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r-other-mott-happy Documentation

2.1-5

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.
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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.
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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.
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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.
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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.
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