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At least 505 records · Page 28Linked to original sources
PubMed2026

Large-scale pleiotropic analysis across cancers reveals shared genetic mechanisms and identifies novel functional genes.

Pleiotropic genetic loci have been increasingly reported in cancer, and identifying genetic variants with pleiotropic associations can reveal shared biological pathways influencing multiple cancers. Using summary statistics from genome-wide association studies for 37 cancer types (N = 433 836), we identified extensive genome-wide and local genetic correlations among cancers. Through pairwise pleiotropic analysis, we identified 75 243 significant pleiotropic single nucleotide polymorphisms (SNPs) across 372 cancer pairs, among which 3472 were lead SNPs with potential regulatory functions. Using FUMA and MAGMA, we identified 2527 pleiotropic risk loci and 4272 candidate pleiotropic genes. Notably, genes such as TERT (5p15.33), POU5F1B (8q24.21), and FANCA (16q24.3) exhibited widespread pleiotropy across multiple cancer types. Pathway enrichment analysis highlighted the critical roles of pigment synthesis, metabolism, and apoptosis in skin-related cancers, while cross-cancer enrichment analysis emphasized pathways related to apoptosis, chromatin structure, and intermediate filaments. We also identified 33 novel functional genes harboring previously unreported cancer risk variants. Drug-gene interaction analysis revealed several repositionable FDA-approved drugs. Importantly, drug sensitivity assays demonstrated that bosutinib and cobimetinib exhibited promising therapeutic potential in breast cancer cell lines. Finally, we developed the PleioCancer database (https://gonglab.hzau.edu.cn/PleioCancer/), providing a comprehensive resource for cancer pleiotropy research. These findings have important implications for carcinogenesis cancer, prevention and treatment.

Humans↗
PubMed1989

Gene function identified by interspecific transformation.

Aspergillus nidulans is able to utilize 2-pyrrolidinone as a nitrogen source while two related Aspergillus species, A. niger and A. terreus, cannot. Mutations in the lamA gene of A. nidulans prevent growth on 2-pyrrolidinone. A plasmid (pLAM7) has been isolated containing the A. nidulans lamA gene and a divergently transcribed adjacent gene of unknown function. Transformation of A. terreus with subclones of pLAM7 showed that both genes are essential for the utilization of a new nitrogen source, 2-pyrrolidinone, in that species. The previously unidentified gene has been designated lamB.

Aspergillus↗
PubMed2003

Molecular clock and gene function.

Molecular phylogenies based on the molecular clock require the comparison of orthologous genes. Orthologous and paralogous genes usually have very different evolutionary fates. In general, orthologs keep the same functions in species, whereas, particularly over a long time span, paralogs diverge functionally and may become pseudogenes or get lost. In eukaryotic genomes, because of the degree of redundancy of genetic information, homologous genes are grouped in gene families, the evolution of which may differ greatly between the various organisms. This implies that each gene in a species does not always have an ortholog in another species and thus, due to multiple duplication events following a speciation, many orthologous clades of paralogs are generated. We are often dealing with a one-to-many or many-to-many relationship between genes. In this paper, we analyze the evolution of two gene families, the p53 gene family and the porin gene family. The evolution of the p53 family shows a one-to-many gene relationship going from invertebrates to vertebrates. In invertebrates only a single gene has been found, while in vertebrates three members of the family, namely p53, p63, and p73, are present. The evolution of porin (VDAC) genes (VDAC1, VDAC2, and VDAC3) is an example of a many-to-many gene relationship going from yeast to mammals. However, the porin gene redundancy found in invertebrates and possibly in some fishes may indicate a tendency to duplicate the genetic material, rather than a real need for function innovation.

Animals↗
PubMed2000

Specific interference with gene function by double-stranded RNA in early mouse development.

The use of double-stranded (ds) RNA is a powerful way of interfering with gene expression in a range of organisms, but doubts have been raised about whether it could be successful in mammals. Here, we show that dsRNA is effective as a specific inhibitor of the function of three genes in the mouse, namely maternally expressed c-mos in the oocyte and zygotically expressed E-cadherin or a GFP transgene in the preimplantation embryo. The phenotypes observed are the same as those reported for null mutants of the endogenous genes. These findings offer the opportunity to study development and gene regulation in normal and diseased cells.

Animals↗
PubMed1996

The tamA gene of Aspergillus nidulans contains a putative zinc cluster motif which is not required for gene function.

