Large scale sequencing by hybridization

R. Shamir, D. Tsur

Research output: Contribution to conferencePaperpeer-review

Abstract

Sequencing by hybridization is a method for reconstructing a DNA sequence based on its k-mer content. This content, called the spectrum of the sequence, can be obtained from hybridization with a universal DNA chip. However, even with a sequencing chip containing all 49 9-mers and assuming no hybridization errors, only about 400 bases-long sequences can be reconstructed unambiguously. Drmanac et al. suggested sequencing long DNA targets by obtaining spectra of many short overlapping fragments of the target, inferring their relative positions along the target and computing spectra of subfragments that are short enough to be uniquely recoverable. Drmanac et al. do not treat the realistic case of errors in the hybridization process. In this paper we study the effect of such errors. We show that the probability of ambiguous reconstruction in the presence of (false negative) errors is close to the probability in the errorless case. More precisely, the ratio between these probabilities is 1 + O(p/(1 - p)4 · 1/d) where d is the average distance between neighboring subfragments, and p is the probability of a false negative. We also obtain lower and upper bounds for the probability of unambiguous reconstruction based on errorless spectrum. For realistic chip sizes, these bounds are tighter than those given by Arratia et al. Finally, we report results on simulations with real DNA sequences, showing that even in the presence of 50% false negative errors, a target of cos-mid length can be recovered with less than 0.1% miscalled bases.

Original languageEnglish
Pages269-277
Number of pages9
DOIs
StatePublished - 2001
Event5th Annual Internatinal Conference on Computational Biology - Montreal, Que., Canada
Duration: 22 May 200126 May 2001

Conference

Conference5th Annual Internatinal Conference on Computational Biology
Country/TerritoryCanada
CityMontreal, Que.
Period22/05/0126/05/01

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