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Showing papers by "Michael Boehnke published in 1990"


Journal Article
TL;DR: Multipoint linkage analysis and consideration of recombination events within pedigrees suggest that DXS 41 and DXS43, and also DXS41 andDXS16, flank RS and thatDXS85 lies outside the intervalDXS41-DXS43.
Abstract: Linkage analysis was performed to evaluate the relationship between the locus for X-linked juvenile retinoschisis (RS) and five X-chromosomal markers-RC8 (DXS9), SE3.2L (DXS16), 99-6 (DXS41), D2 (DXS43), and 782 (DXS85)-all mapped to the interval Xp22.1-p22.3. Seven U.S. families with 56 affected males were studied. No recombinants were found between RS and DXS9 with a maximum lod score (Z) of 4.93 at a recombination fraction of zero. Obligate recombinants were found for RS with DXS16, DXS41, DXS43, and DXS85. Multipoint linkage analysis and consideration of recombination events within pedigrees suggest that DXS41 and DXS43, and also DXS41 and DXS16, flank RS and that DXS85 lies outside the interval DXS41-DXS43. Our pedigrees provide no evidence for genetic heterogeneity of RS, with five of our families individually showing evidence of linkage. (Z greater than 2.0) to the least one of these probes from Xp22.1-p22.3.

38 citations


Journal Article
TL;DR: A new method which maximizes thesum of adjacent two-point maximum lod scores divided by the equivalent number of informative meioses and the previously described method which minimizes the sum of adjacent recombination fraction estimates were found to be the best overall locus-ordering methods for the situations considered, although several other methods also performed well.
Abstract: We carried out a simulation study to compare the power of eight methods for preliminary ordering of multiple genetic loci. Using linkage groups of six loci and a simple pedigree structure, we considered the effects on method performance of locus informativity, interlocus spacing, total distance along the chromosome, and sample size. Method performance was assessed using the mean rank of the true order, the proportion of replicates in which the true order was the best order, and the number of orders that needed to be considered for subsequent multipoint linkage analysis in order to include the true order with high probability. A new method which maximizes the sum of adjacent two-point maximum lod scores divided by the equivalent number of informative meioses and the previously described method which minimizes the sum of adjacent recombination fraction estimates were found to be the best overall locus-ordering methods for the situations considered, although several other methods also performed well.

35 citations


Journal ArticleDOI
TL;DR: Applying both commingling and segregation analyses to samples of simulated pedigree data in which a major locus is segregating in the presence of polygenes and an individual‐specific environmental effect shows limited usefulness as a screening technique for the presence for a single locus.
Abstract: Commingling analysis is commonly used to provide preliminary evidence for a single genetic locus with a major effect on the quantitative trait of interest. In this paper, the effectiveness of commingling analysis as a screening technique to identify samples for segregation analysis is assessed by applying both commingling and segregation analyses to samples of simulated pedigree data in which a major locus is segregating in the presence of polygenes and an individual-specific environmental effect. Under the circumstances simulated here, there is evidence for a single locus from segregation analysis but not from commingling analysis in at least 20% of the samples. No more than 2% of the samples provided evidence for commingling but not for segregation of a single locus. Comparisons of the samples that give evidence for both commingling and segregation, evidence for one but not the other, and no evidence for either show that evidence for commingling depends on the distributional characteristics of the trait in the sample, while support for the single locus from segregation analysis depends on both the distributional characteristics as well as the transmission of the rarer allele from parents to offspring. Since lack of commingling does not rule out the existence of a single locus in the realistic situations considered here, commingling analysis has limited usefulness as a screening technique for the presence for a single locus. In contrast, evidence for commingling does suggest the possibility that a single locus has a major effect on the trait and commingling analysis can provide guidance in the choice of initial parameter estimates for segregation analysis.

21 citations


Journal Article
TL;DR: The results suggest that linkage studies of quantitative traits are practical, particularly if the investigator chooses an efficient sampling design and an efficient strategy to select pedigrees for linkage analysis.
Abstract: Sample-size guidelines for linkage studies of quantitative traits partially determined by a dominant major locus are needed to provide a rough estimate of the amount of pedigree material that should be sampled to map the loci that influence such traits. After pedigrees are sampled, a specific power calculation can be carried out to evaluate the linkage information provided by the sampled pedigrees. Using computer simulation, I provide sample-size guidelines for linkage studies by the method of lod scores of quantitative traits partially determined by a dominant major locus. I consider the effects of a trait model, marker characteristics, and sampling strategy, with particular attention to sampling strategy because it is the one factor which the investigator can fully control. My results suggest that linkage studies of quantitative traits are practical, particularly if the investigator chooses an efficient sampling design and an efficient strategy to select pedigrees for linkage analysis.

