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PubMed2005

Comparative genome sequencing of Drosophila pseudoobscura: chromosomal, gene, and cis-element evolution.

We have sequenced the genome of a second Drosophila species, Drosophila pseudoobscura, and compared this to the genome sequence of Drosophila melanogaster, a primary model organism. Throughout evolution the vast majority of Drosophila genes have remained on the same chromosome arm, but within each arm gene order has been extensively reshuffled, leading to a minimum of 921 syntenic blocks shared between the species. A repetitive sequence is found in the D. pseudoobscura genome at many junctions between adjacent syntenic blocks. Analysis of this novel repetitive element family suggests that recombination between offset elements may have given rise to many paracentric inversions, thereby contributing to the shuffling of gene order in the D. pseudoobscura lineage. Based on sequence similarity and synteny, 10,516 putative orthologs have been identified as a core gene set conserved over 25-55 million years (Myr) since the pseudoobscura/melanogaster divergence. Genes expressed in the testes had higher amino acid sequence divergence than the genome-wide average, consistent with the rapid evolution of sex-specific proteins. Cis-regulatory sequences are more conserved than random and nearby sequences between the species--but the difference is slight, suggesting that the evolution of cis-regulatory elements is flexible. Overall, a pattern of repeat-mediated chromosomal rearrangement, and high coadaptation of both male genes and cis-regulatory sequences emerges as important themes of genome divergence between these species of Drosophila.

Animals↗
PubMed1996

The consequences of phenotypic plasticity in cyclically varying environments: a genetic algorithm study.

By "phenotypic plasticity" we refer to the capacity of a genotype to exhibit different phenotypes, whether in the same or in different environments. We have previously demonstrated that phenotypic plasticity can improve the degree of adaptation achieved via natural selection (Behera & Nanjundiah, 1995). That result was obtained from a genetic algorithm model of haploid genotypes (idealized as one-dimensional strings of genes) evolving in a fixed environment. Here, the dynamics of evolution is examined under conditions of a cyclically varying environment. We find that the rate of evolution, as well as the extent of adaptation (as measured by mean population fitness) is lowered because of environmental cycling. The decrease in adaptation caused by a varying environment can, however, be partly or wholly compensated by an increase in the degree of plasticity that a genotype is capable of. Also, the reduction of population fitness caused by a variable environment can be partially offset by decreasing the total number of genetic loci. We conjecture that an increase in genome size may have been among the factors responsible for the evolution of phenotypic plasticity.

Adaptation, Physiological↗
PubMed2005

Identifying genomic regions for fine-mapping using genome scan meta-analysis (GSMA) to identify the minimum regions of maximum significance (MRMS) across populations.

In order to detect linkage of the simulated complex disease Kofendrerd Personality Disorder across studies from multiple populations, we performed a genome scan meta-analysis (GSMA). Using the 7-cM microsatellite map, nonparametric multipoint linkage analyses were performed separately on each of the four simulated populations independently to determine p-values. The genome of each population was divided into 20-cM bin regions, and each bin was rank-ordered based on the most significant linkage p-value for that population in that region. The bin ranks were then averaged across all four studies to determine the most significant 20-cM regions over all studies. Statistical significance of the averaged bin ranks was determined from a normal distribution of randomly assigned rank averages. To narrow the region of interest for fine-mapping, the meta-analysis was repeated two additional times, with each of the 20-cM bins offset by 7 cM and 13 cM, respectively, creating regions of overlap with the original method. The 6-7 cM shared regions, where the highest averaged 20-cM bins from each of the three offsets overlap, designated the minimum region of maximum significance (MRMS). Application of the GSMA-MRMS method revealed genome wide significance (p-values refer to the average rank assigned to the bin) at regions including or adjacent to all of the simulated disease loci: chromosome 1 (p < 0.0001 for 160-167 cM, including D1), chromosome 3 (p-value < 0.0000001 for 287-294 cM, including D2), chromosome 5 (p-value < 0.001 for 0-7 cM, including D3), and chromosome 9 (p-value < 0.05 for 7-14 cM, the region adjacent to D4). This GSMA analysis approach demonstrates the power of linkage meta-analysis to detect multiple genes simultaneously for a complex disorder. The MRMS method enhances this powerful tool to focus on more localized regions of linkage.

