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A S Olsen

Publications and source records attributed to A S Olsen.

At least 19 recordsLinked to original sources
PubMed1998

Regions of sex-specific hypo- and hyper-recombination identified through integration of 180 genetic markers into the metric physical map of human chromosome 19.

The order of and physical distance between 180 polymorphic markers, many from the Généthon and CHLC genetic maps, have been determined through inclusion of probe-positive cosmids in the metric physical map of human chromosome 19. The markers incorporated into the physical map include 38 genetic markers with heterozygosities of > 0.8 and approximately 120 markers with heterozygosities of > 0.60. The average distance between markers in this integrated map is approximately 320 kb. Clustering of markers is noted in several regions of the chromosome; only 11 intervals exist where the distance between markers is greater than 1 Mb, with the largest gap being 1.6 Mb. The ratio of sex-average genetic distance from the Généthon and CHLC genetic linkage maps to physical distance in the metric map is approximately 1.7 cM/Mb for the entire chromosome but ranges from 4 cM/Mb across the telomeric bands to 1 cM/Mb for the centromeric cytogenetic bands. The recombination distance in males is approximately twice that of females in the most telomeric bands but is only 10-25% of the activity observed in females in the more centromeric bands. Seven regions along the chromosome are noted where the recombination distance between markers in one sex is greater than 10 times the recombination distance in the other sex. The integration of genetic markers into the high-resolution physical map of human chromosome 19 provides a framework for isolation of disease genes and resources for studies of genome organization, such as regions of interesting recombinational activity.

Centromere↗
PubMed1998

A serine/threonine kinase gene defective in Peutz-Jeghers syndrome.

Studies of hereditary cancer syndromes have contributed greatly to our understanding of molecular events involved in tumorigenesis. Here we investigate the molecular background of the Peutz-Jeghers syndrome (PJS), a rare hereditary disease in which there is predisposition to benign and malignant tumours of many organ systems. A locus for this condition was recently assigned to chromosome 19p. We have identified truncating germline mutations in a gene residing on chromosome 19p in multiple individuals affected by PJS. This previously identified but unmapped gene, LKB1, has strong homology to a cytoplasmic Xenopus serine/threonine protein kinase XEEK1, and weaker similarity to many other protein kinases. Peutz-Jeghers syndrome is therefore the first cancer-susceptibility syndrome to be identified that is due to inactivating mutations in a protein kinase.

AMP-Activated Protein Kinase Kinases↗
PubMed1997

The human guanidinoacetate methyltransferase (GAMT) gene maps to a syntenic region on 19p13.3, homologous to band C of mouse chromosome 10, but GAMT is not mutated in jittery mice.

Guanindinoacetate methyltransferase (gene symbol, GAMT) catalyses the synthesis of creatine from guanidinoacetate and S-adensylmethionine. Pathological mutations in the coding region of GAMT were recently identified in two children with symptoms of muscular hypotonia, ataxia, seizures, and abnormal extrapyramidal movements. During contig construction in the telomeric region of human chromosome 19 we identified a cosmid clone carrying the entire GAMT gene. This clone was shown to overlap with cosmids from a contig that was previously mapped to chromosome 19p13.3. The human GAMT gene has a size of about 5 kb and consists of six exons which agree with the published cDNA sequence. Since the mouse mutations jittery/hesitant are located on band C of mouse chromosome 10 in a region of conserved synteny with 19p13.3 and jittery mice exhibit ataxia and abnormal movement behaviour, the genomic sequence of GAMT was determined in wild-type and jittery mice. The coding region of the GAMT gene, however, was not mutated in these mutant mice. Our linkage and sequence data will facilitate the identification of new GAMT mutations in patients suffering from an abnormal creatine metabolism.

Amino Acid Sequence↗
PubMed1997

Chromosomal localization of the human and mouse hyaluronan synthase genes.

