FORGE : A tool to discover cell specific enrichments of GWAS associated SNPs in regulatory regions.

Ian Dunham, Eugene Kulesha, Valentina Iotchkova, Sandro Morganella, Ewan Birney
doi: http://dx.doi.org/10.1101/013045

Genome wide association studies provide an unbiased discovery mechanism for numerous human diseases. However, a frustration in the analysis of GWAS is that the majority of variants discovered do not directly alter protein-coding genes. We have developed a simple analysis approach that detects the tissue-specific regulatory component of a set of GWAS SNPs by identifying enrichment of overlap with DNase I hotspots from diverse tissue samples. Functional element Overlap analysis of the Results of GWAS Experiments (FORGE) is available as a web tool and as standalone software and provides tabular and graphical summaries of the enrichments. Conducting FORGE analysis on SNP sets for 260 phenotypes available from the GWAS catalogue reveals numerous overlap enrichments with tissue–specific components reflecting the known aetiology of the phenotypes as well as revealing other unforeseen tissue involvements that may lead to mechanistic insights for disease.

Using Bayesian multilevel whole-genome regression models for partial pooling of estimation sets in genomic prediction

Frank Technow, L. Radu Totir
doi: http://dx.doi.org/10.1101/012971

Estimation set size is an important determinant of genomic prediction accuracy. Plant breeding programs are characterized by a high degree of structuring, particularly into populations. This hampers establishment of large estimation sets for each population. Pooling populations increases estimation set size but ignores unique genetic characteristics of each. A possible solution is partial pooling with multilevel models, which allows estimating population specific marker effects while still leveraging information across populations. We developed a Bayesian multilevel whole-genome regression model and compared its performance to that of the popular BayesA model applied to each population separately (no pooling) and to the joined data set (complete pooling). As example we analyzed a wide array of traits from the nested association mapping maize population. There we show that for small population sizes (e.g., < 50), partial pooling increased prediction accuracy over no or complete pooling for populations represented in the estimation set. No pooling was superior however when populations were large. In another example data set of interconnected biparental maize populations either partial or complete pooling were superior, depending on the trait. A simulation showed that no pooling is superior when differences in genetic effects among populations are large and partial pooling when they are intermediate. With small differences, partial and complete pooling achieved equally high accuracy. For prediction of new populations, partial and complete pooling had very similar accuracy in all cases. We conclude that partial pooling with multilevel models can maximize the potential of pooling by making optimal use of information in pooled estimation sets.

Common binding by redundant group B Sox proteins is evolutionarily conserved in Drosophila

Sarah H Carl, Steven Russell
doi: http://dx.doi.org/10.1101/012872

Background: Group B Sox proteins are a highly conserved group of transcription factors that act extensively to coordinate nervous system development in higher metazoans while showing both co-expression and functional redundancy across a broad group of taxa. In Drosophila melanogaster, the two group B Sox proteins Dichaete and SoxNeuro show widespread common binding across the genome. While some instances of functional compensation have been observed in Drosophila, the function of common binding and the extent of its evolutionary conservation is not known. Results: We used DamID-seq to examine the genome-wide binding patterns of Dichaete and SoxNeuro in four species of Drosophila. Through a quantitative comparison of Dichaete binding, we evaluated the rate of binding site turnover across the genome as well as at specific functional sites. We also examined the presence of Sox motifs within binding intervals and the correlation between sequence conservation and binding conservation. To determine whether common binding between Dichaete and SoxNeuro is conserved, we performed a detailed analysis of the binding patterns of both factors in two species. Conclusion: We find that, while the regulatory networks driven by Dichaete and SoxNeuro are largely conserved across the drosophilids studied, binding site turnover is widespread and correlated with phylogenetic distance. Nonetheless, binding is preferentially conserved at known cis-regulatory modules and core, independently verified binding sites. We observed the strongest binding conservation at sites that are commonly bound by Dichaete and SoxNeuro, suggesting that these sites are functionally important. Our analysis provides insights into the evolution of group B Sox function, highlighting the specific conservation of shared binding sites and suggesting alternative sources of neofunctionalisation between paralogous family members.