Genetics, Vol. 152, 393-400, May 1999, Copyright © 1999

Evolution of HLA Class II Molecules: Allelic and Amino Acid Site Variability Across Populations

Hugh Salamona, William Klitza, Simon Eastealb, Xiaojiang Gaob, Henry A. Erlichc, Marcello Fernandez-Viñad, Elizabeth A. Trachtenbergc,e, Shannon K. McWeeneya, Mark P. Nelsona, and Glenys Thomsona
a Department of Integrative Biology, University of California, Berkeley, California 94720-3140,
b Human Genetics Group, John Curtin School of Medical Research, The Australian National University, Canberra, ACT 0200, Australia,
c Department of Human Genetics, Roche Molecular Systems, Alameda, California 94501,
d American Red Cross, National Histocompatibility Laboratory, Baltimore, Maryland 21201
e Children's Hospital Oakland Research Institute, Oakland, California 94609

Corresponding author: Glenys Thomson, Department of Integrative Biology, 3060 Valley Life Sciences Bldg., MC#3140, University of California, Berkeley, CA 94720-3140., glenys{at}allele5.biol.berkeley.edu (E-mail)

Communicating editor: A. G. CLARK

Analysis of the highly polymorphic ß1 domains of the HLA class II molecules encoded by the DRB1, DQB1, and DPB1 loci reveals contrasting levels of diversity at the allele and amino acid site levels. Statistics of allele frequency distributions, based on Watterson's homozygosity statistic F, reveal distinct evolutionary patterns for these loci in ethnically diverse samples (26 populations for DQB1 and DRB1 and 14 for DPB1). When examined over all populations, the DQB1 locus allelic variation exhibits striking balanced polymorphism (P < 10-4), DRB1 shows some evidence of balancing selection (P < 0.06), and while there is overall very little evidence for selection of DPB1 allele frequencies, there is a trend in the direction of balancing selection (P < 0.08). In contrast, at the amino acid level all three loci show strong evidence of balancing selection at some sites. Averaged over polymorphic amino acid sites, DQB1 and DPB1 show similar deviation from neutrality expectations, and both exhibit more balanced polymorphic amino acid sites than DRB1. Across ethnic groups, polymorphisms at many codons show evidence for balancing selection, yet data consistent with directional selection were observed at other codons. Both antigen-binding pocket- and non-pocket-forming amino acid sites show overall deviation from neutrality for all three loci. Only in the case of DRB1 was there a significant difference between pocket- and non-pocket-forming amino acid sites. Our findings indicate that balancing selection at the MHC occurs at the level of polymorphic amino acid residues, and that in many cases this selection is consistent across populations.




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