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PubMed1979

'Our load of mutation': reappraisal of an old problem.

H. J. Muller, in a paper in 1950 entitled 'Our load of mutation', predicted the genetic decay of the human species due to increasing mutation pressure combined with relaxation of natural selection. In the meantime, much information on spontaneous and induced mutations in humans has been accumulated, and a reappraisal of Muller's conclusions gives a much less gloomy overall picture. However, a certain increase of malformation and disease can be predicted as a result of ionizing radiation and chemical mutagens. On the other hand, genetic counselling and antenatal diagnosis of genetic anomalies may help to keep the genetic risks within tolerable limits. Research on the biological conditions for the untoward effects of mutagenic chemicals considered necessary for the wellbeing of humans may also help to reduce genetic risks. The extent and kind of the risks as well as possibilities for prevention are discussed with a few examples.

Animals↗
PubMed2000

Iron transport.

Iron homeostasis is maintained by regulating its absorption: Under conditions of deficiency, assimilation is enhanced but iron uptake is otherwise limited to prevent toxicity due to overload. Iron deficiency remains the most important micronutrient deficiency worldwide, but increasing awareness of the genetic basis for iron-loading diseases points to iron overload as a major public health issue as well. Recent identification of mutant alleles causing iron uptake disorders in mice and humans provides new insights into the mechanisms involved in iron transport and its regulation. This article summarizes these discoveries and discusses their impact on our current understanding of iron transport and its regulation.

Absorption↗
PubMed1995

Investigation of the phenylethanolamine N-methyltransferase gene as a candidate gene for hypertension.

Genetic mapping studies have located a gene, Bp1, that accounts for approximately 30% of the genetic variation in the stroke-prone spontaneously hypertensive rat (SHRSP) to a region on chromosome 10 containing the angiotensin-converting enzyme gene. In humans, the gene encoding phenylethanolamine N-methyltransferase (PNMT) was localized near the angiotensin-converting enzyme gene on human chromosome 17. Since most of human chromosome 17 is known to be homologous to rat chromosome 10 and PNMT is known to play a role in blood pressure homeostasis, we reasoned (1) that the rat gene encoding PNMT (Pnmt) may reside on chromosome 10 within the confidence interval containing Bp1 and (2) that Pnmt is a good candidate gene for Bp1. With the use of a somatic cell hybrid panel and genetic mapping techniques, Pnmt mapped within the confidence interval that contains Bp1. To examine further this possibility of Pnmt as a candidate for Bp1, we cloned and characterized Pnmts of the original parental strains, the Wistar-Kyoto rat and SHRSP from the Heidelberg colony. We did not identify any sequence differences between the Wistar-Kyoto rats and SHRSP in the primary structure, in 1077 bp of the 5'-flanking region, or in the 256-bp 3'-end region, making Pnmt an unlikely gene for the genetic basis of salt-loaded hypertension.

Amino Acid Sequence↗
PubMed1997

Interleukin-12 and infectious diseases: a potential novel therapy.

Interleukin-12 (IL-12) is emerging as a central component of both innate and acquired immunity. The multiplicity of biological activities associated with this cytokine, particularly the stimulation of cell-mediated immunity, suggests that it may be crucial in the control of extracellular and intracellular infections. In in vitro studies, IL-12 production is initiated rapidly after infection with a variety of viral, parasitic, fungal and bacterial agents. This induction correlates well with the reported resistance or susceptibility of animals to infection with these agents. Other factors may, however, influence responses in vivo, including host genetic make-up, microbial load and the induction of antagonistic cytokine pathways, notably IL-4 and IL-10. In some situations, IL-12 may direct immune responses to inappropriate pathways, and worsen disease, so that careful consideration of the type of required immune response is needed before IL-12 therapy is initiated. IL-12 treatment may also be useful in promoting protective immune responses to vaccines, allowing systemic immunisation with lower doses, or even normally non-immunogenic preparations, of antigen. Finally, IL-12 has been demonstrated to act in concert with standard antimicrobial chemotherapy in viral, parasitic, fungal and bacterial infections, allowing a reduction in the dose of the agent used and providing hope that such combination therapy may more effectively control drug-resistant strains of infectious agents.

