Animal breeding theory is based on the assumption that traits are controlled by many genes each having small effect, however, genes with a large effect have been identified in favourable circumstances. Where major genes can be identified, and individual animals genotyped, exploitation of the genetic variation can be optimised. Segregation analysis has been proposed as a suitable method for detecting major genes. It involves maximising and comparing the likelihood of the data under different genetic models to ascertain the most likely genetic structure. To identify a major gene the likelihood of the data under a polygenic model is maximised and compared with the maximum likelihood under the mixed model (i.e. containing a major gene and polygenic component). A significant improvement in the likelihood obtained by incorporating the major gene gives evidence for its existence. Equations for the exact mixed model and polygenic likelihoods can be obtained, however the mixed model likelihood involves the integration of a complex function. Several approximations to this likelihood have been investigated. The first effectively retains the integration and approximates crossproduct terms involving the major gene and the polygenic component. The second (Herm) approximates the integration with a summation using the Hermite polynomial. The likelihood has been maximised using a quasi-Newton algorithm. The third and fourth methods are extensions of mixed model methods (in the statistical sense, i.e. including fixed and random effects), which are already familiar to animal breeders. One replaces the integration with a single estimate of the mode of each sire's transmitting ability distribution (ME1), the other estimates three modes one for each possible major genotype of the sire (ME3). These have been implemented using an expectation-maximisation algorithm. The first approximation was thought too complex to extend to include, for example, fixed effects. The operational characteristics of the other three methods have been investigated using simulated data. The Monte-Carlo simulation program uses Boolean algebra to describe the genotype of individuals at each locus and the inheritance of the alleles. Different genetic models have been considered and the data was analysed twice, firstly assuming that the polygenic heritability was known and fixing it at the expected value, secondly estimating the heritability from the data. For all the analyses the simulated data contained 50 sires each with 20 half-sib offspring. Segregation analysis is capable of detecting a major gene segregating in a population and accurately estimating its effect and frequency. Approximations to the mixed model likelihood make the method feasible for large data sets.

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A gene-trap strategy in embryonic stem (ES)cells has been employed to identify and characterise genes involved in heart development. This work describes the characterisation of two gene-trap integrations (R68 and R124), including identification of endogenous trapped gene sequences and analysis to determine the function of the trapped genes. Molecular analysis of the R68 and R124 gene-trap integrations has shown the use of cryptic splice sites within the gene-trap vector indicating the vector has integrated into an exon in both gene-trap cell lines. The unpredicted integration of a gene-trap vector into an exon still results in the expression of the reporter gene. Sequence data indicates a novel gene has been trapped by the R124 gene-trap integration. The structure of the R124 integration in the genome has been predicted based upon sequencing data and restriction fragment length polymorphism analysis. The R124 gene-trap integration has been mapped to chromosome 5 in the mouse genome. Beating cardiomyoctyes generated from the <I>in vitro</I> differentiation of R68 and R124 ES cells express the reporter gene. Embryos heterozygous for the R124 gene-trap integration express reporter gene activity in the developing heart throughout gestation. In the adult the reporter gene is expressed in the heart, kidney, testis, ovary and brain. Function of the trapped gene was assessed by generating animals homozygous for the R124 integration. 60% of animals homozygous for the integration die shortly after birth. This lethality is associated with a right ventricle heart defect. Surviving homozygote males show enlarged hearts and kidneys. The surviving homozygote males are also infertile, histological analysis has shown no mature sperm in the testes of homozygote males.

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