Chromosomes, Human↗
PubMed2003

In-phase implies large likelihood for independent codon model: distinguishing coding from non-coding sequences.

It is proven that under the independent codon model, the likelihood of a DNA coding sequence read according to the correct frame is asymptotically larger than that read with an incorrect frame. Based on this proposition, a single set of probabilities of the codon usage is enough for discriminating the six frames of coding sequences under the independent codon model. The direct coding sequence of Escherichia coli genome is taken as an example to examine the codon independency by using the mutual information and chi2 analysis. The contrast between the coding frame and the two offset frames is evident. A self-learning approach for generating training set is proposed to estimate probability parameters.

Codon↗
PubMed2002

Influence of a putative intermolecular interaction between core and the pre-S1 domain of the large envelope protein on hepatitis B virus secretion.

Virion release of hepatitis B virus (HBV) from hepatocytes is a tightly regulated event. It is a dogma that only the mature HBV genome is preferentially allowed to export from the intracellular compartment (J. Summers and W. S. Mason, Cell 29:403-415, 1982). Recently, an "immature secretion" phenotype of a highly frequent naturally occurring HBV variant containing a leucine residue at amino acid 97 of the core protein was identified. Unlike wild-type HBV, this variant secretes almost equal amounts of mature and immature genomes. This phenomenon is not caused by any instability of core particles or by any deficiency in viral reverse transcription (T. T. Yuan, P. C. Tai, and C. Shih, J. Virol. 73:10122-10128, 1999). In this study, our kinetic analysis of virion secretion of the mutant F97L (phenylalanine to leucine) indicates that the secretion of its immature genome does not occur earlier than that of its mature genome. In addition, the secretion kinetics of the mature genomes are comparable between the wild-type HBV and the mutant F97L. Therefore, the immature secretion phenomenon of mutant F97L is not caused by premature secretion or more efficient secretion. Previously, we hypothesized that the immature secretion phenotype is probably caused by the aberrant interaction between its mutant core and wild-type envelope proteins. Here, we further demonstrated that a pre-S1 envelope mutation at position 119, changing an alanine (A) to a phenylalanine (F), can offset the immature secretion phenotype of the mutant I97L (isoleucine to leucine) and successfully restore the wild-type-like selective export of the mature genome of the double mutant pre-S1-A119F/core-I97L.

Amino Acid Sequence↗
PubMed2000

Human and mouse mitochondrial orthologs of bacterial ClpX.

We have determined the cDNA sequence and exon/intron structure of the human CLPX gene encoding a human ortholog of the E. coli ClpX chaperone and protease subunit. The CLPX gene comprises 14 exons and encodes a 633-amino acid-long precursor polypeptide. The polypeptide contains an N-terminal putative mitochondrial transit peptide, and expression of a full-length ClpX cDNA tagged at its C-terminus (Myc-His) shows that the polypeptide is transported into mitochondria. FISH analysis localized the CLPX gene to human Chromosome (Chr) 15q22.1-22.32. This localization was refined by radiation hybrid mapping placing the CLPX gene 4.6 cR distal to D15S159. Murine ClpX cDNA was sequenced, and the mouse Clpx locus was mapped to a position between 31 and 42 cM offset from the centromere on mouse Chr 9. Experimental observations indicate the presence of a pseudogene in the mouse genome and sequence variability between mouse ClpX cDNAs from different strains. Alignment of the human and mouse ClpX amino acid sequences with ClpX sequences from other organisms shows that they display the typical modular organization of domains with one AAA(+) domain common to a large group of ATPases and several other domains conserved in ClpX orthologs linked by non-conserved sequences. Notably, a C-4 zinc finger type motif is recognized in human and mouse ClpX. This motif of so far unknown function is present only in a subset of the known ClpX sequences.

ATPases Associated with Diverse Cellular Activitie↗
PubMed1996

Length variation, heteroplasmy and sequence divergence in the mitochondrial DNA of four species of sturgeon (Acipenser).

