Abstract
N-ethyl-N-nitrosourea (ENU) mutagenesis is a powerful tool to generate mutants on a large scale efficiently, and to discover genes with novel functions at the whole-genome level in Caenorhabditis elegans, flies, zebrafish and mice, but it has never been tried in large model animals. We describe a successful systematic three-generation ENU mutagenesis screening in pigs with the establishment of the Chinese Swine Mutagenesis Consortium. A total of 6,770 G1 and 6,800 G3 pigs were screened, 36 dominant and 91 recessive novel pig families with various phenotypes were established. The causative mutations in 10 mutant families were further mapped. As examples, the mutation of SOX10 (R109W) in pig causes inner ear malfunctions and mimics human Mondini dysplasia, and upregulated expression of FBXO32 is associated with congenital splay legs. This study demonstrates the feasibility of artificial random mutagenesis in pigs and opens an avenue for generating a reservoir of mutants for agricultural production and biomedical research.
Highlights
Pigs are an important source of meat worldwide and are widely used in biomedical research (Groenen et al, 2012; Prather, 2013; Wernersson et al, 2005)
We show that the ENU-induced mutations in various lines can be mapped. These findings revealed that ENU mutagenesis in pigs is an efficient strategy to identify genes with novel functions and to generate mutants for agricultural production and biomedical research
The results showed that the mutant miniature pig inner ear has only one and a half cochlea turns, top loop fusing, a short modiolus, and stunted growth, which perfectly mimics the syndrome of human Mondini dysplasia (Figure 4E, upper panel)
Summary
Pigs are an important source of meat worldwide and are widely used in biomedical research (Groenen et al, 2012; Prather, 2013; Wernersson et al, 2005). ENU-induced mutagenesis is an effective forward genetic approach for identifying functional genes and generating animal models. ENU is a potent mutagen that primarily induces point mutations and chromosome rearrangements in the genome in a random manner (Russell et al, 1979). The advantages of this approach are that no assumptions are needed regarding the underlying genetic causes of physiologic or biologic processes, and it allows the precise selection of phenotypes of interest (Acevedo-Arozena et al, 2008). The need to annotate functional genomics and to generate ideal large animal models prompted us to conduct a forward genetic screen using ENU in pigs
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