Biomedical subjects

K L Lunetta

Publications and source records attributed to K L Lunetta.

23 records · Page 2Linked to original sources

PubMed1994

Multipoint radiation hybrid mapping: comparison of methods, sample size requirements, and optimal study characteristics.

There are several statistical methods available for analyzing radiation hybrid (RH) data, but little is known about the ordering accuracy we can expect under common study conditions. Using analytic methods and computer simulation, we compared the ordering accuracy of three multipoint statistical methods: minimum breaks (MB), maximum likelihood (ML), and maximum posterior probability (PP). For 8, 12, and 16 markers and all combinations of numbers of hybrids, retention patterns, and marker spacings considered, the probabilities that the true order is identified as the best order were considerably higher with the ML and PP methods than with the MB method. ML and PP performed similarly, but PP tended to give slightly greater support for the best order than did ML. Our results can be used as guidelines for determining sample size requirements and optimal marker spacing for future RH mapping experiments. For equally spaced markers, intermarker spacing of 30 to 50 cR gave the highest probability of correctly ordering all the markers. For randomly spaced markers, 10-20 cR average intermarker spacing resulted in the highest proportion of markers being placed in a 1000:1 framework map. Assuming equal retention in the analysis when a centromeric model would be more appropriate did not affect the ability of the ML method to accurately order the markers, but did influence the distance estimates obtained.

Animals↗

PubMed1991

Inheritance of human plasma dopamine-beta-hydroxylase thermal stability.

Although the structural gene for human dopamine-beta-hydroxylase (DBH) has been cloned, the mechanism by which DBH physical properties and activity are regulated is not well understood. Previous reports have suggested that three-allele or two-locus models may account for the genetic regulation of these traits in human blood. It is an interesting challenge to determine the extent to which quantitative analyses will complement or guide molecular genetic studies. In this study we analyzed data on the physical property of DBH thermal stability and DBH activity in 230 individuals in 53 families in an attempt to clarify genetic mechanisms for the inheritance of these traits. Commingling and segregation analyses of the thermal stability data provided the first clear evidence of a major gene polymorphism for DBH thermal stability analyzed as a quantitative trait. Major gene transmission was supported within a mixed model (chi 2[3] = 13.39, P less than .004). In keeping with earlier findings, similar analyses of DBH activity provided strong evidence of genetic transmission. However, in our data support for a major gene polymorphism was equivocal (chi 2(2) = 2.99, P = .22).

Adolescent↗

PubMedDate not supplied

An allelic variant at the ATM locus is implicated in breast cancer susceptibility.

We have tested a simple procedure, disease association by locus stratification, for identifying breast cancer patients with pathogenetic allelic variants at several candidate loci. The strategy was based on the assumption of epistatic interactions of the candidates. We analyzed 66 independent cases from sib pairs affected with breast cancer that had previously been collected during an investigation of pathogenetic-allele-sharing at the HRAS1 mini-satellite locus. An exon 24 polymorphism of ATM, substituting arginine for proline was associated with breast cancer in these cases with an overall odds ratio of 4.5 (95% confidence interval, 1.2-20.5, nominal p = 0.02, 2-tail Fisher exact test). In the presence of a rare HRAS1 allele, the odds ratio increased to 6.9 (95% CI, 1.2-38.3, p = 0.03). Thus, our procedure identified at least one allelic variant of ATM associated with breast cancer, and indicated that the ATM locus may interact with HRAS1.

Adult↗

PubMedDate not supplied

Refined genetic mapping of juvenile X-linked retinoschisis.

Juvenile X-linked retinoschisis (RS) is an eye disease that causes acuity reduction and peripheral visual field loss typically beginning early in life. In further work towards positional cloning of the RS gene, we restudied our previously reported seven large American families and one additional new family, with a total of 63 affected males. RS linkage analysis using microsatellite repeat markers gave the following results: DXS207 (Z = 24.89, theta = 0.01), DXS987 (Z = 24.04, theta 0.01) and DXS999 (Z = 14.70, theta = 0.00). Recombination events in four individuals were studied further with additional markers (AFM291wf5, DXS443, DXS1052, DXS274 and DXS1226), and a flanking interval was obtained (DXS43, DXS207, DXS987)-RS-(AFM291wf5, DXS443). This study moves the RS centromeric boundary to (AFM291wf5, DXS443), about 5.5 cM closer than the previously reported boundary at DXS274 and narrows the RS inclusion interval to about 3.7 cM (using distances from CEPH family data).

Chromosome Mapping↗

PubMedDate not supplied

Linkage study of Best's vitelliform macular dystrophy (VMD2) in a large North American family.

Best's vitelliform macular dystrophy (VMD2) is an autosomal dominant retinal dystrophy for which the underlying biochemical cause is unknown. We used 11 genetic markers in the vicinity of the VMD2 gene in our study of a large North American family in which macular dystrophy characteristics overlap the broad definition of Best's disease. Significant evidence for linkage was found for markers D11S956 (Z = 5.88, theta = 0.04) and FCER1B (Z = 4.31, theta = 0.00). Recombination events localized the disease gene to the 5-cM interval D11S956-UGB, a genetic inclusion interval that substantially overlaps the VMD2 inclusion interval defined by recombinants at FCER1B and UGB observed by other research groups. The resulting exclusion of ROM1 from the genetic inclusion interval eliminates ROM1 defects as a possible cause of the disease in this family. Linkage studies of many families, including those that share most but not all features with classical Best's disease, will be needed to properly evaluate genetic heterogeneity and the range of phenotypic variation that can result from VMD2 defects.

Adult↗