The uncertain road towards genomic medicine

Article (PDF Available)inTrends in Genetics 28(7):303-5 · June 2012with26 Reads
DOI: 10.1016/j.tig.2012.05.001 · Source: PubMed
Cheap, high-throughput approaches to generating biological data are transforming biology into a data-driven science and promise to similarly transform medicine. However, the road to genomic medicine is paved with challenges and uncertainty.
  • [Show abstract] [Hide abstract] ABSTRACT: Populations that maintain phenotypic divergence in sympatry typically show a mosaic pattern of genomic divergence, requiring a corresponding mosaic of genomic isolation (reduced gene flow). However, mechanisms that could produce the genomic isolation required for divergence-with-gene-flow have barely been explored, apart from the traditional localized effects of selection and reduced recombination near centromeres or inversions. By localizing F(ST) outliers from a genome scan of wild pea aphid host races on a Quantitative Trait Locus (QTL) map of key traits, we test the hypothesis that between-population recombination and gene exchange are reduced over large 'divergence hitchhiking' (DH) regions. As expected under divergence hitchhiking, our map confirms that QTL and divergent markers cluster together in multiple large genomic regions. Under divergence hitchhiking, the nonoutlier markers within these regions should show signs of reduced gene exchange relative to nonoutlier markers in genomic regions where ongoing gene flow is expected. We use this predicted difference among nonoutliers to perform a critical test of divergence hitchhiking. Results show that nonoutlier markers within clusters of F(ST) outliers and QTL resolve the genetic population structure of the two host races nearly as well as the outliers themselves, while nonoutliers outside DH regions reveal no population structure, as expected if they experience more gene flow. These results provide clear evidence for divergence hitchhiking, a mechanism that may dramatically facilitate the process of speciation-with-gene-flow. They also show the power of integrating genome scans with genetic analyses of the phenotypic traits involved in local adaptation and population divergence.
    Full-text · Article · Oct 2012
  • [Show abstract] [Hide abstract] ABSTRACT: Background Speciation reversal: the erosion of species differentiation via an increase in introgressive hybridization due to the weakening of previously divergent selection regimes, is thought to be an important, yet poorly understood, driver of biodiversity loss. Our study system, the Alpine whitefish (Coregonus spp.) species complex is a classic example of a recent postglacial adaptive radiation: forming an array of endemic lake flocks, with the independent origination of similar ecotypes among flocks. However, many of the lakes of the Alpine radiation have been seriously impacted by anthropogenic nutrient enrichment, resulting in a collapse in neutral genetic and phenotypic differentiation within the most polluted lakes. Here we investigate the effects of eutrophication on the selective forces that have shaped this radiation, using population genomics. We studied eight sympatric species assemblages belonging to five independent parallel adaptive radiations, and one species pair in secondary contact. We used AFLP markers, and applied FST outlier (BayeScan, Dfdist) and logistic regression analyses (MatSAM), to identify candidate regions for disruptive selection in the genome and their associations with adaptive traits within each lake flock. The number of outlier and adaptive trait associated loci identified per lake were then regressed against two variables (historical phosphorus concentration and contemporary oxygen concentration) representing the strength of eutrophication. Results Whilst we identify disruptive selection candidate regions in all lake flocks, we find similar trends, across analysis methods, towards fewer disruptive selection candidate regions and fewer adaptive trait/candidate loci associations in the more polluted lakes. Conclusions Weakened disruptive selection and a concomitant breakdown in reproductive isolating mechanisms in more polluted lakes has lead to increased gene flow between coexisting Alpine whitefish species. We hypothesize that the resulting higher rates of interspecific recombination reduce either the number or extent of genomic islands of divergence surrounding loci evolving under disruptive natural selection. This produces the negative trend seen in the number of selection candidate loci recovered during genome scans of whitefish species flocks, with increasing levels of anthropogenic eutrophication: as the likelihood decreases that AFLP restriction sites will fall within regions of heightened genomic divergence and therefore be classified as FST outlier loci. This study explores for the first time the potential effects of human-mediated relaxation of disruptive selection on heterogeneous genomic divergence between coexisting species.
    Full-text · Article · May 2013
  • [Show abstract] [Hide abstract] ABSTRACT: Purpose: The purpose of this study was to examine the motivational, attitudinal, and behavioral predictors of interest in genetic testing (GT) in those with and without awareness of their risk for type 2 diabetes (T2DM). Methods: A convenience sample of adults visiting emergency departments, libraries, or an online research registry was surveyed. Responses from adults without diabetes who reported 1 or more risk factors for T2DM (eg, family history, body mass index > 25) were included in the analyses (n = 265). Results: Participants were 37 ± 11 years old, white (54%), and female (69%), with some college education (53%) and an annual income below $25 000 (44%). Approximately half (52%) expressed interest in GT for T2DM. Individuals were stratified by perceived risk for T2DM (risk aware or risk unaware). Among the risk aware, younger age (P < .04) predicted greater interest in GT. Among the risk unaware, family history of T2DM (P < .008) and preference to know genetic risk (P < .0002) predicted interest in GT. Both groups identified the need for low-cost GT. Conclusions: GT is an increasingly available and accurate tool to predict T2DM risk for patients. In this sample, GT was a salient tool for those with and without awareness of their T2DM risk. Financial accessibility is critical to use of this tool for both groups.
    Full-text · Article · Mar 2014
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