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PubMed2004

Comparison of the genomic structure and variation in the two human sodium-dependent vitamin C transporters, SLC23A1 and SLC23A2.

Vitamin C (L-ascorbic acid) is an essential co-factor for eight mammalian enzymes and quenches reactive oxygen species. Sodium-dependent vitamin C transport is mediated by two transporters, SVCT 1 and SVCT 2, encoded by SLC23A1 and SLC23A2. We characterized the genomic structures of SLC23A1 and SLC23A2, determined the extent of genetic variation and linkage disequilibrium across each gene, analyzed nucleotide diversity to estimate the effect of selective pressure, and compared sequence variation across species. In SLC23A1, the majority of single nucleotide polymorphisms (SNPs) are population-specific in either African Americans or Caucasians, including three of four non-synonymous SNPs. In contrast, most SNPs in SLC23A2 are shared between African Americans and Caucasians, and there are no non-synonymous SNPs in SLC23A2. Our analysis, combined with previous in vitro and in vivo studies, suggests that non-synonymous variation appears to be tolerated in SLC23A1 but not SLC23A2, and that this may be a consequence of different selective pressures following past gene duplication of the sodium-dependent vitamin C transporters. Genetic association studies of these two genes will need to account for the differences in haplotype structure and the population-specific variants. Our data represent a fundamental step toward the application of genetics to refining nutrient recommendations, specifically for vitamin C, and may serve as a paradigm for other vitamins.

Base Composition↗
PubMed2006

Evidence for large inversion polymorphisms in the human genome from HapMap data.

Knowledge about structural variation in the human genome has grown tremendously in the past few years. However, inversions represent a class of structural variation that remains difficult to detect. We present a statistical method to identify large inversion polymorphisms using unusual Linkage Disequilibrium (LD) patterns from high-density SNP data. The method is designed to detect chromosomal segments that are inverted (in a majority of the chromosomes) in a population with respect to the reference human genome sequence. We demonstrate the power of this method to detect such inversion polymorphisms through simulations done using the HapMap data. Application of this method to the data from the first phase of the International HapMap project resulted in 176 candidate inversions ranging from 200 kb to several megabases in length. Our predicted inversions include an 800-kb polymorphic inversion at 7p22, a 1.1-Mb inversion at 16p12, and a novel 1.2-Mb inversion on chromosome 10 that is supported by the presence of two discordant fosmids. Analysis of the genomic sequence around inversion breakpoints showed that 11 predicted inversions are flanked by pairs of highly homologous repeats in the inverted orientation. In addition, for three candidate inversions, the inverted orientation is represented in the Celera genome assembly. Although the power of our method to detect inversions is restricted because of inherently noisy LD patterns in population data, inversions predicted by our method represent strong candidates for experimental validation and analysis.

Biometry↗
PubMed2001

Genetic variation and structure of fisher (Martes pennanti) populations across North America.

Fishers are mid-sized forest carnivores indigenous to North America that experienced sharp population declines from the early 1800s through to the mid-1900s. To evaluate levels of genetic variation within and subdivision among northern fisher populations 459 individuals were genotyped using 13 microsatellite loci. Genetic diversity was found to be slightly lower in re-introduced populations than in adjacent indigenous populations. Furthermore, fisher populations revealed much more genetic structuring than two closely related mustelids. Further investigation is needed to determine if fishers are more philopatric than martens and wolverines or if barriers to dispersal explain the levels of structure identified in this study.

Animals↗
PubMed2006

Reinterpretation of the Brønsted alpha for redox reactions based on the effect of substituents on hydride transfer reaction rates between NAD+ analogues.

Rate and equilibrium constants have been determined spectrophotometrically for two sets of hydride transfer redox reactions between acridine and benzothiazoline derivatives and between pyridine and benzimidazoline derivatives that can be regarded as NAD+/NADH analogues. According to generally accepted ideas of the relation between equilibrium constants, K, and rate constants, k, these reactions would all have Brønsted alpha values close to 0.5 since the equilibrium constants, K, for these reactions range from 10(-1) to 10(2). However, when the structural variation is in the hydride acceptor, the Brønsted alpha is less than 0.5 (0.38 and 0.42, respectively), and when the structural variation is in the hydride donor, the Brønsted alpha is greater than 0.5 (0.63 and 0.61, respectively) for the present systems. The Marcus theory of atom and group transfer can explain the difference of alpha values in terms of the tightness factor in the critical configuration. When the transition state is loose and symmetrical, the deviation of the Brønsted alpha from 0.5 can be obtained by adding or subtracting a tightness factor that depends on the location of the substituents.

