Abstract
Recent advances in gene knockout techniques and the in vivo analysis of mutant mice, together with the advent of large-scale projects for systematic mouse mutagenesis and genome-wide phenotyping, have allowed the creation of platforms for the most complete and systematic analysis of gene function ever undertaken in a vertebrate. The development of high-throughput phenotyping pipelines for these and other large-scale projects allows investigators to search and integrate large amounts of directly comparable phenotype data from many mutants, on a genomic scale, to help develop and test new hypotheses about the origins of disease and the normal functions of genes in the organism. Histopathology has a venerable history in the understanding of the pathobiology of human and animal disease, and presents complementary advantages and challenges to in vivo phenotyping. In this review, we present evidence for the unique contribution that histopathology can make to a large-scale phenotyping effort, using examples from past and current programmes at Lexicon Pharmaceuticals and The Jackson Laboratory, and critically assess the role of histopathology analysis in high-throughput phenotyping pipelines.
Highlights
It was six men of Hindustan To learning much inclined, Who went to see the Elephant (Though all of them were blind), That each by observation Might satisfy his mind...And so these men of Hindustan Disputed loud and long, Each in his own opinion Exceeding stiff and strong, Though each was partly in the right And all were in the wrong.An extract from The Blind Men and the Elephant by John Godfrey Saxe (1816-1887)Use of the mouse as a model organism has proved to be one of the most powerful approaches available in our efforts to understand and cure human disease (Sundberg, 1991; Peters et al, 2007; Rosenthal and Brown, 2007)
The novel insights into the pathogenesis of these diseases in the mouse have contributed to additional investigations into the underlying pathobiology in humans (Flanagan-Steet et al, 2009; Boonen et al, 2011), and serve as an example of the advances made possible through histopathology phenotyping of seemingly normal knockout mice
We have provided examples that illustrate the indispensable role of histopathology as a first-order assay in discovering gene function
Summary
Exploring the elephant: histopathology in high-throughput phenotyping of mutant mice. Recent advances in gene knockout techniques and the in vivo analysis of mutant mice, together with the advent of large-scale projects for systematic mouse mutagenesis and genome-wide phenotyping, have allowed the creation of platforms for the most complete and systematic analysis of gene function ever undertaken in a vertebrate. The development of high-throughput phenotyping pipelines for these and other large-scale projects allows investigators to search and integrate large amounts of directly comparable phenotype data from many mutants, on a genomic scale, to help develop and test new hypotheses about the origins of disease and the normal functions of genes in the organism. We present evidence for the unique contribution that histopathology can make to a large-scale phenotyping effort, using examples from past and current programmes at Lexicon Pharmaceuticals and The Jackson Laboratory, and critically assess the role of histopathology analysis in high-throughput phenotyping pipelines
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