Expression of many nitrogen catabolic enzymes is controlled by nitrogen metabolite repression in Aspergillus nidulans. Although the phenotypes of tamA mutants have implicated this gene in nitrogen regulation, its function is unknown. We have cloned the tamA gene by complementation of a new tamA allele. The tamA sequence shares significant homology with the UGA35/DAL81/DURL gene of Saccharomyces cerevisiae. In vitro mutagenesis of sequences encoding a putative zinc cluster DNA binding domain indicated that this motif is not required for in vivo TamA function.

Amino Acid Sequence↗
PubMed1998

Codon usage and gene function are related in sequences of Arabidopsis thaliana.

In this paper, the relationship between codon usage and the physiological pattern of expression of a gene is investigated while considering a dataset of 815 nuclear genes of Arabidopsis thaliana. Factorial Correspondence Analysis, a commonly used multivariate statistical approach in codon usage analysis, was used in order to analyse codon usage bias gene by gene. The analysis reveals a single major trend in codon usage among genes in Arabidopsis. At one end of the trend lie genes with a highly G/C biased codon usage. This group contains mainly photosynthetic and housekeeping genes which are known to encode the most abundant proteins of the vegetal cell. At the other extreme lie genes with a weaker A/T-biased codon usage. This group contain genes with various functions which exhibits most of the time a strong tissue-specific pattern of expression in relation, for example, to stress conditions. These observations were confirmed by the detailed analysis of codon usage in the multigene family of tubulins and appear to be general in plant species, even as distant from Arabidopsis thaliana as a monocotyledonous plant such as maize.

Arabidopsis↗
PubMed2006

The FOX hunting system: an alternative gain-of-function gene hunting technique.

We have developed a novel gain-of-function system that we have named the FOX hunting system (Full-length cDNA Over-eXpressing gene hunting system). We used normalized full-length cDNA and introduced each cDNA into Arabidopsis by in planta transformation. About 10 000 independent full-length Arabidopsis cDNAs were expressed independently under the CaMV 35S promoter in Arabidopsis. Each transgenic Arabidopsis contained on average 2.6 cDNA clones and was monitored under various categories such as morphological changes, fertility and leaf color. We found 1487 possible morphological mutants from 15 547 transformants. When 115 pale green T(1) mutants were analyzed, 59 lines represented the mutant phenotypes in more than 50% of the T(2) progeny. Characterization of two leaf color mutants revealed the significance of this approach. We also document mutants from several categories and their corresponding full-length cDNAs.

Arabidopsis↗
PubMed1998

Exploring gene function: use of yeast artificial chromosome transgenesis.

Transgenesis is a very powerful tool in functional analysis of proteins and control of gene expression. One of the main drawbacks has been the low levels of expression, lack of tissue specificity, and inappropriate expression frequently observed for transgenes made with small plasmid-based constructs. The use of much larger DNA fragments cloned in yeast artificial clones (YACs), bacterial artificial clones, or P1-based artificial clones has been found to give much better levels of expression, generally very close to that of an endogenous gene, and tissue-specific expression matching that of the endogenous gene. In addition, the large DNA can easily be subtly modified by homologous recombination. This article describes the background and methods of YAC transgenesis.

Animals↗
PubMed1990

The effect of plasmid pKM101 on umuDC gene function enhancing precise excision of transposons.

Mutation in the thr gene with the highest UV-induced reversion frequency has been chosen from a number of mutations arisen from insertion of transposon Tn10 into the umuDC- Salmonella typhimurium. This mutation has been transferred by transduction into the Salmonella strain carrying E. coli umuDC+ genes. umuDC- and umuDC+ Salmonella strains, bearing the same insertion mutation, were used to study the effect of umuDC genes and of plasmid pKM101 on spontaneous and UV-induced precise excision of Tn10. This process, like point mutagenesis, is shown to be umuDC-stimulated. Plasmid pKM101 eliminates the effect of umuDC+ genes on UV-induced Tn10 precise excision, in contrast to its effect on point mutagenesis, and does not enhance spontaneous precise excision of Tn10.

Chromosomes, Bacterial↗
PubMed2006

Testing gene function early in the B cell lineage in mb1-cre mice.

The mb1 gene encodes the Ig-alpha signaling subunit of the B cell antigen receptor and is expressed exclusively in B cells beginning at the very early pro-B cell stage in the bone marrow. We examine here the efficacy of the mb1 gene as a host locus for cre recombinase expression in B cells. We show that by integrating a humanized cre recombinase into the mb1 locus we obtain extraordinarily efficient recombination of loxP sites in the B cell lineage. The results from a variety of reporter genes including the splicing factor SRp20 and the DNA methylase Dnmt1 suggest that mb1-cre is probably the best model so far described for pan-B cell-specific cre expression. The availability of a mouse line with efficient cre-mediated recombination at an early developmental stage in the B lineage provides an opportunity to study the role of various genes specifically in B cell development and function.

