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Biomedical subjects

N B Freimer

Publications and source records attributed to N B Freimer.

33 records · Page 2Linked to original sources
PubMed1996

Attitudes towards bipolar disorder and predictive genetic testing among patients and providers.

Attitudes about bipolar disorder (manic depressive disorder) and genetic testing were investigated. Three groups of subjects were surveyed including members of a manic depressive support group, medical students, and psychiatry residents. The questionnaire was intended to elicit impressions and attitudes about bipolar disorder (BP) from mental health consumers and health care providers with varying levels of personal and professional familiarity with the disorder. Attitudes towards prenatal testing and pregnancy termination were also assessed. The intention hypothetically to terminate a pregnancy was influenced by the likelihood of developing BP a well as the projected course and severity of illness. Nearly half of the total sample would terminate pregnancy if the fetus were definitely to develop an unspecified form of bipolar disorder. Presumed severity of illness was also found to be a modifying factor in the decision, with a low percentage of subjects electing to terminate for a mild course of bipolar disorder and a majority opting for termination in the case of an extremely severe presentation. Support group members were the least likely to terminate a hypothetical pregnancy in the case of a positive prenatal test and were the most likely to desire childhood testing in the absence of preventive or treatment options. The possible implications of these findings, as well as avenues of future research, are discussed.

Abortion, Spontaneous↗
PubMed1995

Mapping genes for psychiatric disorders and behavioral traits.

In the past year, some of the most exciting findings in the genetic investigation of mammalian behavior have been obtained through mapping and through gene manipulation studies in the mouse system. These include the localization of a gene for circadian periodicity in the mouse, gene knockouts of serotonin receptors, and the development of a transgenic model of Alzheimer's disease. The recent development of genetic maps covering the entire human genome and the implementation of new approaches to genetic analysis may now facilitate elucidation of complex behaviors in humans, particularly psychiatric disorders.

Alleles↗
PubMed1995

The distribution of linkage disequilibrium over anonymous genome regions.

Linkage disequilibrium (LD), the association of alleles at different loci, is a powerful tool for genetic mapping and for investigating, at the population level, processes such as recombination, selection, mutation and admixture. Little is known about the distribution of LD across mammalian genomes. Therefore, a survey was undertaken, using microsatellite loci, to evaluate the distribution of LD over several regions of human chromosome 4. Radiation hybrid (RH) and linkage maps provided information on physical and genetic distances between these loci. A Finnish population sample was genotyped using 32 microsatellite loci, and partial marker haplotypes were determined. Assessment of LD was performed, between all pairs of loci, using the Fisher's exact test. LD was detected between several loci that were separated by more than 1 Mb or 1 cM. Detection of LD was strongly associated with small physical distance; its relation to genetic distance was more equivocal. This result may support the hypothesis that linkage maps are relatively inaccurate over small distances. Our results suggest that LD is widely distributed in anonymous regions of the human genome and its use may allow more accurate measurement of small genetic distances than does standard linkage analysis. Alternative explanations are considered for comparisons in which LD is not detected between tightly linked loci.

Alleles↗
PubMed1995

Mapping of a locus for progressive familial intrahepatic cholestasis (Byler disease) to 18q21-q22, the benign recurrent intrahepatic cholestasis region.

A locus for progressive familial intrahepatic cholestasis (PFIC), also known as Byler disease, has been mapped to a 19 cM region of chromosome 18 by a search for shared segments, using patients from the Amish kindred in which the disorder was originally described. A similar liver disease, benign recurrent intrahepatic cholestasis (BRIC), recently has been mapped to the same region, suggesting that these two diseases are caused by mutations in the same gene. Although PFIC and BRIC are clinically distinct diseases, episodic attacks of jaundice and pruritus, with elevated concentrations of bile acid in serum, are seen in both disorders. In PFIC patients, these attacks result in progressive liver damage and death. The clinical and biochemical features of PFIC and BRIC are suggestive of a defect in primary bile acid secretion. The biology of bile secretion is of great interest because of its vital importance in digestion of dietary fats as well as in secretion of xenobiotics and metabolic waste products. Cloning of the gene (or genes) responsible for PFIC and BRIC will likely provide important insights into this pathway.

Alleles↗
PubMed1995

Microsatellite allele frequencies in humans and chimpanzees, with implications for constraints on allele size.

