Web tools for the prioritization of candidate disease genes

Despite increasing sequencing capacity, genetic disease investigation still frequently results in the identification of loci containing multiple candidate disease genes that need to be tested for involvement in the disease. This process can be expedited by prioritizing the candidates prior to testing. Over the last decade, a large number of computational methods and tools have been developed to assist the clinical geneticist in prioritizing candidate disease genes. In this chapter, we give an overview of computational tools that can be used for this purpose, all of which are freely available over the web.

Stage of perinatal development regulates skeletal muscle mitochondrial biogenesis and myogenic regulatory factor genes with little impact of growth restriction or cross-fostering

Foetal growth restriction impairs skeletal muscle development and adult muscle mitochondrial biogenesis. We hypothesized that key genes involved in muscle development and mitochondrial biogenesis would be altered following uteroplacental insufficiency in rat pups, and improving postnatal nutrition by cross-fostering would ameliorate these deficits. Bilateral uterine vessel ligation (Restricted) or sham (Control) surgery was performed on day 18 of gestation. Males and females were investigated at day 20 of gestation (E20), 1 (PN1), 7 (PN7) and 35 (PN35) days postnatally. A separate cohort of Control and Restricted pups were cross-fostered onto a different Control or Restricted mother and examined at PN7. In both sexes, peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1α (PGC-1α), cytochrome c oxidase subunits 3 and 4 (COX III and IV) and myogenic regulatory factor 4 expression increased from late gestation to postnatal life, whereas mitochondrial transcription factor A, myogenic differentiation 1 (MyoD), myogenin and insulin-like growth factor I (IGF-I) decreased. Foetal growth restriction increased MyoD mRNA in females at PN7, whereas in males IGF-I mRNA was higher at E20 and PN1. Cross-fostering Restricted pups onto a Control mother significantly increased COX III mRNA in males and COX IV mRNA in both sexes above controls with little effect on other genes. Developmental age appears to be a major factor regulating skeletal muscle mitochondrial and developmental genes, with growth restriction and cross-fostering having only subtle effects. It therefore appears that reductions in adult mitochondrial biogenesis markers likely develop after weaning.

Genes and song : genetic and social connections in fragmented habitat in a woodland bird with limited dispersal

Understanding the processes leading to population declines in fragmented landscapes is essential for successful conservation management. However, isolating the influence of disparate processes, and dispersal in particular, is challenging. The Grey Shrike-thrush, Colluricincla harmonica, is a sedentary woodland-dependent songbird, with learned vocalizations whose incidence in suitable habitat patches falls disproportionally with decline in tree cover in the landscape. Although it has been suggested that gaps in tree cover might act as barriers to its dispersal, the species remains in many remnants of native vegetation in agricultural landscapes, suggesting that it may have responded to habitat removal and fragmentation by maintaining or even increasing dispersal distances. We quantified population connectivity of the Grey Shrike-thrush in a system fragmented over more than 120 years using genetic (microsatellites) and acoustic (song types) data. First, we tested for population genetic and acoustic structure at regional and local scales in search of barriers to dispersal or gene flow and signals of local spatial structuring indicative of restricted dispersal or localized acoustic similarity. Then we tested for effects of habitat loss and fragmentation on genetic and acoustic connectivity by fitting alternative models of mobility (isolation-by-distance [the null model] and reduced and increased movement models) across treeless vs. treed areas. Birds within 5 km of each other had more similar genotypes and song types than those farther away, suggesting that dispersal and song matching are limited in the region. Despite restricted dispersal detected for females (but not males), populations appeared to be connected by gene flow and displayed some cultural (acoustic) connectivity across the region. Fragmentation did not appear to impact greatly the dispersal of the Grey Shrike-thrush: none of the mobility models fit the genetic distances of males, whereas for females, an isolation-by-distance model could not be rejected in favor of the models of reduced or increased movement through treeless gaps. However, dissimilarities of the song types were more consistent with the model of reduced cultural connectivity through treeless areas, suggesting that fragmentation impedes song type sharing in the Grey Shrike-thrush. Our paper demonstrates that habitat fragmentation hinders important population processes in an Australian woodland bird even though its dispersal is not detectably impacted.