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PubMed1987

The sequence of a sea urchin muscle actin gene suggests a gene conversion with a cytoskeletal actin gene.

We report the nucleotide sequence of the single muscle actin gene of the sea urchin Strongylocentrotus purpuratus. Comparison of the protein-coding sequence of this muscle actin gene (pSpG28) with that of two linked sea urchin cytoskeletal actin genes (pSpG17 and CyIIa) reveals a region of exceptional sequence conservation from codon 61 through codon 120. Furthermore, when silent nucleotide changes are compared, the conservation of this region is still evident (7.9% silent site differences in the conserved region vs 43.3% silent site differences in the rest of the gene when pSpG28 and CyIIa are compared), indicating that the conservation is not due to particularly stringent selection on the portion of the protein encoded by this region of the genes. These observations suggest that a gene conversion has occurred between the muscle actin gene and a cytoskeletal actin gene recently in the evolution of the sea urchin genome. Gene conversion between nonallelic actin genes may thus play a role in maintaining the homogeneity of this highly conserved gene family.

Actins↗

PubMed2002

[Dual gene amplification and selection system with dihydrofolate reductase and glutamine synthetase genes effectively increase the foreign gene expression].

BACKGROUND: To study the effect of gene amplification and selection system with DHFR plus GS and DHFR or GS gene on the foreign gene expression. METHODS: Using the N-terminal truncated hTPO(T184) gene as target gene, two plasmidsre were constructed: pDC- T184 and pGC-T184 where DHFR and GS gene were used respectively as the selective amplification marker. They were cotransfected into CHO dhfr cells to establish dual gene amplification and selection system of DHFR plus GS gen and respectively transfected to establish single gene amplification and selection system of DHFR or GS gene. Three selective methods in dual selective system to compare expression efficiency of hTPO were designed: the first method (DG) was to use drug pressure of MTX, then use MSX; the second method (GD) was reversed; the third method was simultaneously to use MTX and MSX as drug pressure. RESULTS: DHFR+GS dual system had not only higher gene amplification efficiency but also higher level expression. There was no distinct affect in different method of drug pressure. CONCLUSIONS: MTX plus MSX dual drug pressure in dual selection system was an efficient and simple method to increase the expression of foreign gene in mammalian cells.

Animals↗

PubMed1997

Germ-line knockout heterokaryons of an essential alpha-tubulin gene enable high-frequency gene replacement and a test of gene transfer from somatic to germ-line nuclei in Tetrahymena thermophila.

The haploid Tetrahymena thermophila genome contains a single alpha-tubulin (ATU) gene. Using biolistic transformation, we disrupted one of the two copies of the ATU gene in the diploid germ-line micronucleus. The heterozygous germ-line transformants were made homozygous in the micronucleus by mating to a star strain containing a defective micronucleus. This mating, known as round 1 genomic exclusion, resulted in two heterokaryon clones of different mating types which have both copies of the ATU gene knocked out in the micronucleus but only wild-type genes in the polycopy somatic macronucleus. When these heterokaryons were mated, the exconjugant progeny cells did not grow because the new somatic macronuclei do not have any alpha-tubulin genes. However, when these conjugants were transformed with a functional marked ATU gene, viable transformants were obtained that contained the transforming ATU gene at the homologous locus in the new macronucleus. The exconjugant progeny could be rescued at a high efficiency (900 transformants per microg of DNA) with a wild-type ATU gene. Unlike previous macronuclear transformation protocols, this strategy should allow introduction of highly disadvantageous (but viable) mutations into Tetrahymena, providing a powerful tool for molecular and functional studies of essential genes. These knockout heterokaryons were used to demonstrate that gene transfer from somatic macronuclei to germ-line micronuclei occurs rarely if at all.

Animals↗

PubMed2001

Unequal VH gene rearrangement frequency within the large VH7183 gene family is not due to recombination signal sequence variation, and mapping of the genes shows a bias of rearrangement based on chromosomal location.

