Limits on fine mapping of complex traits.
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Chromosome Mapping↗
Biomedical subjects
L Kruglyak
Publications and source records attributed to L Kruglyak.
Parametric and nonparametric linkage analysis: a unified multipoint approach.
In complex disease studies, it is crucial to perform multipoint linkage analysis with many markers and to use robust nonparametric methods that take account of all pedigree information. Currently available methods fall short in both regards. In this paper, we describe how to extract complete multipoint inheritance information from general pedigrees of moderate size. This information is captured in the multipoint inheritance distribution, which provides a framework for a unified approach to both parametric and nonparametric methods of linkage analysis. Specifically, the approach includes the following: (1) Rapid exact computation of multipoint LOD scores involving dozens of highly polymorphic markers, even in the presence of loops and missing data. (2) Non-parametric linkage (NPL) analysis, a powerful new approach to pedigree analysis. We show that NPL is robust to uncertainty about mode of inheritance, is much more powerful than commonly used nonparametric methods, and loses little power relative to parametric linkage analysis. NPL thus appears to be the method of choice for pedigree studies of complex traits. (3) Information-content mapping, which measures the fraction of the total inheritance information extracted by the available marker data and points out the regions in which typing additional markers is most useful. (4) Maximum-likelihood reconstruction of many-marker haplotypes, even in pedigrees with missing data. We have implemented NPL analysis, LOD-score computation, information-content mapping, and haplotype reconstruction in a new computer package, GENEHUNTER. The package allows efficient multipoint analysis of pedigree data to be performed rapidly in a single user-friendly environment.
Algorithms↗
A locus for Fanconi anemia on 16q determined by homozygosity mapping.
We report the results of a genomewide scan using homozygosity mapping to identify genes causing Fanconi anemia, a genetically heterogeneous recessive disorder. By studying 23 inbred families, we detected linkage to a locus causing Fanconi anemia near marker D16S520 (16q24.3). Although -65% of our families displayed clear linkage to D16S520, we found strong evidence (P = .0013) of genetic heterogeneity. This result independently confirms the recent mapping of the FAA gene to chromosome 16 by Pronk et al. Family ascertainment was biased against a previously identified FAC gene on chromosome 9, and no linkage was observed to this locus. Simultaneous search analysis suggested several additional chromosomal regions that could account for a small fraction of Fanconi anemia in our families, but the sample size is insufficient to provide statistical significance. We also demonstrate the strong effect of marker allele frequencies on LOD scores obtained in homozygosity mapping and discuss ways to avoid false positives arising from this effect.
Chromosome Mapping↗
An STS-based map of the human genome.
A physical map has been constructed of the human genome containing 15,086 sequence-tagged sites (STSs), with an average spacing of 199 kilobases. The project involved assembly of a radiation hybrid map of the human genome containing 6193 loci and incorporated a genetic linkage map of the human genome containing 5264 loci. This information was combined with the results of STS-content screening of 10,850 loci against a yeast artificial chromosome library to produce an integrated map, anchored by the radiation hybrid and genetic maps. The map provides radiation hybrid coverage of 99 percent and physical coverage of 94 percent of the human genome. The map also represents an early step in an international project to generate a transcript map of the human genome, with more than 3235 expressed sequences localized. The STSs in the map provide a scaffold for initiating large-scale sequencing of the human genome.
Animals↗
Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results.
Genetic studies are under way for many complex traits, spurred by the recent feasibility of whole genome scans. Clear guidelines for the interpretation of linkage results are needed to avoid a flood of false positive claims. At the same time, an overly cautious approach runs the risk of causing true hints of linkage to be missed. We address this problem by proposing specific standards designed to maintain rigor while also promoting communication.
Genetic Linkage↗
Linkage between sexual orientation and chromosome Xq28 in males but not in females.
