HomozygosityMapper--an interactive approach to homozygosity mapping

Abstract

Homozygosity mapping is a common method for mapping recessive traits in consanguineous families. In most studies, applications for multipoint linkage analyses are applied to determine the genomic region linked to the disease. Unfortunately, these are neither suited for very large families nor for the inclusion of tens of thousands of SNPs. Even if less than 10,000 markers are employed, such an analysis may easily last hours if not days. Here we present a web-based approach to homozygosity mapping. Our application stores marker data in a database into which users can directly upload their own SNP genotype files. Within a few minutes, the database analyses the data, detects homozygous stretches and provides an intuitive graphical interface to the results. The homozygosity in affected individuals is visualized genome-wide with the ability to zoom into single chromosomes and user-defined chromosomal regions. The software also displays the underlying genotypes in all samples. It is integrated with our candidate gene search engine, GeneDistiller, so that users can interactively determine the most promising gene. They can at any point restrict access to their data or make it public, allowing HomozygosityMapper to be used as a data repository for homozygosity-mapping studies. HomozygosityMapper is available at http://www.homozygositymapper.org/.

Figure 1.

Genome-wide homozygosity. This screen shots show the genome-wide homozygosity scores produced by HomozygosityMapper. These are plotted as a bar chart with red bars indicating the most promising genomic regions. Clicking on a bar will zoom into the chromosome harbouring the score. Above the bar chart, the excess or shortage of homozygous genotypes in cases versus controls is depicted. Below the figure, direct links to the most interesting regions are given. All figures depict the Carpenter syndrome study (31).

Figure 2.

Homozygosity in genomic regions. Here the homozygosity within a selected genomic region is shown. The small red bars above the homozygosity bar chart indicate that there is a visible excess of homozygosity in the cases compared to the controls.

Figure 3.

Genotypes view. HomozygosityMapper also displays the single genotypes of all samples. Here, the markers are placed on the x-axis while the samples are on the y-axis, with the patients on top and with red IDs. Genotypes are colour-coded: grey, unknown, blue, heterozygous, red, homozygous stretches (colour saturation reflects the length). This figure also reveals the presence of a single heterozygous marker within the homozygous region (possibly a genotyping error and ignored by HomozygosityMapper). The patient on the bottom is from another family than the first two and does not share the same haplotype over the whole homozygous stretch. This can be seen from the genotypes with the diagonal bar indicating the less abundant of the homozygous genotypes. Users are free to change the limits of the region and can subsequently submit this region to GeneDistiller.