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A J Pakstis

Publications and source records attributed to A J Pakstis.

At least 55 records · Page 3Linked to original sources
PubMed1993

Assignment of the norepinephrine transporter protein (NET1) locus to chromosome 16.

The norepinephrine transporter protein (NET) is the presynaptic reuptake site for norepinephrine and a site of action for several drugs with CNS effects, some of which are therapeutically useful and some of which are drugs of abuse. We used PCR with a somatic cell hybrid panel to obtain a provisional assignment to chromosome 16. We then typed a genetic polymorphism at the NET1 locus in three large multigenerational families and used linkage analysis to confirm the preliminary assignment and to refine the localization to 16q, near the HP locus. Finally, we typed the NET1 RFLP on the CEPH families and the additional linkage data localized NET1 to 16q13-q21, flanked by D16S71 (centromerically) and HP (telomerically).

Carrier Proteins↗
PubMed1993

Eliminating mitochondrial DNA competition for nuclear DNA primers.

Mitochondrial DNA (mtDNA) sequences were synthesized with nuclear DNA (nucDNA) sequence-tagged site (STS) primers by mismatch priming in three independent studies of the human nuclear genome. Mismatch primer binding sites on the mtDNA were identified with from 6- to 10-bp identity at the 3' ends of the primers. In two of three cases, single-stranded mtDNA copies were gel-isolated with intended nucDNA PCR products. During routine screening of the STSs, the radiolabeled gel-isolated products hybridized to polymorphic mtDNA restriction fragments. Intense signals after overnight exposure of radiolabeled PCR probes on Southern blots suggest contaminating mtDNA PCR products. The theoretical annealing temperatures of the mismatches were well below the annealing temperatures of the PCR primers, demonstrating annealing reactions driven by the molar surplus of the primers, that is, mass action. The probability that two primers (either one of a pair or both), designed to amplify nucDNA, will bind to and amplify mtDNA may be as high as 1 in 64, assuming that an identical match with only the 3' hexanucleotide is sufficient for amplification. To circumvent this problem we have developed OLIGFIND, a program that has identified the 104 of 4096 possible hexamers that are not present in human mtDNA. Our results suggest that time could be saved by designing STS primers with one of these 104 hexamers at the 3' end. OLIGFIND can also evaluate primer 3' ends for potential PCR products from mtDNA.

Base Sequence↗
PubMed1992

Linkage map of eight human chromosome 11q markers, including DRD2, spanning 60 cM.

We have constructed a linkage map of eight RFLP markers located on chromosome 11q in the region of the dopamine D2 receptor gene (DRD2) recognized by probe hD2G1. Abnormalities in dopaminergic neurotransmission mediated by this receptor have been implicated in several psychiatric disorders. The map was generated using six large reference families (from 294 to 419 individuals per locus), which are largely independent of the CEPH families, primarily using the LINKMAP and ILINK programs of the LINKAGE package of Lathrop and Lalouel. The most likely order and recombination frequencies are: [sequence: see text] The relative order of D11S84-STMY, DRD2-D11S29, and D11S146-INT2 could not be resolved reliably. There were no significant sex differences in recombination frequency. We introduce here a version of LINKMAP adapted to run under distributed parallel processing (LINDA-LINKMAP). Using pairwise analyses, we have also placed D11S421 proximal to this group.

Chromosome Mapping↗
PubMed1992

Presymptomatic testing using DNA markers for individuals at risk for familial multiple endocrine neoplasia 2A.

The carrier status of 39 at-risk individuals in 6 multiple endocrine neoplasia 2A families was determined using a DNA based test. We were able to calculate a virtual diagnosis (probability greater than 95%) for 77% of the individuals and a probable diagnosis (probability greater than 90%) for 90% of the individuals. This study points out some of the problems of specific pedigree structures that can affect the risk calculation. This study further shows that no single test based on either biochemistry, pathology, or genetics can consistently and unambiguously produce a presymptomatic diagnosis. We also describe two specific examples where DNA testing has helped to resolve clinical uncertainties in at-risk individuals.

Adolescent↗
PubMed1991

Parallelizing genetic linkage analysis: a case study for applying parallel computation in molecular biology.

Parallel computers offer a solution to improve the lengthy computation time of many conventional, sequential programs used in molecular biology. On a parallel computer, different pieces of the computation are performed simultaneously on different processors. LINKMAP is a sequential program widely used by scientists to perform genetic linkage analysis. We have converted LINKMAP to run on a parallel computer, using the machine-independent parallel programming language, Linda. Using the parallelization of LINKMAP as a case study, the paper outlines an approach to converting existing highly iterative programs to a parallel form. The paper describes the steps involved in converting the sequential program to a parallel program. It presents performance benchmarks comparing the sequential version of LINKMAP with the parallel version running on different parallel machines. The paper also discusses alternative approaches to the problem of "load balancing," making sure the computational load is shared as evenly as possible among the available processors.

Chromosome Mapping↗
PubMed1991

Progress in the search for genetic linkage with Tourette syndrome: an exclusion map covering more than 50% of the autosomal genome.

Gilles de la Tourette syndrome is a neuropsychiatric disorder with an autosomal dominant mode of inheritance and reduced penetrance at a single genetic locus. Several research groups have genetic linkage studies underway to detect the chromosomal location of the gene that predisposes for this disorder. Strong and clear evidence of linkage has not yet been produced for Tourette syndrome. This paper presents an overview of the methods and progress of the groups centered at Yale University and Erasmus University in excluding linkage from a large portion of the genome. Our labs have screened 228 genetic marker loci for linkage with a gene for this disorder in a series of affected families in the United States, Canada, The Netherlands, and Norway. More than 50% (and perhaps as much as 66%) of the autosomal genome has now been excluded on the assumption that genetic heterogeneity is not an important factor in the Tourette syndrome pedigrees pooled for this summary.