Journal Article↗
PubMed2002

Shape analysis of symmetric structures: quantifying variation among individuals and asymmetry.

Morphometric studies often consider parts with internal left-right symmetry, for instance, the vertebrate skull. This type of symmetry is called object symmetry and is distinguished from matching symmetry, in which two separate structures exist as mirror images of each other, one on each body side. We explain a method for partitioning the total shape variation of landmark configurations with object symmetry into components of symmetric variation among individuals and asymmetry. This method is based on the Procrustes superimposition of the original and a reflected copy of each landmark configuration and is compatible with the two-factor ANOVA model customary in studies of fluctuating asymmetry. We show a fully multivariate framework for testing the effects in the two-factor model with MANOVA statistics, which also applies to shapes with matching symmetry. We apply the new methods in a small case study of pharyngeal jaws of the Neotropical cichlid fish Amphilophus citrinellus. The analysis revealed that the symmetric component of variation in the pharyngeal jaws is dominated by the contrast between two alternative trophic morphs in this species and that there is subtle but statistically significant directional asymmetry. Finally, we provide some general recommendations for morphometric studies of symmetric shapes.

Analysis of Variance↗
PubMed2006

Evolution of structure and function in the o-succinylbenzoate synthase/N-acylamino acid racemase family of the enolase superfamily.

Understanding how proteins evolve to provide both exquisite specificity and proficient activity is a fundamental problem in biology that has implications for protein function prediction and protein engineering. To study this problem, we analyzed the evolution of structure and function in the o-succinylbenzoate synthase/N-acylamino acid racemase (OSBS/NAAAR) family, part of the mechanistically diverse enolase superfamily. Although all characterized members of the family catalyze the OSBS reaction, this family is extraordinarily divergent, with some members sharing <15% identity. In addition, a member of this family, Amycolatopsis OSBS/NAAAR, is promiscuous, catalyzing both dehydration and racemization. Although the OSBS/NAAAR family appears to have a single evolutionary origin, no sequence or structural motifs unique to this family could be identified; all residues conserved in the family are also found in enolase superfamily members that have different functions. Based on their species distribution, several uncharacterized proteins similar to Amycolatopsis OSBS/NAAAR appear to have been transmitted by lateral gene transfer. Like Amycolatopsis OSBS/NAAAR, these might have additional or alternative functions to OSBS because many are from organisms lacking the pathway in which OSBS is an intermediate. In addition to functional differences, the OSBS/NAAAR family exhibits surprising structural variations, including large differences in orientation between the two domains. These results offer several insights into protein evolution. First, orthologous proteins can exhibit significant structural variation, and specificity can be maintained with little conservation of ligand-contacting residues. Second, the discovery of a set of proteins similar to Amycolatopsis OSBS/NAAAR supports the hypothesis that new protein functions evolve through promiscuous intermediates. Finally, a combination of evolutionary, structural, and sequence analyses identified characteristics that might prime proteins, such as Amycolatopsis OSBS/NAAAR, for the evolution of new activities.

Actinobacteria↗
PubMed2007

Systematic structure-property investigations and ion-sensing studies of pyridine-derivatized donor/acceptor tetrakis(arylethynyl)benzenes.

Nine structural isomers of a tetrakis(arylethynyl)benzene chromophore functionalized with dibutylaniline and pyridine units as respective donors and acceptors have been synthesized and their steady-state spectroscopic parameters investigated. The effects of small structural variations on the electronic absorption and emission spectra have been explored in evaluation of their potential as optical materials components. These structural variations have predictable consequences and thus allow fine-tuning of the optoelectronic properties for specialized applications. Strong solvatochromism is also displayed. Their response to protonation and metal ion complexation caused dynamic shifts in the emission spectra, providing evidence for a stepwise intramolecular charge-transfer switching phenomenon manifested by either hypsochromic or bathochromic shifts in the fluorescence lambda max. These shifts are believed to correlate strongly to the relative energies of the fluorophore's HOMO and LUMO levels. The complete array of compounds represents an interesting set of candidates for fluorescent sensing device components.