We have recently identified a new vertebrate gene family encoding putative hyaluronan (HA) synthases. Three highly conserved related genes have been identified, designated HAS1, HAS2, and HAS3 in humans and Has1, Has2, and Has3 in the mouse. All three genes encode predicted plasma membrane proteins with multiple transmembrane domains and approximately 25% amino acid sequence identity to the Streptococcus pyogenes HA synthase, HasA. Furthermore, expression of any one HAS gene in transfected mammalian cells leads to high levels of HA biosynthesis. We now report the chromosomal localization of the three HAS genes in human and in mouse. The genes localized to three different positions within both the human and the mouse genomes. HAS1 was localized to the human chromosome 19q13.3-q13.4 boundary and Has1 to mouse Chr 17.HAS2 was localized to human chromosome 8q24.12 and Has2 to mouse Chr 15. HAS3 was localized to human chromosome 16q22.1 and Has3 to mouse Chr 8. The map position for HAS1 reinforces the recently reported relationship between a small region of human chromosome 19q and proximal mouse chromosome 17. HAS2 mapped outside the predicted critical region delineated for the Langer-Giedion syndrome and can thus be excluded as a candidate gene for this genetic syndrome.

Animals↗
PubMed1996

Physical mapping of receptor type protein tyrosine phosphatase sigma (PTPRS) to human chromosome 19p13.3.

Receptor type protein tyrosine phosphatase sigma (PTPRS), a member of a subfamily of receptor type protein tyrosine phosphatases, has been mapped to human chromosome 19p13.3 using fluorescence in situ hybridization (FISH) analysis. Hybridization analysis of chromosome 19 library cosmids has revealed several positive clones that are part of a contig located in the same region. The location of this contig was verified since one of the cosmid clones is anchored to a high-resolution FISH map of human chromosome 19p. In addition, the location of this gene relative to previously mapped proximal markers reveals a new point in the human-mouse synteny map by extending the mouse chromosome 17 synteny region in the telomeric direction.

Animals↗
PubMed1996

Physical and genetic mapping of novel microsatellite polymorphisms on human chromosome 19.

We describe here the identification of 11 novel microsatellite polymorphisms on human chromosome 19. These dinucleotide repeat polymorphisms were detected in chromosome 19-specific cosmids that were physically mapped by fluorescence in situ hybridization. For each repeat, flanking oligonucleotide primers were synthesized and the polymerase chain reaction assay was performed on a panel of 100 unrelated individuals to determine the heterozygosity and allele frequencies. To characterize these markers further, genetic and radiation hybrid maps were constructed. These microsatellite polymorphisms will be valuable in further linkage analysis of inherited diseases on chromosome 19p.

Chromosomes, Human, Pair 19↗
PubMed1996

Assembly of a 1-Mb restriction-mapped cosmid contig spanning the candidate region for Finnish congenital nephrosis (NPHS1) in 19q13.1.

We describe the assembly of a 1-Mb cosmid contig and restriction map spanning the candidate region for Finnish congenital nephrosis (NPHS1) in 19q13.1. The map was constructed from 16 smaller contigs assembled by fingerprinting, a BAC and a PAC clone, and 42 previously unmapped cosmids. In most cases, single-step cosmid walks were sufficient to join two previously assembled contigs, and all but one gap was filled from this cosmid contig library. The remaining gap of about 19 kb was spanned with a single BAC and a single PAC clone. EcoRI mapping of a dense set of overlapping clones validated the assembly of the map and indicated a length of 1040 kb for the contig. This high-resolution clone map provides an ideal resource for gene identification through cDNA selection, exon trapping, and DNA sequencing.

Chromosome Mapping↗
PubMed1995

A 30-Mb metric fluorescence in situ hybridization map of human chromosome 19q.

A high-resolution metric physical map of chromosome 19q has been constructed by fluorescence in situ hybridization. The map locates 136 cosmid reference points that span 30 Mb. The reference points are sequentially ordered from centromere to telomere, and the distance between neighboring cosmids is known from 240 partially overlapping, redundant estimates of genomic distances in kilobases separating pairs of cosmids. The average spacing between cosmid reference points is 220 kb, with over 75% of intervals less than 300 kb. Eighty-four genes and polymorphic markers have been assigned to mapped cosmids. The information on order and genomic distances separating pairs of cosmids, both key elements for building physical maps, has furthered the construction and integration of the genetic and physical maps of chromosome 19.

