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New methods in whole-genome haplotyping

Analysis of a study published in a science journal   |   By Dr Anna Pokorska-Bocci   |   Published 12 January 2011
Study: Haplotype-resolved genome sequencing of a Gujarati Indian individual
By: Kitzman J.O. et al. (11 authors total)
In: Nature Biotechnology
What this study set out to do:

To resolve the haplotype of individual human genome sequences in order to complete the description and interpretation of the genome sequence information.

How they went about it:

Large-insert cloning was used to determine the haplotype of a South Asian individual. A library of sequences was produced, mainly derived from only one homologous chromosome at any given location. A second approach was also published recently on using a microfluidic device capable of separating and amplifying homologous copies of each chromosome from a single human cell.


Large-insert cloning data in the first study combined with genome shotgun sequencing allowed the researchers to assemble 94% of ascertained heterozygous SNPs into long haplotype blocks. A comparison of the assembly with HapMap predictions (see previous news) showed similar accuracy for common variants, but better results for rare variants. In the second study, personal haplotypes of four individuals were determined using the SNP array analysis of amplified DNA. The phases of alleles were determined at ~99.8% accuracy for up to ~96% of all assayed SNPs.


The two approaches allow an accurate resolution of the haplotype, but both have important drawbacks. The method used in the first study is based on a library construction (the very process avoided by next generation sequencing methods for genome analysis) and does not allow mapping of full chromosomes. The second method allows the resolution of whole chromosomes, but necessitates a complex isolation of single cells at a specific stage of replication.

Our view:

Haplotype information is essential for comprehensive human genome sequence comparison and analysis, but has been missing from all of the genomes previously sequenced with next-generation sequencing technologies. These two reported complementary approaches to resolve haplotypes are an important step forward for personalised medicine and population genetics, but neither method is ready yet to be used in a clinical setting.

Keywords: DNA Technologies

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