Journal Article↗
PubMed2003

Extinction-colonization dynamics structure genetic variation of spotted sunfish (Lepomis punctatus) in the Florida Everglades.

The population genetics of aquatic animals in the Florida Everglades may be strongly influenced by extinction and colonization dynamics. We combined analyses of allozyme and microsatellite loci to test the hypothesis that two levels of population structure are present for spotted sunfish (Pisces: Centrarchidae: Lepomis punctatus) inhabiting the Everglades. We hypothesized that annual cycles of marsh dry-down increase local-scale genetic variation through a process of local extinction and colonization; we hypothesized that barriers to gene flow by levee/canal systems create a second, regional level of genetic variation. In 1996 and 1997, we sampled spotted sunfish from 11 Everglades sites that were distributed in three regions separated by levees. We documented patterns of genetic variation at 7 polymorphic allozyme loci and 5 polymorphic microsatellite loci. Most genetic variation was present among local populations, according to both types of genetic markers. Furthermore, samples from marsh sites were heterogeneous, while those from canals were not. These data supported our hypothesis that dry-down events and local population dynamics in the marsh have a significant effect on population genetic structure of spotted sunfish. We found no support for our hypothesis that water-management structures superimpose a second level of genetic structure on this species, possibly because canals obscure historical structure by facilitating gene flow or because the complete canal system has been in place for fewer than 20 generations of this species. Our data suggests a continent-island (canal-marsh) structure of populations with high gene flow among regions and recurrent mixing in marshes from canal and creek habitats.

Animals↗
PubMed1984

Structure-dependent variation in the mutagenic, prophage-inducing and antibacterial activities of 5-nitro-2-furamide derivatives.

A comparative survey of the mutagenic, prophage-inducing and antibacterial activities of 3 structure-related series of 5-nitro-furan derivatives including 5-nitro-2-furohydrazide imide, 5-nitro-2-furamide oxime and 5-nitro-2-furohydrazide has been undertaken. Among the compounds assayed, the 5-nitro-2-furohydrazide imide series was found to be most active with regard to mutagenic and antibacterial activities against Salmonella typhimurium TA100 and prophage-inducing activity in Escherichia coli GY5027. A clear correlation was observed between the chemical structure and the mutagenic and prophage-inducing activities which were approximately correlated to the antibacterial activity.

Anti-Bacterial Agents↗
PubMed2026

Climate Gradients and Habitat Discontinuity Structure Genetic Variation in a Spring-Specialist Plant.

BACKGROUND AND AIMS: Groundwater-dependent ecosystems support disproportionate biodiversity in arid regions, yet the population genetics of spring-specialist plants remains poorly understood. Here, we present the first species-wide genetic dataset for crimson monkeyflower (Mimulus verbenaceus, Phrymaceae), a spring-specialist plant distributed in seeps, springs, and associated riparian areas across desert regions of North America. We aim to relate landscape features and climate gradients to the spatial genetic structuring within this system. METHODS: Using genome-wide reduced representation sequencing data consisting of 10,760 SNPs from 175 individuals across 17 populations, we characterized the patterns of genetic differentiation and diversity. Population structure was assessed using ADMIXTURE and Principal Component Analysis. We examined the contributions of climate to range-wide genetic variation in crimson monkeyflower using redundancy analysis. KEY RESULTS: Patterns of genetic differentiation were more consistent with those of spring-specialist animal taxa than those of upland plants or generalist riparian plants. We found strong population structure at both broad regional scales and at fine local scales. While geographic and spatial structuring was a primary driver of genetic structure across all scales, riparian connectivity influenced local patterns of diversity, and adaptation to local climatic variation was more influential at regional scales, with temperature, relative humidity, and a monsoon-driven climate gradient contributing to genetic differentiation. CONCLUSIONS: Our findings highlight the distinctive association with isolated perennial groundwater sources, as well as climate gradients, with genetic variation in this spring-specialist plant. These findings suggest that spring-specialist plants deserve special consideration in ecological theory, management, and conservation.

