCR scores compared with those (n = 56) with an unfavorable combination (VL > 16,000 copies/ml and CD4 cells < 450 x 10(6) cells/l) or the remainder (n = 134) of the cohort (overall P < 0.0001). CONCLUSION: A generalizable genetic scoring algorithm based on seven HLA class I and CCR markers is highly predictive of viremia and immunodeficiency in HIV-1-infected adolescents.

Adolescent↗

PubMed2005

Effect of a protease inhibitor-induced genetic bottleneck on human immunodeficiency virus type 1 env gene populations.

The initiation of drug therapy or the addition of a new drug to preexisting therapy can have a significant impact on human immunodeficiency virus type 1 (HIV-1) populations within a person. Drug therapy directed at reverse transcriptase and protease can result in dramatic decreases in virus load, causing a contraction in the virus population that represents a potential genetic bottleneck as a subset of virus with genomes carrying resistance mutations repopulate the host. While this bottleneck exerts an effect directly on the region that is being targeted by the drugs, it also affects other regions of the viral genome. We have applied heteroduplex tracking assays (HTA) specific to variable regions 1 and 2 (V1/V2) and variable region 3 (V3) of the HIV-1 env gene to analyze the effect of a genetic bottleneck created by the selection of resistance to ritonavir, a protease inhibitor. Subjects were classified into groups on the basis of the extent of the initial drop in virus load and the duration of virus load reduction. Subjects with a strong initial drop in virus load exhibited a loss of heterogeneity in the env region at virus load rebound; in contrast, subjects with a weak initial drop in virus load exhibited little to no loss of heterogeneity at virus load rebound in either region of env examined. The duration of virus load reduction also affected env populations. Subjects that had prolonged reductions exhibited slower population diversification and the appearance of new V1/V2 species after rebound. The longer reduction of virus load in these subjects may have allowed for improved immune system function, which in turn could have selected for new escape mutants. Subjects with rapid rebound quickly reequilibrated the entry env variants back into the resistant population. When the pro gene developed further resistance mutations subsequent to virus load rebound, no changes were observed in V1/V2 or V3 populations, suggesting that the high virus loads allowed the env populations to reequilibrate rapidly. The rapid equilibration of env variants during pro gene sequence transitions at high virus load suggests that recombination is active in defining the HIV-1 sequence population. Conversely, part of the success of suppressive antiviral therapy may be to limit the potential for evolution through recombination, which requires dually infected cells.

Acquired Immunodeficiency Syndrome↗

PubMed2007

Characteristics, causes and evolutionary consequences of male-biased mutation.

Mutation has traditionally been considered a random process, but this paradigm is challenged by recent evidence of divergence rate heterogeneity in different genomic regions. One facet of mutation rate variation is the propensity for genetic change to correlate with the number of germ cell divisions, reflecting the replication-dependent origin of many mutations. Haldane was the first to connect this association of replication and mutation to the difference in the number of cell divisions in oogenesis (low) and spermatogenesis (usually high), and the resulting sex difference in the rate of mutation. The concept of male-biased mutation has been thoroughly analysed in recent years using an evolutionary approach, in which sequence divergence of autosomes and/or sex chromosomes are compared to allow inference about the relative contribution of mothers and fathers in the accumulation of mutations. For instance, assuming that a neutral sequence is analysed, that rate heterogeneity owing to other factors is cancelled out by the investigation of many loci and that the effect of ancestral polymorphism is properly taken into account, the male-to-female mutation rate ratio, alpham, can be solved from the observed difference in rate of X and Y chromosome divergence. The male mutation bias is positively correlated with the relative excess of cell divisions in the male compared to the female germ line, as evidenced by a generation time effect: in mammals, alpham is estimated at approximately 4-6 in primates, approximately 3 in carnivores and approximately 2 in small rodents. Another life-history correlate is sexual selection: when there is intense sperm competition among males, increased sperm production will be associated with a larger number of mitotic cell divisions in spermatogenesis and hence an increase in alpham. Male-biased mutation has implications for important aspects of evolutionary biology such as mate choice in relation to mutation load, sexual selection and the maintenance of genetic diversity despite strong directional selection, the tendency for a disproportionate large role of the X (Z) chromosome in post-zygotic isolation, and the evolution of sex.

Cell Division↗

PubMed1995

Haploidy and androgenesis in Drosophila.

Adrogenesis, development from paternal but not maternal chromosomes, can be induced to occur in some organisms, including vertebrates, but has only been reported to occur naturally in interspecific hybrids of the Sicilian stick insect. Androgenesis has not been described previously in Drosophila. We now report the recovery of androgenetic offspring from Drosophila melanogaster females mutant for a gene that affects an oocyte- and embryo-specific alpha-tubulin. The androgenetic exceptions are X,X diploid females that develop from haploid embryos and express paternal markers on all 4 chromosomes. The exceptional females arise by fusion of haploid cleavage nuclei or failure of newly replicated haploid chromosomes to segregate, rather than fusion of two inseminating sperm. The frequency of androgenetic offspring is greatly enhanced by a partial loss-of-function mutant of the NCD (nonclaret disjunctional) microtubule motor protein, suggesting that wild-type NCD functions is pronuclear fusion. Diploidization of haploid paternal chromosome complements results in complete genetic homozygosity, which could facilitate studies of gene variation and mutational load in populations.

Animals↗

PubMed2004

Polymorphism in the interleukin-10 promoter affects both provirus load and the risk of human T lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis.

To investigate non-human leukocyte antigen candidate genes that influence the outcome of human T cell lymphotropic virus (HTLV) type I infection, we analyzed 6 single-nucleotide polymorphisms in the interleukin (IL)-10 promoter region in 280 patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and 255 HTLV-I-seropositive asymptomatic carriers from an area where HTLV-I is endemic. The IL-10 -592 A allele, which shows lower HTLV-I Tax-induced transcriptional activity than the C allele in the Jurkat T cell line, was associated with a >2-fold reduction in the odds of developing HAM/TSP (P=.011; odds ratio [OR], 0.50 [95% confidence interval, 0.30-0.86]) by reducing the provirus load in the whole cohort (P=.009, analysis of variance). Given the OR and the observed frequency of IL-10 -592 A, we demonstrate that this allele prevents approximately 44.7% (standard deviation, +/-13.1%) of potential cases of HAM/TSP, which indicates that it defines one component of the genetic susceptibility to HAM/TSP in the cohort.

Alleles↗