The distributions of allele sizes at eight simple-sequence repeat (SSR) or microsatellite loci in chimpanzees are found and compared with the distributions previously obtained from several human populations. At several loci, the differences in average allele size between chimpanzees and humans are sufficiently small that there might be a constraint on the evolution of average allele size. Furthermore, a model that allows for a bias in the mutation process shows that for some loci a weak bias can account for the observations. Several alleles at one of the loci (Mfd 59) were sequenced. Differences between alleles of different lengths were found to be more complex than previously assumed. An 8-base-pair deletion was present in the nonvariable region of the chimpanzee locus. This locus contains a previously unrecognized repeated region, which is imperfect in humans and perfect in chimpanzees. The apparently greater opportunity for mutation conferred by the two perfect repeat regions in chimpanzees is reflected in the higher variance in repeat number at Mfd 59 in chimpanzees than in humans. These data indicate that interspecific differences in allele length are not always attributable to simple changes in the number of repeats.

Alleles↗
PubMed1994

Mutational processes of simple-sequence repeat loci in human populations.

Mutational processes of simple sequence repeats (SSRs) in complex genomes are poorly understood. We examined these processes by introducing a two-phase mutation model. In this model, most mutations are single-step changes, but infrequent large jumps in repeat number also occur. We used computer simulations to determine expected values of statistics that reflect frequency distributions of allele size for the two-phase model and two alternatives, the one-step and geometric models. The theoretical expectations for each model were tested by comparison with observed values for 10 SSR loci genotyped in the Sardinian population, whose genetic and demographic histories have been previously reconstructed. The two-phase model provided the best fit to the data for most of these loci in this population. In the analysis we assumed that the loci were neutral and that this population had undergone rapid population growth. Recent observations made for unstable trinucleotide repeats support our suggestion that frequent small changes and rare large changes in repeat number represent two distinct classes of mutation at SSR loci. We genotyped the same 10 loci in Egyptian and sub-Saharan African samples to assess the utility of SSRs for studying the divergence of populations and found that estimates of interpopulation distances from SSRs were similar to those derived from analysis of mitochondrial DNA.

Gene Frequency↗
PubMed1994

Genome screening by searching for shared segments: mapping a gene for benign recurrent intrahepatic cholestasis.

It is now feasible to map disease genes by screening the genome for linkage disequilibrium between the disease and marker alleles. This report presents the first application of this approach for a previously unmapped locus. A gene for benign recurrent intrahepatic cholestasis (BRIC) was mapped to chromosome 18 by searching for chromosome segments shared by only three distantly related patients. The screening results were confirmed by identifying an extended haplotype conserved between the patients. Probability calculations indicate that such segment sharing is unlikely to arise by chance. Searching the genome for segments shared by patients is a powerful empirical method for mapping disease genes. Computer simulations suggest that, in appropriate populations, the approach may be used to localize genes for common diseases.

Cholestasis, Intrahepatic↗
PubMed1993

Genome mapping by arbitrary amplification of yeast artificial chromosomes.

Several methods have been described for using the polymerase chain reaction (PCR) to isolate fragments of DNA for genome mapping. We have developed an approach for isolating discrete fragments by amplifying DNA with single oligonucleotides (10-mers) with arbitrarily selected sequences. The method is rapid and technically simple. We isolated fragments from a contig of three yeast artificial chromosomes (YACs) from the human Xq28 chromosomal region. We purified YACs yWXD37, yWXD348, and yWXD705 from a preparative pulsed field gel. Amplifications of each YAC were performed with single 10-mers as the PCR primers and the products were visualized on agarose gels. These fragments have been successfully used as hybridization probes against Southern blots containing the YACs and against blots containing human genomic DNA and somatic cell hybrids containing Xq28 as their only human constituent. The results have been concordant with the known order of the YACs. We have also successfully combined 10-mers with primers derived from vector arm sequences to isolate YAC ends. We discuss several uses of this method in comparative mapping and in filling in gaps in physical and genetic maps.

Base Sequence↗
PubMed1993

Allele frequencies at microsatellite loci: the stepwise mutation model revisited.

We summarize available data on the frequencies of alleles at microsatellite loci in human populations and compare observed distributions of allele frequencies to those generated by a simulation of the stepwise mutation model. We show that observed frequency distributions at 108 loci are consistent with the results of the model under the assumption that mutations cause an increase or decrease in repeat number by one and under the condition that the product Nu, where N is the effective population size and u is the mutation rate, is larger than one. We show that the variance of the distribution of allele sizes is a useful estimator of Nu and performs much better than previously suggested estimators for the stepwise mutation model. In the data, there is no correlation between the mean and variance in allele size at a locus or between the number of alleles and mean allele size, which suggests that the mutation rate at these loci is independent of allele size.

Alleles↗
PubMed1993

Incorrect specification of marker allele frequencies: effects on linkage analysis.

