MOTIVATION: Simple tandem repeats, microsatellites in particular, have regulatory functions, links to several diseases and applications in biotechnology. There is an immediate need for an accurate tool for detecting microsatellites in newly sequenced genomes. The current available tools are either sensitive or specific but not both; some tools require adjusting parameters manually. RESULTS: We propose Look4TRs, the first application of self-supervised hidden Markov models to discovering microsatellites. Look4TRs adapts itself to the input genomes, balancing high sensitivity and low false positive rate. It auto-calibrates itself. We evaluated Look4TRs on 26 eukaryotic genomes. Based on F measure, which combines sensitivity and false positive rate, Look4TRs outperformed TRF and MISA-the most widely used tools-by 78 and 84%. Look4TRs outperformed the second and the third best tools, MsDetector and Tantan, by 17 and 34%. On eight bacterial genomes, Look4TRs outperformed the second and the third best tools by 27 and 137%. AVAILABILITY AND IMPLEMENTATION: https://github.com/TulsaBioinformaticsToolsmith/Look4TRs. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MOTIVATION: Since the dawn of the bioinformatics field, sequence alignment scores have been the main method for comparing sequences. However, alignment algorithms are quadratic, requiring long execution time. As alternatives, scientists have developed tens of alignment-free statistics for measuring the similarity between two sequences. RESULTS: We surveyed tens of alignment-free k-mer statistics. Additionally, we evaluated 33 statistics and multiplicative combinations between the statistics and/or their squares. These statistics are calculated on two k-mer histograms representing two sequences. Our evaluations using global alignment scores revealed that the majority of the statistics are sensitive and capable of finding similar sequences to a query sequence. Therefore, any of these statistics can filter out dissimilar sequences quickly. Further, we observed that multiplicative combinations of the statistics are highly correlated with the identity score. Furthermore, combinations involving sequence length difference or Earth Mover's distance, which takes the length difference into account, are always among the highest correlated paired statistics with identity scores. Similarly, paired statistics including length difference or Earth Mover's distance are among the best performers in finding the K-closest sequences. Interestingly, similar performance can be obtained using histograms of shorter words, resulting in reducing the memory requirement and increasing the speed remarkably. Moreover, we found that simple single statistics are sufficient for processing next-generation sequencing reads and for applications relying on local alignment. Finally, we measured the time requirement of each statistic. The survey and the evaluations will help scientists with identifying efficient alternatives to the costly alignment algorithm, saving thousands of computational hours. AVAILABILITY: The source code of the benchmarking tool is available as Supplementary Materials.