Much of the nonrandom usage of V, D, and J genes in the Ab repertoire is due to different frequencies with which gene segments undergo V(D)J rearrangement. The recombination signal sequences flanking each segment are seldom identical with consensus sequences, and this natural variation in recombination signal sequence (RSS) accounts for some differences in rearrangement frequencies in vivo. Here, we have sequenced the RSS of 19 individual V(H)7183 genes, revealing that the majority have one of two closely related RSS. One group has a consensus heptamer, and the other has a nonconsensus heptamer. In vitro recombination substrate studies show that the RSS with the nonconsensus heptamer, which include the frequently rearranging 81X, rearrange less well than the RSS with the consensus heptamer. Although 81X differs from the other 7183-I genes at three positions in the spacer, this does not significantly increase its recombination potency in vitro. The rearrangement frequency of all members of the family was determined in microMT mice, and there was no correlation between the in vitro recombination potential and V(H) gene rearrangement frequency in vivo. Furthermore, genes with identical RSS rearrange at different frequencies in vivo. This demonstrates that other factors can override differences in RSS potency in vivo. We have also determined the gene order of all V(H)7183 genes in a bacterial artificial chromosome contig and show that most of the frequently rearranging genes are in the 3' half of the region. This suggests that chromosomal location plays an important role in nonrandom rearrangement of the V(H)7183 genes.

Animals↗

PubMed2003

Interleukin-10 gene -627 allele variants, not interleukin-I beta gene and receptor antagonist gene polymorphisms, are associated with atopic bronchial asthma.

Asthma is an airway hyperresponsive disease characterized by the expression of multiple inflammatory genes, including cytokines. Interleukin-I and interleukin-10 (IL-1 and IL-10) are cytokines that might play a role in the process of inflammation and are therefore considered to be involved in the pathogenesis of bronchial asthma. The aim of this study was to test whether the polymorphisms of the promoter region and exon 5 of the IL-1 gene, intron 2 of the IL-1Ra gene, and -627 nucleotide (C/A) of the IL-10 gene could be genetic markers for the susceptibility of bronchial asthma. A normal control group made up of 47 healthy volunteers and 117 patients with bronchial asthma were examined in this study. We analyzed the variable number of tandem repeats at intron 2 of the IL-1Ra gene for the polymorphisms by polymerase chain reaction (PCR). PCR-based restriction analysis of the IL-1 gene polymorphisms of the promoter region and exon 5 was carried out by the endonucleases Ava I and Taq I, respectively. The IL-10 gene -627 C/A polymorphisms were investigated by PCR-based restriction analysis. The distribution of CC homozygotes in the IL-10 gene was significantly lower in asthma patients than in controls (P=0.013, OR=3.599, 95% CI=1.240 approximately 10.441). The polymorphisms studied in the IL-1 genes did not reveal any significant association with bronchial asthma when compared with the control group (promoter region by chi-square test, P=0.627; exon 5 region by Fisher's exact test, P=0.403). Only two alleles of the IL-1Ra gene corresponding to one and two copies of an 86-base pair sequence repeat were identified by PCR in the control group. There were three alleles found in the asthmatic patient group. The results revealed no significant differences between normal individuals and asthma patients (P=0.454, Fisher's exact test). The IL-10 gene -627 "A" allele is an associated risk factor of developing atopic asthma.

Adolescent↗

PubMed1993

Selective expression of foreign genes in glioma cells: use of the mouse myelin basic protein gene promoter to direct toxic gene expression.

