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PubMedDate not supplied

Two AGAMOUS-like MADS-box genes from Taihangia rupestris (Rosaceae) reveal independent trajectories in the evolution of class C and class D floral homeotic functions.

Duplicate genes may be retained by sub- and/or neofunctionalization through changes in gene expression and/or coding sequence, and therefore have the potential to contribute to the genetic robustness and diversification of an organism. In this study, two MADS-box genes were isolated from Taihangia rupestris, a core eudicot species belonging to the Rosaceae. Sequence and phylogenetic analyses revealed that they are clade members of the euAG and PLE lineages, respectively, and hence the two genes are named TrAG (Taihangia rupestris AGAMOUS) and TrSHP (Taihangia rupestris SHATTERPROOF). Southern blot analysis shows that TrSHP is a single-copy gene in the T. rupestris genome. In situ hybridization analyses show that both TrAG and TrSHP are mainly expressed in the stamens, carpels, and ovules. When the stamen primordia are firstly observed, TrAG is initially expressed in the floral meristem domain that will initiate stamens and carpels. In contrast, no TrSHP signal is observed at this developmental stage. At late stages of carpel development, TrAG expression is detected in the ovules, ovaries, and developing styles and stigmas, whereas TrSHP expression is tightly restricted to the ovules. The transgenic Arabidopsis plants containing 35S::TrAG and 35S::TrSHP, respectively, showed similar phenotypes, including homeotic conversions of sepals into carpelloid structures bearing ovules and petals into staminoid organs, and the fruits shattering prematurely along the dehiscence zone. In addition, the phenotype of the transgenic 35S::TrSHP Arabidopsis plants revealed that perianth abscission was inhibited. Yeast two-hybrid assays indicated that TrAG can interact with TrSEP3, whereas TrSHP cannot. The data suggest that the euAG and PLE paralogs, TrAG and TrSHP, may have subfunctionalized and/or neofunctionalized through changes in expression patterns and accumulating variations in the coding regions. Taking these findings together with those available expression and functional data from Arabidopsis and other species, we conclude that the compensatory ways vary among the euAG and PLE lineage pairs in eudicot species.

Blotting, Southern↗
PubMed2006

Cigarette smoking strongly modifies the association of LOC387715 and age-related macular degeneration.

We used iterative association mapping to identify a susceptibility gene for age-related macular degeneration (AMD) on chromosome 10q26, which is one of the most consistently implicated linkage regions for this disorder. We employed linkage analysis methods, followed by family-based and case-control association analyses, using two independent data sets. To identify statistically the most likely AMD-susceptibility allele, we used the Genotype-IBD Sharing Test (GIST) and conditional haplotype analysis. To incorporate the two most important known AMD risk factors--smoking and the Y402H variant of the complement factor H gene (CFH)--we used logistic regression modeling to test for gene-gene and gene-environment interactions in the case-control data set and used the ordered-subset analysis to account for genetic linkage heterogeneity in the family-based data set. Our results strongly implicate a coding change (Ala69Ser) in the LOC387715 gene as the second major identified AMD-susceptibility allele, confirming earlier suggestions. This variant's effect on AMD is statistically independent of CFH and is of similar magnitude to the effect of Y402H. The overall effect is driven primarily by a strong association in smokers, since we observed significant evidence for a statistical interaction between the LOC387715 variant and a history of cigarette smoking. This gene-environment interaction is supported by statistically independent family-based and case-control analysis methods. We estimate that CFH, LOC387715, and cigarette smoking together explain 61% of the population-attributable risk (PAR) of AMD. The adjusted PAR percentage estimates are 20% for smoking, 36% for LOC387715, and 43% for CFH. We demonstrate, for the first time, that a genetic susceptibility coupled with a modifiable lifestyle factor such as cigarette smoking confers a significantly higher risk of AMD than either factor alone.

Aged↗
PubMed1989

Codon reassignment (codon capture) in evolution.

The genetic code, once thought to be "frozen," shows variations from the universal code. Variations are found in mitochondria, Mycoplasma, and ciliated protozoa. The variations result from reassignment of codons, especially stop codons. The reassignments take place by disappearance of a codon from coding sequences, followed by its reappearance in a new role. Simultaneously, a changed anticodon must appear. We discuss the role of directional mutation pressure in the events, and we also describe the possibility that such events have taken place during early evolution of the genetic code and can occur during its present evolution.

Animals↗
PubMed1985

Conservation of the secondary structure of protein during evolution and the role of the genetic code.