Mimulus↗
PubMed2004

Human vitamin K-dependent GAS6: gene structure, allelic variation, and association with stroke.

The product of the growth arrest-specific gene 6 (GAS6), a ligand for the Axl, Sky, and Mer tyrosine kinase receptors, is a vitamin K-dependent protein, structurally related to anticoagulant protein S. Gas6-deficient mice are protected against thrombosis, demonstrating the importance of this protein in the cardiovascular system. The present study was aimed at determining the human GAS6 intron-exon structure and analyzing the gene for the presence of allelic variants that could be associated with atherothrombotic disease. Online analyses allowed us to localize 15 GAS6 exons and to determine the sequence of their intron-flanking regions, in a chromosome 13 region spanning 43.8 kb of DNA. SSCP analysis of PCR-amplified GAS6 exons with their intron-flanking regions from a minimum of 12 control DNA samples, revealed the presence of eight different variants, which were confirmed to be single nucleotide polymorphisms (SNPs). Three of them (c.1263G>C, c.1332C>T, and c.1869T>C) are localized in exons 11, 12, and 14, and appear to be neutral since they do not modify the encoded amino acid. The other SNPs (c.280+170C>G, c.712+26G>A, c.713-155C>T, c.834+7G>A, and c.1478-94C>G) are in introns 3, 7, 8, and 12. A preliminary analysis of five of these SNPs in a group of 110 healthy controls and 188 patients with atherothrombotic disease has revealed statistically significant differences between controls and stroke patients in the allelic distributions of one of these variants (c.834+7G>A in intron 8). The SNP identification in GAS6 reported here would be very useful in future association studies aimed at determining the physiologic role of GAS6 in stroke and other human diseases.

Alleles↗
PubMed2005

Microsatellite variation and structure of 28 populations of the common wetland plant, Lychnis flos-cuculi L., in a fragmented landscape.

Habitat fragmentation is known to cause genetic differentiation between small populations of rare species and decrease genetic variation within such populations. However, common species with recently fragmented populations have rarely been studied in this context. We investigated genetic variation and its relationship to population size and geographical isolation of populations of the common plant species, Lychnis flos-cuculi L., in fragmented fen grasslands. We analysed 467 plants from 28 L. flos-cuculi populations of different sizes (60 000-54 000 flowering individuals) in northeastern Switzerland using seven polymorphic microsatellite loci. Genetic differentiation between populations is small (F(ST) = 0.022; amova; P < 0.001), suggesting that gene flow among populations is still high or that habitat fragmentation is too recent to result in pronounced differentiation. Observed heterozygosity (H(O) = 0.44) significantly deviates from Hardy-Weinberg equilibrium, and within-population inbreeding coefficient F(IS) is high (0.30-0.59), indicating a mixed mating breeding system with substantial inbreeding in L. flos-cuculi. Gene diversity is the only measure of genetic variation which decreased with decreasing population size (R = 0.42; P < 0.05). While our results do not indicate pronounced effects of habitat fragmentation on genetic variation in the still common L. flos-cuculi, the lower gene diversity of smaller populations suggests that the species is not entirely unaffected.

Altitude↗
PubMed1995

Developing microsatellite markers for insect population structure: complex variation in a checkerspot butterfly.

We isolated and characterized two microsatellite markers from the genome of the endangered checkerspot butterfly Melitaea cinxia L. In Finland, this species only survives on the Aland islands, where it exhibits a highly fragmented metapopulation structure on small meadows. Four alleles were observed at the locus CINX1 and nine at CINX4; the total gene diversities at the two loci were HT = 0.34 and 0.80, respectively. A pilot survey showed moderate gene frequency differentiation among meadows (local populations; FLM = 0.1) and among metapopulations c. 30 km apart (FMT = 0.2). Contrary to prior expectation, distinct feeding larval groups collected in the spring did not represent offspring of single females. There was a conspicuous excess of homozygotes within local populations (FIL = 0.35), which can hardly be attributed to population structure alone; this urges caution in straightforward interpretation of microsatellite phenotype data.

Animals↗
PubMed1993

Structural modification patterns from agonists to antagonists and their application to drug design--a new serotonin (5-HT3) antagonist series.

