title: On the design of clone-based haplotyping.
abstract: BACKGROUND
  Haplotypes are important for assessing genealogy and disease susceptibility of individual genomes,but are difficult to obtain with routine sequencing approaches. Experimental haplotype reconstruction based on assembling fragments of individual chromosomes is promising, but with variable yields due to incompletely understood parameter choices.
  
  
  RESULTS
  We parameterize the clone-based haplotyping problem in order to provide theoretical and empirical assessments of the impact of different parameters on haplotype assembly. We confirm the intuition that long clones help link together heterozygous variants and thus improve haplotype length. Furthermore, given the length of the clones, we address how to choose the other parameters, including number of pools, clone coverage and sequencing coverage, so as to maximize haplotype length. We model the problem theoretically and show empirically the benefits of using larger clones with moderate number of pools and sequencing coverage. In particular, using 140 kb BAC clones, we construct haplotypes for a personal genome and assemble haplotypes with N50 values greater than 2.6 Mb. These assembled haplotypes are longer and at least as accurate as haplotypes of existing clone-based strategies, whether in vivo or in vitro.
  
  
  CONCLUSIONS
  Our results provide practical guidelines for the development and design of clone-based methods to achieve long range, high-resolution and accurate haplotypes.
authors.forename: Christine
authors.initials: C
authors.lastname: Lo
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.forename: Jehyuk
authors.initials: J
authors.lastname: Lee
authors.forename: Kimberly
authors.initials: K
authors.lastname: Robasky
authors.forename: Susan
authors.initials: S
authors.lastname: Byrne
authors.forename: Carolina
authors.initials: C
authors.lastname: Lucchesi
authors.forename: John
authors.initials: J
authors.lastname: Aach
authors.forename: George
authors.initials: G
authors.lastname: Church
authors.forename: Vineet
authors.initials: V
authors.lastname: Bafna
authors.forename: Kun
authors.initials: K
authors.lastname: Zhang
mesh_terms: D000465:Algorithms; D022202:Chromosomes, Artificial, Bacterial; D003001:Cloning, Molecular; D020451:Contig Mapping / Q000379:methods* / Q000706:statistics & numerical data; D015894:Genome, Human; D006680:HLA Antigens / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D058889:Molecular Typing / Q000379:methods* / Q000706:statistics & numerical data; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA
chemical_list: D006680:HLA Antigens
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