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PubMed2004

Disruption of ferroportin 1 regulation causes dynamic alterations in iron homeostasis and erythropoiesis in polycythaemia mice.

Coding region mutations in the principal basolateral iron transporter of the duodenal enterocyte, ferroportin 1 (FPN1), lead to autosomal dominant reticuloendothelial iron overload in humans. We report the positional cloning of a hypermorphic, regulatory mutation in Fpn1 from radiation-induced polycythaemia (Pcm) mice. A 58 bp microdeletion in the Fpn1 promoter region alters transcription start sites and eliminates the iron responsive element (IRE) in the 5' untranslated region, resulting in increased duodenal and hepatic Fpn1 protein levels during early postnatal development. Pcm mutants, which are iron deficient at birth, exhibited increased Fpn1-mediated iron uptake and reticuloendothelial iron overload as young adult mice. Additionally, Pcm mutants displayed an erythropoietin (Epo)-dependent polycythemia in heterozygotes and a hypochromic, microcytic anemia in homozygotes. Interestingly, both defects in erythropoiesis were transient, correcting by young adulthood. Delayed upregulation of the negative hormonal regulator of iron homeostasis, hepcidin (Hamp), during postnatal development correlates strongly with profound increases in Fpn1 protein levels and polycythemia in Pcm heterozygotes. Thus, our data suggest that a Hamp-mediated regulatory interference alleviates the defects in iron homeostasis and transient alterations in erythropoiesis caused by a regulatory mutation in Fpn1.

Aging↗
PubMed2006

Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome.

BACKGROUND: Congenital long-QT syndrome (LQTS) is a primary arrhythmogenic syndrome stemming from perturbed cardiac repolarization. LQTS, which affects approximately 1 in 3000 persons, is 1 of the most common causes of autopsy-negative sudden death in the young. Since the sentinel discovery of cardiac channel gene mutations in LQTS in 1995, hundreds of mutations in 8 LQTS susceptibility genes have been identified. All 8 LQTS genotypes represent primary cardiac channel defects (ie, ion channelopathy) except LQT4, which is a functional channelopathy because of mutations in ankyrin-B. Approximately 25% of LQTS remains unexplained pathogenetically. We have pursued a "final common pathway" hypothesis to elicit novel LQTS-susceptibility genes. With the recent observation that the LQT3-associated, SCN5A-encoded cardiac sodium channel localizes in caveolae, which are known membrane microdomains whose major component in the striated muscle is caveolin-3, we hypothesized that mutations in caveolin-3 may represent a novel pathogenetic mechanism for LQTS. METHODS AND RESULTS: Using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing, we performed open reading frame/splice site mutational analysis on CAV3 in 905 unrelated patients referred for LQTS genetic testing. CAV3 mutations were engineered by site-directed mutagenesis and the molecular phenotype determined by transient heterologous expression into cell lines that stably express the cardiac sodium channel hNa(v)1.5. We identified 4 novel mutations in CAV3-encoded caveolin-3 that were absent in >1000 control alleles. Electrophysiological analysis of sodium current in HEK293 cells stably expressing hNa(v)1.5 and transiently transfected with wild-type and mutant caveolin-3 demonstrated that mutant caveolin-3 results in a 2- to 3-fold increase in late sodium current compared with wild-type caveolin-3. Our observations are similar to the increased late sodium current associated with LQT3-associated SCN5A mutations. CONCLUSIONS: The present study reports the first CAV3 mutations in subjects with LQTS, and we provide functional data demonstrating a gain-of-function increase in late sodium current.

Amino Acid Sequence↗
PubMed2005

Multiple loops of the dihydropyridine receptor pore subunit are required for full-scale excitation-contraction coupling in skeletal muscle.