We have previously demonstrated that retrovirus-mediated genes were transferred to mouse glioma cells in a meningeal gliomatosis model (Yamada et al.: Japanese Journal of Cancer Research 83:1244-1247, 1992). This retrovirus vector contains the Escherichia coli. beta-galactosidase (beta-gal) gene as a marker for integration of the lacZ gene, which is controlled by the SV40 early promoter. We investigated whether lacZ genes could be specifically controlled in mouse glioma cells by glial-specific promoters, including the 2.5 kb 5' flanking region of the mouse glial fibrillary acidic protein (GFAP) gene, the 1.3 kb 5' flanking region of the myelin basic protein (MBP) gene, and the 1.5 kb 5' flanking region of the myelin proteolipid protein (PLP) gene. Psi-2 packaging cells were transfected with each retrovirus vector (GFAP promoter-, MBP promoter-, and PLP promoter-lacZ) and the infectious virus particles were recovered from the supernatants. Blue staining for beta-gal was detected in various fibroblast, myeloma, and glioma cell lines transduced with the retrovirus BAG vector. On the other hand, blue staining was only detected in glioma cells after transduction with the lacZ gene-bearing retrovirus controlled by glial-specific promoters. The strongest promoter activity was detected after transduction with the retrovirus in which the MBP promoter controlled the lacZ gene. Mouse glioma cells transduced with retrovirus containing the MBP promoter directing the herpes simplex virus type 1 thymidine kinase (HTK) gene were extremely sensitive to ganciclovir, while the parental cells and cells transduced with retrovirus containing the lacZ gene were not sensitive to ganciclovir.(ABSTRACT TRUNCATED AT 250 WORDS)

3T3 Cells↗

PubMed1975

The effect of gene concentration and relative gene dosage on gene output in Escherichia coli.

The differential rate of synthesis of several Escherichia coli gene products was measured under conditions in which the average number of copies of the corresponding chromosomal gene had been changed by altering the replication velocity of the chromosome. The data show that in steady state exponential cultures the output of genes in a fully repressed, fully derepressed, or non-repressible state is proportional to the average number of copies of the gene per unit mass (gene: mass ratio) and does not depend on the number of copies of the gene relative to all other genes (gene: DNA ratio). In contrast, the output of a gene which was under regulation by endogenously generated effectors was independent of such changes in gene frequency. The relationship found between the number of copies of a gene per unit of cell mass and enzyme output provides a new method for determining the location of the chromosome origin and the direction of replication in bacteria.

Alleles↗

PubMed1983

The alpha promoter regulator-ovalbumin chimeric gene resident in human cells is regulated like the authentic alpha 4 gene after infection with herpes simplex virus 1 mutants in alpha 4 gene.

Human TK- 143 cells were converted to TK+ phenotype with a plasmid containing the native herpes simplex virus 1 (HSV-1), thymidine kinase, a beta gene, and a chimeric ovalbumin gene consisting of the coding sequences of the ovalbumin gene linked to the promoter-regulatory region of the HSV-1 alpha 4 gene. Comparison of the synthesis of ovalbumin and the alpha 4 gene product in the converted cells infected with ts mutants in alpha 4 gene and incubated at the permissive (33 degrees C) and nonpermissive (39 degrees C) temperatures revealed the following. (i) The synthesis of both ovalbumin and alpha 4 gene product was transiently induced at the permissive temperature but continued at elevated levels for many hours at the nonpermissive temperature. (ii) The synthesis of both ovalbumin and alpha 4 gene products resumed when the infected cells were shifted from permissive to nonpermissive temperature after the shut-off of alpha protein synthesis. (iii) Although both the beta-TK and alpha 4-ovalbumin chimeric genes were covalently linked on the same plasmid, each was regulated independently. We conclude that alpha gene regulation is determined solely by (a) the inducer and (b) the induction sequence contained in the promoter-regulatory region and not by the location or the higher order structure of the immediate environment of the gene.

DNA, Recombinant↗

PubMed2004

The putative elaiophylin biosynthetic gene cluster in Streptomyces sp. DSM4137 is adjacent to genes encoding adenosylcobalamin-dependent methylmalonyl CoA mutase and to genes for synthesis of cobalamin.