The extent of mtDNA length variation and heteroplasmy as well as DNA sequences of the control region and two tRNA genes were determined for four North American sturgeon species: Acipenser transmontanus, A. medirostris, A. fulvescens and A. oxyrhnychus. Across the Continental Divide, a division in the occurrence of length variation and heteroplasmy was observed that was concordant with species biogeography as well as with phylogenies inferred from restriction fragment length polymorphisms (RFLP) of whole mtDNA and pairwise comparisons of unique sequences of the control region. In all species, mtDNA length variation was due to repeated arrays of 78-82-bp sequences each containing a D-loop strand synthesis termination associated sequence (TAS). Individual repeats showed greater sequence conservation within individuals and species rather than between species, which is suggestive of concerted evolution. Differences in the frequencies of multiple copy genomes and heteroplasmy among the four species may be ascribed to differences in the rates of recurrent mutation. A mechanism that may offset the high rate of mutation for increased copy number is suggested on the basis that an increase in the number of functional TAS motifs might reduce the frequency of successfully initiated H-strand replications.

Animals↗
PubMed2001

17beta-estradiol inhibition of NADPH oxidase expression in human endothelial cells.

We investigated the hypothesis that the antiatherosclerotic effect of 17beta-estradiol (E2) is due to a shift in the nitric oxide (NO)/superoxide (O2-) balance in the vessel wall, thereby increasing the bioavailability of NO. In human umbilical vein cultured endothelial cells, E2 (1-100 nmol/l), but not 17alpha-estradiol, caused a time- and concentration-dependent decrease in expression of the NADPH oxidase subunit gp91phox (up to 60% inhibition at both the mRNA and protein level). This effect was prevented by coincubation with the estrogen receptor antagonists tamoxifen and ICI 182,780 (1 micromol/l each). Within the same concentration range, E2 also up-regulated endothelial nitric oxide synthase expression ( approximately twofold). Moreover, preincubation of the cells with E2 or a gp91phox antisense oligonucleotide significantly decreased their capacity to generate O2- on phorbol ester stimulation (i.e., assembly of the active NADPH oxidase complex). Blockade of NO synthase activity, on the other hand, had no effect on phorbol ester-stimulated O2- formation. In addition, E2 (100 nmol/l) inhibited the increase in adhesion molecule and chemokine expression in cells exposed to cyclic strain. Cyclic strain enhanced endothelial O2- formation, thereby offsetting the inhibitory effect of NO on the expression of these gene products. E2 thus seems to act as an antioxidant at the genomic level which by improving the NO/O2- balance normalizes expression of proatherosclerotic gene products in endothelial cells.

Arteriosclerosis↗
PubMed2003

Genome-wide transcriptional changes during the lag phase of Saccharomyces cerevisiae.

The set of physiological and metabolic changes occurring immediately after inoculation and during the lag phase is thought to be of vital importance for optimal offset of fermentation. The transcriptional changes taking place during the lag phase after inoculation of a late-respiratory-phase yeast culture into fresh, minimal medium were investigated by use of Yeast GeneFilters. In response to the nutritional up-shift, 240 open reading frames were at least five-fold induced and 122 were at least five-fold repressed. These genes were hierarchically clustered according to their lag-phase expression patterns. The majority of the induced genes were most highly induced early in the lag phase, whereas strong repression generally occurred later. Clustering of the genes showed that many genes with similar roles had similar expression patterns. Repressed genes, however, did not cluster as tightly according to function as induced genes. Genes involved in RNA and protein synthesis and processing showed a peak in expression early in the lag phase, except most ribosomal protein genes, which were induced early and whose expression was sustained. Genes involved in chromatin/chromosome structure showed late induction. The correlation between function and expression pattern for these genes indicates regulation by similar mechanisms. Much of the transcriptional response observed appeared to be due to the presence of glucose in the new medium.

Amino Acids↗
PubMed2004

Properties of overlapping genes are conserved across microbial genomes.