Chromosome Mapping↗
PubMed1990

Gilles de la Tourette syndrome is not linked to D2-dopamine receptor.

Gilles de la Tourette syndrome has an important genetic component; the pathophysiology of this disorder may involve the dopamine system. We tested a D2-dopamine receptor (locus DRD2, recognized by probe hD2G1) for genetic linkage with Gilles de la Tourette syndrome. Using a genetic linkage map of the region of DRD2 on the long arm of chromosome 11 and restriction fragment length polymorphism data from a total of four markers (DRD2 itself, D11S84, D11S29, and PBGD), we were able to exclude linkage of this candidate gene and Gilles de la Tourette syndrome in two extended kindreds segregating for Gilles de la Tourette syndrome. This rules out causation of Gilles de la Tourette syndrome by mutation in DRD2 in the kindreds studied under the genetic assumptions we employed; use of the map and multipoint linkage analyses also allowed us to exclude a Gilles de la Tourette syndrome susceptibility locus from a larger genetic region.

Chromosome Mapping↗
PubMed1990

Genetic and physical mapping and population studies of a fibronectin receptor beta-subunit-like sequence on human chromosome 19.

A cDNA clone of the beta subunit of human fibronectin receptor (FNRB) detects two different polymorphic loci: (a) a codominant system previously mapped to the pericentromeric region of chromosome 10, the site of the functional FNRB gene; and (b) a dominant system not linked to the first one or to any chromosome 10 marker tested. This second polymorphism is characterized by the presence or absence of a band (or a set of bands). We have used linkage analysis and biotin-labeled in situ hybridization to map this dominant polymorphism to the short arm of chromosome 19; we hypothesize that it may be due to the insertion of part of the cDNA from the chromosome 10 gene into chromosome 19. This "insertion" is polymorphic in all populations studied.

Chromosome Mapping↗
PubMed1990

Segregation and linkage analyses of Tourette's syndrome and related disorders.

Segregation and linkage analyses were performed with data from a large Tourette's syndrome (TS) multigenerational kindred. Results of segregation analyses were remarkably similar to some reported earlier and suggest that the mode of transmission is consistent with autosomal dominant inheritance. The analyses were done using three diagnostic schemes to specify affected family members (TS only; TS or chronic tics [CT]; and TS, CT or obsessive compulsive disorder [OCD]). The estimates of penetrance for the genotypes AA, Aa and aa (A denotes the susceptibility allele) in the analyses including relatives with TS, CT or OCD were 0.99, 0.99 and 0.00, respectively, for males and 0.70, 0.70 and 0.00 for females. Pairwise linkage analyses with 140 marker loci failed to identify a linked marker. However, approximately 30 percent of the genome was excluded as the site of the hypothesized locus for TS.

Child↗
PubMed1990

The genetic defect in multiple endocrine neoplasia type 2A maps next to the centromere of chromosome 10.

Multiple endocrine neoplasia type 2A (MEN2A) is a rare cancer syndrome that is inherited in an apparently autosomal dominant fashion. Previous linkage studies had assigned the MEN2A locus to chromosome 10 in the pericentromeric region. We recently have described several new easily scorable RFLPs for the chromosome 10-specific alpha satellite DNA (the D10Z1) locus that is known, on the basis of previous in situ hybridization experiments, to lie at the centromere. We report here tight linkage between MEN2A and D10Z1, as demonstrated by a maximum lod score of 12.02 at the recombination frequency of zero (1-lod-unit support interval 0-4 cM), indicating that the genetic defect in MEN2A lies in the immediate vicinity of the centromere. By means of a set of ordered polymorphic DNA markers from the pericentromeric region, multipoint as well as pairwise linkage analyses place the MEN2A locus at the middle of a small region (approximately 11 cM) bracketing the centromere with FNRB (at 10p11.2) and RBP3 (at 10q11.2) on either side, providing further support for the centromeric location of the MEN2A locus. Marked sex difference in recombination frequencies exists in this pericentromeric region: significantly (P less than .01) more female than male crossovers were observed across all of the adjacent intervals D10S24-FNRB, FNRB-D10Z1, and D10Z1-RBP3. However, a sex difference was not seen in the 7-cM interval from RBP3 to D10S5, suggesting that large variation in the sex difference in recombination can occur over small chromosomal regions.(ABSTRACT TRUNCATED AT 250 WORDS)

Centromere↗
PubMed1989

Close linkage of MEN2A with RBP3 locus in Japanese kindreds.

The gene responsible for multiple endocrine neoplasia type 2A (MEN2A) has recently been assigned to the pericentromeric region of chromosome 10 in European Caucasian kindreds by linkage analysis using a DNA marker, interstitial retinol-binding protein 3 (RBP3). We have found tight linkage between the MEN2A and RBP3 loci in Japanese MEN2A kindreds. The maximum lod score is 5.19 at a recombination fraction of 0.00. This result suggests that mutation of a certain gene close to RBP3 is responsible for MEN2A irrespective of ethnic backgrounds.

Female↗
PubMed1989

Molecular genetic studies in schizophrenia.

Despite many years of research, the genetic factors in schizophrenia are not well understood. Recent developments in DNA technology allow new methods of testing genetic hypotheses in the etiology of this debilitating disorder. We have found evidence against linkage of schizophrenia in a Swedish kindred to markers on chromosome 5; another research group has reported positive evidence for linkage to this same chromosomal region in British and Icelandic families. This article presents a set of data expanded from our previous report, discusses the issue of heterogeneity, and reviews the current status of linkage studies in schizophrenia.

Chromosomes, Human, Pair 5↗