Haplotype sorting using human fosmid clone end-sequence pairs.

An important goal of human genetics and genomics is to understand the complete spectrum of genetic variation across a specific human haplotype. By combining information from a dense SNP map with fosmid end-sequence pairs (ESPs) aligned to the human genome reference sequence, we have developed a simple method to resolve human haplotypes using a previously developed clone resource. By partitioning ESPs into either haplotype, we have generated a haplotype-specific clone map for eight diploid genomes (four Yoruba African and four non-African samples). On average, 59% of each haploid genome is covered by haplotype-assigned clones with an N50 length of 110 kbp. By comparing this clone-based haplotype map against HapMap phased data sets, we estimate an error rate of 0.71% when trio information is available and 6.6% in its absence. We present these data in the form of an interactive browser that allows clones corresponding to specific haplotypes to be recovered and sequenced within these eight human genomes. As an example, we sequenced 165 fosmid clone inserts to generate 6.8 Mbp of sequenced haplotypes, and demonstrate its utility in uncovering phase-switching errors and for the discovery of novel SNPs especially in Asian and African samples. We discuss the potential application of this resource in understanding the pattern of genetic variation in complex regions of the genome that may not be adequately resolved by next-generation sequencing technology or SNP haplotype imputation.