Biomedical subjects
R White
Publications and source records attributed to R White.
Mapping genes for manic-depression and schizophrenia with DNA markers.
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Unequal crossingover between homologous chromosomes is not the major mechanism involved in the generation of new alleles at VNTR loci.
To investigate the hypothesis that unequal exchange between homologous chromosomes is involved when new alleles are generated at VNTR loci, we used genetic linkage maps to identify flanking markers surrounding a VNTR marker locus. The minisatellite probe lambda MS1 was selected, as the hypervariable locus it detects undergoes spontaneous generation of new alleles in the germline at a rate of approximately 5%. Multipoint linkage analysis placed lambda MS1 within a cluster of polymorphic marker loci on chromosome 1p. Using the two closest flanking markers, CMM8 and YNZ2, we were able to characterize 12 new-allele events in terms of crossingover between the flanking markers. Statistical analysis of these data has allowed us to reject the model that assumes that events generating new alleles always involve unequal exchange between homologous chromosomes at meiosis.
Loss of 3p or 11p alleles is associated with testicular cancer tumors.
Constitutional and tumor genotypes defined by polymorphic DNA markers were examined in 31 testicular cancer patients. Constitutional karyotypes were analyzed and clinical data presented. We analyzed 11 loci representing 8 chromosomes, including regions frequently deleted in other types of cancer. Loss of 3p or 11p sequences was detected in 8 of 28 heterozygotes (28%) and in 5 of 20 heterozygotes (25%). This gives a combined total loss of 40%. The other autosomal loci tested showed no loss or a loss of less than 10% of alleles. We suggest that this loss of heterozygosity for genetic material on chromosome 3p or on 11p is nonrandom and important in the development of a major subset of testicular neoplasms.
Twenty loci form a continuous linkage map of markers for human chromosome 2.
We have used a combination of 20 DNA markers and 1 protein electromorph, defining 20 loci, to construct a genetic linkage map of chromosome 2. These markers form a continuous linkage group of 306 cM in males and 529 cM in females. Female map distances varied from approximately twofold higher to equivalence from those of males across the map. Among the DNA markers are six well-distributed, highly polymorphic markers reflecting loci that contain a variable number of tandem repeats that will be highly efficient anchor points for the eventual application of this map to studies of human genetic disease.
Twenty-five loci form a continuous linkage map of markers for human chromosome 7.
We have constructed a primary genetic linkage map from DNA markers that define 25 loci on chromosome 7. The markers form a continuous linkage group of 141 cM in males and 340 cM in females; female genetic distances were on average more than twofold higher than those in males throughout the chromosome. The average heterozygosity of the loci was 45%. A subset of the markers can be used for efficient application of this map to studies of human genetic disease.
Characterization of eight VNTR loci by agarose gel electrophoresis.
Allelic frequencies and their confidence intervals were obtained for eight independent VNTR loci from a sample of more than 75 Utah Caucasians. Using high-resolution agarose gel electrophoresis, we were able to resolve alleles at the D17S5 locus that differed by only one repeating unit; it was therefore possible to name the alleles according to the number of repeating units each contained. Two a priori probabilities were calculated for each VNTR locus separately and for all eight loci jointly: (i) the "power of exclusion" for an alleged father/mother/child trio and for an alleged parent/child duo, and (ii) the "probability of matching" when two unrelated individuals or two siblings are genotyped.
A genetic linkage map of markers for human chromosome 20.
A continuous genetic linkage map with five polymorphic DNA markers, including one that defines a locus containing a variable number of tandem repeats (VNTR), has been constructed from genotypic analysis of 59 large reference families. The map spans a genetic distance of 105 cM in males and 115 cM in females and provides initial anchor points for a high-resolution map of human chromosome 20.
Loss of heterozygosity on chromosome 10 in human glioblastoma multiforme.
Recessive mutations, revealed by loss of the wild-type allele, have been associated with the development of a variety of cancers in children and adults. Polymorphic chromosome 10 markers were used to screen paired tumor and lymphocyte DNA samples in 13 patients with glioblastoma multiforme. Ten patients showed loss of constitutional heterozygosity in the tumor samples. This finding suggests that a recessive gene involved in the development of glioblastoma multiforme is present on chromosome 10.
Twenty-eight loci form a continuous linkage map of markers for human chromosome 1.
We have used a combination of 30 serological, protein electromorphic, and DNA markers defining 28 loci to construct a linkage map of chromosome 1. These markers form a continuous linkage group of 320 cM in males and 608 cM in females; female genetic distances were on average twofold higher than those of males across the map. Among the DNA markers are 10 highly polymorphic markers reflecting loci that contain a variable number of tandem repeats, well distributed over the length of the chromosome, that will be highly efficient anchor points for application of this map to studies of human genetic disease.
Frequent recombination is observed in the distal end of the long arm of chromosome 14.
We have constructed a high-resolution map of the distal region (q32) of the long arm of human chromosome 14, with 11 loci including 6 variable number of tandem repeat markers. The map covers 66 cM in males and 53 cM in females. The recombination frequency in this region is more than five times that expected in a region of this physical size, and in our data set the frequency in males was higher than that in females at some intervals. This unusually high density of crossingover occurs in a part of chromosome 14 where translocations are frequently observed in somatic cells.
Molecular dissection of a contiguous gene syndrome: frequent submicroscopic deletions, evolutionarily conserved sequences, and a hypomethylated "island" in the Miller-Dieker chromosome region.