A type I PKS gene probe obtained from RAPB of the rapamycin producer Streptomyces hygroscopicus, strongly hybridised to 92 out of 1120 cosmids from a genomic library of the elaiophylin-producing strain Streptomyces sp. DSM4137. Partial cosmid sequencing suggested the presence of 10 separate sequences encoding type I PKS genes. One entire DNA sequence was obtained and found exactly to match the gene organisation expected for the biosynthesis of the unusual macrodiolide polyketide elaiophylin. The putative elaiophylin gene cluster contains five large open-reading frames encoding typical modular polyketide synthases, which together catalyse the synthesis of the octaketide monomer of elaiophylin. Other genes were identified that would be required for provision of the ethylmalonate extender unit, for the synthesis and attachment of 2-deoxy-L-fucose and in regulation, or in export of the product. Immediately adjacent to the putative elaiophylin biosynthetic gene cluster is a 30-kbp region containing the gene for adenosylcobalamin-dependent methylmalonyl CoA mutase and also genes involved in the biosynthesis of the cobalamin cofactor. Analysis of the latter gene set confirms the view that cbiD of the anaerobic pathway and cobF in the aerobic pathway catalyse the same methylation of precorrin-5. The proximity of these genes to the putative elaiophylin gene cluster can best be rationalised if in this organism succinyl-CoA is a significant source of the methylmalonate units for complex polyketide biosynthesis.

Carbohydrates↗

PubMed1998

Contiguous gene syndrome due to deletion of the first three exons of the Kallmann gene and complete deletion of the steroid sulphatase gene.

OBJECTIVE: Large terminal or interstitial deletions of the 22.3 region on the short arm of the X chromosome cause contiguous gene syndromes. Kallmann syndrome (hypogonadotrophic hypogonadism with anosmia or hyposmia) associated with X-linked ichthyosis, due to a contiguous gene syndrome, is an uncommon finding. Genetic defects have been demonstrated in the Xp22.3 region, explaining the presence of one or both entities in affected individuals. In this report we describe the molecular findings of a patient with Kallmann syndrome and X-linked ichthyosis. PATIENT: A 20-year-old subject with hypogonadism, anosmia and generalized ichthyosis was studied endocrinologically, biochemically and molecularly. MEASUREMENTS: Levels of LH, FSH, GH, testosterone, oestradiol and cortisol were determined basally and after specific stimulation tests. Enzymatic activity of steroid sulphatase was measured in leucocytes. Polymerase chain reaction of the 14 exons of the Kallmann gene and of the 5' and 3' extremes of the steroid sulphatase gene was performed in genomic DNA. RESULTS: A partial deletion from exon 1 to exon 3 of the Kallmann gene, as well as a complete deletion of the steroid sulphatase gene were observed. CONCLUSIONS: A patient bearing a contiguous gene syndrome with partial deletion of the Kallmann syndrome gene and complete deletion of the steroid sulphatase gene is described. This is the first time a mutation in the conserved cysteine-rich N-terminal region which corresponds to the whey acidic protein motif of the Kallmann gene has been characterized, thus demonstrating the importance of this specific region for the function of the gene.

Adult↗

PubMed1999

The -700/-310 fragment of the apolipoprotein A-IV gene combined with the -890/-500 apolipoprotein C-III enhancer is sufficient to direct a pattern of gene expression similar to that for the endogenous apolipoprotein A-IV gene.

Spatial gene expression in the intestine is mediated by specific regulatory sequences. The three genes of the apoA-I/C-III/A-IV cluster are expressed in the intestine following cephalocaudal and crypt-to-villus axes. Previous studies have shown that the -780/-520 enhancer region of the apoC-III gene directs the expression of the apoA-I gene in both small intestinal villi and crypts, implying that other unidentified elements are necessary for a normal intestinal pattern of apoA-I gene expression. In this study, we have characterized transgenic mice expressing the chloramphenicol acetyltransferase gene under the control of different regions of the apoC-III and apoA-IV promoters. We found that the -890/+24 apoC-III promoter directed the expression of the reporter gene in crypts and villi and did not follow a cephalocaudal gradient of expression. In contrast, the -700/+10 apoA-IV promoter linked to the -500/-890 apoC-III enhancer directed the expression of the reporter gene in enterocytes with a pattern of expression similar to that of the endogenous apoA-IV gene. Furthermore, linkage of the -700/-310 apoA-IV distal promoter region to the -890/+24 apoC-III promoter was sufficient to restore the appropriate pattern of intestinal expression of the reporter gene. These findings demonstrate that the -700/-310 distal region of the apoA-IV promoter contains regulatory elements that, in combination with proximal promoter elements and the -500/-890 enhancer, are necessary and sufficient to restrict apoC-III and apoA-IV gene expression to villus enterocytes of the small intestine along the cephalocaudal axis.