Structural variations from agonists to their selective antagonists seemed to follow certain patterns. To analyze the variation patterns in the structural modification processes in past examples as well as to utilize the "common" variation patterns as possible principles to design new selective antagonistic drugs, the structures of agonists and their antagonists were superimposed on a two-dimensional grid template composed of regular hexagons and the topological similarities and dissimilarities of substructural elements between agonists and antagonists were examined. Between several pairs of neurotransmitter amines and their "selective" antagonists, similar patterns were disclosed in their structural modification processes. The generalized structural modification patterns were successfully applied as guiding principles to design and identify a new prototype structure of the 5-HT3 antagonist. The prototype structure was optimized by use of QSAR procedures leading to a compound which shows a potent antiemetic activity as well as a powerful gastrointestinal-motility modulation.

Animals↗
PubMed1983

Polymorphism and diversity in the Tla gene system.

The TL products of mouse strains carrying the Tlaa, Tlad, and Tlae haplotypes were analyzed by comparative peptide mapping. As expected from their known serologic differences, TL antigens from strain A (Tlaa), A.CA strain (Tlad) and P/J strain (Tlae) mice showed structural variation. However, comparable variations were also observed in the TL product derived from strains expressing the serologically indistinguishable Tlaa allele (A, NFS/N, SJL/J, C57BR, and C58) demonstrating additional unexpected polymorphism in the TL system. When compared with the structural diversity of the H-2 K and D gene products, the structural variation of the TL antigens was small. Taken together, the results of our analysis of the TL products suggest that Tla polymorphism is more extensive than previously thought; however, the structural diversity of the products is still low compared with K and D gene products.

Alleles↗
PubMed2002

A solid-supported, enantioselective synthesis suitable for the rapid preparation of large numbers of diverse structural analogues of (-)-saframycin A.

A 10-step solid-supported, enantioselective synthesis suitable for the rapid preparation of large numbers of diverse structural analogues of saframycin A is described. The synthetic route, which bears analogy to solid-phase peptide synthesis, involves the directed condensation of N-protected alpha-amino aldehyde reactants. A novel dual linker was developed for attachment of intermediates to the solid support via a C-protective group, a substituted morpholino nitrile derivative. The route employs a novel diastereospecific cyclorelease mechanism, supports structural variation at multiple sites in the saframycin core, and obviates the need for chromatographic purification of the products or any intermediate. To demonstrate the feasibility of structural variation at multiple sites, a matrix of 16 saframycin A analogues was prepared by parallel synthesis with simultaneous variation of two sites. This work is notable not only as a preliminary step toward large-scale library construction but also as an example of the use of sequential stereoselective C-C bond-forming reactions on the solid phase for the preparation of natural product analogues.

Alkaloids↗
PubMed2003

The foldback-like transposon Galileo is involved in the generation of two different natural chromosomal inversions of Drosophila buzzatii.

Chromosomal inversions are the most common type of genome rearrangement in the genus Drosophila. Although the potential of transposable elements (TEs) for generating inversions has been repeatedly demonstrated in the laboratory, little is known on their role in the generation of natural inversions, which are those effectively contributing to the adaptation and/or evolution of species. We have cloned and sequenced the two breakpoints of the polymorphic inversion 2q7 of D. buzzatii. The sequence analysis of the breakpoint regions revealed the presence in the inverted chromosomes of large insertions, formed by complex assemblies of transposons, that are absent from the chromosomes without the inversion. Among the transposons inserted, the Foldback-like element Galileo, that was previously found responsible of the generation of the widespread inversion 2j of D. buzzatii, is present at both 2q7 breakpoints and is the most likely inducer of the inversion. A detailed study of the nucleotide and structural variation in the breakpoint regions of six chromosomal lines with the 2q7 inversion detected no nucleotide differences between them, which suggests a monophyletic and recent origin. In contrast, a remarkable degree of structural variation was observed in the same six chromosomal lines. It thus appears that the two breakpoints of the inverted chromosomes have become genetically unstable hotspots, as was previously found for the 2j inversion breakpoints. The possibility that this instability is caused by structural properties of Foldback elements is discussed.

Animals↗