Mutation region detection and haplotype assembly

基因突變區域檢測及單體型組裝

Student thesis: Doctoral Thesis

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Author(s)

  • Wenjuan CUI

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Detail(s)

Awarding Institution
Supervisors/Advisors
Award date2 Oct 2013

Abstract

In this thesis, we study two important problems in computational biology and bioinformatics, mutation region detection and haplotype assembly. Linkage analysis is the first step in the search for a disease gene. Linkage studies have facilitated the identification of several hundred human genes that can harbor mutations leading to a disease phenotype. In Chapter 2, we study a very important case, where the sampled individuals are closely related, but the pedigree is not given. This situation happens very often when the individuals share a common ancestor 6 or more generations ago. To our knowledge, no algorithm can give good results for this case. To solve this problem, we first developed some heuristic algorithms for haplotype inference without any given pedigree. We propose a model using the parsimony principle that can be viewed as an extension of the model first proposed by Dan Gusfield. Our heuristic algorithm uses Clark's inference rule to infer haplotype segments. We ran our program both on the simulated data and a set of real data from the phase II HapMap database. Experiments show that our program performs well. The recall value is from 90% to 99% in various cases. This implies that the program can report more than 90% of the true mutation regions. The value of precision varies from 29% to 90%. When the precision is 29%, the size of the reported regions is three times that of the true mutation region. This is still very useful for narrowing down the range of the disease gene location. Our program can complete the computation for all the tested cases, where there are about 110,000 SNPs on a chromosome, within 20 seconds. For mutation region detection problem, there is another version where the pedigree is not given and a database of confirmed haplotypes is given as reference instead. To infer the allele-sharing status of a set of individuals with the database of confirmed haplotypes, the shared center(SC) problem was proposed. The closest shared center (CSC) problem, which is the minimization version of the SC problem, is a core to solve the mutation region detection problem in this case. In chapter 3, we design a polynomial time approximation scheme for the CSC problem, i.e., for any fixed number ϵ ∈(0, 1), our algorithm can find a feasible solution with objective value no more than (1+ϵ)d*, where d* is the optimal objective value of the input instance for the CSC problem. Single nucleotide polymorphisms (SNPs) are the most common form of genetic variation in human DNA. The sequence of SNPs in each of the two copies of a given chromosome in a diploid organism is referred to as a haplotype. Haplotype information has many applications such as gene disease diagnoses, drug design, etc. The haplotype assembly problem is defined as follows: Given a set of fragments sequenced from the two copies of a chromosome of a single individual, and their locations in the chromosome, which can be pre-determined by aligning the fragments to a reference DNA sequence, the goal here is to reconstruct two haplotypes (h1; h2) from the input fragments. Existing algorithms do not work well when the error rate of fragments is high. In chapter 4, we design an algorithm that can give accurate solutions, even if the error rate of fragments is high. We first give a dynamic programming algorithm that can give exact solutions to the haplotype assembly problem. The time complexity of the algorithm is O(n x 2t x t), where n is the number of SNPs, and t is the maximum coverage of a SNP site. The algorithm is slow when t is large. To solve the problem when t is large, we further propose a heuristic algorithm on the basis of the dynamic programming algorithm. Experiments show that our heuristic algorithm can give very accurate solutions. We have tested our algorithm on a set of benchmark datasets. Experiments show that our algorithm can give very accurate solutions. It outperforms most of the existing programs when the error rate of the input fragments is high.

    Research areas

  • Mutation (Biology), Bioinformatics, Computational biology, Single nucleotide polymorphisms, Mathematical models