Bioinformatics Advance Access originally published online on September 17, 2004
Bioinformatics 2005 21(8):1730-1732; doi:10.1093/bioinformatics/bth488
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HaploPainter: a tool for drawing pedigrees with complex haplotypes
1Gene Mapping Center, Max Delbrueck Center (MDC) for Molecular Medicine Berlin-Buch, Germany
2Institute of Medical Genetics, Charité—University Medicine of Berlin Berlin, Germany
3Cologne Center for Genomics (CCG), University of Cologne Germany
*To whom correspondence should be addressed.
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Abstract |
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Summary: HaploPainter is a user-friendly pedigree-drawing application with special features for easy visualization of complex haplotype information. It has been developed to facilitate gene mapping in Mendelian diseases in terms of fast and reliable definition of the smallest critical interval harbouring the underlying gene defect. HaploPainter is written in Perl and may be used for visualization of haplotypes calculated by any of the common linkage programs. With special features like haplotype compression or the ability of marker section cut-out it particularly addresses the requirements for viewing large haplotypes as obtained by using for genome scans high-density marker panels of many thousands of single nucleotide polymorphisms (SNPs).
Availability: http://haplopainter.sourceforge.net/
Contact: holger.thiele{at}uni-koeln.de
Construction and visualization of haplotypes is an essential step in gene mapping projects. It is often instrumental in choosing the right region for further follow-up. Moreover, it defines precisely the size of the critical interval by pinpointing the location of the recombination breakpoints in the families under investigation. While a graphical presentation of haplotypes is very useful for interpretation and publication of genotyping data, there is only inadequate software support available. Existing solutions as implemented in Cyrillic (Chapman, 1990), Pedigree/Draw (Mamelka et al., 1990), CoPE (Brun-Samarcq et al., 1999) or Pelican (Dudbridge et al., 2004) either suffer from lack of user-friendliness, limited data compatibility, or insufficient drawing alternatives for haplotypes.
Recently, we performed several genome scans with the Affymetrix GeneChip® Human Mapping 10K SNP (single nucleotide polymorphism) array (Janecke et al., 2004; Kaindl et al., 2004; Uhlenberg et al., 2004). The new approach, using >10 000 SNPs instead of about 400 microsatellites as DNA markers in genome-wide linkage studies, clearly revealed the shortcomings of the existing solutions for haplotyping. Dealing with very long haplotypes composed of hundreds of SNPs was impossible with any existing software and turned out to be a time consuming bottleneck in our data analysis. This prompted us to develop HaploPainter as a user-friendly tool for the handling of haplotype information in extended pedigrees. In particular, we aimed at a clearly arranged presentation of large marker blocks and have therefore implemented features like selective definition and narrowing of marker regions or haplotype compression at a chosen length.
The program is written in Perl/Tk, running under Windows and Linux. The algorithms are all oriented at practical considerations. The majority of families should be drawable without extensive computational time. Every family is represented in a single multidimensional array data structure which is built up following a top-to-bottom strategy. In case of loops the order of sibs is randomly chosen, keeping loop-starting and connecting family members close to each other. Further optimization is performed by minimization of line crossings. From this point different pedigree drawing solutions may be found. Although the majority of simple and moderately complex pedigrees were drawn correctly, there are limitations, for example, when a person occurs in different generations, that is, in the typical ‘backcross’ situation of animal breeds. This can be avoided by allowing for person duplications. We will implement this feature into future versions of HaploPainter.
HaploPainter accepts haplotype outputs from Simwalk (Weeks et al., 1995), Allegro (Gudbjartsson et al., 2000), Genehunter (Kruglyak et al., 1996) and Merlin (Abecasis et al., 2002). Any supplementary information provided by programs like Simwalk is discarded at this stage. Points of recombination are recognized using HaploPainter's own algorithm. Starting at the p-telomer, the program identifies the first informative marker revealing that linkage phase has changed. Pedigree data are imported either in a pre- or post-makeped format as provided by standard linkage files. Map information can be easily added in a file format used by Mega2 [Mukhopadhyay et al. (2001) in http://www.rfcgr.mrc.ac.uk/Menu/Help/mega2/]. Up to three lines of case information may be attached to each person using an excel sheet-like table format. After drawing of the pedigree, the following modifications are possible. Symbols can be moved per drag-and-drop and haplotype phases can be switched by double clicking on uninformative marker alleles. Many different drawing styles are selectable from the configuration menu. The output from HaploPainter can be similar to what is shown in Figure 1. The graphic is directly printable or can be exported as a postscript file.
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In conclusion, there is a growing need for the support of haplotype drawing in pedigrees. Many programs suitable for haplotype calculation like Genehunter, Merlin, Simwalk or Allegro are insufficient in proper visual presentation. We offer a platform-independent, Perl-based solution, HaploPainter, as an open source software for the scientific community to fill this gap. Features like haplotype compression and the ability of marker section cut-out are particularly helpful for viewing large SNP-derived haplotypes. The software is equipped with an intuitive graphical interface and is powerful enough to draw even complex consanguineous pedigrees. It is addressed to geneticists and physicians handling human pedigrees with the necessity of graphical haplotype representation.
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Acknowledgments |
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We would like to thank our colleagues and guests of the Gene Mapping Center at the MDC for advice and software testing. This work was funded by the Federal Ministry of Science and Education of Germany through the National Genome Research Network.
Received on July 6, 2004; revised on August 16, 2004; accepted on August 16, 2004
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