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At least 1,297 records · Page 72Linked to original sources
PubMed2026

Adaptive deletion of functional duplicate genes in Drosophila.

Gene deletion is traditionally viewed as a nonadaptive mechanism that eliminates functional redundancy, yet emerging evidence indicates that it disproportionately affects tissue-specific duplicates with unique functions. Here, we test whether gene deletion preferentially removes weakly constrained, degenerating duplicates or instead eliminates functionally active duplicates through an adaptive process. To identify the evolutionary and functional factors that determine which duplicates are lost, we systematically analyzed 100 gene deletion events in Drosophila by integrating sequence, expression, interaction, and structural data. We uncovered a strong bias toward the loss of younger child copies among functionally unique duplicates, whereas no such bias was observed for redundant duplicates. Contrary to expectations under relaxed constraint, deleted functionally unique genes evolve more slowly, show higher expression, engage in more protein-protein interactions, and do not exhibit elevated structural divergence or intrinsic disorder relative to redundant duplicates. When compared with single-copy genes, deleted functionally unique genes display similar evolutionary rates, slightly lower expression, greater network connectivity, comparable structural divergence, and lower intrinsic disorder. These patterns suggest that deletion frequently affects functionally active rather than degenerate genes. Collectively, our results support the hypothesis that gene deletion in Drosophila can represent an adaptive process acting on transiently functional duplicates, potentially driven by either genome streamlining or context-dependent deleterious effects.

evolution↗
PubMed1995

Pollen specificity elements reside in 30 bp of the proximal promoters of two pollen-expressed genes.

Functional analyses previously identified minimal promoter regions required for maintaining high-level expression of the late anther tomato LAT52 and LAT59 genes in tomato pollen. Here, we now define elements that direct pollen specificity. We used a transient assay system consisting of two cell types that differentially express the LAT genes and both "loss-of-function" and "gain-of-function" approaches. Linker substitution mutants analyzed in the transient assay and in transgenic plants identified 30-bp proximal promoter regions of LAT52 and LAT59 that are essential for their expression in pollen and that confer pollen specificity when fused to the heterologous cauliflower mosaic virus 35S core promoter. In vivo competition experiments demonstrated that a common trans-acting factor interacts with the pollen specificity region of both LAT gene promoters and suggested that a common mechanism regulates their coordinate expression. Adjacent upstream elements, the 52/56 box in LAT52 and the 56/59 box in LAT59, are involved in modulating the level of expression in pollen. The 52/56 box may be a target for the binding of a member of the GT-1 transcription factor family.

Base Sequence↗
PubMed2000

Decoupled evolution of coding region and mRNA expression patterns after gene duplication: implications for the neutralist-selectionist debate.

The neutralist perspective on molecular evolution maintains that the vast majority of mutations affecting gene function are neutral or deleterious. After a gene duplication where both genes are retained, it predicts that original and duplicate genes diverge at clock-like rates. This prediction is usually tested for coding sequences, but can also be applied to another important aspect of gene function, the genes' expression pattern. Moreover, if both sequence and expression pattern diverge at clock-like rates, a correlation between divergence in sequence and divergence in expression patterns is expected. Duplicate gene pairs with more highly diverged sequences should also show more highly diverged expression patterns. This prediction is tested for a large sample of duplicated genes in the yeast Saccharomyces cerevisiae, using both genome sequence and microarray expression data. Only a weak correlation is observed, suggesting that coding sequence and mRNA expression patterns of duplicate gene pairs evolve independently and at vastly different rates. Implications of this finding for the neutralist-selectionist debate are discussed.

Biological Evolution↗
PubMed2003

Hirschsprung disease is linked to defects in neural crest stem cell function.

Genes associated with Hirschsprung disease, a failure to form enteric ganglia in the hindgut, were highly up-regulated in gut neural crest stem cells relative to whole-fetus RNA. One of these genes, the glial cell line-derived neurotrophic factor (GDNF) receptor Ret, was necessary for neural crest stem cell migration in the gut. GDNF promoted the migration of neural crest stem cells in culture but did not affect their survival or proliferation. Gene expression profiling, combined with reverse genetics and analyses of stem cell function, suggests that Hirschsprung disease is caused by defects in neural crest stem cell function.

Animals↗
PubMed2006

Tissue-specific transgenic and knockout mice.

