A human model for multigenic inheritance: Phenotypic expression in Hirschsprung disease requires both the RET gene and a new 9q31 locus

Reduced penetrance in genetic disorders may be either dependent or independent of the genetic background of gene carriers. Hirschsprung disease (HSCR) demonstrates a complex pattern of inheritance with ≈50% of familial cases being heterozygous for mutations in the receptor tyrosine kinase RET. Even when identified, the penetrance of RET mutations is only 50–70%, gender-dependent, and varies with the extent of aganglionosis. We searched for additional susceptibility genes which, in conjunction with RET, lead to phenotypic expression by studying 12 multiplex HSCR families. Haplotype analysis and extensive mutation screening demonstrated three types of families: six families harboring severe RET mutations (group I); and the six remaining families, five of which are RET-linked families with no sequence alterations and one RET-unlinked family (group II). Although the presence of RET mutations in group I families is sufficient to explain HSCR inheritance, a genome scan reveals a new susceptibility locus on 9q31 exclusively in group II families. As such, the gene at 9q31 is a modifier of HSCR penetrance. These observations imply that identification of new susceptibility factors in a complex disease may depend on classification of families by mutational type at known susceptibility genes.

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Inclui notas explicativas e bibliográficas

A first trial of retrospective collaboration for positional cloning in complex inheritance: Assay of the cytokine region on chromosome 5 by the Consortium on Asthma Genetics (COAG)

The central problem of complex inheritance is to map oligogenes for disease susceptibility, integrating linkage and association over samples that differ in several ways. Combination of evidence over multiple samples with 1,037 families supports loci contributing to asthma susceptibility in the cytokine region on 5q [maximum logarithm of odds (lod) = 2.61 near IL-4], but no evidence for atopy. The principal problems with retrospective collaboration on linkage appear to have been solved, providing far more information than a single study. A multipoint lod table evaluated at commonly agreed reference loci is required for both collaboration and metaanalysis, but variations in ascertainment, pedigree structure, phenotype definition, and marker selection are tolerated. These methods are invariant with statistical methods that increase the power of lods and are applicable to all diseases, motivating collaboration rather than competition. In contrast to linkage, positional cloning by allelic association has yet to be extended to multiple samples, a prerequisite for efficient combination with linkage and the greatest current challenge to genetic epidemiology.

Seeing properties of an invisible object: Feature inheritance and shine-through

We characterize a class of spatio-temporal illusions with two complementary properties. Firstly, if a vernier stimulus is flashed for a short time on a monitor and is followed immediately by a grating, the latter can express features of the vernier, such as its offset, its orientation, or its motion (feature inheritance). Yet the vernier stimulus itself remains perceptually invisible. Secondly, the vernier can be rendered visible by presenting gratings with a larger number of elements (shine-through). Under these conditions, subjects perceive two independent “objects” each carrying their own features. Transition between these two domains can be effected by subtle changes in the spatio-temporal layout of the grating. This should allow psychophysicists and electrophysiologists to investigate feature binding in a precise and quantitative manner.

Trials of the beta model for complex inheritance.

Theoretical advantages of nonparametric logarithm of odds to map polygenic diseases are supported by tests of the beta model that depends on a single logistic parameter and is the only model under which paternal and maternal transmissions to sibs of specified phenotypes are independent. Although it does not precisely describe recurrence risks in monozygous twins, the beta model has greater power to detect family resemblance or linkage than the more general delta model which describes the probability of 0, 1, or 2 alleles identical by descent (ibd) with two parameters. Available data on ibd in sibs are consistent with the beta model, but not with the equally parsimonious but less powerful gamma model that assumes a fixed probability of 1/2 for 1 allele ibd. Additivity of loci on the liability scale is not disproven. A simple equivalence extends the beta model to multipoint analysis.

Logarithm of odds (lods) for linkage in complex inheritance.

Lod scores provide a method to unify linkage tests based on identity by descent and identity in marker state while permitting selection of the most informative individuals through their disease-related phenotypes and markers in relatives. After parametric lods are reviewed, a nonparametric approach that depends on a single logistic parameter beta is introduced. Lods for parents tested or unknown are derived, multiple pairwise mapping is presented, and power is shown to be good even for moderately small values of beta. Comparison of parametric and nonparametric approaches (yet to be made) will provide for polygenes the efficiency and reliability that lod scores gave to mapping of major loci 40 years ago.

Uniparental inheritance of mitochondrial and chloroplast genes: mechanisms and evolution.

In nearly all eukaryotes, at least some individuals inherit mitochondrial and chloroplast genes from only one parent. There is no single mechanism of uniparental inheritance: organelle gene inheritance is blocked by a variety of mechanisms and at different stages of reproduction in different species. Frequent changes in the pattern of organelle gene inheritance during evolution suggest that it is subject to varying selective pressures. Organelle genes often fail to recombine even when inherited biparentally; consequently, their inheritance is asexual. Sexual reproduction is apparently less important for genes in organelles than for nuclear genes, probably because there are fewer of them. As a result organelle sex can be lost because of selection for special reproductive features such as oogamy or because uniparental inheritance reduces the spread of cytoplasmic parasites and selfish organelle DNA.