Chromosome Mapping↗
PubMed1995

High-resolution genetic and physical mapping of multiple epiphyseal dysplasia and pseudoachondroplasia mutations at chromosome 19p13.1-p12.

Multiple epiphyseal dysplasia (MED) and pseudoachondroplasia (PSACH) are autosomal dominant chondrodysplasias that have similar phenotypes at both clinical and cytological levels. With the recent mapping of PSACH and one form of MED (EDM1) to the pericentromeric region of chromosome 19, it is likely that the disease mutations are allelic. D19S212 and D19S215, genetic markers flanking the EDM1/PSACH locus, have been localized in a chromosome 19 physical map consisting of cosmid contigs ordered by high-resolution FISH. These two markers define an interval of approximately 3.1 Mb at the 19p13.1-p12 boundary. With as many as five informative crossovers within the D19S212-D19S215 interval in one family with EDM1 and one family with a mild form of PSACH, recombination mapping at greater resolution was undertaken. From cosmid contigs physically mapped within the D19S212-D19S215 interval, four new dinucleotide repeat polymorphisms have been identified. Analysis of recombinant haplotypes in the two families has narrowed the possible location of the EDM1/PSACH gene to an interval of approximately 600 kb.

Base Sequence↗
PubMed1995

Interstitial duplication 19p.

We report on a 9-month-old girl with an interstitial duplication of 19p, developmental delay, and multiple anomalies including bifrontal prominence, obtuse frontonasal angle, short columella, additional midline philtral pillar, midline ridge on the tongue, vertical midline ridge at the mental symphysis, and a complex congenital heart defect including severe branch pulmonary artery stenosis, secundum atrial septal defect (ASD), and several ventricular septal defects (VSDs). Use of fluorescent in situ hybridization (FISH) with chromosome 19-specific probes showed a direct duplication of bands 19p13.13 and 19p13.2.

Abnormalities, Multiple↗
PubMed1995

Physical maps of human alpha (1,3)fucosyltransferase genes FUT3-FUT6 on chromosomes 19p13.3 and 11q21.

Sialyl Lewis x and related fucosylated glycans are differentially expressed in human cells and form ligands for selectin adhesion receptors. alpha(1,3)Fucosyltransferases (FUTs) that complete their biosynthesis also show tissue specificity. We have established physical maps of the FUT3-6 loci to study regulation of this gene family. FUT4 has previously been localized to chromosome 11q21; FUT3, FUT6, and now FUT5 are localized to chromosome 19p13.3. Conventional and pulsed-field gel electrophoresis mapping of total genomic DNA and large genomic clones were used to generate a fine map of both loci, defining the order, orientation, and distances between FUTs. A P1 clone with all three 19p FUT genes in tandem orientation was isolated and used to study regions flanking FUT3, -5, and -6. Our studies provide preliminary information to study regulation of human FUT genes.

Chromosome Mapping↗
PubMed1995

Pseudoachondroplasia and multiple epiphyseal dysplasia due to mutations in the cartilage oligomeric matrix protein gene.

Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) are dominantly inherited chondrodysplasias characterized by short stature and early-onset osteoarthrosis. The disease genes in families with PSACH and MED have been localized to an 800 kilobase interval on the short arm of chromosome 19. Recently the gene for cartilage oligomeric matrix protein (COMP) was localized to chromosome 19p13.1. In three patients with these diseases, we identified COMP mutations in a region of the gene that encodes a Ca++ binding motif. Our data demonstrate that PSACH and some forms of MED are allelic and suggest an essential role for Ca++ binding in COMP structure and function.

Achondroplasia↗
PubMed1995

An integrated metric physical map of human chromosome 19.

A metric physical map of human chromosome 19 has been generated. The foundation of the map is sets of overlapping cosmids (contigs) generated by automated fingerprinting spanning over 95% of the euchromatin, about 50 megabases (Mb). Distances between selected cosmid clones were estimated using fluorescence in situ hybridization in sperm pronuclei, providing both order and distance between contigs. An average inter-marker separation of 230 kb has been obtained across the non-centromeric portion of the chromosome. Various types of larger insert clones were used to span gaps between contigs. Currently, the map consists of 51 'islands' containing multiple clone types, whose size, order and relative distance are known. Over 450 genes, genetic markers, sequence tagged sites (STSs), anonymous cDNAs, and other markers have been localized. In addition, EcoRI restriction maps have been generated for > 41 Mb (approximately 83%) of the chromosome.