We have extended our analysis of the role of the long arm of the X chromosome (Xq28) in sexual orientation by DNA linkage analyses of two newly ascertained series of families that contained either two gay brothers or two lesbian sisters as well as heterosexual siblings. Linkage between the Xq28 markers and sexual orientation was detected for the gay male families but not for the lesbian families or for families that failed to meet defined inclusion criteria for the study of sex-linked sexual orientation. Our results corroborate the previously reported linkage between Xq28 and male homosexuality in selected kinships and suggest that this region contains a locus that influences individual variations in sexual orientation in men but not in women.
Base Sequence↗
A nonparametric approach for mapping quantitative trait loci.
Genetic mapping of quantitative trait loci (QTLs) is performed typically by using a parametric approach, based on the assumption that the phenotype follows a normal distribution. Many traits of interest, however, are not normally distributed. In this paper, we present a nonparametric approach to QTL mapping applicable to any phenotypic distribution. The method is based on a statistic ZW, which generalizes the nonparametric Wilcoxon rank-sum test to the situation of whole-genome search by interval mapping. We determine the appropriate significance level for the statistic ZW, by showing that its asymptotic null distribution follows an Ornstein-Uhlenbeck process. These results provide a robust, distribution-free method for mapping QTLs.
Animals↗
Complete multipoint sib-pair analysis of qualitative and quantitative traits.
Sib-pair analysis is an increasingly important tool for genetic dissection of complex traits. Current methods for sib-pair analysis are primarily based on studying individual genetic markers one at a time and thus fail to use the full inheritance information provided by multipoint linkage analysis. In this paper, we describe how to extract the complete multipoint inheritance information for each sib pair. We then describe methods that use this information to map loci affecting traits, thereby providing a unified approach to both qualitative and quantitative traits. Specifically, complete multipoint approaches are presented for (1) exclusion mapping of qualitative traits; (2) maximum-likelihood mapping of qualitative traits; (3) information-content mapping, showing the extent to which all inheritance information has been extracted at each location in the genome; and (4) quantitative-trait mapping, by two parametric methods and one nonparametric method. In addition, we explore the effects of marker density, marker polymorphism, and availability of parents on the information content of a study. We have implemented the analysis methods in a new computer package, MAPMAKER/SIBS. With this computer package, complete multipoint analysis with dozens of markers in hundreds of sib pairs can be carried out in minutes.
Chromosome Mapping↗
High-resolution genetic mapping of complex traits.
Positional cloning requires high-resolution genetic mapping. To plan a positional cloning project, one needs to know how many informative meioses will be required to narrow the search for a disease gene to an acceptably small region. For a simple Mendelian trait studied with linkage analysis, the answer is straightforward. In this paper, we address the situation of a complex trait studied with affected-relative-pair methods. We derive mathematical formulas for the size of an appropriate confidence region, as a function of the relative risk attributable to the gene. Using these results, we provide graphs showing the number of relative pairs required to narrow the gene hunt to an interval of a given size. For example, we show that localizing a gene to 1 cM requires a median of 200 sib pairs for a locus causing a fivefold increased risk to an offspring and 700 sib pairs for a locus causing a twofold increased risk. We discuss the implications of these results for the positional cloning of genes underlying complex traits.
Alleles↗
Rapid multipoint linkage analysis of recessive traits in nuclear families, including homozygosity mapping.
Homozygosity mapping is a powerful strategy for mapping rare recessive traits in children of consanguineous marriages. Practical applications of this strategy are currently limited by the inability of conventional linkage analysis software to compute, in reasonable time, multipoint LOD scores for pedigrees with inbreeding loops. We have developed a new algorithm for rapid multipoint likelihood calculations in small pedigrees, including those with inbreeding loops. The running time of the algorithm grows, at most, linearly with the number of loci considered simultaneously. The running time is not sensitive to the presence of inbreeding loops, missing genotype information, and highly polymorphic loci. We have incorporated this algorithm into a software package, MAPMAKER/HOMOZ, that allows very rapid multipoint mapping of disease genes in nuclear families, including homozygosity mapping. Multipoint analysis with dozens of markers can be carried out in minutes on a personal workstation.
Algorithms↗
Photon splitting in a plane-wave field.
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Journal Article↗