PubMed Health⌕ Search

Biomedical subjects

J C Murray

Publications and source records attributed to J C Murray.

At least 19 recordsLinked to original sources
PubMed2026

Genetic-epigenetic interactions (meQTLs) in orofacial clefts etiology.

Understanding how genetic variants influence disease risk through molecular mechanisms remains a central challenge in complex disease genetics. Nonsyndromic orofacial clefts (OFCs) exemplify this challenge, with most risk loci residing in non-coding regions. We hypothesized that common genetic variants influence OFC risk by modulating DNA methylation at regulatory elements through methylation quantitative trait loci (meQTLs). We analyzed 10 OFC-associated SNPs against genome-wide DNA methylation profiles in 409 cases and 456 controls, identifying 23 potential meQTLs. Findings were validated using 358 cleft-discordant sibling pairs with MethyLight assays. We performed formal mediation analysis, genotype-tissue interaction and cross-referenced with the mQTL Database to assess developmental timing. Nine meQTLs were validated, including rs987525 (8q24)-cg16561172 (MYC) (P = 9.6 × 10⁻⁶), which mapped to a mesendoderm-active enhancer upstream of MYC. Genotype × tissue interaction confirmed tissue-specificity (P = 1.00 × 10- 3), with stronger effects in oral-derived tissue (saliva). Additional validated SNP-CpG associations involved MAFB-PLCG1, NOG-PPM1E, FOXE1-FRZB, and SPRY2-LGR4. While effect sizes correlated between tissues (r = 0.81), formal mediation analysis indicated individual CpG sites do not fully mediate SNP-phenotype relationships, suggesting coordinated epigenetic mechanisms. Most associations showed peak effects during childhood, while 8q24 showed unique adult-specific patterns. We identified genetic variants influencing methylation at craniofacial regulatory elements, and provided a mechanistic link for a major risk locus, 8q24, with tissue-specific effects in saliva. While individual CpG sites did not fully mediate the genetic risk, our findings identified specific regulatory regions where coordinated epigenetic changes may contribute to OFC susceptibility.

Humans↗
PubMed2025

Genetic-epigenetic interactions (meQTLs) in orofacial clefts etiology.

OBJECTIVES: Nonsyndromic orofacial clefts (OFCs) involve complex genetic and environmental factors, with over 60 risk loci accounting for only a minority of estimated heritability and residing in non-coding regions with unclear functional relevance. We hypothesize that some genetic variants alter orofacial cleft risk by modifying DNA methylation (DNAm) at regulatory sequences essential for craniofacial development, acting as methylation quantitative trait loci (meQTLs). METHODS: We analyzed 10 well-established OFC-associated SNPs against genome-wide DNAm profiles in 409 cases and 456 controls, identifying 23 potential meQTLs. We validated findings using 358 cleft-discordant sibling pairs analyzed with quantitative MethyLight assays. Cross-referencing with the mQTL Database assessed temporal patterns across human development. Functional annotation used GeneHancer and craniofacial enhancer databases. RESULTS: Nine meQTLs were successfully replicated, including the highly significant rs987525 (8q24) - cg16561172 (MYC) association (P = 9.610E-6). This association mapped to a mesendoderm-active enhancer upstream of MYC, providing mechanistic explanation for the longstanding 8q24 cleft locus. Additional validated associations involved MAFB-PLCG1, NOG-PPM1E, FOXE1-FRZB, and SPRY2-LGR4 interactions. Independent differential methylation analysis revealed significant differences between discordant siblings at three CpG sites. Cross-referencing confirmed concordance with population-level methylation effects, with childhood representing the critical developmental window for most associations. CONCLUSIONS: This systematic meQTL characterization in OFCs demonstrates that genetic variants influence disease risk through epigenetic mechanisms. The 8q24-MYC regulatory pathway evidence provides crucial mechanistic insight into a major OFC risk locus. These findings bridge genetic associations with functional consequences, address missing heritability challenges, and suggest potential biomarkers and therapeutic targets for OFC prevention and treatment.

