Giuseppe Lancia

SNPs Problems, Complexity, and Algorithms

Single nucleotide polymorphisms (SNPs) are the most frequent form of human genetic variation. They are of fundamental importance for a variety of applications including medical diagnostic and drug design. They also provide the highest-resolution genomic fingerprint for tracking disease genes. This paper is devoted to algorithmic problems related to computational SNPs validation based on genome assembly of diploid organisms. In diploid genomes, there are two copies of each chromosome. A description of the SNPs sequence information from one of the two chromosomes is called SNPs haplotype. The basic problem addressed here is the Haplotyping, i.e., given a set of SNPs prospects inferred from the assembly alignment of a genomic region of a chromosome, find the maximally consistent pair of SNPs haplotypes by removing data errors related to DNA sequencing errors, repeats, and paralogous recruitment. In this paper, we introduce several versions of the problem from a computational point of view. We show that the general SNPs Haplotyping Problem is NP-hard for mate-pairs assembly data, and design polynomial time algorithms for fragment assembly data.We give a network-flow based polynomial algorithm for the Minimum Fragment Removal Problem, and we show that the Minimum SNPs Removal problem amounts to finding the largest independent set in a weakly triangulated graph.

A polynomial time approximation scheme for minimum routing cost spanning trees

Given an undirected graph with nonnegative costs on the edges, the routing cost of any of its spanning trees is the sum over all pairs of vertices of the cost of the path between the pair in the tree. Finding a spanning tree of minimum routing cost is NP-hard, even when the costs obey the triangle inequality. We show that the general case is in fact reducible to the metric case and present a polynomial-time approximation scheme valid for both versions of the problem. In particular, we show how to build a spanning tree of an n-vertex weighted graph with routing cost at most

1001 optimal PDB structure alignments: integer programming methods for finding the maximum contact map overlap.

(1+epsilon)

Haplotyping as perfect phylogeny: a direct approach.

of the minimum in time

Haplotyping Populations by Pure Parsimony: Complexity of Exact and Approximation Algorithms

O(n^{O({frac{1}{epsilon}}% )})

101 optimal PDB structure alignments: a branch-and-cut algorithm for the maximum contact map overlap problem

. Besides the obvious connection to network design, trees with small routing cost also find application in the construction of good multiple sequence alignments in computational biology. nThe communication cost spanning tree problem is a generalization of the minimum routing cost tree problem where the routing costs of different pairs are weighted by different requirement amounts. We observe that a randomized O(log n log log n)-approximation for this problem follows directly from a recent result of Bartal, where n is the number of nodes in a metric graph. This also yields the same approximation for the generalized sum-of-pairs alignment problem in computational biology.

Opportunities for Combinatorial Optimization in Computational Biology

Protein structure comparison is a fundamental problem for structural genomics, with applications to drug design, fold prediction, protein clustering, and evolutionary studies. Despite its importance, there are very few rigorous methods and widely accepted similarity measures known for this problem. In this paper we describe the last few years of developments on the study of an emerging measure, the contact map overlap (CMO), for protein structure comparison. A contact map is a list of pairs of residues which lie in three-dimensional proximity in the proteins native fold. Although this measure is in principle computationally hard to optimize, we show how it can in fact be computed with great accuracy for related proteins by integer linear programming techniques. These methods have the advantage of providing certificates of near-optimality by means of upper bounds to the optimal alignment value. We also illustrate effective heuristics, such as local search and genetic algorithms. We were able to obtain for the first time optimal alignments for large similar proteins (about 1,000 residues and 2,000 contacts) and used the CMO measure to cluster proteins in families. The clusters obtained were compared to SCOP classification in order to validate the measure. Extensive computational experiments showed that alignments which are off by at most 10% from the optimal value can be computed in a short time. Further experiments showed how this measure reacts to the choice of the threshold defining a contact and how to choose this threshold in a sensible way.

