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PubMed1982

Natural variation in yeast RNA polymerase A. Formation of a mosaic RNA polymerase A in a meiotic segregant from an interspecific hybrid.

There is a natural variation in the molecular structure of RNA polymerase A isolated from several genetically distant yeast species, Saccharomyces cerevisiae, Saccharomyces douglasii, Schizosaccharomyces pombe, and Candida tropicalis. Several biochemical criteria were used to identify their homologous polypeptide components. Based on these correlations, the minimal subunit composition of S. cerevisiae (and Saccharomyces carlsbergensis) RNA polymerase A was tentatively defined as A190, A135, A40, A27, A23, A19, and A14.5. Without the two Saccharomyces species, S. cerevisiae and S. douglasii, 7 of 13 polypeptides of enzyme A(A49, A43, A40, A34.5, A19, A14.5, and A14) differ slightly in molecular weight and can be resolved by electrophoresis on polyacrylamide gel. The RNA polymerase A isolated from the diploid interspecific hybrid contains all the polypeptides characteristic of the two parents. One meiotic segregant had a hybrid RNA polymerase A with five of the polymorphic polypeptides (A49, A43, A19, A14.5, and A14) coming from S. douglasii and two (A40 and A34.5) from S. cerevisiae. In three successive backcrosses with S. cerevisiae, all the genes for S. douglasii polypeptides were shown to recombine although parental ditype tetrads predominated in the four four-spored asci examined. Thus, the genes for the seven polymorphic polypeptides are not clustered: they lie on at least three different chromosomes.

Ascomycota↗
PubMed2000

Natural variation in the amino acid sequence around the HIV type 1 glycoprotein 160 cleavage site and its effect on cleavability, subunit association, and membrane fusion.

To assess the natural variation of the structure of the cleavage site as well as the N-terminal region of gp41 for the cytopathogenicity of HIV-1, syncytium-inducing (SI) and non-syncytium-inducing (NSI) virus isolates were obtained from HIV-1-infected patients. In addition, the coreceptor usage of the isolates was determined by infection of primary macrophages and PM-1 cells. DNA sequences encoding the C-terminal 41 amino acid residues of gp120 and the 64 amino acid N-terminal residues of gp41 were amplified by the polymerase chain reaction and inserted into the Env expression vector pNLA1. When transfected into HeLa-T4(+) cells, all the recombinant plasmids, including those with inserts from NSI isolates, led to the formation of processed glycoprotein and to syncytium formation. One construct displayed significant lowered fusion capacity and had an amino acid exchange in the first position of the gp41 N terminus (gp41, 512A-->S) leading to a decreased association of the SU and TM subunits. Four constructs derived from two isolates of the same patient showed an unusual gp41 N terminus (gp41, 514G-->P) and a slightly diminished fusion capacity due to a decreased cleavability. This indicates that the major determinants for the SI and NSI phenotypes are not located around the gp160 cleavage site and that the N terminus of gp41 plays a minor role in the processing and fusion capacity of wild-type HIV-1 isolates.

Amino Acid Sequence↗
PubMed2006

Genomic regulation of natural variation in cortical and noncortical brain volume.

BACKGROUND: The relative growth of the neocortex parallels the emergence of complex cognitive functions across species. To determine the regions of the mammalian genome responsible for natural variations in cortical volume, we conducted a complex trait analysis using 34 strains of recombinant inbred (Rl) strains of mice (BXD), as well as their two parental strains (C57BL/6J and DBA/2J). We measured both neocortical volume and total brain volume in 155 coronally sectioned mouse brains that were Nissl stained and embedded in celloidin. After correction for shrinkage, the measured cortical and noncortical brain volumes were entered into a multiple regression analysis, which removed the effects of body size and age from the measurements. Marker regression and interval mapping were computed using WebQTL. RESULTS: An ANOVA revealed that more than half of the variance of these regressed phenotypes is genetically determined. We then identified the regions of the genome regulating this heritability. We located genomic regions in which a linkage disequilibrium was present using WebQTL as both a mapping engine and genomic database. For neocortex, we found a genome-wide significant quantitative trait locus (QTL) on chromosome 11 (marker D11Mit19), as well as a suggestive QTL on chromosome 16 (marker D16Mit100). In contrast, for noncortex the effect of chromosome 11 was markedly reduced, and a significant QTL appeared on chromosome 19 (D19Mit22). CONCLUSION: This classic pattern of double dissociation argues strongly for different genetic factors regulating relative cortical size, as opposed to brain volume more generally. It is likely, however, that the effects of proximal chromosome 11 extend beyond the neocortex strictly defined. An analysis of single nucleotide polymorphisms in these regions indicated that ciliary neurotrophic factor (Cntf) is quite possibly the gene underlying the noncortical QTL. Evidence for a candidate gene modulating neocortical volume was much weaker, but Otx1 deserves further consideration.

