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Pakiet: r-other-mott-happy (2.1-4) [universe]

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GNU R package for fine-mapping complex diseases

Most phenotypes of medical importance can be measured quantitatively, and in many cases the genetic contribution is substantial, accounting for 40% or more of the phenotypic variance. Considerable efforts have been made to isolate the genes responsible for quantitative genetic variation in human populations, but with little success, mostly because genetic loci contributing to quantitative traits (quantitative trait loci, QTL) have only a small effect on the phenotype. Association studies have been proposed as the most appropriate method for finding the genes that influence complex traits. However, family-based studies may not provide the resolution needed for positional cloning, unless they are very large, while environmental or genetic differences between cases and controls may confound population-based association studies.

These difficulties have led to the study of animal models of human traits. Studies using experimental crosses between inbred animal strains have been successful in mapping QTLs with effects on a number of different phenotypes, including behaviour, but attempts to fine-map QTLs in animals have often foundered on the discovery that a single QTL of large effect was in fact due to multiple loci of small effect positioned within the same chromosomal region. A further potential difficulty with detecting QTLs between inbred crosses is the significant reduction in genetic heterogeneity compared to the total genetic variation present in animal populations: a QTL segregating in the wild need not be present in the experimental cross.

The idea behind this package is that when multiple strains of animals that differ in their susceptibility to multiple diseases are bread over multiple generations, then one can analyse the contribution that a particular genetic locus has to each of those diseases. While in the past this approach has been performed for one disease at a time, this tool extends the statistics for allowing multiple crosses and thus save animal lifes. A larger stock of animals with more generations to keep them will further help producing larger numbers of observable cross-over events and thus help increasing the resolution of the mapping.

happy is an R interface into the HAPPY C package for fine-mapping Quantitative Trait Loci (QTL) in Heterogenous Stocks (HS). An HS is an advanced intercross between (usually eight) founder inbred strains of mice. HS are suitable for fine-mapping QTL. It uses a multipoint analysis which offers significant improvements in statistical power to detect QTLs over that achieved by single-marker association.

The happy package is an extension of the original C program happy; it uses the C code to compute the probability of descent from each of the founders, at each locus position, but the happy packager allows a much richer range of models to be fit to the data.

Further details can be found in

 Proc. Natl. Acad. Sci. USA, 10.1073/pnas.230304397.

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