Understanding which cytosolic domains of the dihydropyridine receptor participate in excitation-contraction (EC) coupling is critical to validate current structural models. Here we quantified the contribution to skeletal-type EC coupling of the alpha1S (CaV1.1) II-III loop when alone or in combination with the rest of the cytosolic domains of alpha1S. Chimeras consisting of alpha1C (CaV1.2) with alpha1S substitutions at each of the interrepeat loops (I-II, II-III, and III-IV loops) and N- and C-terminal domains were evaluated in dysgenic (alpha1S-null) myotubes for phenotypic expression of skeletal-type EC coupling. Myotubes were voltage-clamped, and Ca2+ transients were measured by confocal line-scan imaging of fluo-4 fluorescence. In agreement with previous results, the alpha1C/alpha1S II-III loop chimera, but none of the other single-loop chimeras, recovered a sigmoidal fluorescence-voltage curve indicative of skeletal-type EC coupling. To quantify Ca2+ transients in the absence of inward Ca2+ current, but without changing the external solution, a mutation, E736K, was introduced into the P-loop of repeat II of alpha1C. The Ca2+ transients expressed by the alpha1C(E736K)/alpha1S II-III loop chimera were approximately 70% smaller than those expressed by the Ca2+-conducting alpha1C/alpha1S II-III variant. The low skeletal-type EC coupling expressed by the alpha1C/alpha1S II-III loop chimera was confirmed in the Ca2+-conducting alpha1C/alpha1S II-III loop variant using Cd2+ (10(-4) M) as the Ca2+ current blocker. In contrast to the behavior of the II-III loop chimera, Ca2+ transients expressed by an alpha1C/alpha1S chimera carrying all tested skeletal alpha1S domains (all alpha1S interrepeat loops, N- and C-terminus) were similar in shape and amplitude to wild-type alpha1S, and did not change in the presence of the E736K mutation or in the presence of 10(-4) M Cd2+. Controls indicated that similar dihydropyridine receptor charge movements were expressed by the non-Ca2+ permeant alpha1S(E1014K) variant, the alpha1C(E736K)/alpha1S II-III loop chimera, and the alpha1C(E736K)/alpha1S chimera carrying all tested alpha1S domains. The data indicate that the functional recovery produced by the alpha1S II-III loop is incomplete and that multiple cytosolic domains of alpha1S are necessary for a quantitative recovery of the EC-coupling phenotype of skeletal myotubes. Thus, despite the importance of the II-III loop there may be other critical determinants in alpha1S that influence the efficiency of EC coupling.

Aniline Compounds↗
PubMed1997

Characterization of point mutations in patients with X-linked ichthyosis. Effects on the structure and function of the steroid sulfatase protein.

X-linked ichthyosis is the result of steroid sulfatase (STS) deficiency. While most affected individuals have extensive deletions of the STS gene, point mutations have been reported in three patients (1). In this study, we identify an additional three point mutations and characterize the effects of all six mutations on STS activity and expression. All six are unique single base pair substitutions. The mutations are located in a 105-amino acid region of the C-terminal half of the polypeptide. Five of the six mutations involve the substitutions of Pro or Arg for Trp372, Arg for His444, Tyr for Cys446, or Leu for Cys341. The other mutation is in a splice junction and results in a frameshift causing premature termination of the polypeptide at residue 427. All the affected residues are conserved to some degree within the sulfatase family. The six mutations were reproduced in normal STS cDNA and transiently expressed in STS-deficient cells. All six mutant vectors direct the expression of STS protein that lacks enzymatic activity. The mutant polypeptides show a shift in mobility on SDS-PAGE and resistance to proteinase K digestion when translated in the presence of dog pancreas microsomes, indicating glycosylation and normal translocation.

Animals↗
PubMed2000

A naturally occurring sequence variation that creates a YY1 element is associated with increased cystic fibrosis transmembrane conductance regulator gene expression.

We have identified previously a novel complex mutant allele in the cystic fibrosis transmembrane conductance regulator (CFTR) gene in a patient affected with cystic fibrosis (CF). This allele contained a mutation in CFTR exon 11 known to cause CF (S549R(T>G)), associated with the first alteration described so far in the minimal CFTR promoter region (-102T>A). Studies on genotype-phenotype correlations revealed striking differences between patients carrying mutation (S549R(T>G)) alone, who had a severe disease, and patients carrying the complex allele (-102(T>A)+S549R(T>G)), who exhibited milder forms of CF. We thus postulated that the sequence change (-102T>A) may attenuate the effects of the severe (S549R(T>G)) mutation through regulation of CFTR expression. Analysis of transiently transfected cell lines with wild-type and -102A variant human CFTR-directed luciferase reporter genes demonstrates that constructs containing the -102A variant (which creates a Yin Yang 1 (YY1) core element) increases CFTR expression significantly. Electrophoretic mobility shift assays indicate that the -102 site is located in a region of multiple DNA-protein interactions and that the -102A allele recruits specifically an additional nuclear protein related to YY1. The finding that the YY1-binding allele causes a significant increase in CFTR expression in vitro may allow a better understanding of the milder phenotype observed in patients who carry a severe CF mutation within the same gene.