Most current linkage analyses make use of highly polymorphic DNA markers. Assigning correct allele frequencies for these markers may be extremely difficult in particular study populations. Designation of erroneous frequencies may result in false-positive evidence for linkage, as well as in failure to correctly exclude linkage. These effects are most pronounced in small pedigrees with key individuals unavailable for typing. The power to correctly detect true linkage does not appear to be greatly affected by inaccurate allele frequencies. Before linkage analyses are performed for specific pedigrees, it is recommended that simulation analyses be performed, followed by uncertainty and sensitivity analyses.

Alleles↗
PubMed1992

Isolation and characterization of a highly polymorphic human locus (DXS455) in proximal Xq28.

Human Xq28 is highly gene dense with over 27 loci. Because most of these genes have been mapped by linkage to polymorphic loci, only one of which (DXS52) is informative in most families, a search was conducted for new, highly polymorphic Xq28 markers. From a cosmid library constructed using a somatic cell hybrid containing human Xq27.3----qter as the sole human DNA, a human-insert cosmid (c346) was identified and found to reveal variation on Southern blot analyses with female DNA digested with any of several different restriction endonucleases. Two subclones of c346, p346.8 and p346.T, that respectively identify a multiallelic VNTR locus and a frequent two-allele TaqI polymorphism were isolated. Examination of 21 unrelated females showed heterozygosity of 76 and 57%, respectively. These two markers appeared to be in linkage equilibrium, and a combined analysis revealed heterozygosity in 91% of unrelated females. Families segregating the fragile X syndrome with key Xq28 crossovers position this locus (designated DXS455) between the proximal Xq28 locus DXS296 (VK21) and the more distal locus DXS374 (1A1), which is proximal to DXS52. DXS455 is therefore the most polymorphic locus identified in Xq28 and will be useful in the genetic analysis of this gene dense region, including the diagnosis of nearby genetic disease loci by linkage.

Alleles↗
PubMed1991

Spinal muscular atrophy is not the result of mutations at the beta-hexosaminidase or GM2-activator locus.

The disease locus for the clinically heterogeneous childhood spinal muscular atrophies (SMA) maps to the chromosome 5 subregion, 5q11.2-13.3. The beta-subunit of beta-D-N-acetylhexosaminidase (hexosaminidase) (EC 3.2.1.52) (Hex B) maps to the same region, and the protein required for substrate recognition by this enzyme, GM2-activator protein, likewise maps to chromosome 5. We have investigated the possibility of allelic variation among some forms of SMA and hexosaminidase deficiency. Recombination between the Hex B and SMA loci eliminates this enzyme as a candidate site for defects causing the illness. Furthermore, we show that, despite previous evidence to the contrary, the GM2-activator locus does not map to chromosome 5, thereby eliminating it as a candidate gene for SMA.

Amino Acid Sequence↗
PubMed1989

Deletion mapping of DNA markers to a region of chromosome 5 that cosegregates with schizophrenia.

Two independent lines of evidence support the localization of a schizophrenia susceptibility locus to the proximal long arm of chromosome 5. A partial trisomy of chromosome 5 (5q11.2-q13.3) cosegregates with the disorder in a Canadian family of Chinese descent, and DNA markers from proximal 5q cosegregate with schizophrenia (plus related disorders) in families of British and Icelandic descent. We constructed a human:hamster hybrid cell line (HHW 1064) whose only human complement is a chromosome 5 that is missing the trisomic region associated with schizophrenia. In combination with a "matched" cell hybrid (HHW 105) containing an intact chromosome 5, we physically mapped DNA markers relative to the trisomy. "Schizophrenia-linked" DNA markers p105-153Ra (D5S39) and p105-599Ha (D5S76) map within the trisomy and proximal to the 5q11.2 breakpoint, respectively. The hybrid cell lines HHW 105 and HHW 1064 together provide a means to identify and generate syntenic DNA markers to further investigate the location of a schizophrenia locus.

Animals↗
PubMed1978

The role of cell wall carbohydrates in binding of microorganisms to mouse peritoneal exudate macrophages.

The recognition by macrophages of unopsonized bacteria was studied, employing a binding assay, performed at 4 degrees C. Various Gram positive and Gram negative bacteria were shown to bind to glass-adherent mouse peritoneal exudate cells under these conditions, Str. pneumoniae being the only exception. The binding could be inhibited by pretreatment of the macrophage monolayers with various monosaccharides. The role of particular components of the bacterial cell wall in binding was examined further using different strains of K. aerogenes and S. typhimurium with a known cell wall composition and mutant strains deficient in certain sugars. The ability of a particular constituent to inhibit binding was found to correlate closely with its presence in the bacterial cell wall. It is concluded, that this form of binding, mediated by cell wall carbohydrates represents a primitive recognition mechanism enabling phagocytes to bind microorganisms.

Animals↗