Animals↗
PubMed2005

Assessing natural variations in gene expression in humans by comparing with monozygotic twins using microarrays.

Quantitative variation in gene expression in humans is the outcome of various factors, including differences in genetic background, gender, age, and environment. However, the extent of the influence of these factors on gene expression is not clear. We attempted to address this issue by carrying out gene expression profiling in blood leukocytes with 13 individuals (including 5 pairs of monozygotic twins) on 10,000 genes using HG-U95Av2 oligonucleotide microarrays. The proportion of differentially expressed genes between monozygotic twins was low (up to 1.76%). Most of the variations belonged to the least variable category. These genes, exhibiting "random variations," did not show clear preference to any functional class, although "signaling and communication" and "immune and related functions" generally topped the list. The extent of variation in gene expression increased in comparisons between unrelated individuals (up to 14.13%). Most of the genes (89%) exhibiting random variations in twins also varied in expression in unrelated individuals. As with twins, signaling and communication topped the list, and substantial variations were observed in all three categories: least variable, moderately variable, and most variable. An important outcome of this study was that the housekeeping genes were nearly insensitive to random variations but appeared to be more susceptible to genetic differences. However, the highly expressed housekeeping genes exhibited low variation and appeared to be insensitive to all known factors. Gene expression profiling in monozygotic twins can provide useful data for the assessment of natural variation in gene expression in humans.

Adult↗
PubMed2006

Natural variation for carbohydrate content in Arabidopsis. Interaction with complex traits dissected by quantitative genetics.

Besides being a metabolic fuel, carbohydrates play important roles in plant growth and development, in stress responses, and as signal molecules. We exploited natural variation in Arabidopsis (Arabidopsis thaliana) to decipher the genetic architecture determining carbohydrate content. A quantitative trait locus (QTL) approach in the Bay-0 x Shahdara progeny grown in two contrasting nitrogen environments led to the identification of 39 QTLs for starch, glucose, fructose, and sucrose contents representing at least 14 distinct polymorphic loci. A major QTL for fructose content (FR3.4) and a QTL for starch content (ST3.4) were confirmed in heterogeneous inbred families. Several genes associated with carbon (C) metabolism colocalize with the identified QTL. QTLs for senescence-related traits, and for flowering time, water status, and nitrogen-related traits, previously detected with the same genetic material, colocalize with C-related QTLs. These colocalizations reflect the complex interactions of C metabolism with other physiological processes. QTL fine-mapping and cloning could thus lead soon to the identification of genes potentially involved in the control of different connected physiological processes.

Arabidopsis↗
PubMed2002

Unusual genetic architecture of natural variation affecting drug resistance in Drosophila melanogaster.

Naturally occurring genetic variation was quantified for survival time of adult Drosophila melanogaster exposed to chronic ingestion of the drugs nicotine, caffeine, dopamine, tyramine and octopamine. Responses to nicotine, tyramine and octopamine were genetically correlated in both sexes, whereas caffeine response correlated with starvation resistance. However, there is also genetic variation that is specific for each of the drugs. Females tended to be more resistant than males to nicotine and caffeine but sex-by-genotype interactions were also seen for these drugs and for the response to dopamine. An unusual and complex genetic architecture was observed in crosses between lines with different responses to caffeine ingestion. Additive and dominance components were clearly seen from the analysis of F1 individuals, but increased female resistance to caffeine in backcross generations and increased male sensitivity in F2 generations confused the interpretation of possible epistatic contributions.

Analysis of Variance↗
PubMed2002

The genetics of phytate and phosphate accumulation in seeds and leaves of Arabidopsis thaliana, using natural variation.