The Miller-Dieker syndrome (MDS), composed of characteristic facial abnormalities and a severe neuronal migration disorder affecting the cerebral cortex, is caused by visible or submicroscopic deletions of chromosome band 17p13. Twelve anonymous DNA markers were tested against a panel of somatic cell hybrids containing 17p deletions from seven MDS patients. All patients, including three with normal karyotypes, are deleted for a variable set of 5-12 markers. Two highly polymorphic VNTR (variable number of tandem repeats) probes, YNZ22 and YNH37, are codeleted in all patients tested and make molecular diagnosis for this disorder feasible. By pulsed-field gel electrophoresis, YNZ22 and YNH37 were shown to be within 30 kilobases (kb) of each other. Cosmid clones containing both VNTR sequences were identified, and restriction mapping showed them to be less than 15 kb apart. Three overlapping cosmids spanning greater than 100 kb were completely deleted in all patients, providing a minimum estimate of the size of the MDS critical region. A hypomethylated island and evolutionarily conserved sequences were identified within this 100-kb region, indications of the presence of one or more expressed sequences potentially involved in the pathophysiology of this disorder. The conserved sequences were mapped to mouse chromosome 11 by using mouse-rat somatic cell hybrids, extending the remarkable homology between human chromosome 17 and mouse chromosome 11 by 30 centimorgans, into the 17p telomere region.
Family characteristics and measures of behavior in foster and nonfoster children.
Behavior scores of maltreated children in foster care were compared with those of a homogeneous group of children who had never been in care. Mean scores for foster children were significantly higher than those for controls. After controlling for group differences in family structure and stability, differences in behavior scores between groups were not significant.
Linkage maps of human chromosomes.
Finding the chromosomal location of human genes that heretofore have been defined solely by phenotypes, in particular clinical phenotypes that are transmitted in Mendelian fashion in families, is an early and often crucial step in the process of identifying the molecular basis of a disease. Recent progress in construction of chromosomal maps of genetically linked DNA markers has made almost the entire human genome accessible to linkage studies in families that are segregating genetic defects. Construction of linkage maps requires a panel of three-generation families for genotyping, a large number of polymorphic markers, and sophisticated computer programs for analysis of genotypic data. After a locus harboring a deleterious mutation has been identified by linkage to a mapped marker, a high-resolution map of the region can be constructed with new markers derived from cosmid libraries, to narrow the search for the gene in question. For example, this strategy has been pursued in the effort to characterize the gene responsible for familial adenomatous polyposis. When a target region has been narrowed to about 1 centiMorgan, corresponding to roughly a million base pairs in physical distance, other techniques of molecular biology can be brought to bear to isolate and clone the actual gene.
Oestrogen receptor mRNA and a related RNA transcript in mouse ovaries.
Oestrogen receptor mRNA expression in mouse ovaries was analysed by Northern blotting of total RNA using 32P-labelled RNA probes complementary to different functional domains of the oestrogen receptor. The approximately 6.5 kb mouse oestrogen receptor mRNA transcript was present in immature and adult ovaries at extremely low abundance compared with uterus and oviduct. Using a probe complementary to the steroid-binding domain of the oestrogen receptor (probe EF), a novel RNA transcript of approximately 1.5 kb was also found in the ovaries but was absent from uterus and oviduct. The melting temperature of the hybrid produced by the approximately 1.5 kb transcript with probe EF was approximately 10 degrees C lower than that produced by authentic oestrogen receptor mRNA, which demonstrates incomplete sequence homology between the two transcripts and indicates that the approximately 1.5 kb RNA is not a truncated form of oestrogen receptor mRNA. Furthermore, the approximately 1.5 kb RNA lacks the DNA-binding domain found in the oestrogen receptor. The approximately 1.5 kb RNA, but not oestrogen receptor mRNA, was enriched in total RNA from isolated granulosa cells compared with residual ovarian tissue. The encoded product of this novel oestrogen receptor-related RNA could be a steroid-binding protein involved in oestrogen action in the ovaries.
Patency and durability of small diameter silicone rubber vascular prostheses.
This study evaluated the long-term patency and durability of 6 mm internal diameter (ID), 18-30 micron pore size replamineform silicone rubber vascular prostheses as canine aortic interposition and arteriovenous (A-V) grafts. Six prostheses (6 mm ID x 8 cm length) were evaluated as aortic grafts for 24 to 30 months, and 10 prostheses (6 mm ID x 8-10 cm length) were studied as A-V grafts from 2 weeks to 10 months. Three of the A-V prostheses were punctured for sham dialysis once or twice/week with two 16 gauge needles (total of approximately 50 needle punctures). The porous wall of the silicone rubber prostheses was incorporated with capillaries and fibrohistiocytic cellular elements from 2 weeks of implantation. This cellular incorporation remained constant up to 2 1/2 years. Needle puncture of the arteriovenous grafts over a 3 to 5 month period produced no complications such as thrombosis, perigraft hematoma formation or bleeding through the puncture site. The silicone rubber sealed the holes with no evidence of tearing. Explanted prostheses had no evidence of enlargement or false aneurysm formation. This study supports our hypothesis that Replamineform silicone rubber prostheses are hemocompatable and demonstrate long-term durability for dialysis access. Clinical evaluation of this graft is planned in the near future.
Attractive facility--a positive factor in treating alcoholism.
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Isolation and mapping of a polymorphic DNA sequence (cTB14.36) on chromosome 10 [D10S35].
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