In this communication we demonstrate, in a group of modern proteins, following an algorithm described by Argyle (1980), that the ordination of the amino acids in terms of the most frequent substitutions agrees with the conservation of the alpha-helix, beta-sheet, and beta-turn formation tendencies during evolution. The same correspondence has been demonstrated for the conservation of the physico-chemical properties in the amino acid substitutions. Both parameters are similar in showing higher correlation with the most frequent amino acid substitutions than with the feasibility of changes at the level of the respective codons. Some kind of restrictions for the expression of the genomic changes, due to the conservation of the secondary structure of proteins and/or the physicochemical properties of the substituted amino acids, could account for the differences found between the distribution of the amino acid substitutions and the most probable codon changes.

Amino Acids↗
PubMed2002

[Predictive genetic testing - change in paradigms for prevention and health care?].

The post-genomic era promises to offer new insights into the nature of disease, its prevention, and treatment. But now that there is a draft code of the human genome, what does this knowledge mean and how might it be applied? How to use genetic information to promote health and prevent disease - the fundamental mission of public health - will be one of the most challenging tasks in future. Assessing the benefits and risks of predictive genetic testing and the efficacy of early interventions as well as exploring complex issues that have emerged (e. g., rapid commercialization of genetic tests, availability of and access to interventions, and potencial discrimination) call for public health leadership.

Forecasting↗
PubMed1995

Heterogeneous expression of glycoprotein Ib, IX and V in platelets from two patients with Bernard-Soulier syndrome caused by different genetic abnormalities.

Bernard-Soulier syndrome (BSS) is a rare inherited bleeding disorder, which is caused by deficiency or decrease of the platelet GPIb/IX/V complex. Analysis of two patients with BSS by flow cytometry of the blood revealed different expression patterns of the components of the GPIb/IX/V complex. In case 1, GPIX was completely absent but residual amounts of GPIb alpha and GPV were detectable; in case 2, GPIb alpha was completely absent. We amplified the coding regions of GPIb alpha, GPIb beta, GPV, and GPIX from the patients' genomic DNA with the polymerase chain reaction (PCR) and sequenced the PCR products. in case 1, we identified a point mutation in the GPIX coding region that changes the codon for tryptophan-126 (TGG) to a nonsense codon (TGA). In case 2, we found a deletion of nucleotide within seven adenine repeats at the position of 1932 to 1938 in the coding region of GPIb alpha, which causes a frame shift that results in 58 altered amino acids and a premature stop codon. These genetic changes alter the transmembrane domain of GPIX or GPIb alpha and, therefore, would prevent proper insertion of the proteins in the plasma membrane. Thus, abnormality of a single component protein (GPIX or GPIb alpha) alters the assembly of the GPIb/IX/V complex and causes heterogeneous surface expression of GPIb alpha, GPV and GPIX.

Adult↗
PubMed2005

A single nucleotide polymorphism based approach for the identification and characterization of gene expression modulation using MassARRAY.

Single nucleotide polymorphisms (SNPs) are the most common form of genetic variation. Their abundance and the ease with which they can be assayed have lead to their use in applications beyond simple genotyping. One such application is the quantitative determination of transcript levels associated with distinct alleles or haplotypes found in promoters and coding regions of genes. These changes in expression due to allelic variation are often associated with additional genomic or transcript modifications such as DNA methylation or RNA editing. Here, we describe the use of an integrated genetic analysis platform, based on matrix-assisted laser desorption/ionisation-time-of-flight (MALDI-TOF) to first, discover coding SNPs (cSNPs); second, use these cSNPs to identify and analyze allele-specific expression; and third, from this knowledge to further analyze methylation patterns as a putative cause for the allele-specific expression. An established model involving allele-specific expression profiles of the human tumor protein 73 (TP73) gene is presented as an example to outline and validate data obtained from the MassARRAY platform. The availability of a single integrated platform to assay stable and dynamic variation at the genomic and transcript level greatly simplifies complex functional genomic studies.

5' Untranslated Regions↗
PubMed2005

Global gene mining and the pharmaceutical industry.

