Abstract
BackgroundDamage to nerve cells and axons leading to neurodegeneration is a characteristic feature of many neurological diseases. The degree of genetic influence on susceptibility to axotomy-induced neuronal death has so far been unknown. We have examined two gene regions, Vra1 and Vra2, previously linked to nerve cell loss after ventral root avulsion in a rat F2 intercross between the DA and PVG inbred rat strains.Methodology/Principal FindingsIn this study, we use two generations (G8 and G10 cohorts) of an advanced intercross line between DA and PVGav1 to reproduce linkage to Vra1 and to fine-map this region. By isolating the effect from Vra1 in congenic strains, we demonstrate that Vra1 significantly regulates the loss of motoneurons after avulsion. The regulatory effect mediated by Vra1 thus resides in a congenic fragment of 9 megabases. Furthermore, we have used the advanced intercross lines to give more support to Vra2, originally detected as a suggestive QTL.Conclusions/SignificanceThe results demonstrated here show that naturally occurring allelic variations affect susceptibility to axotomy-induced nerve cell death. Vra1 and Vra2 represent the first quantitative trait loci regulating this phenotype that are characterized and fine mapped in an advanced intercross line. In addition, congenic strains provide experimental evidence for the Vra1 effect on the extent of injury-induced neurodegeneration. Identification of the underlying genetic variations will increase our understanding of the regulation and mechanisms of neurodegeneration.
Highlights
Many diseases of the central nervous system (CNS) are characterized by neuron/axon damage leading to neurodegeneration
Fine mapping of Vra1 using an advanced intercross line Two generations, the G8 and G10 of a DAxPVG av1 AIL were used for finemapping of Vra1 and Vra2
Nerve cell counts in the parental control strain demonstrated 47% and 38% mean nerve cell survival in PVGav1 and DA strains, respectively, corresponding to a 23% relative increase in survival in PVGav1 compared to DA
Summary
Many diseases of the central nervous system (CNS) are characterized by neuron/axon damage leading to neurodegeneration. Most genes that are involved in common complex diseases are likely to be evolutionarily conserved, vary between diseased individuals, and only modestly affect risk. This makes disease predisposing genes difficult to identify, and so far only a small number of genes regulating complex traits have been characterized. Further intercrossing generates an advanced intercross line (AIL), which increases the genetic resolution and allows for fine mapping of QTLs identified in a genome wide linkage analysis. This has proven fruitful for resolving the genetic contribution to complex traits such as autoimmune neuroinflammation, reviewed in [4]. We have examined two gene regions, Vra and Vra, previously linked to nerve cell loss after ventral root avulsion in a rat F2 intercross between the DA and PVG inbred rat strains
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