There are numerous examples from the genomes of viruses, mitochondria, and chromosomes that adjacent genes can overlap, sharing at least one nucleotide. Overlaps have been hypothesized to be involved in genome size minimization and as a regulatory mechanism of gene expression. Here we show that overlapping genes are a consistent feature (approximately one-third of all genes) across all microbial genomes sequenced to date, have homologs in more microbes than do non-overlapping genes, and are therefore likely more conserved. In addition, the size, phase (reading frame offset), and distribution, among other characteristics, of overlapping genes are most consistent with the hypothesis that overlaps function in the regulation of gene expression. The upstream sequences and conservation of overlapping orthologs of two model organisms from the genus Prochlorococcus that have significantly different GC-content, and therefore different nucleotide sequences for orthologs, are also consistent with small overlapping sequence regions and programmed shifts in reading frame as a common mechanism in the regulation of microbial gene expression.

Computational Biology↗
PubMed2000

Ontogeny of telomerase in chicken: impact of downregulation on pre- and postnatal telomere length in vivo.

Telomeres are the termini of linear chromosomes composed of tandem repeats of a conserved DNA sequence. Telomerase provides a mechanism for proliferating cells to offset telomeric sequence erosion by synthesizing new repeats onto the end of each parental DNA strand. Reduced or absent telomerase activity can lead to telomere shortening and genome instability. Telomeres and telomerase have not previously been characterized during ontogeny of any avian species. In the present study, telomerase activity in the chicken model was examined from early differentiation embryos through to adulthood. Telomerase activity was detected in all early embryos (preblastula through neurula) and in tissues throughout organogenesis. Subsequently, telomerase was downregulated in the majority of somatic tissues, either pre- or postnatally. A subset of tissues, such as intestine, immune and reproductive organs, exhibited constitutive activity. The impact of telomerase downregulation on telomere length was investigated and a telomere reduction of 3.2 kb in somatic tissues compared with germ line was observed in 5-year-old adults. The present results suggest that the telomere clock function is a conserved feature of avians as well as mammals. Knowledge regarding the relationships among telomerase regulation, proliferation/senescence profiles and differentiation status will be useful for numerous applications of chicken cells.

Animals↗
PubMed1989

Arterial pressure and aging.

Systolic arterial pressure increases with aging. This increase encompasses both the clinically normal and hypertensive ranges of pressure and is due in part to arterial stiffening. To what extent it may be modulated by life style changes that accompany aging is unknown. The stiffer arterial tree transmits the pulse wave with a higher velocity such that reflected waves return to the aortic root during the ejection period. This causes the aortic impedance to increase at this time, leading to a late peak in systolic pressure. Cardiac adaptation to these vascular changes include left ventricular hypertrophy and prolonged Ca2+ activation of contractile proteins leading to prolonged contraction. The resultant delayed contractile relaxation, in part, leads to a slower velocity of early left ventricular filling; however, this is offset by an enhanced atrial contribution to filling. These myocardial adaptations with aging, which in animal models appear, in part at least, to be controlled from within the genome permit a relatively normal heart volume and ejection fraction in the presence of chronically elevated afterload. These changes that occur with aging in otherwise healthy individuals can occur at a younger age in clinical hypertensives and can be produced in young experimental animals by hypertension. Thus, aging has sometimes been referred to as blunted hypertension, or hypertension as accelerated aging.

Aging↗
PubMed2025

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

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

Eucalyptus↗
PubMed2007

Plant Gene and Alternatively Spliced Variant Annotator. A plant genome annotation pipeline for rice gene and alternatively spliced variant identification with cross-species expressed sequence tag conservation from seven plant species.

The completion of the rice (Oryza sativa) genome draft has brought unprecedented opportunities for genomic studies of the world's most important food crop. Previous rice gene annotations have relied mainly on ab initio methods, which usually yield a high rate of false-positive predictions and give only limited information regarding alternative splicing in rice genes. Comparative approaches based on expressed sequence tags (ESTs) can compensate for the drawbacks of ab initio methods because they can simultaneously identify experimental data-supported genes and alternatively spliced transcripts. Furthermore, cross-species EST information can be used to not only offset the insufficiency of same-species ESTs but also derive evolutionary implications. In this study, we used ESTs from seven plant species, rice, wheat (Triticum aestivum), maize (Zea mays), barley (Hordeum vulgare), sorghum (Sorghum bicolor), soybean (Glycine max), and Arabidopsis (Arabidopsis thaliana), to annotate the rice genome. We developed a plant genome annotation pipeline, Plant Gene and Alternatively Spliced Variant Annotator (PGAA). Using this approach, we identified 852 genes (931 isoforms) not annotated in other widely used databases (i.e. the Institute for Genomic Research, National Center for Biotechnology Information, and Rice Annotation Project) and found 87% of them supported by both rice and nonrice EST evidence. PGAA also identified more than 44,000 alternatively spliced events, of which approximately 20% are not observed in the other three annotations. These novel annotations represent rich opportunities for rice genome research, because the functions of most of our annotated genes are currently unknown. Also, in the PGAA annotation, the isoforms with non-rice-EST-supported exons are significantly enriched in transporter activity but significantly underrepresented in transcription regulator activity. We have also identified potential lineage-specific and conserved isoforms, which are important markers in evolutionary studies. The data and the Web-based interface, RiceViewer, are available for public access at http://RiceViewer.genomics.sinica.edu.tw/.