Journal Article↗
PubMed2002

Mechanisms of central nervous system viral persistence: the critical role of antibody and B cells.

Contributions of humoral and cellular immunity in controlling neurotropic mouse hepatitis virus persistence within the CNS were determined in B cell-deficient J(H)D and syngeneic H-2(d) B cell+ Ab-deficient mice. Virus clearance followed similar kinetics in all mice, confirming initial control of virus replication by cellular immunity. Nevertheless, virus reemerged within the CNS of all Ab-deficient mice. In contrast to diminished T cell responses in H-2(b) B cell-deficient muMT mice, the absence of B cells or Ab in the H-2(d) mice did not compromise expansion, recruitment into the CNS, or function of virus-specific CD4+ and CD8+ T cells. The lack of B cells and lymphoid architecture thus appears to manifest itself on T cell responses in a genetically biased manner. Increasing viral load did not enhance frequencies or effector function of virus-specific T cells within the CNS, indicating down-regulation of T cell responses. Although an Ab-independent antiviral function of B cells was not evident during acute infection, the presence of B cells altered CNS cellular tropism during viral recrudescence. Reemerging virus localized almost exclusively to oligodendroglia in B cell+ Ab-deficient mice, whereas it also replicated in astrocytes in B cell-deficient mice. Altered tropism coincided with distinct regulation of CNS virus-specific CD4+ T cells. These data conclusively demonstrate that the Ab component of humoral immunity is critical in preventing virus reactivation within CNS glial cells. B cells themselves may also play a subtle role in modulating pathogenesis by influencing tropism.

Animals↗
PubMed2000

The level of HIV infection of macrophages is determined by interaction of viral and host cell genotypes.

The outcome of HIV infection in vivo and in vitro depends on the interaction of viral and cellular genotypes. Analysis of infection of blood monocyte-derived macrophages by primary HIV strains shows that approximately one-third of 32 isolates was consistently high-replicating, one-third was consistently low-replicating, and one-third was dependent on the donor of the macrophages (i.e., variable). HIV isolates from patients with AIDS showed enhanced replication within macrophages and predominant use of CCR5 for entry, although 13% did use CXCR4. Tissue isolates from brain and CSF showed an enhanced ability to infect 1-day-old monocytes compared with blood isolates from patients with AIDS. The ability of primary isolates to infect neonatal or adult monocytes maturing into macrophages or placental macrophages correlated directly with the extent of CCR5 expression. Studies of macrophages from pairs of identical twins and unrelated donors showed genetic control over CCR5 expression, which was independent of the CCR5delta32 genotype. Furthermore, these studies showed a marked host-cell genetic effect on the variable primary HIV strains. Although CCR5 was essential for the entry of most primary isolates, it was not the essential "bottleneck" determining productivity of infection. The location of this bottleneck in the HIV replication cycle differs according to viral strain and host-cell donor, but it was exerted before the stage of reverse transcription in 80-90% of cases. Such host-cell genetic factors may affect viral load in vivo where macrophages are the predominant target cells.

Acquired Immunodeficiency Syndrome↗
PubMed1990

[Adrenaline and noradrenaline levels in 10-12-year-old boys during a mathematics test].

Blood plasma adrenaline and noradrenaline levels were measured using radio-enzyme techniques in 53 normally intelligent boys aged 10 to 12 years with and without Attention Deficit Disorders. The measurements were performed while the subjects were at rest and during a calculation load test. An anticipatory effect in the release of catecholamine and phasic phenomena were observed. Intelligence and mental lability are implicated in catecholamine release during load situations als well as genetic factors.

Child↗
PubMed2001

Genetic clustering of hepatitis C virus strains and severity of recurrent hepatitis after liver transplantation.

