Sequences of 95 Human Haplotypes Reveal Extreme Coding Variation in Genes Other Than Highly Polymorphic and

The most polymorphic part of the human genome, the encodes over 160 proteins of diverse function. Half of them, including the and genes, are directly involved in immune responses. Consequently, the region strongly associates with numerous diseases and clinical therapies. Notoriously, the region has been intractable to high-throughput analysis at complete sequence resolution, and current reference haplotypes are inadequate for large-scale studies. To address these challenges, we developed a method that specifically captures and sequences the 4.8-Mbp region from genomic DNA. For 95 homozygous cell lines we assembled, de novo, a set of high-fidelity contigs and a sequence scaffold, representing a mean 98% of the target region. Included are six alternative reference sequences of the human genome that we completed and refined. Characterization of the sequence and structural diversity of the region shows the approach accurately determines the sequences of the highly polymorphic and genes and the complex structural diversity of complement factor It has also uncovered extensive and unexpected diversity in other genes; an example is , which encodes a lung mucin and exhibits more coding sequence alleles than any or gene studied here. More than 60% of the coding sequence alleles analyzed were previously uncharacterized. We have created a substantial database of robust reference haplotype sequences that will enable future population scale studies of this complicated and clinically important region of the human genome.