Phytate (myo-inositol-1,2,3,4,5,6-hexakisphosphate, InsP6) is the most abundant P-containing compound in plants, and an important anti-nutritional factor, due to its ability to complex essential micro-nutrients, e.g. iron and zinc. Analysis of natural variation for InsP6 and Pi accumulation in seeds and leaves for a large number of accessions of Arabidopsis thaliana, using a novel method for InsP6 detection, revealed a wide range of variation in InsP6 and Pi levels, varying from 7.0 mg to 23.1 mg of InsP6 per gram of seed. Quantitative trait locus (QTL) analysis of InsP6 and Pi levels in seeds and leaves, using an existing recombinant inbred line population, was performed in order to identify a gene(s) that is (are) involved in the regulation of InsP6 accumulation. Five genomic regions affecting the quantity of the InsP6 and Pi in seeds and leaves were identified. One of them, located on top of chromosome 3, affects all four traits. This QTL appears as the major locus responsible for the observed variation in InsP6 and Pi contents in the L er/Cvi RIL population; the L er allele decreases the content of both InsP6 and Pi in seeds and in leaves. The InsP6/Pi locus was further fine-mapped to a 99-kb region, containing 13 open reading frames. The maternal inheritance of the QTL and the positive correlation between InsP6 and total Pi levels both in seeds and in leaves indicate that the difference in InsP6 level between L er and Cvi is likely to be caused by a difference in transport rather than by an alteration in the biosynthesis. Therefore, we consider the vacuolar membrane ATPase subunit G, located in the region of interest, as the most likely candidate gene for InsP6/Pi.

Arabidopsis↗
PubMed2005

Impact of natural variation in bacterial F17G adhesins on crystallization behaviour.

Since the introduction of structural genomics, the protein has been recognized as the most important variable in crystallization. Recent strategies to modify a protein to improve crystal quality have included rationally engineered point mutations, truncations, deletions and fusions. Five naturally occurring variants, differing in 1-18 amino acids, of the 177-residue lectin domain of the F17G fimbrial adhesin were expressed and purified in identical ways. For four out of the five variants crystals were obtained, mostly in non-isomorphous space groups, with diffraction limits ranging between 2.4 and 1.1 A resolution. A comparative analysis of the crystal-packing contacts revealed that the variable amino acids are often involved in lattice contacts and a single amino-acid substitution can suffice to radically change crystal packing. A statistical approach proved reliable to estimate the compatibilities of the variant sequences with the observed crystal forms. In conclusion, natural variation, universally present within prokaryotic species, is a valuable genetic resource that can be favourably employed to enhance the crystallization success rate with considerably less effort than other strategies.

Adhesins, Bacterial↗
PubMed2003

Natural variation in nucleolar dominance reveals the relationship between nucleolus organizer chromatin topology and rRNA gene transcription in Arabidopsis.

In genetic hybrids, nucleolus formation on chromosomes inherited from only one parent is the epigenetic phenomenon, nucleolar dominance. By using Arabidopsis suecica, the allotetraploid hybrid of Arabidopsis thaliana and Arabidopsis arenosa, natural variation in nucleolar dominance was found to occur, providing a unique opportunity to examine homologous nucleolus organizer regions (NORs) in their active and inactive states. In A. suecica strain LC1, NORs derived from A. arenosa are active, whereas A. thaliana-derived NORs are silenced. In A. suecica strain 9502, NORs of both parental species are active. When active, NORs are partially, but not fully, decondensed. Both active and inactive LC1 NORs colocalize with the nucleolus, contradicting the long-standing assumption that rRNA gene transcription drives nucleolus association. Collectively, these observations clarify the relationships among NOR chromatin topology, rRNA gene transcription, and NOR-nucleolus associations. A. suecica strains LC1 and 9502 have each lost one pair of A. thaliana NORs during evolution, and amplified fragment-length polymorphism analysis further indicates that these strains are genetically very similar. These data suggest that nucleolar dominance can result from subtle genetic or epigenetic variation but is not a trait fundamental to a given interspecies hybrid combination.

Arabidopsis↗
PubMed2003

Natural variations in maternal care are associated with estrogen receptor alpha expression and estrogen sensitivity in the medial preoptic area.