The influence of viral factors on the severity of hepatitis C virus (HCV)-related liver disease is controversial. We studied 68 liver transplant patients with recurrent hepatitis C, of whom 53 were infected by genotype 1 strains. Relationships between core sequences, serum HCV RNA levels, and fibrosis scores for each patient were analyzed in pairwise fashion 5 years after transplantation. We used Mantel's test, a matrix correlation method, to evaluate the correspondence between measured genetic distances and observed phenotypic differences. No clear relationship was found when all 68 patients were analyzed. In contrast, when the 53 patients infected by genotype 1 strains were analyzed, a strong positive relationship was found between genetic distance and differences in 5-year fibrosis scores (P = 0.001) and differences in virus load (P = 0.009). In other words, the smaller the genetic distance between two patients' viral core sequences, the smaller the difference between the two patients' fibrosis scores and viral replication levels. No relationship was found between genetic distance and differences in age, sex, or immunosuppression. In multivariate analysis, the degree of fibrosis was negatively related to the virus load (r = -0.68; P = 0.003). In the particular setting of liver transplantation, and among strains with closely related phylogenetic backgrounds (genotype 1), this study points to a correlation between the HCV genetic sequence and the variability of disease expression.

Genotype↗
PubMed1996

Passive load and angiotensin II evoke differential responses of gene expression and protein synthesis in cardiac myocytes.

This study introduced an improved model of loaded adult cardiocytes to address a proposed requirement for angiotensin II (Ang II) in the transduction pathway between load on the cardiac myocyte and its early anabolic responses of gene expression and acceleration of protein synthesis. The isolated cardiocytes were subjected to passive load by step increments of stretch and responded with proportional acceleration of protein synthesis in both adult and neonatal cardiocytes; this response was unaltered by 1 mumol/L [Sar1, Ile8]Ang II, an antagonist peptide to Ang II. Ang II from 1 nmol/L to 10 mumol/L did not increase protein synthesis after 4 hours in adult cardiocytes nor at 100 nmol/L in neonatal cardiocytes. However, 100 nmol/L Ang II did increase [3H]phenylalanine incorporation into neonatal cardiocyte protein over a 24-hour period by 10%, whereas passive load increased [3H]phenylalanine incorporation into protein by 30%, which was not blocked by [Sar1, Ile8]Ang II. Thus, the anabolic effect of load does not require ANG II to increase either 4-hour protein synthesis in both adult and neonatal cardiocytes or 24-hour [3H]phenylalanine incorporation into protein in neonatal cardiocytes. The genetic response of the cardiocyte to load was examined by assessing c-fos and Na+-Ca2+ exchanger mRNA levels, because there are rapidly expressed at the onset of cardiac pressure overload. The c-fos mRNA was increased fourfold within 1 hour after 100 nmol/L Ang II treatment of either adult or neonatal cardiocytes. This c-fos induction was blocked by [Sar1, Ile8]Ang II. One hour after loading of adult cardiocytes, induction of c-fos expression was increased threefold; this was also blocked by [Sar1, Ile8]Ang II. Thus, load-induced c-fos expression was Ang II dependent in adult cardiocytes. In contrast, exchanger mRNA levels were increased threefold 1 hour after loading of adult cardiocytes, but this increased expression was not blocked by [Sar1, Ile8]Ang II. For additional comparison, c-fos expression was induced by Ang II and phorbol myristate acetate, which did not induce exchanger expression; conversely, exchanger expression was induced by veratridine, which did not increase c-fos expression. Thus, separate c-fos and exchanger expression pathways can be differentiated in adult cardiocytes. This study demonstrated that Ang II is not required for load to initiate the anabolic processes of accelerated protein synthesis or enhanced Na+-Ca2+ exchanger expression pathways can be differentiated in adult cardiocytes. This study demonstrated that Ang II is not required for load to initiate the anabolic processes of accelerated protein synthesis or enhanced Na+-Ca2+ exchanger gene expression in cardiocytes; however, load induced c-fos expression is Ang II dependent.

Angiotensin II↗
PubMed1986

Effect of oral salt loading on blood pressure and lymphocyte sodium metabolism in borderline hypertension.