Practical Algorithms and Fixed-Parameter Tractability for the Single Individual SNP Haplotyping Problem

A full haplotype map of the human genome will prove extremely valuable as it will be used in large-scale screens of populations to associate specific haplotypes with specific complex genetic-influenced diseases. A haplotype map project has been announced by NIH. The biological key to that project is the surprising fact that some human genomic DNA can be partitioned into long blocks where genetic recombination has been rare, leading to strikingly fewer distinct haplotypes in the population than previously expected (Helmuth, 2001; Daly et al., 2001; Stephens et al., 2001; Friss et al., 2001). In this paper we explore the algorithmic implications of the no-recombination in long blocks observation, for the problem of inferring haplotypes in populations. This assumption, together with the standard population-genetic assumption of infinite sites, motivates a model of haplotype evolution where the haplotypes in a population are assumed to evolve along a coalescent, which as a rooted tree is a perfect phylogeny. We consider the following algorithmic problem, called the perfect phylogeny haplotyping problem (PPH), which was introduced by Gusfield (2002) - given n genotypes of length m each, does there exist a set of at most 2n haplotypes such that each genotype is generated by a pair of haplotypes from this set, and such that this set can be derived on a perfect phylogeny? The approach taken by Gusfield (2002) to solve this problem reduces it to established, deep results and algorithms from matroid and graph theory. Although that reduction is quite simple and the resulting algorithm nearly optimal in speed, taken as a whole that approach is quite involved, and in particular, challenging to program. Moreover, anyone wishing to fully establish, by reading existing literature, the correctness of the entire algorithm would need to read several deep and difficult papers in graph and matroid theory. However, as stated by Gusfield (2002), many simplifications are possible and the list of future work in Gusfield (2002) began with the task of developing a simpler, more direct, yet still efficient algorithm. This paper accomplishes that goal, for both the rooted and unrooted PPH problems. It establishes a simple, easy-to-program, O(nm(2))-time algorithm that determines whether there is a PPH solution for input genotypes and produces a linear-space data structure to represent all of the solutions. The approach allows complete, self-contained proofs. In addition to algorithmic simplicity, the approach here makes the representation of all solutions more intuitive than in Gusfield (2002), and solves another goal from that paper, namely, to prove a nontrivial upper bound on the number of PPH solutions, showing that that number is vastly smaller than the number of haplotype solutions (each solution being a set of n pairs of haplotypes that can generate the genotypes) when the perfect phylogeny requirement is not imposed.

Structural alignment of large—size proteins via lagrangian relaxation

In this paper we address the pure parsimony haplotyping problem: Find a minimum number of haplotypes that explains a given set of genotypes. We prove that the problem is APX-hard and present a 2k- 1-approximation algorithm for the case in which each genotype has at most k ambiguous positions. We further give a new integer-programming formulation that has (for the first time) a polynomial number variables and constraints. Finally, we give approximation algorithms, not based on linear programming, whose running times are almost linear in the input size.

Banishing Bias from Consensus Sequences

Structure comparison is a fundamental problem for structural genomics. A variety of structure comparison methods were proposed and several protein structure classification servers e.g., SCOP, DALI, CATH, were designed based on them, and are extensively used in practice. This area of research continues to be very active, being energized bi-annually by the CASP folding competitions, but despite the extraordinary international research effort devoted to it, progress is slow. A fundamental dimension of this bottleneck is the absence of rigorous algorithmic methods. A recent excellent survey on structure comparison by Taylor et.al. [23] records the state of the art of the area: In structure comparison, we do not even have an algorithm that guarantees an optimal answer for pairs of structures …nIn this paper we provide the first rigorous algorithm for structure comparison. Our method is based on developing an effective integer linear programming (IP) formulation of protein structure contact maps overlap (CMO), and a branch-and-cut strategy that employs lower-bounding heuristics at the branch nodes. Our algorithms identified a gallery of optimal and near-optimal structure alignments for pairs of proteins from the Protein Data Bank with up to 80 amino acids and about 150 contacts each — problems of instance size of about 300. Although these sizes also reflect our current limitations, these are the first provable optimal and near-optimal algorithms in the literature for a measure of structure similarity which sees extensive practical use. At the heart of our success in finding optimal alignments is a reduction of the CMO optimization to the maximum independent set (MIS) problem on special graphs. For CMO instances of size 300, the corresponding MIS graph instance contains about 10,000 nodes. While our algorithms are able to solve to optimality MIS problem of these sizes, the known optimal algorithms for the MIS on general graphs can at present only solve instances with up to a few hundred nodes. This is the first effective use of IP methods in protein structure comparison; the biomolecular structure literature contains only one other effective IP method devoted to RNA comparison, due to Lenhof et.al. [18].nThe hybrid heuristic approach that worked well for providing lower bounds in the branch and cut algorithm was tried on large proteins in a test set suggested by Jeffrey Skolnick. It involved 33 proteins classified into four families: Flavodoxin-like fold CheY-related, Plastocyanin, TIM Barrel, and Ferratin. Out of the set of all 528 pairwise structure alignments, we have validated the clustering with a 98.7% accuracy (1.3% false negatives and 0% false positives).