Showing papers by "Michael Boehnke published in 1988"

Absence of linkage of chromosome 21q21 markers to familial Alzheimer's disease

Abstract: Alzheimer's disease is the most common form of dementia among the elderly population. Although the etiology is unknown, inheritance plays a role in the pathogenesis of the disease. Recent work indicates that an autosomal dominant gene for Alzheimer's disease is located on chromosome 21 at band q21. In the present study of a group of autopsy-documented kindreds, no evidence for linkage was found between familial Alzheimer's disease (FAD) and chromosome 21q21 markers (D21S1/D21S72 and the amyloid beta gene). Linkage to the D21S1/D21S72 locus was excluded at recombination fractions (theta) up to 0.17. Linkage to the amyloid gene was excluded at theta = 0.10. Apparent recombinants were noted in two families for the amyloid gene and in five families for the D21S1/D21S72 locus. These data indicate that FAD is genetically heterogeneous.

Estimation of mutation rates based on the analysis of polypeptide constituents of cultured human lymphoblastoid cells.

Abstract: A subclone of a human diploid lymphoblastoid cell line, TK-6, with consistently high cloning efficiency has been used to estimate the rates of somatic mutations on the basis of protein variation detected by two-dimensional polyacrylamide gel electrophoresis. A panel of 267 polypeptide spots per gel was screened, representing the products of approximately 263 unselected loci. The rate of human somatic mutation in vitro was estimated by measuring the proportion of protein variants among cell clones isolated at various times during continuous exponential growth of a TK-6 cell population. Three mutants of spontaneous origin were observed, giving an estimated spontaneous rate of 6 x 10(-8) electrophoretic mutations per allele per cell generation (i.e., 1.2 x 10(-7) per locus per cell generation). Following treatment of cells with N-ethyl-N-nitrosourea, a total of 74 confirmed variants at 54 loci were identified among 1143 clones analyzed (approximately 601,000 allele tests). The induced variants include 65 electromorphs which exhibit altered isoelectric charge and/or apparent molecular weight and nine nullimorphs for each of which a gene product was not detected at its usual location on the gel. The induced frequency for these 65 structural gene mutants is 1.1 x 10(-4) per allele. An excess of structural gene mutations at ten known polymorphic loci and repeat mutations at these and other loci suggest nonrandomness of mutation in human somatic cells. Nullimorphs occurring at three heterozygous loci in TK-6 cells may be caused by genetic processes other than structural gene mutation.

Family risk index as a measure of familial heterogeneity of cancer risk: A population-based study in metropolitan detroit

Abstract: A family risk index was developed that compares the distribution of an endpoint in all families (regardless of disease status) with multiple, random, internal comparison groups. This index incorporates the person-time approach to adjust for risk due to age, birth cohort, sex, and race. It was validated and applied to a population-based sample of 51,714 individuals in 3,277 families from metropolitan Detroit to evaluate the role of familial risk factors in the development of cancer. Interviews took place between June 1973 and July 1977. A measure of familial heterogeneity of risk was used to determine whether cancer risk in families differed from cancer risk in randomly generated comparison groups of the same age, sex, race, birth cohort, and size distributions. For cancers of all sites combined, familial heterogeneity of risk was expressed in the study sample both as lower risk than expected among some families and as higher risk than expected among some families. It is estimated that 27% of the variability in cancer occurrence in the families is due to familial factors.

Comparison of sequential and fixed-structure sampling of pedigrees in complex segregation analysis of a quantitative trait.

Abstract: In designing a study to demonstrate the existence of a major locus for a quantitative trait, an investigator chooses a sampling rule to ascertain pedigrees. The choice of sampling rule can significantly affect the study's power. Here, we compare two types of sampling rules for family studies: fixed-structure rules, in which the same set of relatives are sampled for each proband, and sequential rules, in which the relative or relatives to be sampled next may depend on the trait values of the individuals already observed. We compare fixed-structure and sequential sampling in the setting of extended pedigrees, a quantitative trait, and the genetic mixed model. Using computer simulation, we show that sequential sampling can increase power to detect segregation at a dominant major locus by over 60% in comparison with fixed-structure sampling. Just as important, this substantially increased power is obtained with an easily implemented sampling rule, one that might reasonably be employed in a family study of a quantitative trait.

Nonrandom distribution of structural mutants in ethylnitrosourea-treated cultured human lymphoblastoid cells.

Abstract: Two-dimensional polyacrylamide gel electrophoresis has been used to detect somatic cell gene mutations altering protein structure, following ethylnitrosourea treatment of cultured human lymphoblastoid cells. A total of 267 polypeptides encoded by 263 loci were scored in a series of 1143 lymphoblastoid clones. Sixty-five electrophoretic mutants were detected at a total of 49 loci. Sixteen of the 65 mutations were phenotypically repeat mutations, occurring at 11 loci. Furthermore, structural mutations occurred more frequently at loci known to be polymorphic. These results provide evidence that the mutations that are detectable at the protein level by two-dimensional polyacrylamide gel electrophoresis do not occur at random and that their frequency is greater among polymorphic loci.

Synergism of mutant frequencies in the mouse lymphoma cell mutagenicity assay by binary mixtures of methyl methanesulfonate and ethyl methanesulfonate.

Abstract: The effect of mixed mutagen exposures on the rate and type of induced mutants was studied in the L5178Y/TK+/-----TK-/- mouse lymphoma cell mutagenicity assay. In this assay, exposure to ethyl methanesulfonate (EMS) results in more mutants that form large colonies than small colonies. Exposure to methyl methanesulfonate (MMS) results in more mutants that form small colonies than large colonies. Other reports in the literature suggest that large colony TK-/- mutants appear to result from small-scale, perhaps single-gene mutations, and that small-colony TK-/- mutants appear to be associated with chromosomal mutations. Treating cells for 4 h with simple, 2-component mixtures containing 6.45 micrograms/ml MMS and either 261, 392, 560 or 712 micrograms/ml EMS resulted in synergism of mutants at each mixture level. The frequencies of total mutants were synergized 12, 20, 35 and 72%, respectively, in mixed exposures with graded doses of EMS, above the sums of the mixture components. Small colony mutants were synergized to a greater extent than large colony mutants. The frequencies of small colony mutants in mixed exposures were increased 31, 54, 73 and 123%, respectively, while the frequencies of large colony mutants were increased -7, -6, 11 and 39%. Statistical analyses provide strong evidence of synergism (within the limits of the assay) for total and small-colony mutants at all doses of EMS tested, and for large-colony mutants above 400 micrograms/ml EMS. Similar magnitudes of synergism resulted when other constant levels of MMS (4.30 or 8.60 micrograms/ml) were mixed with the same graded doses of EMS. The degree of synergism was dependent on EMS concentration but not on MMS concentration.