Lactating rats exhibit stable individual differences in pup licking/grooming (LG) over the first week postpartum. Such naturally occurring variations in maternal behavior are associated with differences in estrogen-inducible oxytocin receptors in the medial preoptic area (MPOA) of the hypothalamus. We compared levels of ER alpha and ER beta mRNA in the MPOA of lactating High or Low LG mothers as well as in their nonlactating, female offspring, which inherit the maternal phenotype of their mothers. Among lactating females, High LG females exhibited significantly elevated levels of ER alpha mRNA compared with Low LG females. Likewise, the adult, virgin female offspring of High LG mothers showed higher levels of ER alpha mRNA in the MPOA compared with those of Low LG mothers. There were no group differences in levels of ER beta mRNA. Differences in ER alpha protein expression in the MPOA were confirmed using Western blot analysis. To further characterize the effects of estrogen in the MPOA, cFos immunoreactivity was compared in ovariectomized, adult offspring of High and Low LG dams treated with estradiol or oil. Increased cFos activity in the anterior ventral nucleus of the MPOA was observed in estradiol-treated High LG, but not Low LG females. These findings suggest that natural variations in maternal care are associated with differences in ER alpha expression in the MPOA and that such differences are transmitted from the mother to her female offspring.

Animals↗
PubMed2004

Natural variation of drug susceptibility in wild-type human immunodeficiency virus type 1.

Wild-type viruses from the ViroLogic phenotype-genotype database were evaluated to determine the upper confidence limit of the drug susceptibility distributions, or "biological cutoffs," for the PhenoSense HIV phenotypic drug susceptibility assay. Definition of the natural variation in drug susceptibility in wild-type human immunodeficiency virus (HIV) type 1 isolates is necessary to determine the prevalence of innate drug resistance and to assess the capability of the PhenoSense assay to reliably measure subtle reductions in drug susceptibility. The biological cutoffs for each drug, defined by the 99th percentile of the fold change in the 50% inhibitory concentration distributions or the mean fold change plus 2 standard deviations, were lower than those previously reported for other phenotypic assays and lower than the clinically relevant cutoffs previously defined for the PhenoSense assay. The 99th percentile fold change values ranged from 1.2 (tenofovir) to 1.8 (zidovudine) for nucleoside reverse transcriptase RT inhibitors (RTIs), from 3.0 (efavirenz) to 6.2 (delavirdine) for nonnucleoside RTIs, and from 1.6 (lopinavir) to 3.6 (nelfinavir) for protease inhibitors. To evaluate the potential role of intrinsic assay variability in the observed variations in the drug susceptibilities of wild-type isolates, 10 reference viruses with different drug susceptibility patterns were tested 8 to 30 times each. The median coefficients of variation in fold change for the reference viruses ranged from 12 to 18% for all drugs except zidovudine (32%), strongly suggesting that the observed differences in wild-type virus susceptibility to the different drugs is related to intrinsic virus variability rather than assay variability. The low biological cutoffs and assay variability suggest that the PhenoSense HIV assay may assist in defining clinically relevant susceptibility cutoffs for resistance to antiretroviral drugs.

Anti-HIV Agents↗
PubMed1986

Natural variation of tyrosyl-tRNA synthetase and comparison with engineered mutants.

We report the cloning and sequence analysis of the gene for the tyrosyl-tRNA synthetase from Bacillus caldotenax and properties of the gene product. The amino acid sequence of the tyrosyl-tRNA synthetase was found to be 99% homologous with the corresponding enzyme from B. stearothermophilus, with only four amino acid differences. Two of these natural variations were found to involve active site residues of the enzyme and correspond to mutations that have been engineered previously in vitro. One, Thr-51----Ala-51, produced a more active enzyme, possessing a higher value of kcat/KM for ATP. Position 51 is a "hot spot" in the tyrosyl-tRNA synthetase, differing in enzymes derived from Escherichia coli, B. stearothermophilus, and B. caldotenax. The other, His-48----Asn-48, is found to be a neutral mutation but is in one of the rare regions that are conserved with other aminoacyl-tRNA synthetases. The equivalence of histidine and asparagine at position 48 extends the homology in this region to more enzymes. These residues, His-Ile-Gly-His, and now His-Ile-Gly-Asn, form part of the binding site for ATP in the transition state of the reaction. Although B. caldotenax is an obligate thermophile with an optimal growth temperature of 80 degrees C, as much as 20 degrees C above the growth optima of strains of Bacillus stearothermophilus, its tyrosyl-tRNA synthetase has an identical thermal stability in vitro to that from B. stearothermophilus.

