The 85th Annual Meeting of the American Association of Physical Anthropologists (2016)


Ancient alleles and complex structural variation of pathogen receptors at the glycophorin locus

ELLEN M. LEFFLER1, GAVIN BAND1, KIRK A. ROCKETT1,2, QUANG SI LE1, DOMINIC P. KWIATKOWSKI1,2 and CHRIS C.A. SPENCER1.

1Wellcome Trust Centre for Human Genetics, University of Oxford, 2Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus

April 14, 2016 3:15, Imperial Ballroom B Add to calendar

The glycophorin locus has recently been identified in genome-wide scans for both ancient balancing selection and severe malaria susceptibility, but the underlying functional mechanisms remain uncharacterized. This locus encodes three genes, GYPA, GYPB, and GYPE, that result from great-ape specific duplication events, with the first two underlying the MNS blood group system and serving as red blood cell surface receptors for pathogens including the malaria parasite Plasmodium falciparum and several viruses. Copy number variation has been reported between humans and chimpanzees as well as within human populations, but analyses are complicated by the high sequence similarity among the three homologous copies, each about 100 kb, which makes read mapping and variant calling problematic. We sought to characterize structural variation across the region by developing a hidden Markov model to infer large copy number changes from sequence coverage data. We apply the method to worldwide 1000 Genomes Phase 3 populations and identify multiple large deletions and duplications, observing marked differences in variant frequencies across continents. In particular, we find two distinct deletions of GYPB reaching 5% or higher frequency in Africa and a duplication of GYPB and part of GYPA up to 2% frequency in East Asia. We assess the potential functional impact of rearrangement of regulatory elements and fusion gene products. Finally, integrating genotypes at these variants into haplotypes, we evaluate evidence for balancing selection and relate the structural variation to alleles shared between human and chimpanzee.

This work is supported by the Wellcome Trust [097364/Z/11/Z].