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Balancing selection is common in the extended MHC region but most alleles with opposite risk profile for autoimmune diseases are neutrally evolving

Rachele Cagliani1, Stefania Riva1, Uberto Pozzoli1, Matteo Fumagalli12, Giacomo P Comi3, Nereo Bresolin13, Mario Clerici45 and Manuela Sironi1*

Author Affiliations

1 Scientific Institute IRCCS E. Medea, 23842 Bosisio Parini (LC), Italy

2 Bioengineering Department, Politecnico di Milano, 20133 Milan, Italy

3 Dino Ferrari Centre, Department of Neurological Sciences, University of Milan, IRCCS Ospedale Maggiore Policlinico, Mangiagalli and Regina Elena Foundation, 20100 Milan, Italy

4 Chair of Immunology, Department of Biomedical Sciences and Technologies LITA Segrate, University of Milano, 20090 Milano, Italy

5 Fondazione Don C. Gnocchi, IRCCS, 20148 Milano, Italy

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BMC Evolutionary Biology 2011, 11:171  doi:10.1186/1471-2148-11-171

Published: 17 June 2011



Several susceptibility genetic variants for autoimmune diseases have been identified. A subset of these polymorphisms displays an opposite risk profile in different autoimmune conditions. This observation open interesting questions on the evolutionary forces shaping the frequency of these alleles in human populations.

We aimed at testing the hypothesis whereby balancing selection has shaped the frequency of opposite risk alleles.


Since balancing selection signatures are expected to extend over short genomic portions, we focused our analyses on 11 regions carrying putative functional polymorphisms that may represent the disease variants (and the selection targets). No exceptional nucleotide diversity was observed for ZSCAN23, HLA-DMB, VARS2, PTPN22, BAT3, C6orf47, and IL10; summary statistics were consistent with evolutionary neutrality for these gene regions. Conversely, CDSN/PSORS1C1, TRIM10/TRIM40, BTNL2, and TAP2 showed extremely high nucleotide diversity and most tests rejected neutrality, suggesting the action of balancing selection. For TAP2 and BTNL2 these signatures are not secondary to linkage disequilibrium with HLA class II genes. Nonetheless, with the exception of variants in TRIM40 and CDSN, our data suggest that opposite risk SNPs are not selection targets but rather have accumulated as neutral variants.


Data herein indicate that balancing selection is common within the extended MHC region and involves several non-HLA loci. Yet, the evolutionary history of most SNPs with an opposite effect for autoimmune diseases is consistent with evolutionary neutrality. We suggest that variants with an opposite effect on autoimmune diseases should not be considered a distinct class of disease alleles from the evolutionary perspective and, in a few cases, the opposite effect on distinct diseases may derive from complex haplotype structures in regions with high genetic diversity.

autoimmune disease; balancing selection; opposite risk profile; extended MHC region