Journal Article↗
PubMed1992

Identification and genetic mapping of a homeobox gene to the 4p16.1 region of human chromosome 4.

A human craniofacial cDNA library was screened with a degenerate oligonucleotide probe based on the conserved third helix of homeobox genes. From this screening, we identified a homeobox gene, H6, which shared only 57-65% amino acid identity to previously reported homeodomains. H6 was physically mapped to the 4p16.1 region by using somatic cell hybrids containing specific deletions of human chromosome 4. Linkage data from a single-stranded conformational polymorphism derived from the 3' untranslated region of the H6 cDNA placed this homeobox gene more than 20 centimorgans proximal of the previously mapped HOX7 gene on chromosome 4. Identity comparisons of the H6 homeodomain with previously reported homeodomains reveal the highest identities to be with the Nk class of homeobox genes in Drosophila melanogaster.

Amino Acid Sequence↗
PubMed1992

Construction of a human chromosome 4 YAC pool and analysis of artificial chromosome stability.

In order to construct a human chromosome 4-specific YAC library, we have utilized pYAC4 and a mouse/human hybrid cell line HA(4)A in which the only human chromosome present is chromosome 4. From this cell line, approximately 8Mb of chromosome 4 have been cloned. The library includes 65 human-specific clones that range in size from 30kb to 290kb, the average size being 108kb. In order to optimize the manipulation of YAC libraries, we have begun to investigate the stability of YACs containing human DNA in yeast cells; these studies will also determine if there are intrinsic differences in the properties of chromosomes containing higher eukaryotic DNAs. We are examining two kinds of stability: 1] mitotic stability, the ability of the YAC to replicate and segregate properly during mitosis, and 2] structural stability, the tendency of the YAC to rearrange. We have found that the majority of YACs examined are one to two orders of magnitude less stable than authentic yeast chromosomes. Interestingly, the largest YAC analyzed displayed a loss rate typical for natural yeast chromosomes. Our results also suggest that increasing the length of an artificial chromosome improves its mitotic stability. One YAC that showed a very high frequency of rearrangement by mitotic recombination proved to be a mouse/human chimera. In contrast to studies using total human DNA, the frequency of chimeras (i.e., mouse/human) in the YAC pool appeared to be low.

Blotting, Southern↗
PubMed1992

Generalized papular xanthomatosis in mycosis fungoides.

Xanthomas can occur in association with underlying lymphoproliferative disease, or they can result from lipid deposition in damaged or altered skin. We report a case of generalized papular xanthomas that developed in a patient with Sézary syndrome. The xanthomas were composed of foamy histiocytes that were shown by immunoperoxidase staining to be of the monocyte/macrophage lineage. Electron microscopic studies revealed lipid vacuoles, lysosomes, and myelin figures but no Birbeck granules, features that are consistent with a non-X histiocytosis. Generalized papular xanthomatosis has not been previously described in a patient with cutaneous T-cell lymphoma.

Aged↗
PubMed1992

Flavone acetic acid as a modifier of endothelial cell function.

Flavone acetic acid (FAA) causes significant regression of larger established tumors in murine systems in vivo, but is only slightly toxic in vitro. This in vivo effect is thought to be indirect, or immunological, rather than a direct cytotoxic effect on tumor cells. Using the WHFIB fibrosarcoma, which grows both in vivo and in vitro, and the murine endothelial cell line B10, we have studied the effect of FAA on the survival of tumor and endothelial cells in vitro. The times taken for 1 mg ml-1 FAA to reduce survival to 0.1 surviving fraction were 63 hr for B10 and greater than 85 hr for WHFIB in vitro. WHFIB tumors in vivo were more sensitive than tumor cells in vitro, a single dose of 150 mg kg-1 FAA inducing a tumor growth delay of 10 days at treatment size + 2 mm. As FAA is more toxic to tumor-bearing animals than to those which are non-tumor bearing the effect of tumor conditioned medium on the cytotoxicity of FAA toward B10 cells was studied; no enhanced effect was seen. As FAA is only weakly cytotoxic in vitro to endothelial cells, and even less so to tumor cells, sublethal effects of FAA on endothelial cell function in vitro were studied. The permeability of monolayers of human unbilical vein endothelial cells (HUVEC) in vitro is transiently increased by FAA. Also, procoagulant activity of HUVEC is induced by FAA and this activity is further enhanced in the presence of a factor isolated from Meth-A tumor cells.

