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Potential large animal models for gene therapy of human genetic diseases of immune and blood cell systems.

ABSTRACT: Genetic mutations involving the cellular components of the hematopoietic system--red blood cells, white blood cells, and platelets--manifest clinically as anemia, infection, and bleeding. Although gene targeting has recapitulated many of these diseases in mice, these murine homologues are limited as translational models by their small size and brief life span as well as the fact that mutations induced by gene targeting do not always faithfully reflect the clinical manifestations of such mutations in humans. Many of these limitations can be overcome by identifying large animals with genetic diseases of the hematopoietic system corresponding to their human disease counterparts. In this article, we describe human diseases of the cellular components of the hematopoietic system that have counterparts in large animal species, in most cases carrying mutations in the same gene (CD18 in leukocyte adhesion deficiency) or genes in interacting proteins (DNA cross-link repair 1C protein and protein kinase, DNA-activated catalytic polypeptide in radiation-sensitive severe combined immunodeficiency). Furthermore, we describe the potential of these animal models to serve as disease-specific preclinical models for testing the efficacy and safety of clinical interventions such as hematopoietic stem cell transplantation or gene therapy before their use in humans with the corresponding disease.

SUBMITTER: Bauer TR

PROVIDER: S-EPMC2806185 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Potential large animal models for gene therapy of human genetic diseases of immune and blood cell systems.

Bauer Thomas R TR Adler Rima L RL Hickstein Dennis D DD

ILAR journal 20090101 2

Genetic mutations involving the cellular components of the hematopoietic system--red blood cells, white blood cells, and platelets--manifest clinically as anemia, infection, and bleeding. Although gene targeting has recapitulated many of these diseases in mice, these murine homologues are limited as translational models by their small size and brief life span as well as the fact that mutations induced by gene targeting do not always faithfully reflect the clinical manifestations of such mutation ...[more]

PMID: 19293460

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Project description:BACKGROUND:The animal model is a key tool in quantitative genetics and has been used extensively to estimate fundamental parameters, such as additive genetic variance or heritability. An implicit assumption of animal models is that all founder individuals derive from a single population. This assumption is commonly violated, for instance in crossbred livestock or when a meta-population is split into genetically differentiated subpopulations. Ignoring that base populations are genetically heterogeneous and thus split into different 'genetic groups' may lead to biased parameter estimates, especially for additive genetic variance. To avoid such biases, genetic group animal models, which account for the presence of more than one genetic group, have been proposed. Unfortunately, the method to date is only computationally feasible when the breeding values of the groups are allowed to differ in their means, but not in their variances. RESULTS:We present an extension of the animal model that permits estimation of group-specific additive genetic variances. This is achieved by employing group-specific relatedness matrices for the breeding value components to different genetic groups. We derive these matrices by decomposing the full relatedness matrix via the generalized Cholesky decomposition, and by scaling the respective matrix components for each group. We propose a computationally convenient approximation for the matrix component that encodes for the Mendelian sampling variance, and show that this approximation is not critical. In addition, we explain why segregation variances are often negligible when analyzing the complex polygenic traits that are frequently the focus of evolutionary ecologists and animal breeders. Simulations and an example from an insular meta-population of house sparrows in Norway with three distinct genetic groups illustrate that the method is successful in estimating group-specific additive genetic variances, and that segregation variances are indeed negligible in the empirical example. CONCLUSIONS:Quantifying differences in additive genetic variance within and among populations is of major biological interest in ecology, evolution, and animal and plant breeding. The proposed method allows to estimate such differences for subpopulations that form a connected set of populations, and may thus also be useful to study temporal or spatial variation of additive genetic variances.

Dataset Information

Potential large animal models for gene therapy of human genetic diseases of immune and blood cell systems.

Publications

Potential large animal models for gene therapy of human genetic diseases of immune and blood cell systems.

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