Animals↗
PubMed2006

A survey of essential gene function in the yeast cell division cycle.

Mutations impacting specific stages of cell growth and division have provided a foundation for dissecting mechanisms that underlie cell cycle progression. We have undertaken an objective examination of the yeast cell cycle through flow cytometric analysis of DNA content in TetO(7) promoter mutant strains representing 75% of all essential yeast genes. More than 65% of the strains displayed specific alterations in DNA content, suggesting that reduced function of an essential gene in most cases impairs progression through a specific stage of the cell cycle. Because of the large number of essential genes required for protein biosynthesis, G1 accumulation was the most common phenotype observed in our analysis. In contrast, relatively few mutants displayed S-phase delay, and most of these were defective in genes required for DNA replication or nucleotide metabolism. G2 accumulation appeared to arise from a variety of defects. In addition to providing a global view of the diversity of essential cellular processes that influence cell cycle progression, these data also provided predictions regarding the functions of individual genes: we identified four new genes involved in protein trafficking (NUS1, PHS1, PGA2, PGA3), and we found that CSE1 and SMC4 are important for DNA replication.

Alleles↗
PubMed1987

A cloned human ribosomal protein gene functions in rodent cells.

Cloned fragments of human ribosomal protein S14 DNA (RPS14) were transfected into cultured Chinese hamster (CHO) cells. Transient expression assays indicated that DNA with as little as 31 base pairs of upstream flanking sequence was transcribed into a polyadenylated, 650-base mRNA that is largely bound to the polyribosomes. In these respects the exogenous human S14 message appeared to function normally in CHO cells. Interestingly, transcription of human RPS14 did not require the TATA sequence located 26 base pairs upstream of exon 1. Stably transformed clones were selected from cultures of emetine-resistant CHO cells (Emr-2) after transfection with pSV2Neo-human RPS14 constructs. Human RPS14 complemented the mutationally based drug resistance of the Chinese hamster cells, demonstrating that the cloned human ribosomal protein gene is functional in rodent cells. Analysis of transformed cells with different amounts of integrated RPS14 indicated that human S14 mRNA levels are not tightly regulated by CHO cells. In contrast, the steady-state S14 level fluctuated only slightly, if at all, in transformed clones whose S14 message contents differed by more than 30-fold. These data support the conclusion that expression of human RPS14 is regulated, at least partially, posttranscriptionally.

Animals↗
PubMed2002

The maize dek1 gene functions in embryonic pattern formation and cell fate specification.

Mutants in the maize defective kernel1 (dek1) gene are blocked in embryogenesis and the endosperm is chalky and lacks an aleurone layer. Here we show that intermediate alleles result in embryos that lack a shoot axis while weak alleles result in endosperms with mosaic aleurone and deformed plants with epidermal cells that resemble bulliform cells, a specialized epidermal cell type. This indicates that dek1 functions in embryonic pattern formation, cell fate specification and pattern formation in the leaf epidermis, and cell fate specification in the endosperm. Thus, the dek1 gene product appears to control different cellular-developmental processes depending on cellular context. The phenotype of the weak dek1-Dooner allele resembles the crinkly4 (cr4) mutant phenotype. Double mutants between dek1 and cr4 showed elements of epistasis, additivity and synergy, suggesting that the gene products may function in overlapping developmental processes. cr4 transcript was detectable in dek1 mutant kernels indicating that DEK1 was not required for Cr4 transcript accumulation. To test whether DEK1 regulated the ligand for the CR4 receptor kinase, a genetic mosaic analysis was performed. The dek1 phenotype appeared to be generally cell-autonomous, leading to the conclusion that it was not likely to produce a diffusible signal molecule, and therefore was not likely to regulate the CR4 ligand.

Body Patterning↗
PubMed1994

Yeast chromosome III: new gene functions.