Animals↗
PubMed1992

The CEPH consortium linkage map of human chromosome 2.

This paper describes the Centre d'Etude du Polymorphisme Humain (CEPH) consortium linkage map of chromosome 2. The map contains 36 loci defined by genotyping generated from the CEPH family DNAs. A total of 73 different markers were typed by 14 contributing laboratories; of these, 36 loci are ordered on the map with likelihood support of at least 1000:1. Markers are placed along the length of the chromosome but no markers were available to anchor the map at either telomere or the centromere. Multilocus linkage analysis has produced male, female, and sex-averaged maps extending for 261, 430, and 328 cM, respectively. The sex-averaged map contains five intervals greater than 15 cM and the mean genetic distance between the 36 uniquely placed loci is 9.1 cM.

Chromosome Mapping↗
PubMed1992

Genetic and physical maps of human chromosome 4 based on dinucleotide repeats.

Characterization of inherited variations within tandem arrays of dinucleotide repeats has substantially advanced the construction of genetic maps using linkage approaches over the last several years. Using a backbone of 10 newly identified microsatellite repeats on human chromosome 4 and 6 previously identified short tandem repeat element polymorphisms, we have constructed several genetic maps and a physical map of human chromosome 4. The genetic and physical maps are in complete concordance with each other. The genetic maps include a 15-locus microsatellite-based linkage map, a framework map of high support incorporating a total of 39 independent loci, a 25-locus high-heterozygosity, easily used index map, and a gene-based comprehensive map that provides the best genetic location for 35 genes mapped to chromosome 4. The 16 microsatellite markers are each localized to one of nine regions of chromosome 4, delineated by a panel of somatic cell hybrids. These results demonstrate the utility of PCR-based repeat elements for the construction of genetic maps and provide a valuable resource for continued high-resolution mapping of chromosome 4 and of genetic disorders to this chromosome.

Base Sequence↗
PubMed1992

Linkage of Rieger syndrome to the region of the epidermal growth factor gene on chromosome 4.

Rieger syndrome is an autosomal dominant disorder of morphogenesis in which previous cytogenetic arrangements have suggested chromosome 4 as a candidate chromosome. Using a group of highly polymorphic short tandem repeat polymorphisms (STRP), including a new tetranucleotide repeat for epidermal growth factor (EGF), significant linkage of Rieger syndrome to 4q markers has been identified. Tight linkage to EGF supports its role as a candidate gene, although a recombinant in an unaffected individual has been identified. This study demonstrates the utility of using polymorphic STRP markers when only a limited number of small families are available for study.

Abnormalities, Multiple↗
PubMed1992

Characterization of the human HOX 7 cDNA and identification of polymorphic markers.

cDNA clones for a human HOX 7 gene obtained with homologous clones of Drosophila were used in human gene mapping studies. The human cDNA clone was isolated from a library constructed from human embryonic craniofacial material. The sequence of the cDNA demonstrates significant homology with mouse HOX 7. A search for RFLPs identified MboII and BstEII variants. A CA dinucleotide repeat with 5 alleles was also identified and allowed placement of HOX 7 into a defined linkage map. Evidence for linkage disequilibrium was found with markers tested. These results place the human HOX 7 gene in a defined position on 4p.