Amino Acid Sequence↗
PubMed2006

Genetic mapping of natural variation in potassium concentrations in shoots of Arabidopsis thaliana.

Naturally-occurring variation in K(+) concentrations between plant genotypes is potentially exploitable in a number of ways, including altering the relationship between K(+) accumulation and growth, enhancing salinity resistance, or improving forage quality. However, achieving these requires greater insight into the genetic basis of the variation in tissue K(+) concentrations. To this end, K(+) concentrations were measured in the shoots of 70 Arabidopsis thaliana accessions and a Cape Verdi Island/Landsberg erecta recombinant inbred line (RIL) population. The shoot K(+) concentrations expressed on the basis of fresh matter (KFM) or dry matter (KDM) were both broadly and normally distributed as was the shoot dry matter content per unit fresh weight (DMC). Using the data from the RILs, four quantitative trait loci (QTL) were identified for KFM and three for KDM. These were located on chromosomes 2, 3, 4, and 5. Two of the QTLs for KFM overlapped with those for KDM. None of these QTLs overlapped with those for fresh weight or dry weight, but the QTL for KDM located on chromosome 3 overlapped with one for DMC. In silico analysis was used to identify known or putative K(+) and cation transporter genes whose loci overlapped with the QTLs. In most cases, multiple genes were identified and the possible role of their gene products in determining shoot K(+) concentrations is discussed.

Arabidopsis↗
PubMed2004

In vitro selection of an archaeal RNase P RNA mimics natural variation.

Archaeal and bacterial RNase P RNAs are similar in sequence and secondary structure, but in the absence of protein, the archaeal RNAs are much less active and require extreme ionic conditions for activity. To assess how readily the activity of the archaeal RNA alone could be improved by small changes in sequence, in vitro selection was used to generate variants of a Methanobacterium formicicum RNase P RNA: Bacillus subtilus pre-tRNA(Asp) self-cleaving conjugate RNA. Functional variants were generated with a spectrum of mutations that were predominately consistent with natural variation in this RNA. Variants generated from the selection had cleavage rates comparable to that of wild type; variants with improved cleavage rates or lower ionic requirements were not obtained. This suggests that the RNase P RNAs of Bacteria and Archaea are globally optimized and the basis for the large biochemical differences between these two types of RNase P RNA is distributed in the molecule.

Archaea↗
PubMed2000

Pain genes?: natural variation and transgenic mutants.

Like many other complex biological phenomena, pain is starting to be studied at the level of the gene. Advances in molecular biological technology have allowed the cloning, mapping, and sequencing of genes, and also the ability to disrupt their function entirely (i.e. via transgenic knockouts). With these new tools at hand, pain researchers have begun in earnest the task of defining (a) which of the 70,000-150,000 mammalian genes are involved in the mediation of pain, and (b) which of the pain-relevant genes are polymorphic, contributing to both natural variation in responses and pathology. Although there are only a few known examples in which single gene mutations in humans are associated with pain conditions (e.g. an inherited form of migraine and congenital insensitivity to pain), it is likely that others will be identified. Concurrently, a variety of genes have been implicated in both the transmission and control of "pain" messages in animals. The present review summarizes current progress to these ends, focusing on both transgenic (gene-->behavior) and classical genetic (behavior-->gene) approaches in both humans and laboratory mice.

Analgesia↗
PubMed2002

Heart rate and energy expenditure of incubating wandering albatrosses: basal levels, natural variation, and the effects of human disturbance.

