Linkage disequilibrium mapping via cladistic analysis of single-nucleotide polymorphism haplotypes

We present a novel approach to disease-gene mapping via cladistic analysis of single-nucleotide polymorphism (SNP) haplotypes obtained from large-scale, population-based association studies, applicable to whole-genome screens, candidate-gene studies, or fine-scale mapping. Clades of haplotypes are tested for association with disease, exploiting the expected similarity of chromosomes with recent shared ancestry in the region flanking the disease gene. The method is developed in a logistic-regression framework and can easily incorporate covariates such as environmental risk factors or additional unlinked loci to allow for population structure. To evaluate the power of this approach to detect disease-marker association, we have developed a simulation algorithm to generate high-density SNP data with short-range linkage disequilibrium based on empirical patterns of haplotype diversity. The results of the simulation study highlight substantial gains in power over single-locus tests for a wide range of disease models, despite overcorrection for multiple testing.     

Association mapping via regularized regression analysis of single-nucleotide-polymorphism haplotypes in variable-sized sliding windows

Large-scale haplotype association analysis, especially at the whole-genome level, is still a very challenging task without an optimal solution. In this study, we propose a new approach for haplotype association analysis that is based on a variable-sized sliding-window framework and employs regularized regression analysis to tackle the problem of multiple degrees of freedom in the haplotype test. Our method can handle a large number of haplotypes in association analyses more efficiently and effectively than do currently available approaches. We implement a procedure in which the maximum size of a sliding window is determined by local haplotype diversity and sample size, an attractive feature for large-scale haplotype analyses, such as a whole-genome scan, in which linkage disequilibrium patterns are expected to vary widely. We compare the performance of our method with that of three other methods--a test based on a single-nucleotide polymorphism, a cladistic analysis of haplotypes, and variable-length Markov chains--with use of both simulated and experimental data. By analyzing data sets simulated under different disease models, we demonstrate that our method consistently outperforms the other three methods, especially when the region under study has high haplotype diversity. Built on the regression analysis framework, our method can incorporate other risk-factor information into haplotype-based association analysis, which is becoming an increasingly necessary step for studying common disorders to which both genetic and environmental risk factors contribute.     

Linkage mapping of sex-specific differences

Most current linkage analyses assume identical fractions of meiotic recombination between homologous marker loci of the two sexes. This assumption is not realistic, because considerable sex-related differences have been observed in recombination fraction. In this paper, a general EM-based algorithm is presented to estimate sex-specific recombination fractions for a mixed set of molecular markers segregating differently in a full-sib family derived from two heterozygous parents. The asymptotic variances of the estimates of linkage specifically for each of the parents are evaluated using a numerical analysis based on information functions. This approach will have important implications for precise gene mapping based on sex-specific linkage maps.     

Linkage mapping reveals sex-dimorphic map distances in a passerine bird

Linkage maps are lacking for many highly influential model organisms in evolutionary research, including all passerine birds. Consequently, their full potential as research models is severely hampered. Here, we provide a partial linkage map and give novel estimates of sex-specific recombination rates in a passerine bird, the great reed warbler (Acrocephalus arundinaceus). Linkage analysis of genotypic data at 51 autosomal microsatellites and seven markers on the Z-chromosome (one of the sex chromosomes) from an extended pedigree resulted in 12 linkage groups with 2-8 loci. A striking feature of the map was the pronounced sex-dimorphism: males had a substantially lower recombination rate than females, which resulted in a suppressed autosomal map in males (sum of linkage groups: 110.2 cM) compared to females (237.2 cM; female/male map ratio: 2.15). The sex-specific recombination rates will facilitate the building of a denser linkage map and cast light on hypotheses about sex-specific recombination rates.     

Linkage mapping in populations with karyotypic rearrangements

A simulation study was used to examine the consequences of karyotypic rearrangements on molecular genetic map construction. Two groups of 50 datasets were created for F2 populations segregating for a reciprocal translocation of chromosomal segments or a reciprocal translocation and inversion. Multiple attempts were made to construct maps for each dataset using MapMaker/EXP. As expected, the markers from segments involved in the translocation formed one linkage group. Maps that corresponded to the known marker order within a segment could be constructed by the following method. The separation of markers distal to the translocation breakpoints into their respective segments could be made by constructing multiple maps, using distinct orders of marker entry, and observing the variances in intermarker distances: variances between pairs of markers from the same segment were an order of magnitude less compared to pairs where markers were from different segments. The order of markers within a segment could be determined from combining the pairwise linkage results from multiple maps, or from maps including all markers from a segment. No bias in map distances was observed. These results indicate that, under conditions similar to those tested, genetic maps corresponding to the segments conserved in translocations can be constructed.     

Linkage mapping of a severe X-linked mental retardation syndrome.

A four-generation Swedish family with a new type of X-linked mental retardation syndrome was recently reported by Gustavson et al. The complex syndrome includes microcephaly, severe mental retardation, optical atrophy with decreased vision or blindness, severe hearing defect, characteristic facial features, spasticity, seizures, and restricted joint motility. The patients die during infancy or early in childhood. Twenty-one family members, including two affected males, were available for study. Linkage analysis was conducted in the family by using 11 RFLP markers and 10 VNTR markers spread along the X chromosome. A hypervariable short tandem repeat of DXS294 at Xq26 showed a peak two-point lod score of 3.35 at zero recombination fraction. Calculations using the same markers revealed a multipoint peak lod score of 3.65 at DXS294. Crossover events with the centromeric marker DXS424 and the telomeric marker DXS297 delimit a probable region for the gene localization. It is noteworthy that hte disease loci of two other syndromes with overlapping clinical manifestations recently were shown by Turner et al. and Pettigrew et al. to be linked to markers at Xq26.     

Linkage mapping of domestication loci in a large maize teosinte backcross resource

An ultimate objective of QTL mapping is cloning genes responsible for quantitative traits. However, projects seldom go beyond segments <5 cM without subsequent breeding and genotyping lines to identify additional crossovers in a genomic region of interest. We report on a QTL analysis performed as a preliminary step in the development of a resource for map-based cloning of domestication and improvement genes in corn. A large backcross (BC)1 population derived from a cross between maize (Zea mays ssp. mays) and teosinte (ssp. parviglumis) was grown for the analysis. A total of 1749 progenies were genotyped for 304 markers and measured for 22 morphological traits. The results are in agreement with earlier studies showing a small number of genomic regions having greater impact on the morphological traits distinguishing maize and teosinte. Despite considerable power to detect epistasis, few QTL interactions were identified. To create a permanent resource, seed of BC1 plants was archived and 1000 BC2S6 BC1-derived lines are in development for fine mapping and cloning. The identification of four BC1 progeny with crossovers in a single gene, tb1, indicated that enough derived lines already exist to clone many QTL without the need to generate and identify additional crossovers.