Amino Acid Sequence↗
PubMed1992

Localization of two new DNA markers on the linkage map of human chromosome 6q.

Recently, an autosomal homolog of the dystrophin gene (DMDL) was identified on chromosome 6q24. As part of our analysis of the DMDL locus, we endeavoured to isolate DNA markers to further define the genetic map of this region. We have isolated and characterized two new genetic markers in the region of the DMDL locus, the RFLP D6S129 and a (CA)n dinucleotide repeat polymorphism within the DMDL gene itself and have positioned them on the existing genetic map of chromosome 6q. These markers will be important in testing the hypothesis that the DMDL gene is the locus responsible for autosomal forms of neuromuscular disease.

Base Sequence↗
PubMed1992

Genetic marker study of dentinogenesis imperfecta.

DGI-II has been linked to the group specific component (Gc) on 4q and to interferon induced protein 10 (INP10) on 4q. We studied a three generation family with DGI-II along with a four generation DGI-II family to more precisely place DGI-II in the existing genetic map of 4q and to determine if genetic heterogeneity existed between various DGI-II families. Affected family members had brownish discoloration of the teeth, enamel fracturing and radiographic evidence of coronal and radicular pulp chamber obliteration. Thirteen polymorphic markers on 4q were studied including D4S35, D4S1, ALB, Gc, MGSA, AR, INP10, ADH3, FGFB, EGF, IL2, IF, and MNS. Gc and MNS blood group antigen typing were done using commercial SERA. Restriction fragment length polymorphism analysis using Southern blotting was done on the remaining markers. Pairwise linkage analysis was performed using the procedures of Morton. Tight linkage between DGI-II and eleven genetic markers, including Gc and EGF, was excluded. The tightest linkage with DGI-II was identified with the probe INP10 at theta = 0.0 with lod = +3.91. However, INP10 RFLP differences were detected between the families, such that DGI-II correlated with different alleles in each family. Results from this study demonstrated that DGI-II may possibly arise from more than one genetic mutation.

Alleles↗
PubMed1992

Collagen metabolism in the murine colon following X irradiation.

Female CBA mice, aged 16 weeks, were irradiated to the total pelvic region with either single doses (5-20 Gy) or two equal fractions (10- to 30-Gy total dose, 24-h interval) of 240 kV X rays. Total protein and collagen synthesis rates, collagen breakdown, and net collagen content of the colon were measured at various times postirradiation using a radioisotope incorporation method and HPLC analysis. Immunohistochemical staining and computerized image analysis were used to assess the relative amounts of collagen types I and III at various times postirradiation, in various regions of the colon. Total protein and collagen synthesis rates were elevated above control levels at 4 and 8 weeks postirradiation, as was collagen degradation. Values had returned to control levels by 16 weeks postirradiation, and there were no further changes up to 71 weeks postirradiation. The net amount of collagen in the colon did not change relative to controls at any time during the investigation. There was, however, increased immunohistochemical staining for collagen type I 52 weeks postirradiation in all regions of the colon and decreased staining of type III in the circular muscle layer and villi. Altered ratios of these two collagen isotypes are consistent with changes in mechanical properties of the tissue.

Animals↗
PubMed1992

Genetic linkage map of facioscapulohumeral muscular dystrophy and five polymorphic loci on chromosome 4q35-qter.

A genetic map of five polymorphic markers in the area of the facioscapulohumeral muscular dystrophy (FSHD) gene on chromosome 4q35-qter has been constructed. With these five markers, a number of recombinants have been identified that allow ordering of the marker and the disease loci. The most likely locus order and the relative position of the FSHD gene supported by the recombinants is centromere-D4S171-F11-D4S187-D4S163-D4S139-FS HD-telomere. However, at least one recombination event appears to be inconsistent with this order and suggests a location of FSHD proximal to D4S139.

Base Sequence↗