Animals↗

PubMed1989

Three mitochondrial tRNA genes from Arabidopsis thaliana: evidence for the conversion of a tRNAPhe gene into a tRNATyr gene.

Three tRNA genes have been isolated from a genomic library of Arabidopsis thaliana: a tRNASer (GCU), a tRNATyr (GUA) and a tRNAGlu (UUC) genes. These genes are located closely on the same DNA fragment. The tRNASer and the tRNAGlu genes have both 99% sequence similarity with their mitochondrial counterparts from higher plants indicating that these three tRNA genes are mitochondrial. The tRNATyr gene shows a particular high sequence similarity with the mitochondrial tRNAPhe pseudogene from maize, and both genes are flanked by a tRNASer gene in the upstream region. Extensive sequence comparisons of the Arabidopsis thaliana mitochondrial sequence containing the three tRNA genes and the corresponding region from maize and soybean mitochondria have shown evidence that the tRNA Tyr gene has been generated from a mitochondrial tRNAPhe gene. The conversion was accomplished by three genetic events: a 4 base-pair deletion, a mutation and a recombination, which led to the transformation of the acceptor stem and the anticodon.

Base Sequence↗

PubMed2005

The Arabidopsis HOMOLOGY-DEPENDENT GENE SILENCING1 gene codes for an S-adenosyl-L-homocysteine hydrolase required for DNA methylation-dependent gene silencing.

Genes introduced into higher plant genomes can become silent (gene silencing) and/or cause silencing of homologous genes at unlinked sites (homology-dependent gene silencing or HDG silencing). Mutations of the HOMOLOGY-DEPENDENT GENE SILENCING1 (HOG1) locus relieve transcriptional gene silencing and methylation-dependent HDG silencing and result in genome-wide demethylation. The hog1 mutant plants also grow slowly and have low fertility and reduced seed germination. Three independent mutants of HOG1 were each found to have point mutations at the 3' end of a gene coding for S-adenosyl-l-homocysteine (SAH) hydrolase, and hog1-1 plants show reduced SAH hydrolase activity. A transposon (hog1-4) and a T-DNA tag (hog1-5) in the HOG1 gene each behaved as zygotic embryo lethal mutants and could not be made homozygous. The results suggest that the homozygous hog1 point mutants are leaky and result in genome demethylation and poor growth and that homozygous insertion mutations result in zygotic lethality. Complementation of the hog1-1 point mutation with a T-DNA containing the gene coding for SAH hydrolase restored gene silencing, HDG silencing, DNA methylation, fast growth, and normal seed viability. The same T-DNA also complemented the zygotic embryo lethal phenotype of the hog1-4 tagged mutant. A model relating the HOG1 gene, DNA methylation, and methylation-dependent HDG silencing is presented.

Adenosylhomocysteinase↗

PubMed1992

Genotoxic-stress-response genes and growth-arrest genes. gadd, MyD, and other genes induced by treatments eliciting growth arrest.