We studied the changes in heart rate (HR) associated with metabolic rate of incubating and resting adult wandering albatrosses (Diomedea exulans) on the Crozet Islands. Metabolic rates of resting albatrosses fitted with external HR recorders were measured in a metabolic chamber to calibrate the relationship between HR and oxygen consumption (V(O(2))) (V(O(2))=0.074 x HR+0.019, r(2)=0.567, P<0.001, where V(O(2)) is in ml kg(-1) min(-1) and HR is in beats min(-1)). Incubating albatrosses were then fitted with HR recorders to estimate energy expenditure of albatrosses within natural field conditions. We also examined the natural variation in HR and the effects of human disturbance on nesting birds by monitoring the changes in HR. Basal HR was positively related to the mass of the individual. The HR of incubating birds corresponded to a metabolic rate that was 1.5-fold (males) and 1.8-fold (females) lower than basal metabolic rate (BMR) measured in this and a previous study. The difference was probably attributable to birds being stressed while they were held in the metabolic chamber or wearing a mask. Thus, previous measurements of metabolic rate under basal conditions or for incubating wandering albatrosses are likely to be overestimates. Combining the relationship between HR and metabolic rate for both sexes, we estimate that wandering albatrosses expend 147 kJ kg(-1) day(-1) to incubate their eggs. In addition, the cost of incubation was assumed to vary because (i) HR was higher during the day than at night, and (ii) there was an effect of wind chill (<0 degrees C) on basal HR. The presence of humans in the vicinity of the nest or after a band control was shown to increase HR for extended periods (2-3 h), suggesting that energy expenditure was increased as a result of the disturbance. Lastly, males and females reacted differently to handling in terms of HR response: males reacted more strongly than females before handling, whereas females took longer to recover after being handled.

Adaptation, Physiological↗
PubMed1988

Molecular evolution of the Escherichia coli chromosome. I. Analysis of structure and natural variation in a previously uncharacterized region between trp and tonB.

We present the sequence of a 3500-bp region of the Escherichia coli strain K12 chromosome lying between the tryptophan operon and the tonB gene. Analysis of the sequence yields six open reading frames that have properties characteristic of genes for proteins. The reading frames are closely spaced, and putative transcription units and control sites compose over 95% of the DNA. The sequences of several wild strains of E. coli have been determined for a large segment of the region described. Comparison of these sequences reveals the effects of base substitutions, DNA rearrangements, and recombination. In the regions presumably expressed as polypeptides, most of the natural variation results from synonymous substitutions. However, the DNA rearrangements identified have end points within the open reading frames and disrupt them in a variety of ways. The effects of genetic recombination between strains, recently found to be significant on a large scale in E. coli, are also apparent in the region between trp and tonB.

Base Sequence↗
PubMed2004

Quantitative trait loci affecting natural variation in Drosophila longevity.

Limited life span and senescence are universal phenomena, controlled by genetic and environmental factors whose interactions both limit life span and generate variation in life span between individuals, populations and species. To understand the genetic architecture of longevity it is necessary to know what loci affect variation in life span, what are the allelic effects at these loci and what molecular polymorphisms define quantitative trait locus (QTL) alleles. Here, we used quantitative complementation tests to determine whether genes that regulate longevity also contribute to naturally occurring variation in Drosophila life span. Inbred strains derived from a natural population were crossed to stocks containing null mutations (m) or deficiencies (Df) uncovering the candidate genes, maintained over a Balancer (Bal) chromosome. We measured the life span of the resulting F(1) genotypes, +(i)/m (Df) and +(i)/Bal, where +(i) denotes one of the i natural alleles. Failure of the QTL alleles to complement the candidate gene mutation is indicated by a significant cross (mutant versus wild-type allele of the candidate gene) by inbred line interaction term from analysis of variance of life span. Failure to complement indicates a genetic interaction between the candidate gene allele and the naturally occurring life span QTL, and implicates the candidate gene as potential cause of variation in longevity. Of the 16 candidate regions and genes tested, Df(2L)c17, Df(3L)Ly, Df(3L)AC1 and Df(3R)e-BS2 showed significant failure to complement wild-type alleles in both sexes, and an Alcohol dehydrogenase mutant failed to complement in females. Several genes that regulate life span (e.g., Superoxide dismutase, Catalase, and rosy) complemented the life span effects of wild-derived alleles, suggesting little natural variation affecting longevity at these loci, at least in this sample of alleles. Quantitative complementation tests are therefore useful for identifying QTL contributing to segregating genetic variation in life span in nature.

Aging↗