Alleles↗
PubMed2000

Phenotypic effects of overexpression of the MMAC1 gene in prostate epithelial cells.

The prostate cancer cell lines PC3 and LNCaP have been shown to lack expression of the tumour suppressor gene MMAC1/PTEN, in contrast to the immortalized non-tumorigenic epithelial lines PNT1a and PNT2. We have measured the effects of reintroduction of wild type (wt) and mutant MMAC1 genes on to these genetic backgrounds, using gene constructs expressing either wt MMAC1 or various mutants deficient in the dual specificity phosphatase domain of the protein. Over-expression of wild type PTEN protein induced cell shrinkage and rounding, but did not result in increased levels of classical apoptosis. Permanently transfected lines containing the MMAC1 gene could only be obtained from the PNT cells, as PTEN expression resulted in rapid loss of both tumour lines. In contrast, mutation of the phosphatase domain resulted in partial attenuation of the phenotypic effects of MMAC1 after transient transfection, and also allowed the derivation of permanent tumour cell lines containing the mutated MMAC1 gene. The results suggest that re-expression of wt PTEN is incompatible with survival of human prostate cancer cells in vitro, and that the full biological activity of this common tumour suppressor requires functions additional to the established protein and lipid phosphatase activities in epithelial systems.

Cell Line↗
PubMed1988

Mutational analysis of the chicken beta-globin enhancer reveals two positive-acting domains.

We report a mutational analysis of the chicken beta-globin enhancer, using transient expression in primary embryonic erythrocytes. A series of 27 scanning mutants differing only by consecutive 4-base substitutions was tested. Previous experiments, using protection from DNase I digestion, demonstrated four regions in the enhancer that bind factors. Mutations in two of the four regions (denoted I and III) have no effect on enhancer activity. The other two regions (II and IV) mediate all of the positive-acting activity. Region II appears to consist of two subregions, mutation in either of which leads to the same loss in activity as mutation of both. Like region II, mutation of either half of region IV results in reduced enhancer activity. However, in contrast to region II, mutation of both halves of region IV results in more loss of enhancer activity than either single mutation. These data suggest that the half-sites in region II must interact in order to cause enhancement, whereas the half-sites in region IV act independently. Triplications of regions II or IV are able to enhance to a similar degree as the parental enhancer, but single copies of regions II or IV enhance only weakly. Thus, as measured by transient expression in embryonic erythrocytes, the beta-globin enhancer may involve the action of as few as three DNA-binding proteins acting at two sites.

Acetyltransferases↗
PubMed2006

Investigation of the functional roles of the MELAL and GQXXRXG motifs of the human noradrenaline transporter using cysteine mutants.

The study examines the roles of the highly conserved MELAL and GQXXRXG motifs, located in the second transmembrane domain and the first intracellular loop of the human noradrenaline transporter (hNET). We have previously shown that this region does not directly participate in the NET substrate translocation pathway [Sucic, S., and Bryan-Lluka, L.J., 2005. Roles of transmembrane domain 2 and the first intracellular loop in human noradrenaline transporter function: pharmacological and SCAM analysis. J. Neurochem. 94, 1620-1630.], while the current report focuses on the importance of this region in determining other functional properties of the hNET. Mutation to cysteine of the wild-type residues was carried out by site-directed mutagenesis of hNET cDNA. The wild-type and mutant hNETs were expressed in transiently transfected COS-7 cells and the effects of these mutations were pharmacologically examined. The results indicate that the GQXXRXG motif is important for the binding of cocaine, but not antidepressants. The hN120C mutant caused an 11-fold increase in the binding affinity of cocaine, compared to the wild-type hNET, while hQ118C, hY119C, hR121C and hE122C showed smaller increases. Interestingly, the apparent affinities of cocaine for some of these mutants were either decreased or unchanged, contrasting with the effects observed from the binding studies. The hE113C mutant in the MELAL motif caused very marked (over 400-fold) reductions in the binding affinities of substrates, but had no effects on the binding affinities of cocaine or antidepressants. Overall, the MELAL and GQXXRXG motifs are important determinants of NET cell surface expression and substrate and inhibitor binding. The results further suggest that the binding sites for substrates, cocaine and antidepressants on the NET are distinct but overlapping.

Amino Acid Motifs↗
PubMed2000

Novel mutations in the microsomal triglyceride transfer protein gene causing abetalipoproteinemia.