A randomized double-blind cross-over trial was performed to test the effects of oral salt loading (normal diet + 200 mmol NaCl/day for 4 weeks followed by normal diet + 400 mmol/day for 1 week) against placebo on blood pressure and lymphocyte sodium homeostasis in 10 young borderline hypertensive men, genetically predisposed for essential hypertension. Salt loading caused no significant changes in blood pressure levels, lymphocyte sodium content and efflux. In conclusion, our subjects seem insensitive to a few weeks of excessive salt intake.

Blood Pressure↗
PubMed2001

Mouse strain differences determine severity of iron accumulation in Hfe knockout model of hereditary hemochromatosis.

Hereditary hemochromatosis (HH) is a common disorder of iron metabolism caused by mutation in HFE, a gene encoding an MHC class I-like protein. Clinical studies demonstrate that the severity of iron loading is highly variable among individuals with identical HFE genotypes. To determine whether genetic factors other than Hfe genotype influence the severity of iron loading in the murine model of HH, we bred the disrupted murine Hfe allele onto three different genetically defined mouse strains (AKR, C57BL/6, and C3H), which differ in basal iron status and sensitivity to dietary iron loading. Serum transferrin saturations (percent saturation of serum transferrin with iron), hepatic and splenic iron concentrations, and hepatocellular iron distribution patterns were compared for wild-type (Hfe +/+), heterozygote (Hfe +/-), and knockout (Hfe -/-) mice from each strain. Although the Hfe -/- mice from all three strains demonstrated increased transferrin saturations and liver iron concentrations compared with Hfe +/+ mice, strain differences in severity of iron accumulation were striking. Targeted disruption of the Hfe gene led to hepatic iron levels in Hfe -/- AKR mice that were 2.5 or 3.6 times higher than those of Hfe -/- C3H or Hfe -/- C57BL/6 mice, respectively. The Hfe -/- mice also demonstrated strain-dependent differences in transferrin saturation, with the highest values in AKR mice and the lowest values in C3H mice. These observations demonstrate that heritable factors markedly influence iron homeostasis in response to Hfe disruption. Analysis of mice from crosses between C57BL/6 and AKR mice should allow the mapping and subsequent identification of genes modifying the severity of iron loading in this murine model of HH.

Animals↗
PubMed2026

Cellular transcriptomic signatures underpinning the heterogeneity of depression in Alzheimer's disease.

INTRODUCTION: Late-onset Alzheimer's disease (LOAD) and major depressive disorder (MDD) share genetic etiologies. Here, we investigated brain transcriptomic landscapes to gain insights into shared and divergent molecular and biological etiologies across LOAD and MDD. METHODS: Brain single-nucleus RNA sequencing (snRNA-seq) datasets from cognitively normal older and young individuals and LOAD patients stratified by comorbid MDD were analyzed to identify differential expressed genes (DEGs). Using cell type-specific DEGs we performed biological pathway and intercellular-communication networks analyses. We investigated shared DEGs across MDD and LOAD cohorts and sex-specific DEGs. Results were validated by comparison with four transcriptomic and proteomic studies of MDD and depression. RESULTS: MDD-associated dysregulated genes and pathways were shared between LOAD and cognitive-normal individuals, including JUNB and DUSP1 in glutamatergic neurons, and PRAM1 and SNX9 in microglia. DEGs shared between the MDD and LOAD cohorts included HSPA1A and NDUFB7 in glutamatergic neurons. Sex interaction analysis identified numerous new DEGs in the MDD cohorts, whereas there were ≈5 to 10 times more DEGs in female than in male individuals. LOAD and MDD common microglial pathways included neuronal injury, stress, peroxisome proliferator-activated receptor (PPAR) signaling and interferon alpha/beta signaling. DISCUSSION: LOAD and MDD exhibited common molecular profiles, dysregulated pathways, and cellular communication changes. MDD develops earlier in life, thus, our findings provide a window into early molecular and biological processes preceding LOAD-onset.

Humans↗
PubMed2006

Interference among deleterious mutations favours sex and recombination in finite populations.