Worldwide efforts are ongoing in optimizing medical treatment by searching for the right medicine at the right dose for the individual. Metabolism is regulated by polymorphisms, which may be tested by relatively simple SNP analysis, however requiring DNA from the test individuals. Target genes for the efficiency of a given medicine or predisposition of a given disease are also subject to population studies, e.g., in Iceland, Estonia, Sweden, etc. For hypothesis testing and generation, several bio-banks with samples from patients and healthy persons within the pharmaceutical industry have been established during the past 10 years. Thus, more than 100,000 samples are stored in the freezers of either the pharmaceutical companies or their contractual partners at universities and test institutions. Ethical issues related to data protection of the individuals providing samples to bio-banks are several: nature and extent of information prior to consent, coverage of the consent given by the study person, labeling and storage of the sample and data (coded or anonymized). In general, genetic test data, once obtained, are permanent and cannot be changed. The test data may imply information that is not beneficial to the patient and his/her family (e.g., employment opportunities, insurance, etc.). Furthermore, there may be a long latency between the analysis of the genetic test and the clinical expression of the disease and wide differences in the disease patterns. Consequently, information about some genetic test data may stigmatize patients leading to poor quality of life. This has raised the issue of 'genetic exceptionalism' justifying specific regulation of use of genetic information. Discussions on how to handle sampling and data are ongoing within the industry and the regulatory sphere, the European Agency for the Evaluation of Medicinal Products (EMEA) having issued a position paper, the Council for International Organizations of Medical Sciences (CIOMS) having a working group on this issue, and the European Society of Human Genetics preparing background paper on 'Polymorphic sequence variants in medicine: Technical, social, legal and ethical issues. Pharmacogenetics as an example'. Within the European project Privacy in Research Ethics and Law (PRIVIREAL), recommendations for common European guidelines for membership in research ethical committees have been discussed, balancing the interests and assuring independence and legal competence. Good decision making, assuring legality of protocols and assessment of data protection is suggested to be part of any evaluation of protocols.

Drug Industry↗
PubMed1990

The rIIA gene of bacteriophage T4. I. Its DNA sequence and discovery of a new open reading frame between genes 60 and rIIA.

We have determined the DNA sequence of the rIIA gene and have discovered a small open reading frame, rIIA.1, between genes 60 and rIIA. The predicted molecular weights of these proteins are 82,840 for rIIA and 8,124 for rIIA.1. The rIIA protein has a repeated motif which suggests that the gene has evolved by duplication. It also has a motif which suggests that it belongs to a group of ompR-like proteins that control regulation of gene expression in response to changes in the external environment. We have sequenced three different missense mutants whose mutations lie in the Ala segment of the rIIA genetic map. All three changes are found within the first 35 bp of the rIIA coding sequence. The region of control of protein synthesis is identical in the rIIA gene and in gene 44 of T4. We relate this finding to the high sensitivity of both RNAs to translational repression by the T4 regA gene product.

Amino Acid Sequence↗
PubMed1995

Molecular genetics of the ABO histo-blood group system.

Molecular genetic study of the histo-blood group ABO system has elucidated the allelic basis of this genetic locus. Comparison of the nucleotide sequence has identified in the coding region differences which change amino acid sequences of the glycosyltransferases coded by these genes. Effects of the differences (mutations) on the specificity and activity of the glycosyltransferases have been examined.

ABO Blood-Group System↗
PubMed2002

Compositional syntax from cultural transmission.

A growing body of work demonstrates that syntactic structure can evolve in populations of genetically identical agents. Traditional explanations for the emergence of syntactic structure employ an argument based on genetic evolution: Syntactic structure is specified by an innate language acquisition device (LAD). Knowledge of language is complex, yet the data available to the language learner are sparse. This incongruous situation, termed the "poverty of the stimulus," is accounted for by placing much of the specification of language in the LAD. The assumption is that the characteristic structure of language is somehow coded genetically. The effect of language evolution on the cultural substrate, in the absence of genetic change, is not addressed by this explanation. We show that the poverty of the stimulus introduces a pressure for compositional language structure when we consider language evolution resulting from iterated observational learning. We use a mathematical model to map the space of parameters that result in compositional syntax. Our hypothesis is that compositional syntax cannot be explained by understanding the LAD alone: Compositionality is an emergent property of the dynamics resulting from sparse language exposure.

Cultural Evolution↗
PubMedDate not supplied

BRCA1 germline mutations in Cypriot breast cancer patients from 26 families with family history.

Germline mutations in the BRCA1 gene are causative for a variable number of hereditary breast/ovarian cancers. The data presented in this study are based on genetic analysis of the BRCA1 gene in 49 DNA samples from breast cancer patients with a positive family history. A combination of manual direct DNA sequencing and SSCP analysis was used to screen the entire coding region of BRCA1. Overall 13 variants were detected which included 5 missense mutations, 3 polymorphisms and 5 intronic changes. Further genetic analysis of the 13 variants was carried out using 50 control DNA samples. Our results showed that 12 out of the 13 variants detected in the DNA of the patients group, were also present in the control group. It appears that the Greek Cypriot families studied so far have an unexpectebly low frequency of deleterious mutations in the BRCA1 gene. This is the first report on BRCA1 mutation analysis in Cyprus.

Adult↗
PubMed2005

Clinical features and outcome of childhood minimal change nephrotic syndrome: is genetics involved?