Abetalipoproteinemia (ABL) is an inherited disease characterized by the virtual absence of apolipoprotein B (apoB)-containing lipoproteins from plasma. Only limited numbers of families have been screened for mutations in the microsomal triglyceride transfer protein (MTP) gene. To clarify the genetic basis of clinical diversity of ABL, mutations of the MTP gene have been screened in 4 unrelated patients with ABL. Three novel mutations have been identified: a frameshift mutation caused by a single adenine deletion at position 1389 of the cDNA, and a missense mutation, Asn780Tyr, each in homozygous forms; and a splice site mutation, 2218-2A-->G, in a compound heterozygous form. The frameshift and splice site mutations are predicted to encode truncated forms of MTP. When transiently expressed in Cos-1 cells, the Asn780Tyr mutant MTP bound protein disulfide isomerase (PDI) but displayed negligible MTP activity. It is of interest that the patient having the Asn780Tyr mutation, a 27-year-old male, has none of the manifestations characteristic of classic ABL even though his plasma apoB and vitamin E were virtually undetectable. These results indicated that defects of the MTP gene are the proximal cause of ABL.

Abetalipoproteinemia↗
PubMed1994

Myb and Ets related transcription factors are required for activity of the human lck type I promoter.

The lck gene, which encodes a lymphoid-specific Src family tyrosine kinase, is transcribed from two promoters that are differentially utilized during T cell development. We have shown previously that the human lck type I promoter, which is preferentially expressed in immature thymocytes, requires a binding site (-97 to -90) for the Ets family of transcription factors for its activity in Jurkat T leukemia cells. Three putative Myb binding sites (-86 to -82, -77 to -72 and -59 to -54) were analysed for their ability to activate the lck type I promoter. In vitro assays demonstrated specific binding of purified, bacterially expressed c-Myb DNA binding domain to the Myb (-59 to -54) site. Transient transfection assays using the site-directed mutants of the lck type I promoter in Jurkat cells revealed that mutation of the Myb (-59 to -54) site abolished transcriptional activity. In transiently transfected HeLa cells, the lck type I promoter was activated by co-transfection with a vector that expresses c-Myb. This c-Myb dependent activation required the presence of intact Myb and Ets binding sites, indicating that the expressed c-Myb functions with endogenous Ets related transcription factors to activate the lck type I promoter. This effect was further enhanced by co-transfection with vectors that express either Ets1 or Ets2. These results demonstrate that Myb and Ets related transcription factors synergistically activate the human lck type I promoter.

Base Sequence↗
PubMed1996

Expression and molecular analysis of mutations in prolidase deficiency.

Prolidase (E.C.3.4.13.9) cleaves iminodipeptides. Prolidase deficiency (PD; McKusick 170100) is an autosomal recessive disorder with highly variable penetrance. We have identified two novel alleles in the prolidase gene (PEPD) by direct sequencing of PCR-amplified cDNA from a PD individual asymptomatic at age 11 years: a 551G-->A transition in exon 8 (R184Q) and a 833G-->A transition in exon 12 (G278D). To assess the biochemical phenotypes of these and two previously identified PEPD mutations (G448R and delE452), we have designed a transient-expression system for prolidase in COS-1 cells. The enzyme was expressed as a fusion protein carrying an N-terminal tag, the HA1 epitope of influenza hemagglutinin, allowing its immunological discrimination from the endogenous enzyme with a monoclonal antibody. Expression of the R184Q mutation produced 7.4% of control enzymatic activity whereas the expression of the G278D, G448R, and delE452 mutations produced inactive enzymes. Western analysis of the R184Q, G278D, and G448R prolidases revealed stable immunoreactive material whereas the delE452 prolidase was not detectable. Pulse-chase metabolic labeling of cells followed by immunoprecipitation revealed that the delE452 mutant protein was synthesized but had an increased rate of degradation.

Alleles↗
PubMed2001

Nuclear factor-kappaB is constitutively active in C-cell carcinoma and required for RET-induced transformation.