Sex and recombination are widespread, but explaining these phenomena has been one of the most difficult problems in evolutionary biology. Recombination is advantageous when different individuals in a population carry different advantageous alleles. By bringing together advantageous alleles onto the same chromosome, recombination speeds up the process of adaptation and opposes the fixation of harmful mutations by means of Muller's ratchet. Nevertheless, adaptive substitutions favour sex and recombination only if the rate of adaptive mutation is high, and Muller's ratchet operates only in small or asexual populations. Here, by tracking the fate of modifier alleles that alter the frequency of sex and recombination, we show that background selection against deleterious mutant alleles provides a stochastic advantage to sex and recombination that increases with population size. The advantage arises because, with low levels of recombination, selection at other loci severely reduces the effective population size and genetic variance in fitness at a focal locus (the Hill-Robertson effect), making a population less able to respond to selection and to rid itself of deleterious mutations. Sex and recombination reveal the hidden genetic variance in fitness by combining chromosomes of intermediate fitness to create chromosomes that are relatively free of (or are loaded with) deleterious mutations. This increase in genetic variance within finite populations improves the response to selection and generates a substantial advantage to sex and recombination that is fairly insensitive to the form of epistatic interactions between deleterious alleles. The mechanism supported by our results offers a robust and broadly applicable explanation for the evolutionary advantage of recombination and can explain the spread of costly sex.

Alleles↗
PubMed2005

Iron loading and morbidity among relatives of HFE C282Y homozygotes identified either by population genetic testing or presenting as patients.

BACKGROUND AND AIMS: Although most cases of hereditary haemochromatosis are associated with homozygosity for the C282Y mutation of the HFE gene, clinical penetrance varies and other genes may modify disease expression. If so, relatives from clinically affected families, by inheriting such genes, may accumulate more iron. To seek evidence for this, we compared iron status and morbidity in unselected first degree relatives of two groups of index cases from South Wales, namely asymptomatic C282Y homozygotes identified by genetic screening of blood donors (n = 56) and C282Y homozygous haemochromatosis patients presenting clinically (n = 60). METHODS: All participating relatives had a structured interview, clinical assessment, and laboratory investigations. Health related quality of life was measured (SF-36 version 2). RESULTS: In total, 92% of 180 eligible first degree relatives were interviewed in the "screened" family group and 85% of 143 eligible relatives in the "patient" group. Of 59 relatives homozygous for C282Y, 76% of men and 32% of women had the "iron phenotype" (raised transferrin saturation and serum ferritin). Logistic regression modelling of the iron phenotype risk showed that 42% of the initial model deviance could be explained by homozygosity for C282Y, another 6% by lifestyle factors, and 6% by being male. Family group membership was not a significant risk factor. Morbidity and SF-36 scores did not differ significantly either between C282Y homozygotes and relatives lacking C282Y, or between C282Y homozygotes from the "screened" and "patient" groups. Serious morbidity (including cirrhosis) was low in both groups of relatives. CONCLUSIONS: HFE C282Y homozygosity has a high penetrance for iron accumulation but a low clinical penetrance. Lack of excess morbidity among C282Y homozygous relatives of index cases who presented clinically suggests that residual unknown genetic or environmental factors do not greatly influence clinical outcome among C282Y homozygotes.

Adolescent↗
PubMed2006

Natural selection on floral traits of female Silene dioica by a sexually transmitted disease.

Floral traits endowing high reproductive fitness can also affect the probability of plants contracting sexually transmitted diseases. We explore how variations in floral traits influence the fitness of Silene dioica females in their interactions with pollinators carrying pollen or spores of the sterilizing anther-smut fungus Microbotryum violaceum. We collected healthy and infected plants in a highly diseased population and grew them under conditions that 'cure' infected individuals, and used standard regression methods to detect natural selection on floral traits. Narrow-sense heritabilities, coefficients of additive genetic variation (CV(A)) and genetic correlations among traits were estimated from paternal half-sib groups. Pollinator preferences imposed strong direct and directional selection on traits affecting female attractiveness and pollen-/spore-capturing abilities. Levels of additive genetic variance were high in these traits, suggesting that rapid responses to selection are possible. By considering our results in the light of spatial and temporal heterogeneity resulting from the colonization dynamics typical for this species, we suggest that the conflicting selective effects of pollen/spore loads lead to the maintenance of genetic variation in these traits.