Base Sequence↗
PubMed2001

Soybean genomic survey: BAC-end sequences near RFLP and SSR markers.

We are building a framework physical infrastructure across the soybean genome by using SSR (simple sequence repeat) and RFLP (restriction fragment length polymorphism) markers to identify BACs (bacterial artificial chromosomes) from two soybean BAC libraries. The libraries were prepared from two genotypes, each digested with a different restriction enzyme. The BACs identified by each marker were grouped into contigs. We have obtained BAC- end sequence from BACs within each contig. The sequences were analyzed by the University of Minnesota Center for Computational Genomics and Bioinformatics using BLAST algorithms to search nucleotide and protein databases. The SSR-identified BACs had a higher percentage of significant BLAST hits than did the RFLP-identified BACs. This difference was due to a higher percentage of hits to repetitive-type sequences for the SSR-identified BACs that was offset in part, however, by a somewhat larger proportion of RFLP-identified significant hits with similarity to experimentally defined genes and soybean ESTs (expressed sequence tags). These genes represented a wide range of metabolic functions. In these analyses, only repetitive sequences from SSR-identified contigs appeared to be clustered. The BAC-end sequences also allowed us to identify microsynteny between soybean and the model plants Arabidopsis thaliana and Medicago truncatula. This map-based approach to genome sampling provides a means of assaying soybean genome structure and organization.

Algorithms↗
PubMed2006

Sexual reproduction selects for robustness and negative epistasis in artificial gene networks.

The mutational deterministic hypothesis for the origin and maintenance of sexual reproduction posits that sex enhances the ability of natural selection to purge deleterious mutations after recombination brings them together into single genomes. This explanation requires negative epistasis, a type of genetic interaction where mutations are more harmful in combination than expected from their separate effects. The conceptual appeal of the mutational deterministic hypothesis has been offset by our inability to identify the mechanistic and evolutionary bases of negative epistasis. Here we show that negative epistasis can evolve as a consequence of sexual reproduction itself. Using an artificial gene network model, we find that recombination between gene networks imposes selection for genetic robustness, and that negative epistasis evolves as a by-product of this selection. Our results suggest that sexual reproduction selects for conditions that favour its own maintenance, a case of evolution forging its own path.

Animals↗
PubMed1998

Deleterious mutation accumulation and the regeneration of genetic resources.

The accumulation of mildly deleterious mutations accompanying recurrent regeneration of plant germ plasm was modeled under regeneration conditions characterized by different amounts of selection and genetic drift. Under some regeneration conditions (sample sizes >/=75 individuals and bulk harvesting of seed) mutation accumulation was negligible, but under others (sample sizes <75 individuals or equalization of seed production by individual plants) mutation numbers per genome increased significantly during 25-50 cycles of regeneration. When mutations also are assumed to occur (at elevated rates) during seed storage, significant mutation accumulation and fitness decline occurred in 10 or fewer cycles of regeneration regardless of the regeneration conditions. Calculations also were performed to determine the numbers of deleterious mutations introduced and remaining in the genome of an existing variety after hybridization with a genetic resource and subsequent backcrossing. The results suggest that mutation accumulation has the potential to reduce the viability of materials held in germ plasm collections and to offset gains expected by the introduction of particular genes of interest from genetic resources.

Alleles↗