As discussed throughout this paper, many mammalian DDI genes are associated with growth responses, including both positive responses to growth stimulation and negative responses involving transient growth arrest and terminal differentiation. It is interesting that several immediate-early genes encoding transcription factors, the jun genes, are DDI, are induced by terminal differentiation, and also are associated with positive growth responses. In negative growth-response genes, their control is complex and almost certainly involves multiple regulatory mechanisms. The role of growth-arrest genes after exposure to DNA-damaging agents is currently not known, but as growth arrest can have a protective effect on cells exposed to DNA-damaging agents in both bacteria and eukaryotes, some protective role(s) for the gadd genes may exist. Whatever the roles are for the individual gadd genes, the response of the gadd genes to DNA-damaging agents and other growth-arrest signals has been highly conserved during mammalian evolution, and it is likely that this stress response, as reflected by induction of one or more gadd genes, is present in most or perhaps all mammalian cells. Our findings that the gadd group overlaps with another group of growth-arrest genes, the MyD, indicate that these two groups combined define a new class of genes whose protein products are likely to play a role in cell growth cessation.

Aging↗

PubMed1985

Transfection of mouse fibroblast cells with a promoterless herpes simplex virus thymidine kinase gene: number of integrated gene copies and structure of single and amplified gene sequences.

Plasmids carrying the herpes simplex virus thymidine kinase (tk) gene were used to transfect thymidine kinase-deficient cells of the mouse fibroblast cell line LM(tk-). Individual cell clones were cultivated in selective hypoxanthine-aminopterin-thymidine medium to determine the number of integrated plasmid copies which was almost always in the range of one to three copies per genome. In contrast, cells transfected with plasmids carrying a promoterless "truncated" tk gene typically contained between 10 and 25 copies per genome. Surprisingly, when the truncated tk gene was transfected together with a simian virus 40 DNA segment, including its transcriptional enhancer, the number of integrated tk gene copies was always low, between one and three copies per genome. We have analyzed the genomic organization of integrated truncated tk genes by blot hybridization of restricted cellular DNA and concluded that integrated units of plasmid DNA molecules are arranged in tandem arrays which remain stable in most cases for many cell generations. In only 1 of ca. 20 cell clones did we observe a retraction and expansion of the number of integrated promoterless tk genes as a response to the removal or readdition of selective pressure. Surprisingly, the thymidine kinase activity determined in extracts from cells growing in selective hypoxanthine-aminopterin-thymidine medium (high numbers of integrated tk gene copies) was nearly the same as the enzymatic activity in cells growing in nonselective medium (low copy numbers). Moreover, Northern blots of polyadenylated RNA, extracted from cells growing under selective and nonselective conditions, showed that, in both cases, the major species of tk-specific transcripts was ca. 1.5 kilobases in size, as expected for a tk-specific mRNA containing the entire coding region of the gene. Thus, disproportionate DNA replication appeared not to be essential for an active tk gene expression in these cells. We discuss possible pathways leading to the formation of tandem arrays of integrated truncated tk genes and the conditions required for disproportionate DNA replication in the unique case in which we found a retraction and expansion of tk gene copy numbers as a response to selective growth conditions.

Animals↗

PubMed2003

Gene trap mutagenesis of hnRNP A2/B1: a cryptic 3' splice site in the neomycin resistance gene allows continued expression of the disrupted cellular gene.

BACKGROUND: Tagged sequence mutagenesis is a process for constructing libraries of sequenced insertion mutations in embryonic stem cells that can be transmitted into the mouse germline. To better predict the functional consequences of gene entrapment on cellular gene expression, the present study characterized the effects of a U3Neo gene trap retrovirus inserted into an intron of the hnRNP A2/B1 gene. The mutation was selected for analysis because it occurred in a highly expressed gene and yet did not produce obvious phenotypes following germline transmission. RESULTS: Sequences flanking the integrated gene trap vector in 1B4 cells were used to isolate a full-length cDNA whose predicted amino acid sequence is identical to the human A2 protein at all but one of 341 amino acid residues. hnRNP A2/B1 transcripts extending into the provirus utilize a cryptic 3' splice site located 28 nucleotides downstream of the neomycin phosphotransferase start codon. The inserted Neo sequence and proviral poly(A) site function as an 3' terminal exon that is utilized to produce hnRNP A2/B1-Neo fusion transcripts, or skipped to produce wild-type hnRNP A2/B1 transcripts. This results in only a modest disruption of hnRNPA2/B1 gene expression. CONCLUSIONS: Expression of the occupied hnRNP A2/B1 gene and utilization of the viral poly(A) site are consistent with an exon definition model of pre-mRNA splicing. These results reveal a mechanism by which U3 gene trap vectors can be expressed without disrupting cellular gene expression, thus suggesting ways to improve these vectors for gene trap mutagenesis.