Analysis of genetically engineered mice is crucial for our understanding of the in vivo function of genes and proteins in the whole organism. This includes inactivation of a gene or the generation of specific mutations. The development of knockout and transgenic technologies in the mouse, therefore, represents a powerful tool for elucidating gene function, for modeling of human diseases, and potentially for the evaluation of drugs. In particular, conditional gene targeting applying the Cre/loxP-mediated recombination system is increasingly used to evaluate the role of the gene of interest in a cell-type-specific or even inducible manner. The experimental steps start with the characterization of the gene locus, followed by construction of a vector, gene targeting in ES cells, and establishment of mouse lines carrying the desired mutation. These are then bred to transgenic mice expressing Cre recombinase in a tissue-specific manner, thus allowing gene inactivation in a cell type of interest.

Animals↗
PubMed1980

Adenovirus type 12 gene 401 function and temperature sensitivity of cytochalasin B effects on transformed cells.

Rat (3Y1) cells transformed by wild-type adenovirus type 12 or the temperature-sensitive mutant ts401 with an active function required for transformation maintenance were exposed at the permissive(36 degrees) or nonpermissive (40 degrees) temperature to cytochalasin B (CB). At 40 degrees, the ts401-transformed cells, but not the wild-type transformants, exhibited, at least partially, the untransformed 3Y1 cell phenotype; most of the cells became bi- and trinucleated and DNA synthesis was inhibited. AT 36 degrees, both groups of cells became highly multinucleated, and there was no apparent inhibition of DNA synthesis by CB. These characteristics were exhibited also by the wild-type transformants at 40 degrees. These findings provide additional evidence that an active 401 gene function is required for maintenance of the adenovirus-transformed cell phenotype.

Adenoviruses, Human↗
PubMed2005

The gene trap resource: a treasure trove for hemopoiesis research.

The laboratory mouse is an invaluable tool for functional gene discovery because of its genetic malleability and a biological similarity to human systems that facilitates identification of human models of disease. A number of mutagenic technologies are being used to elucidate gene function in the mouse. Gene trapping is an insertional mutagenesis strategy that is being undertaken by multiple research groups, both academic and private, in an effort to introduce mutations across the mouse genome. Large-scale, publicly funded gene trap programs have been initiated in several countries with the International Gene Trap Consortium coordinating certain efforts and resources. We outline the methodology of mammalian gene trapping and how it can be used to identify genes expressed in both primitive and definitive blood cells and to discover hemopoietic regulator genes. Mouse mutants with hematopoietic phenotypes derived using gene trapping are described. The efforts of the large-scale gene trapping consortia have now led to the availability of libraries of mutagenized ES cell clones. The identity of the trapped locus in each of these clones can be identified by sequence-based searching via the world wide web. This resource provides an extraordinary tool for all researchers wishing to use mouse genetics to understand gene function.

Animals↗
PubMed1999

Synexpression groups in eukaryotes.

In 1960, Jacob and Monod described the bacterial operon, a cluster of functionally interacting genes whose expression is tightly coordinated. Global expression analysis has shown that the highly coordinate expression of genes functioning in common processes is also a widespread phenomenon in eukaryotes. These sets of co-regulated genes, or 'synexpression groups', show a striking parallel to the operon, and may be a key determinant facilitating evolutionary change leading to animal diversity.

Animals↗
PubMed2004

Regulation of immunoglobulin heavy-chain gene rearrangements.

Regulated assembly of antigen receptor gene segments to produce functional genes is a hallmark of B- and T-lymphocyte development. The immunoglobulin heavy-chain (IgH) and T-cell receptor beta-chain genes rearrange first in B and T lineages, respectively. Both loci require two recombination events to assemble functional genes; D-to-J recombination occurs first followed by V-to-DJ recombination. Despite similarities in overall rearrangement patterns, each locus has unique regulatory features. Here, we review the characteristics of IgH gene rearrangements such as developmental timing, deletion versus inversion, DH gene segment utilization, ordered recombination of VH gene segments, and feedback inhibition of rearrangement in pre-B cells. We summarize chromatin structural features of the locus before and during recombination and, wherever possible, incorporate these into working hypotheses for understanding regulation of IgH gene recombination. The picture emerges that the IgH locus is activated in discrete, independently regulated domains. A domain encompassing DH and JH gene segments is activated first, within which recombination is initiated. VH genes are activated subsequently and, in part, by interleukin-7. These observations lead to a model for feedback inhibition of IgH rearrangements.

Animals↗
PubMed2002

Perspective: the ovarian kaleidoscope database-II. Functional genomic analysis of an organ-specific database.

