Computing the Tandem Duplication Distance is NP-Hard

Abstract

In computational biology, tandem duplication is an important biological phenomenon which can occur either at the genome or at the DNA level. A tandem duplication takes a copy of a genome segment and inserts it right after the segment---this can be represented as the string operation AXB⇒AXXB. Tandem exon duplications have been found in many species such as human, fly, and worm and have been largely studied in computational biology. The tandem duplication (TD) distance problem we investigate in this paper is defined as follows: given two strings S and T over the same alphabet Σ, compute the smallest sequence of TDs required to convert S to T. The natural question of whether the TD distance can be computed in polynomial time was posed in 2004 by Leupold et al. and had remained open, despite the fact that TDs have received much attention ever since. In this paper, we focus on the special case when all characters of S are distinct. This is known as the exemplar TD distance, which is of special relevance in bioinformatics. We first prove that this problem is NP-hard when the alphabet size is unbounded, settling the 16-year-old open problem. We then show how to adapt the proof to |Σ|=4, hence proving the NP-hardness of the TD problem for any |Σ|≥4. One of the tools we develop for the reduction is a new problem called Cost-Effective Subgraph, for which we obtain W[1]-hardness results that might be of independent interest. We finally show that computing the exemplar TD distance between S and T is fixed-parameter tractable. Our results open the door to many other questions, and we conclude with several open problems.