The pathogenesis of minimal change nephrotic syndrome (MCNS) is still unknown. We performed a clinical and genetic evaluation of 104 adults (mean age 35 years) who presented with MCNS in childhood (mean follow-up 30 years). Clinical data and the present health status were evaluated. Also, the genes encoding the four major slit diaphragm proteins, nephrin, podocin, Neph1 and CD2-associated protein were sequenced in 38 patients with MCNS of varying severity. MCNS presented at the mean age of 5 years, and 80% of the patients relapsed 1-28 (median 3) times during childhood. The 14 subjects (14%) who had proteinuric episodes still in adulthood had a refractory disease already as children. The participants did not show a strong tendency for allergy or immune diseases, and no familial clustering of MCNS was observed. The genetic analyses revealed heterozygous amino acid changes in nephrin and podocin in 10 of the 38 patients studied. On the other hand, the genes coding for Neph1 and CD2AP were highly conserved and no amino acid substitutions were detected. In conclusion, MCNS is a multifactorial disease, in which genetics play a minor role. Allelic variants of the podocyte proteins may, however, modify the phenotype in occasional individuals.

Adaptor Proteins, Signal Transducing↗
PubMed1989

The multiple codes of nucleotide sequences.

Nucleotide sequences carry genetic information of many different kinds, not just instructions for protein synthesis (triplet code). Several codes of nucleotide sequences are discussed including: (1) the translation framing code, responsible for correct triplet counting by the ribosome during protein synthesis; (2) the chromatin code, which provides instructions on appropriate placement of nucleosomes along the DNA molecules and their spatial arrangement; (3) a putative loop code for single-stranded RNA-protein interactions. The codes are degenerate and corresponding messages are not only interspersed but actually overlap, so that some nucleotides belong to several messages simultaneously. Tandemly repeated sequences frequently considered as functionless "junk" are found to be grouped into certain classes of repeat unit lengths. This indicates some functional involvement of these sequences. A hypothesis is formulated according to which the tandem repeats are given the role of weak enhancer-silencers that modulate, in a copy number-dependent way, the expression of proximal genes. Fast amplification and elimination of the repeats provides an attractive mechanism of species adaptation to a rapidly changing environment.

Amino Acid Sequence↗
PubMed1995

Genetic code deviations in the ciliates: evidence for multiple and independent events.

In several species of ciliates, the universal stop codons UAA and UAG are translated into glutamine, while in the euplotids, the glutamine codon usage is normal, but UGA appears to be translated as cysteine. Because the emerging position of this monophyletic group in the eukaryotic lineage is relatively late, this deviant genetic code represents a derived state of the universal code. The question is therefore raised as to how these changes arose within the evolutionary pathways of the phylum. Here, we have investigated the presence of stop codons in alpha tubulin and/or phosphoglycerate kinase gene coding sequences from diverse species of ciliates scattered over the phylogenetic tree constructed from 28S rRNA sequences. In our data set, when deviations occur they correspond to in frame UAA and UAG coding for glutamine. By combining these new data with those previously reported, we show that (i) utilization of UAA and UAG codons occurs to different extents between, but also within, the different classes of ciliates and (ii) the resulting phylogenetic pattern of deviations from the universal code cannot be accounted for by a scenario involving a single transition to the unusual code. Thus, contrary to expectations, deviations from the universal genetic code have arisen independently several times within the phylum.

Animals↗
PubMed1985

Construction and characterization of a library of metallothionein coding sequence mutants.

New possibilities for experimental investigation of the metallothionein system at the DNA, RNA, and protein levels are now available via a library of metallothionein coding sequence mutants. Appropriate treatment in vitro with sodium bisulfite of the sense or antisense DNA strands in M13 phage vectors and propagation in Escherichia coli BD1528 (ung-) produced two unique collections in the library containing either C to T or G to A transition mutations in the codons at low and high frequencies. The strategy for mutagenesis takes advantage of degeneracy in the genetic code so that no cysteine codons are replaced in the CT mutants while all are subject to change in the GA collection. Two hundred and sixty-four clones from the library have been sequenced and G to A transitions affecting each of the 20 cysteine codons in metallothionein have been detected. Other mutations in codons for amino acids proposed to be important for metallothionein function have also been identified.

Amino Acid Sequence↗
PubMed1988

A computer program to display codon changes caused by mutagenesis.

A FORTRAN program for displaying the correspondence between codon changes and different possible base changes is presented. Changes of both single bases and dimers are considered. The user can specify the mutagenesis spectrum. Additionally, the user can choose whether or not to consider single or double events in a codon and whether or not to consider the possibility that the change of two bases (a dimer) can overlap a codon boundary. Furthermore, a variety of ways may be chosen to display and summarize the codon changes that can result from the specified mutagenesis. A user-supplied sequence or the genetic code table can be analyzed.

Codon↗