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Interactions of selection, linkage and drift in the dynamics of polygenic characters.

We study the dynamics under directional truncation selection of the genetic variability of a quantitative character controlled by a finite number of possibly linked loci with additive effects. After the first generation of selection, the build-up of linkage disequilibria (Bulmer effect) is analytically demonstrated from a genetical point of view in an infinite population. In the following generations, the dynamics of the system in a finite population are predicted using analytic recurrences under a multi-normal approximation, and computer simulations. The effects of recombination on the dynamics of linkage disequilibria induced by selection and drift, and the consequences for the additive genetic variance are then analysed and discussed from the simulation results. Compared to the rapid exploitation of genetic variability promoted by high recombination rates, low recombination rates promote an early storage of genetic variability in repulsion associations of alleles and a possible late release of genetic variance in the population, so that the variability of the character may be maintained over a longer period of time. In some cases, favourable recombination events in tightly linked systems induce an increase of the additive variance of the character, which may explain some results observed in long-term selection experiments. Our results emphasize that the joint effects of selection, linkage and drift must not be neglected in theoretical quantitative genetics, and require further investigation.

Computer Simulation↗

Genetic analysis of collagen-induced arthritis in rats: a polygenic model for rheumatoid arthritis predicts a common framework of cross-species inflammatory/autoimmune disease loci.

Collagen-induced arthritis (CIA) is a useful model for dissecting the genetic patterns underlying susceptibility to rheumatoid arthritis (RA) and related chronic/inflammatory autoimmune diseases. CIA exhibits three phenotypes characteristic of autoimmune disease pathogenesis: abnormal levels of immune reactivity to self antigens; chronic inflammation of target organs expressing that specific autoantigen; activation and direct participation of invading mononuclear cells and resident tissue fibroblasts in organ damage. Over 25 different quantitative trait loci (QTL) regulating arthritis severity and autoantibody in rats with CIA are mapped. QTL-congenic strains show that certain CIA-QTLs can modulate arthritis independently These monogenic models are proving to be highly informative for fine mapping and function studies, revealing gender effects and evidence of gene clusters. Recent genome scans of RA populations identified RA-susceptibility loci in chromosome regions homologous to rat chromosomal segments housing CIA-QTLs. Also, CIA-QTLs frequently co-localize with susceptibility QTLs mapped in other rat arthritis models induced with non-immunogenic adjuvant oils and/or in rat autoimmune models of multiple sclerosis and diabetes. Common autoimmunity genes and inflammation genes important to several human diseases are likely being detected in the various rat disease models. Continued dissection of the genetic underpinnings of rat arthritis models should provide candidate genes for investigation in human patients and lead to a clearer understanding of the complex genetics of RA.

Animals↗