Specific point mutations of the RET proto-oncogene have been demonstrated to be responsible for multiple endocrine neoplasia (MEN) types 2A and 2B, for familial medullary thyroid carcinoma (MTC) syndromes, as well as for sporadic MTC. Here we show that nuclear factor (NF)-kappaB is activated in RET-associated C-cell carcinoma specimens. TT cells, a human MTC cell line expressing MEN 2A type RET, display transcriptionally active RelA(p65) in the nucleus. NF-kappaB activity in these cells is attributable to constitutive IkappaB kinase (IKK) activity and high turn over of IkappaBalpha. RET harboring the mutations C634R (MEN 2A) or M918T (MEN 2B), in contrast to wild-type RET, activates a NF-kappaB-dependent reporter construct upon transient transfection in HeLa cells. We show that the prototype RET mutation C634R enhances phosphorylation of IkappaBalpha by IKKbeta but not by IKKalpha. RET-induced NF-kappaB and IKKbeta activity requires Ras function but does neither involve the classical mitogen-activated protein kinase kinase/extracellular signal-regulated kinase nor the phosphoinositide 3-kinase/Akt pathways. In contrast, RET-induced NF-kappaB activity is dependent on Raf and MEKK1. Inhibition of constitutive NF-kappaB activity results in cell death of TT cells and blocks focus formation induced by oncogenic forms of RET in NIH 3T3 cells. These results suggest that RET-mediated carcinogenesis critically depends on IKK activity and subsequent NF-kappaB activation.

3T3 Cells↗
PubMed1984

Effect of ruv mutations on recombination and DNA repair in Escherichia coli K12.

Mutation of the ruv gene of E. coli is associated with sensitivity to radiation, and filamentous growth after transient inhibition of DNA synthesis. The filamentation of ruv strains is abolished by mutations in sfiA or sfiB that prevent SOS induced inhibition of cell division, but this does not restore resistance to UV radiation. Double mutants carrying both ruv and uvr mutations are considerably more sensitive to UV radiation than the single mutants, but there is no additive effect of ruv with recA, recF, recB, or recC mutations. ruv mutations have little effect on conjugal recombination in wild-type strains but confer recombination deficiency and extreme sensitivity to ionizing radiation in recBC sbcB strains. These results, together with the fact that ruv strains are excision proficient and mutable by UV light, are interpreted to suggest that the ruv + product is involved in recombinational repair of damaged DNA rather than in cell division as suggested by Otsuji et al. (1974).

Bacterial Proteins↗
PubMed2003

Functional analysis of MCCA and MCCB mutations causing methylcrotonylglycinuria.

Methylcrotonylglycinuria (MCG; MIM 210200) is an autosomal recessive inherited human disorder caused by the deficiency of 3-methylcrotonyl-CoA carboxylase (MCC, E.C.6.4.1.4), involved in leucine catabolism. This mitochondrial enzyme is one of the four biotin-dependent carboxylases known in humans. MCC is composed of two different types of subunits, alpha and beta, encoded by the nuclear genes MCCA and MCCB, respectively, recently cloned and characterized. Several mutations have been identified, in both genes, the majority are missense mutations along with splicing mutations and small insertions/deletions. We have expressed four missense mutations, two MCCA and two MCCB mapping to highly evolutionarily conserved residues, by transient transfection of SV40-transformed deficient fibroblasts in order to confirm their pathogenic effect. All the missense mutations expressed resulted in null or severely diminished MCC activity providing direct evidence that they are disease-causing ones. The MCCA mutations have been analysed in the context of three-dimensional structural information modelling the changes in the crystallized biotin carboxylase subunit of the Escherichia coli acetyl-CoA carboxylase. The apparent severity of all the MCC mutations contrasts with the variety of the clinical phenotypes suggesting that there are other cellular and metabolic unknown factors that affect the resulting phenotype.

Amino Acid Sequence↗
PubMed2003

Analysis of an IL-10 polymorphism in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic disorder of the lung parenchyma. We have demonstrated changes in IL-10 protein production by alveolar macrophages (AMs) from patients with IPF, which we hypothesise could be because of an IL-10 gene polymorphism. We have screened the coding sequence and 3' untranslated region of IL-10 for polymorphisms using single-standard conformational polymorphism analysis. A novel polymorphism was identified resulting in a G to A substitution of +43 nucleotides from the start codon changing glycine to arginine at amino acid 15 of the signal peptide sequence. We have introduced the signal peptide mutation into the IL-10 gene and compared secretion of the mutant and wild-type forms after transient transfection of COS-7 cells. Our studies showed that the signal peptide mutation did not have a significant effect on secretion at 24 h post-transfection (P=0.4529 by Mann-Whitney test). However, by 48 h there are significantly lower levels of mutant IL-10 (P=0.0515). There were no differences in the level of cell-associated IL-10 at either 24 or 48 h (P=0.9296 and 0.4268). We suggest that the mutation could affect the efficiency of protein translocation and signal peptide cleavage resulting in lower levels of IL-10 protein secretion.

