Defining window-boundaries for genomic analyses using smoothing spline techniques

Background: High-density genomic data is often analyzed by combining information over windows of adjacent markers. Interpretation of data grouped in windows versus at individual locations may increase statistical power, simplify computation, reduce sampling noise, and reduce the total number of tests performed. However, use of adjacent marker information can result in over- or under-smoothing, undesirable window boundary specifications, or highly correlated test statistics. We introduce a method for defining windows based on statistically guided breakpoints in the data, as a foundation for the analysis of multiple adjacent data points. This method involves first fitting a cubic smoothing spline to the data and then identifying the inflection points of the fitted spline, which serve as the boundaries of adjacent windows. This technique does not require prior knowledge of linkage disequilibrium, and therefore can be applied to data collected from individual or pooled sequencing experiments. Moreover, in contrast to existing methods, an arbitrary choice of window size is not necessary, since these are determined empirically and allowed to vary along the genome. Results: Simulations applying this method were performed to identify selection signatures from pooled sequencing F-ST data, for which allele frequencies were estimated from a pool of individuals. The relative ratio of true to false positives was twice that generated by existing techniques. A comparison of the approach to a previous study that involved pooled sequencing F-ST data from maize suggested that outlying windows were more clearly separated from their neighbors than when using a standard sliding window approach. Conclusions: We have developed a novel technique to identify window boundaries for subsequent analysis protocols. When applied to selection studies based on F-ST data, this method provides a high discovery rate and minimizes false positives. The method is implemented in the R package GenWin, which is publicly available from CRAN.