MHCcluster, a method for functional clustering of MHC molecules.
Immunogenetics. 2013, Jun 18.
1Center for Biological Sequence Analysis,
Technical University of Denmark,
DK-2800 Lyngby, Denmark
2Instituto de Investigaciones Biotecnolo#gicas, Universidad Nacional de San Martin, San Martin, Buenos Aires, Argentina,
2ALK, Boege Alle 6, DK-2970 Hoersholm, Denmark,
4Division of Experimental Immunology,
Institute of Medical Microbiology and Immunology,
University of Copenhagen, Denmark
The identification of peptides binding to major histocompatibility
complexes (MHC) is a critical step in the understanding of T cell
immune responses. The human MHC genomic region (HLA) is extremely
polymorphic comprising several thousand alleles, many encoding a
distinct molecule. The potentially unique specificities remain
experimentally uncharacterized for the vast majority of HLA molecules.
Likewise, for nonhuman species, only a minor fraction of the known MHC
molecules have been characterized. Here, we describe a tool,
MHCcluster, to functionally cluster MHC molecules based on their
predicted binding specificity. The method has a flexible web interface
that allows the user to include any MHC of interest in the analysis.
The output consists of a static heat map and graphical tree-based
visualizations of the functional relationship between MHC variants and
a dynamic TreeViewer interface where both the functional relationship
and the individual binding specificities of MHC molecules are
visualized. We demonstrate that conventional sequence-based clustering
will fail to identify the functional relationship between molecules,
when applied to MHC system, and only through the use of the predicted
binding specificity can a correct clustering be found. Clustering of
prevalent HLA-A and HLA-B alleles using MHCcluster confirms the
presence of 12 major specificity groups (supertypes) some however with
highly divergent specificities. Importantly, some HLA molecules are
shown not to fit any supertype classification. Also, we use MHCcluster
to show that chimpanzee MHC class I molecules have a reduced functional
diversity compared to that of HLA class I molecules. MHCcluster is
available at www.cbs.dtu.dk/services/MHCcluster-2.0 .