ENU Large-scale Mutagenesis and Quantitative Trait Linkage (QTL) Analysis in Mice: Novel Technologies for Searching Polygenetic Determinants of Craniofacial Abnormalities

Abstract

Discrepancies in size and shape of the jaws are the underlying etiology in many orthodontic and orthognathic surgery patients. Genetic factors combined with environmental interactions have been postulated to play a causal or contributory role in these craniofacial abnormalities. Along with the soon-to-be-available complete human and mouse genomic sequence data, mouse mutants have become a valuable tool in the functional mapping of genes involved in the development of human maxillofacial dysmorphologies. We review two powerful methods in such efforts: N-ethyl-N-nitrosourea (ENU) large-scale mutagenesis and quantitative trait linkage (QTL) analysis. The former aims at producing a plethora of novel variants of particular trait(s), and ultimately mapping the point mutations responsible for the appearance of these new traits. In contrast, the latter applies intensive breeding and mapping techniques to identify multiple loci (and, subsequently, genes) contributing to the phenotypic difference between the tested strains. A prerequisite for either approach to studying variations in the traits of interest is the application of effective mouse cephalometric phenotype analysis and rapid DNA mapping techniques. These approaches will produce a wealth of new data on critical genes that influence the size and shape of the human face.

Genetic Analysis of Craniofacial Traits in the Medaka

“…A number of studies have analyzed morphological phenotypes as quantitative traits in mice (Cheverud et al 1997;Dohmoto et al 2002;Nishimura et al 2003;Lang et al 2005). The LOD scores in our study of medaka are similar to those obtained in mice.…”

“…The LOD scores in our study of medaka are similar to those obtained in mice. When craniofacial traits were analyzed in .100 mice, a few QTL were identified for each trait with highest LOD scores of 5 (Dohmoto et al 2002;Nishimura et al 2003). When skeletal morphology was analyzed in 200 F 2 mice, 7.3 was the highest LOD score and most traits were mapped to between 1 and 5 genomic regions (Lang et al 2005).…”

“…There is currently no standard efficient method for measuring craniofacial traits, however. Different laboratories utilize various techniques and refine these methods as needed (for example, Klingenberg et al 2001Klingenberg et al , 2004Albertson et al 2003;Nishimura et al 2003). The present method for determining craniofacial traits is effective and facilitates repeated trials on a two-dimensional display.…”

The mouse genome

“…An extremely dynamic consortium dealing with all these problems, the Complex Trait Consortium or CTC, was created in the spring of 2002, by a group of expert scientists who decided to identify research priorities and tools to tackle the problems related to quantitative inheritance in the mouse model. The goals of the consortium have been published in several scientific journals (Glazier et al 2002;Abiola et al 2003;Nishimura et al 2003;Churchill et al 2004;Pletcher and Wiltshire 2004;Singer et al 2004). In short, they are preparing and collecting the tools that would allow relating specific haplotypes (or segments) of the mouse genome, identified by a particular set of SNPs, with a particular phenotype identified by a QTL (Petkov et al 2004;.…”

Analysis of breeding and pathology helps refine management practices of a large-scale N′-ethyl-N′-nitrosourea mouse mutagenesis programme

“…1 Mouse ENU mutagenesis has increased the pool of mutants in many areas of biology, helped identify novel genes involved in physiological processes and disease, and assisted in assigning functions to genes. 2 The contribution of ENU mutagenesis to different areas has been the subject of an increasing number of specialist reviews, for example in host defence, allergy and autoimmunity, 3 craniofacial abnormalities, 4 male infertility 5 and behaviour. 6 ENU is a commonly used mutagen for phenotype-driven screens in mice.…”