**Non-parametric and semi-parametric support estimation using SEquential RESampling random walks on biomolecular sequences**

**Abstract: **Non-parametric and semi-parametric resampling procedures are widely used to perform support estimation in computational biology and bioinformatics. Among the most widely used methods in this class is the standard bootstrap method, which consists of random sampling with replacement. While not requiring assumptions about any particular parametric model for resampling purposes, the bootstrap and related techniques assume that sites are independent and identically distributed (i.i.d.). The i.i.d. assumption can be an over-simplification for many problems in computational biology and bioinformatics. In particular, sequential dependence within biomolecular sequences is often an essential biological feature due to biochemical function, evolutionary processes such as recombination, and other factors.

To relax the simplifying i.i.d. assumption, we propose a new non-parametric/semi- parametric sequential resampling technique that generalizes “Heads-or-Tails” mirrored inputs, a simple but clever technique due to Landan and Graur. The generalized procedure takes the form of random walks along either aligned or unaligned biomolecular sequences. We refer to our new method as the SERES (or “SEquential RESampling”) method.

To demonstrate the flexibility of the new technique, we apply SERES to two different applications – one involving aligned inputs and the other involving unaligned inputs. Using simulated and empirical data, we show that SERES-based support estimation yields comparable or typically better performance compared to state-of-the-art methods for both applications.