One year after the release of the sequence of yeast chromosome III, we have re-examined its open reading frames (ORFs) by computer methods. More than 61% of the 171 probable gene products have significant sequence similarities in the current databases; as many as 54% have already known functions or are related to functionally characterized proteins, allowing partial prediction of protein function, 11 percentage points more than reported a year ago; 19% are similar to proteins of known three-dimensional structure, allowing model building by homology. The most interesting new identifications include a sugar kinase distantly related to ribokinases, a phosphatidyl serine synthetase, a putative transcription regulator, a flavodoxin-like protein, and a zinc finger protein belonging to a distinct subfamily. Several ORFs have similarities to uncharacterized proteins, resulting in new families in search of a function'. About 54% of ORFs match sequences from other phyla, including numerous fragments in the database of expressed sequence tags (ESTs). Most significant similarities to ESTs are with proteins in conserved families widely represented in the databases. About 30% of ORFs contain one or more predicted transmembrane segments. The increase in the power of functional and structural prediction comes from improvements in sequence analysis and from richer databases and is expected to facilitate substantially the experimental effort in characterizing the function of new gene products.

Amino Acid Sequence↗
PubMed1987

The role of suppressor T cells in the expression of immune response gene function.

Mechanisms underlying major histocompatibility complex (MHC)-linked immune response (Ir) gene regulation of immune responses have been the subject of considerable interest and debate in recent years. Two general mechanisms have been proposed to account for antigen-specific, Ir gene-mediated unresponsiveness. In one, defective antigen presentation resulted from the failure of processed nominal antigen and Ia antigen to associate on the antigen presenting cell membrane in a manner sufficient for helper T cell (Th cell) activation. By contrast, it has been proposed that selected Th cell clones were deleted from the repertoire during ontogeny or otherwise rendered unresponsive to the antigen-Ia complex, i.e., functionally deleted. Either of these mechanisms would account for the deficient activation of antigen-specific, Th cells observed in genetic low or nonresponder mice. In addition, the failure of mice to respond to certain antigens under Ir gene control has been attributed to the activation of specific suppressor T (Ts) cells. The latter mechanism might be considered a corollary or subset of the clonal deletion model. However, an important distinction exists. In the case of active, Ts cell-mediated Ir gene regulation, genetic low responder animals should retain the capacity for antigen-induced activation of Th cells, or Th cell activity should be demonstrable in these mice. In this communication, experiments are described which are designed to evaluate the possibility that active Ts cell-mediated regulatory mechanisms were of general importance in mediating Ir gene-related unresponsiveness.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Biosynthesis of anthraquinones by interspecies cloning of actinorhodin biosynthesis genes in streptomycetes: clarification of actinorhodin gene functions.

Streptomyces galilaeus ATCC 31133 and ATCC 31671, producers of the anthracyclines aclacinomycin A and 2-hydroxyaklavinone, respectively, formed an anthraquinone, aloesaponarin II, when they were transformed with DNA from Streptomyces coelicolor containing four genetic loci, actI, actIII, actIV, and actVII, encoding early reactions in the actinorhodin biosynthesis pathway. Subcloning experiments indicated that a 2.8-kilobase-pair XhoI fragment containing only the actI and actVII loci was necessary for aloesaponarin II biosynthesis by S. galilaeus ATCC 31133. Aloesaponarin II was synthesized via the condensation of 8 acetyl coenzyme A equivalents, followed by a decarboxylation reaction as demonstrated by [1,2-13C2]acetate feeding experiments. S. coelicolor B22 and B159, actVI blocked mutants, also formed aloesaponarin II as an apparent shunt product. Mutants of S. coelicolor blocked in several other steps in actinorhodin biosynthesis did not synthesize aloesaponarin II or other detectable anthraquinones. When S. galilaeus ATCC 31671 was transformed with the DNA carrying the actI, actIII, and actVII loci, the recombinant strain produced both aloesaponarin II and aklavinone, suggesting that the actinorhodin biosynthesis DNA encoded a function able to deoxygenate 2-hydroxyaklavinone to aklavinone. When S. galilaeus ATCC 31671 was transformed with a plasmid carrying only the intact actIII gene (pANT45), aklavinone was formed exclusively. These experiments indicate a function for the actIII gene, which is the reduction of the keto group at C-9 from the carboxy terminus of the assembled polyketide to the corresponding secondary alcohol. In the presence of the actIII gene, anthraquinones or anthracyclines formed as a result of dehydration and aromatization lack an oxygen function on the carbon on which the keto reductase operated. When S. galilaeus ATCC 31671 was transformed with the DNA carrying the actI, actVII, and actIV loci, the recombinant strain produced two novel anthraquinones, desoxyerythrolaccin, the 3-hydroxy analog of aloesaponarin II, and 1-O-methyldesoxyerythrolaccin. The results obtained in these experiments together with earlier data suggest a pathway for the biosynthesis of actinorhodin and related compounds by S. coelicolor.

Anthraquinones↗