Flowers↗
PubMed2004

Accelerated autoimmune disease in MRL/MpJ-Fas(lpr) but not in MRL/MpJ following immunization with high load of syngeneic late apoptotic cells.

Numerous studies have shown that autoantigens may be clustered in the blebs of apoptotic cells. However, it is not yet clear in what circumstances apoptotic cells could be immunogenic rather than tolerogenic when interacting with macrophages, dendritic cells, and B cells. In order to further study this question we compared immunization of high load of syngeneic late apoptotic cells in two genetically close pro-autoimmune mice strains: MRL/MpJ and MRL/MpJ-Fas(lpr). We show that high apoptotic load could accelerate the generation of anti-dsDNA and anticardiolipin, and the extent of kidney disease, in MRL/MpJ-Fas(lpr) but could not generate autoimmunity in MRL/MpJ. Thus, in this model, a high load of apoptotic cells could augment the autoimmune response in established autoimmunity, but did not generate de novo autoimmune response in pro-autoimmune mice. Taken together with previous observations, apoptotic cell load may modify autoimmune disease generating either immune inhibition and down regulation of autoimmunity or immune stimulation and acceleration of an autoimmune disease.

Animals↗
PubMed2005

An immune control model for viral replication in the CNS during presymptomatic HIV infection.

The brain is targeted by human immunodeficiency virus type 1 (HIV-1) during the course of untreated infection, leading to cognitive impairment, neurological damage and HIV encephalitis (HIVE). To study early dynamics of HIV entry into the brain, we examined a unique autopsy series of samples obtained from 15 untreated individuals who died in the presymptomatic stages of infection from non-HIV causes. HIV was detected and quantified by limiting dilution PCR and genetically characterized in the V3 region of env. Limiting dilution was shown to be essential for correct estimation of genetic partitioning between brain- and lymphoid-associated HIV populations. While no actively expressing HIV-infected cells were detected by immunohistochemistry, variable and generally extremely low levels of proviral DNA were detected in presymptomatic brain samples. V3 region sequences were frequently genetically distinct from lymphoid-associated HIV variants, with association index (AI) values similar to those observed in cases of HIVE. Infiltration of CD8 lymphocytes in the brain was strongly associated with expression of activation markers (MHCII; R = 0.619; P < 0.05), the presence of HIV-infected cells (proviral load; R = 0.608; P < 0.05) and genetic segregation of brain variants from populations in lymphoid tissue (AI value, R = -0.528; P approximately 0.05). CD8 lymphocytes may thus limit replication of HIV seeded into the brain in early stages of infection. Neurological complications in AIDS occur when this control breaks down, due to systemic immunosuppression from HIV that destroys CD8 lymphocyte function and/or through the evolution of more aggressive neuropathogenic variants.

Adult↗
PubMed2004

On the optimality of the genetic code, with the consideration of termination codons.

The existence of nonrandom patterns in codon assignments is supported by many statistical and biochemical studies. The canonical genetic code is known to be highly efficient in minimizing the effects of mistranslation errors and point mutations. For example, it is known that when an error induces the conversion of an amino acid to another, the biochemical properties of the resulting amino acid are usually very similar to that of the original. Prior studies include many attempts at quantitative estimation of the fraction of randomly generated codes which, based upon load minimization, score higher than the canonical genetic code. In this study, we took into consideration both the relative frequencies of amino acids and nonsense mistranslations, factors which had been previously ignored. Incorporation of these parameters, resulted in a fitness function (phi) which rendered the canonical genetic code to be highly optimized with respect to load minimization. Considering termination codons, we applied a biosynthetic version of the coevolution theory, however, with low significance. We employed a revised cost for the precursor-product pairs of amino acids and showed that the significance of this approach depends on the cost measure matrix used by the researcher. Thus, we have compared the two prominent matrices, point accepted mutations 74-100 (PAM(74-100)) and mutation matrix in our study.

Amino Acids↗