In the postgenomic era, it is now possible to investigate the function of all human genes to provide an integrated view of physiology and pathophysiology. An organ-based approach has been used to set up a database integrating existing text-based literature on individual ovarian genes and their sequence-based data in the GenBank. The Ovarian Kaleidoscope database (OKdb) has accumulated nearly one thousand individual gene pages that are searchable based on gene function, cellular localization, chromosomal position, ovarian cell type, ovarian function, mutant phenotypes, and other criteria. The present review exemplifies the use of this organ-based database in setting up gene pathway maps for DNA array analysis, identifying key gene networks essential for infertility phenotypes, comparing chromosomal synteny regions for finding candidate fertility genes, categorizing cell-specific and hormonally coregulated genes for promoter analysis, and documenting potential ligands and receptors in the paracrine regulation of follicular development. The present global analysis of gene function and relationships in an organ-specific manner provides a functional genomic paradigm for the future understanding of the physiology and pathophysiology of diverse organs.

Animals↗
PubMed2003

Mutagenesis strategies for identifying novel loci associated with disease phenotypes.

The systematic identification of the function of all the genes in the mammalian genome is one of the major scientific challenges for the 21st century. A comprehensive insight into mammalian gene function will illuminate our understanding of the genetic bases of disease. Mouse mutagenesis is a powerful tool for the study of mammalian gene function. Most recently, a number of approaches employing the chemical mutagen ethylnitrosourea (ENU) have been utilised by mouse geneticists to deliver a substantial new collection of mouse disease models. The growing mouse mutant archive provides a powerful resource for the identification of novel genes involved with human genetic disease.

Animals↗
PubMed1998

A new apparently functional IGVK gene (VkLa) present in some individuals only.

We describe a hitherto unknown functional IGKV gene, VkLa, belonging to the IGKV1 subgroup with exon 2 having only 94% similarity to the closest known IGKV gene, 1-13/1D-13 (L4/L18a). Genomic DNA sequences spanning from 5' of the decanucleotide box to 3' of the heptamer (649 bp) were cloned and sequenced from four individuals. The new gene encodes the conserved amino acids in the exons and contains no apparent defects in known regulatory intron sequences such as pd-box, dc-box, TATA-box, CCCT-elements, splice-sequences, initiation codon, and heptamer sequence. VkLa is therefore potentially functional and, correspondingly, we found transcripts of properly rearranged VkLa with somatical hypermutations. VkLa was found in 12 of 57 (21%) healthy Caucasians by a nested polymerase chain reaction and subsequent sequencing of exon 2. This finding shows that there is more inter-individual variation in the available IGKV gene repertoire than was hitherto assumed. Finally, we describe a minor correction in the IGKV1D-43 (L23) gene sequence.

Amino Acid Sequence↗
PubMed2002

Complementation of a defective human adenovirus by an otherwise incompatible ovine adenovirus recombinant carrying a functional E1A gene.

All known human adenoviruses are classified as mastadenoviruses, while the ovine adenovirus (OAdV) serotype 7 is the prototype of the atadenoviruses, a proposed new genus. OAdV replicates abortively in human cell types and has potential as a gene transfer vector. However, the function of OAdV nonstructural genes is poorly understood and it is unclear whether OAdV replication might be complemented by a replicating human AdV in coinfected cells. To investigate possible interactions three human cell lines were singly infected with OAdV or human AdV5 or doubly infected. The development of a cytopathic effect and genome replication was monitored over three passages in each cell type. No significant OAdV replication occurred in any of the cell types examined either in the presence or in the absence of replicating AdV5. No aberrant AdV5 genome products were detected in coinfected cells. In contrast, in coinfected cells an OAdV recombinant that expressed the AdV5 E1A gene was able to promote the replication of an AdV5 E1A-deficient mutant, demonstrating trans-complementation between appropriate viruses. These findings have implications for the biosafety of OAdV vectors and their possible utility for enhancing gene delivery.

Adenoviridae↗
PubMed2000

Recent developments in molecular genetics of Candida albicans.

The frequency of opportunistic infections caused by the fungus Candida albicans is very high and is expected to continue to increase as the number of immunocompromised patients rises. Research initiatives to study the biology of this organism and elucidate its pathogenic determinants have therefore expanded significantly during the last 5-10 years. The past few years have also brought continuous improvement in the techniques to study gene function by gene inactivation and by regulated gene expression and to study gene expression and protein localization by using gene reporter systems. As steadily more genomic sequence information from this human fungal pathogen becomes available, we are entering a new era in antimicrobial research. However, many of the currently available molecular genetics tools are poorly adapted to a genome-wide functional analysis in C. albicans, and further development of these tools is hampered by the asexual and diploid nature of this organism. This review outlines recent advances in the development of molecular tools for functional analysis in C. albicans and summarizes current knowledge about the genomic and genetic variability of this important human fungal pathogen.

