Schmid, K; Yang, Z; (2008) The Trouble with Sliding Windows and the Selective Pressure in BRCA1. PLOS ONE , 3 (11) , Article e3746. 10.1371/journal.pone.0003746.

Preview

PDF 1375986.pdf Download (325kB)

Abstract

Sliding-window analysis has widely been used to uncover synonymous (silent, dS) and nonsynonymous (replacement, dN) rate variation along the protein sequence and to detect regions of a protein under selective constraint (indicated by dN<dS) or positive selection (indicated by dN>dS). The approach compares two or more protein-coding genes and plots estimates d̂S and d̂N from each sliding window along the sequence. Here we demonstrate that the approach produces artifactual trends of synonymous and nonsynonymous rate variation, with greater variation in d̂S than in d̂N. Such trends are generated even if the true dS and dN are constant along the whole protein and different codons are evolving independently. Many published tests of negative and positive selection using sliding windows that we have examined appear to be invalid because they fail to correct for multiple testing. Instead, likelihood ratio tests provide a more rigorous framework for detecting signals of natural selection affecting protein evolution. We demonstrate that a previous finding that a particular region of the BRCA1 gene experienced a synonymous rate reduction driven by purifying selection is likely an artifact of the sliding window analysis. We evaluate various sliding-window analyses in molecular evolution, population genetics, and comparative genomics, and argue that the approach is not generally valid if it is not known a priori that a trend exists and if no correction for multiple testing is applied.

Download activity - last month

Export as XMLCSVJSON

Download activity - last 12 months

Export as JSONCSVXML

Downloads by country - last 12 months

Export as XMLJSONCSV

Archive Staff Only

View Item