Base Sequence↗
PubMed1994

Human chromosome 19p: a fluorescence in situ hybridization map with genomic distance estimates for 79 intervals spanning 20 Mb.

A physical map of human chromosome 19p has been constructed by fluorescence in situ hybridization of cosmids to metaphase chromosomes and sperm pronuclear interphases. The map spans approximately 20 Mb and was generated with 141 multiple, partially overlapping estimates of genomic distances for 79 intervals separating 80 sequentially ordered cosmid reference points. The average distance separating pairs of cosmids was 250 kb, with a range from 50 to 700 kb; 75% of the intervals were estimated to be less than or equal to 300 kb and only 8 intervals were between 500 and 700 kb. Cosmids positive for 33 genes or gene families and 5 polymorphic markers were included among the mapped elements. The fluorescence in situ hybridization map will be useful for furthering the integration of the physical and genetic maps of 19p and for placing newly identified markers within a few hundred kb of their neighbors.

Analysis of Variance↗
PubMed1993

Automated production of high density cosmid and YAC colony filters using a robotic workstation.

We report here on a system for automated preparation of high-density colony filters of arrayed libraries using the high density replicating system (HDR) for the Beckman Biomek 1000 robotic workstation. This system, consisting of a 96-pin tool, a sterilization station and controlling software, transfers samples from microplates onto target membranes in arrays up to 36 times the density of a 96-well microplate. The transfer operation can be completely automated with the addition of the Biomek Side Loader System, which consists of a robotic arm capable of transferring plates and filters between the Biomek working tablet and a storage area. Using the complete system, we are able to plate 32 replica filters (8 x 12 cm), each containing the clones from 16 different microplates (i.e., 1536 clones per filter), in a 16-h overnight run without any operator intervention. We describe conditions used for transfer of bacterial yeast colonies and fixation of DNA to the membranes, and we illustrate hybridization results obtained with cosmid and YAC filters.

Biotechnology↗
PubMed1992

Order and genomic distances among members of the carcinoembryonic antigen (CEA) gene family determined by fluorescence in situ hybridization.

Fluorescence in situ hybridization was used to establish the order of, and to estimate genomic distances among, members of the carcinoembryonic antigen (CEA) and pregnancy-specific glycoprotein (PSG) subgroups on chromosome 19. Fluorescence in situ hybridization to metaphase chromosomes localized the PSG subgroup telomeric to the CEA subgroup. Cosmid clones containing sequences for individual genes in the CEA and PSG subgroups were also hybridized to human sperm pronuclear and somatic interphase nuclear chromatin targets. The mapping results lead to the gene order cen-CGM7-CEA-NCA-CGM1-BGP-CGM9-CGM8-PSG-te l. The genomic distances between selected pairs of gene family members were estimated from the physical distances between hybridization sites measured in pronuclei. The CEA-PSG gene family region is estimated to span 1.1 to 1.2 Mb.

Carcinoembryonic Antigen↗
PubMed1992

Evolution of the mammalian G protein alpha subunit multigene family.

Heterotrimeric guanine nucleotide binding proteins (G proteins) transduce extracellular signals received by transmembrane receptors to effector proteins. The multigene family of G protein alpha subunits, which interact with receptors and effectors, exhibit a high level of sequence diversity. In mammals, 15 G alpha subunit genes can be grouped by sequence and functional similarities into four classes. We have determined the murine chromosomal locations of all 15 G alpha subunit genes using an interspecific backcross derived from crosses of C57BL/6J and Mus spretus mice. These data, in combination with mapping studies in humans, have provided insight into the events responsible for generating the genetic diversity found in the mammalian alpha subunit genes and a framework for elucidating the role of the G alpha subunits in disease.

Animals↗