Adult↗
PubMed1996

Bone tissue-specific transcription of the osteocalcin gene: role of an activator osteoblast-specific complex and suppressor hox proteins that bind the OC box.

Bone-specific expression of the osteocalcin gene is transcriptionally controlled. Deletion analysis of osteocalcin promoter sequences by transient transfection of osseous (ROS 17/2.8) and nonosseous (R2 fibroblast) cells revealed that the most proximal 108 nucleotides are sufficient to confer tissue-specific expression. By gel mobility shift assays with wild-type and mutated oligonucleotides and nuclear extracts from several different cell lines we identified a novel transcription factor complex which exhibits sequence-specific interactions with the primary transcriptional element, the OC box (nt -99 to -76). This OC box binding protein (OCBP) is present only in osteoblast-like cells. Methylation interference demonstrated association of the factor with OC box sequences overlapping the Msx homeodomain consensus binding site. By assaying several mutations of the OC box, both in gel shift and transient transfection studies using ROS 17/2.8, we show the following. First, binding of OCBP correlates with osteocalcin promoter activity in ROS 17/2.8 cells. Increased binding leads to a 2-3-fold increase in transcription, while decreased binding results in transcription 30-40% of control. Second, homeodomain protein binding suppresses transcription. However, Msx expression is critical for full development of the bone phenotype as determined by antisense studies. Last, we show that one of the mutations of the OC box permits expression of osteocalcin in non-osseous cell lines. In summary, we demonstrate association of at least two classes of tissue-restricted transcription factors with the OC box element, the OCBP and Msx proteins, supporting the concept that these sequences contribute to defining tissue specificity.

Animals↗
PubMed2003

Prothrombin G20210A mutation, but not factor V Leiden, is a risk factor in patients with persistent foramen ovale and otherwise unexplained cerebral ischemia.

BACKGROUND: Paradoxical embolism via persistent foramen ovale (PFO) is suspected to be a frequent cause of stroke in younger patients. We investigated whether the prevalence of the risk factors for venous thrombosis factor V Leiden (FVL) and prothrombin G20210A mutation (PT G20210A) is increased in this group of patients. METHODS: We examined FVL and PT G20210A mutation in 220 patients (group 1) with cerebral ischemia associated with a PFO and without other etiology, in 196 patients with cerebral ischemia of an etiology other than PFO (group 2), and in 362 healthy subjects (group 3) from the same region in Germany. RESULTS: Heterozygosity for the PT G20210A mutation was more common in group 1 (5.0%) than in group 3 (1.4%; sex- and age-adjusted odds ratio 3.66; 95% CI 1.25-10.75; p = 0.01). By contrast, the mutation was not more common in group 2 (2.6%; odds ratio 1.50; 95% CI 0.42-5.41; p = 0.5). Prevalences of FVL were not different between groups. CONCLUSIONS: We identified PT G20210A but not FVL - the strongest genetic risk factor for deep venous thrombosis - to be significantly associated with stroke attributed to PFO. These findings rise doubts about the concept of paradoxical brain embolism as the dominating mechanism in stroke associated with PFO.

Adult↗
PubMedDate not supplied

Environmentally constrained mutation and adaptive evolution in Salmonella.

The relationship between environment and mutation is complex [1]. Claims of Lamarkian mutation [2] have proved unfounded [3-5]; it is apparent, however, that the external environment can influence the generation of heritable variation, through either direct effects on DNA sequence [6] or DNA maintenance and copying mechanisms [7-10], or as a consequence of evolutionary processes [11-16]. The spectrum of mutational events subject to environmental influence is unknown [6] and precisely how environmental signals modulate mutation is unclear. Evidence from bacteria suggests that a transient recombination-dependent hypermutational state can be induced by starvation [5]. It is also apparent that changes in the mutability of specific loci can be influenced by alterations in DNA topology [10,17]. Here we describe a remarkable instance of adaptive evolution in Salmonella which is caused by a mutation that occurs in intermediate-strength osmotic environments. We show that the mutation is not 'directed' and describe its genetic basis. We also present compelling evidence in support of the hypothesis that the mutational event is constrained by signals transmitted from the external environment via changes in the activity of DNA gyrase.

Adaptation, Physiological↗