15 citations


Journal ArticleDOI
TL;DR: Comparison of clinical and neuropathological features in spinopontine atrophy and Machado-Joseph disease, both in Portuguese and non-Portuguese families, reveals clinical and pathological similarities and differences between the two.
Abstract: • A family of German extraction with progressive ataxia, eye movement abnormalities, peripheral sensory loss, and spinal muscular atrophy of adult onset is described. Three members came to autopsy, and neuropathologically, the major changes included varying degrees of atrophy of the basis pontis and degeneration of the spinocerebellar tracts, Clarke's columns, anterior horn neurons, and fasciculus gracilis. The dentate nucleus was spared, and there was slight neuron loss from the substantia nigra in one patient. Clinically and neuropathologically, our family resembles that reported by Boiler and Segarra as having spinopontine atrophy. However, several kindreds with similar findings have recently been described as having Azorean or Machado-Joseph disease in non-Portuguese families. Comparison of clinical and neuropathological features in spinopontine atrophy and Machado-Joseph disease, both in Portuguese and non-Portuguese families, reveals clinical and pathological similarities and differences between the two. The major differences in our patients include only minor extraocular movement abnormality and absence of protuberant eyes, and muscular rigidity clinically, and the sparing of the substantia nigra and the dentate nucleus neuropathologically. These differences suggest that spinopontine atrophy, as manifested in our family, is distinct from Machado-Joseph disease. Our family showed no linkage to the HLA locus on chromosome 6.

15 citations


Journal Article
TL;DR: This work describes a new strategy to select pedigrees for linkage analysis on the basis of the expected number of potentially informative meioses in each pedigree and demonstrates that this informative-meioses strategy provides an efficient and more general means to selectpedigree for a linkage study of a quantitative trait.
Abstract: With evidence of segregation at a major locus for a quantitative trait having been found, a logical next step is to select a subset of the pedigrees to include in a linkage study to map the major locus. Ideally this subset should include much of the linkage information in the sample but include only a fraction of the pedigrees. We previously described a strategy for selecting pedigrees for linkage analysis of a quantitative trait on the basis of a pedigree likelihood-ratio statistic. For quantitative traits controlled by a major locus with a rare dominant allele, the likelihood-ratio strategy extracted nearly all the information for linkage while typically requiring marker data on only about one-third of the pedigrees. Here, we describe a new strategy to select pedigrees for linkage analysis on the basis of the expected number of potentially informative meioses in each pedigree. We demonstrate that this informative-meioses strategy provides an efficient and more general means to select pedigrees for a linkage study of a quantitative trait.

11 citations


Journal Article
TL;DR: It is demonstrated that the molecular mechanism underlying tumor cell escape in this model is the spontaneous emergence of variants that have undergone kappa L chain gene "re-rearrangement" before positive selection by the anti-Id antibody.
Abstract: We have previously identified Id- tumor vaiants that emerge after anti-Id mAb therapy of the murine B cell lymphoma 38C13. This report characterizes the molecular basis for these variants. By using a modification of the polymerase chain reaction (PCR), mu and kappa Ig loci were sequenced from nine Id- variants derived directly by anti-Id immunoselection in vivo. Ig kappa loci sequence analysis was also performed from 10 additional variants amplified directly from tumor cells in vitro without immunoselection. We demonstrate that the molecular mechanism underlying tumor cell escape in this model is the spontaneous emergence of variants that have undergone kappa L chain gene "re-rearrangement" before positive selection by the anti-Id antibody. A second round of re-rearrangement was also demonstrated to occur within primary tumor variants. Re-rearrangement of the 38C13 tumor cell Ig kappa locus is strongly biased toward use of variable kappa genes within the conserved V kappa-Ox1 gene family, although their use is not exclusive. With the use of RNA PCR re-rearrangement was documented to occur in vitro at a frequency of approximately 1.0 x 10(-5)/cell. These findings may have important implications for the application of anti-Id antibodies as a therapeutic approach for human lymphomas and for understanding of the Ig gene rearrangement process.

11 citations