3' Untranslated Regions↗

PubMed2006

A model of gene-gene and gene-environment interactions and its implications for targeting environmental interventions by genotype.

BACKGROUND: The potential public health benefits of targeting environmental interventions by genotype depend on the environmental and genetic contributions to the variance of common diseases, and the magnitude of any gene-environment interaction. In the absence of prior knowledge of all risk factors, twin, family and environmental data may help to define the potential limits of these benefits in a given population. However, a general methodology to analyze twin data is required because of the potential importance of gene-gene interactions (epistasis), gene-environment interactions, and conditions that break the 'equal environments' assumption for monozygotic and dizygotic twins. METHOD: A new model for gene-gene and gene-environment interactions is developed that abandons the assumptions of the classical twin study, including Fisher's (1918) assumption that genes act as risk factors for common traits in a manner necessarily dominated by an additive polygenic term. Provided there are no confounders, the model can be used to implement a top-down approach to quantifying the potential utility of genetic prediction and prevention, using twin, family and environmental data. The results describe a solution space for each disease or trait, which may or may not include the classical twin study result. Each point in the solution space corresponds to a different model of genotypic risk and gene-environment interaction. CONCLUSION: The results show that the potential for reducing the incidence of common diseases using environmental interventions targeted by genotype may be limited, except in special cases. The model also confirms that the importance of an individual's genotype in determining their risk of complex diseases tends to be exaggerated by the classical twin studies method, owing to the 'equal environments' assumption and the assumption of no gene-environment interaction. In addition, if phenotypes are genetically robust, because of epistasis, a largely environmental explanation for shared sibling risk is plausible, even if the classical heritability is high. The results therefore highlight the possibility--previously rejected on the basis of twin study results--that inherited genetic variants are important in determining risk only for the relatively rare familial forms of diseases such as breast cancer. If so, genetic models of familial aggregation may be incorrect and the hunt for additional susceptibility genes could be largely fruitless.

Environment↗

PubMed1986

Tissue and gene specific hypomethylation of the human parathyroid hormone gene: association with parathyroid hormone gene expression in parathyroid glands.

An association between decreased cytosine methylation at specific sites adjacent to or within eukaryotic genes and increased gene expression has been described. To determine if tissues secreting PTH show hypomethylation within the vicinity of the PTH gene, we compared the degree of cytosine methylation in DNA from parathyroid glands and control tissues (leukocytes, anterior pituitary, posterior pituitary, and placenta). We digested DNA with HpaII (which cleaves only unmethylated CCGG sequences) and MspI [which cleaves CCGG and C 5-methyl cytosine GG], hybridized the DNA fragments to a PTH complementary DNA probe, and scanned autoradiograms of Southern blots. After MspI digestion all tissues yielded equivalent amounts of a single hybridizing fragment of 6.7 kilobases. The degree of hypomethylation at sites within and flanking the PTH gene was determined as the ratio of the amount of hybridizing fragments obtained by methylation-sensitive digestion (HpaII) relative to methylation-insensitive digestion (MspI). DNA from all parathyroid glands showed significantly greater hypomethylation of the PTH gene than did DNA from control tissues that did not express the PTH gene. Despite variability in the levels of secretory activity of the different parathyroid glands, we found no significant differences in the degree of hypomethylation of the PTH gene. In contrast to the PTH gene studies, hypomethylation was not seen using GH probe on the same blots. Our findings thus suggest that tissue and gene specific hypomethylation of the PTH gene is associated with expression of the gene.

Adenoma↗