Candida albicans↗
PubMed2002

Characterization of three new members of the Arabidopsis thaliana calmodulin gene family: conserved and highly diverged members of the gene family functionally complement a yeast calmodulin null.

Three genes encoding members of the EF-hand family of Ca2+-binding proteins were identified from Arabidopsis thaliana (L.) Heynh. sequences deposited in the expressed sequence tag and genomic sequence databases. Full-length cDNAs for each of the genes, Cam7, Cam8, and Cam9, were sequenced. Cam7 encodes a conventional 16.8-kDa, 148-amino-acid calmodulin protein (CaM). In contrast, Cam8 and 9 encode highly diverged isoforms of the protein that share 73 and 49% amino acid sequence identity, respectively, with CaM7. RNA gel blot and reverse transcription-polymerase chain reaction experiments revealed that each of the genes is expressed in leaves, flowers and siliques. To test the functional properties of the polypeptides encoded by these genes, they were expressed in Escherichia coli and the yeast Saccharomyces cerevisiae. Each was purified by Ca2+-dependent hydrophobic affinity chromatography. CaM7, but neither CaM8 nor CaM9, formed a complex with a basic amphiphilic helical peptide in the presence of Ca2+ that could be identified by gel electrophoresis. In spite of these in vitro differences, each of the sequences functionally substituted for yeast CMD1 to maintain viability. Isolation of yeast strains complemented by Cam9 required selection against the plasmid harboring wild-type yeast sequences, whereas complementation by Cam7 and Cam8 did not. These results suggest that the mechanism of action of CaM8 and CaM9 is similar to that of more conventional CaM sequences. CaM9, and to a lesser degree CaM8, however, appear to represent Ca2+-binding sensor proteins that interact with a more limited set of target proteins than do more conventional CaM isoforms.

Amino Acid Sequence↗
PubMed1986

Phenotypic characterization of 10 methanol oxidation mutant classes in Methylobacterium sp. strain AM1.

Twenty-five methanol oxidation mutants of the facultative methylotroph Methylobacterium sp. strain AM1 have been characterized by complementation analysis and assigned to 10 complementation groups, Mox A1, A2, A3, and B through H (D. N. Nunn and M. E. Lidstrom, J. Bacteriol. 166:582-591, 1986). In this study we have characterized each of the mutants belonging to the 10 Mox complementation groups for the following criteria: phenazine methosulfate-dichlorophenolindophenol dye-linked methanol dehydrogenase activity; methanol-dependent whole-cell oxygen consumption; the presence or absence of methanol dehydrogenase protein by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting; the absorption spectra of purified mutant methanol dehydrogenase proteins; and the presence or absence of the soluble cytochrome c proteins of Methylobacterium sp. strain AM1, as determined by reduced-oxidized difference spectra and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. With this information, we have proposed functions for each of the genes deficient in the mutants of the 10 Mox complementation groups. These proposed gene functions include two linked genes that encode the methanol dehydrogenase structural protein and the soluble cytochrome cL, a gene encoding a secretion function essential for the synthesis and export of methanol dehydrogenase and cytochrome cL, three gene functions responsible for the proper association of the pyrrolo-quinoline quinone prosthetic group with the methanol dehydrogenase apoprotein, and four positive regulatory gene functions controlling the expression of the ability to oxidize methanol.

Alcohol Oxidoreductases↗
PubMed1998

ATM: from gene to function.

The identification of ATM , the gene responsible for the pleiotropic recessive disease ataxia telangiectasia, has initiated extensive research to determine the functions of its multifaceted protein product. The ATM protein belongs to a family of protein kinases that share similarities at their C-terminal region with the catalytic domain of phosphatidylinositol 3-kinases. Studies with ataxia telangiectasia (A-T) cells and Atm-deficient mice have shown that ATM is a key regulator of multiple signaling cascades which respond to DNA strand breaks induced by damaging agents or by normal processes, such as meiotic or V(D)J recombination. These responses involve the activation of cell cycle checkpoints, DNA repair and apoptosis. Other roles outside the cell nucleus might be carried out by the cytoplasmic fraction of ATM. In addition, ATM appears to function as a 'caretaker', suppressing tumorigenesis in specific T cell lineages.

Animals↗