摘要:

A maximum-likelihood method is developed to estimate the frequency distribution of undetected mutations (presumably point mutations, small deletions, insertions) along a gene, where the gene extends over a long stretch of DNA. In each family, the point of the mutation is potentially at a different location within the gene. In this sense, there is genetic heterogeneity among families and the method estimates the proportion of families whose mutation is at (or in the vicinity of) a given point inside the gene. Our method is applied to a sample of 75 families with Duchenne muscular dystrophy in which the disease mutation remained undetected. We find two preferential regions for these undetected mutations, with an estimated 85% of families having their mutation in one region and the remaining 15% of families in the other. The new method is expected to be useful in finding small mutations in any of the currently known large genes.

ISSN:0001-5652    

DOI:10.1159/000154393

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Thousands of polymorphic microsatellite loci are now mapped in the human genome, most of which exhibit a large number of segregating alleles. For forensic, evolutionary and gene mapping applications, it is important to establish intralocus allelic independence at these loci. We develop a test for intralocus allelic independence based on repeat size differences between alleles within genotypes of individuals, and show its relationship with the intraclass correlation of allele sizes within loci. Applications of this test to 13 short tandem repeat loci in 4 subpopulations indicate that the distribution of size differences of alleles has adequate power to detect intralocus dependence of alleles caused by population substructure. In addition, size differences between randomly chosen alleles provide information regarding heterozygosity and contiguity of allele sizes at the locus, which by themselves do not necessarily indicate the presence of population substructure.

ISSN:0001-5652    

DOI:10.1159/000154394

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Current clinical diagnostic techniques for the detection of small duplications and deletions include microscopic cytogenetics with Giemsa banding and FISH. An alternative approach is to use genetic markers, to detect duplications and deletions. The application of this technique to the entire genome as a test for segmental aneusomy requires a method for selecting a panel of markers that could be used and an estimate of the statistical power. We have developed a computer program, DECIDE, that performs these tasks. Given an input map of markers, DECIDE generates a near optimal list of markers and estimates the probability of detecting monosomy or trisomy of varying physical size. We demonstrate the program on a large map of markers obtained from the Southampton and CEPH databases. We conclude that this approach to screening for duplications and deletions is theoretically possible and would have a power comparable to routine Giemsa-banded chromosome analysis.

ISSN:0001-5652    

DOI:10.1159/000154395

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Analysis of linkage data has typically been carried out assuming genotyping errors are absent. Recent studies have shown, however, that the impact of ignoring genotyping errors can be great, especially in dense marker maps [Buetow, Am J Hum Genet 1991;49:985–994; Lincoln and Lander, Genomics 1992;14:604-610]. Because most organisms exhibit positive chiasma interference, we use the χ2model [Foss et al., Genetics 1993;144:681–691] to examine the role interference plays in the estimation of genetic distance in the presence of genotyping errors. For simplicity, we confine our analyses to samples of 1,000 fully informative gametes. Our results support previous findings that ignoring errors inflates distance estimates. The larger the error rate, the greater the inflation. For a given error rate, the relative error in estimated genetic distance is greatest when interference is known to be weak or absent. An approximation to relative error which quantifies the relation to distance, error rate, and interference is provided. Robustness of estimation to error misspecification is also investigated. When the assumed error rate is too low, distance is overestimated while interference is underestimated. The situation is reversed when too large an error rate is assumed (interference is overestimated, and distance underestimated). Unfortunately, the joint estimation of distance and interference is not very robust to error misspecifica

ISSN:0001-5652    

DOI:10.1159/000154396

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Nonsyndromic cleft lip with or without cleft palate is a common birth defect, affecting approximately 1 in 1,000 Caucasian newborns. Thirty-five multiplex families from the mid-Atlantic region of the United States and 22 families from central Mexico with a nonsyndromic form of cleft lip with or without cleft palate were selected for a linkage analysis. A tetranucleotide repeat marker (D2S443) located on the same yeast artificial chromosome as the transforming growth factor alpha locus was tested for linkage to a putative susceptibility Mendelian locus under varying levels of pentrance. No evidence for linkage between D2S443 and a susceptibility locus for cleft lip with or without cleft palate was found. Insight is given to explain this outcome in spite of the statistically significant associations found by other investigators.

ISSN:0001-5652    

DOI:10.1159/000154397

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Risch [Am J Hum Genet 1990;46:229-253] recently developed a likelihood method for testing genetic linkage using affected sib pairs. This paper proposes a reparameterization of the Risch likelihood in terms of genetic variance components divided by the affected-sib-pair ascertainment probability. The new parameters allow for ease of interpretation, particularly for multilocus models. A single-degree-of-freedom test of the total disease genetic effect at a marker locus can be constructed that has power comparable to the likelihood ratio ‘triangle’ test. Extension of the models to other types of relative pairs is also discussed. The models may be used in genome scanning and in studying single or multilocus models of inherita

ISSN:0001-5652    

DOI:10.1159/000154398

出版商:S. Karger AG    

年代:1997

数据来源: Karger