Machado, L., Hardwick, R. J., Bowdrey, J., Bogle, H., Knowles, T., Sironi, M. and Hollox, E. J. (2012) Evolutionary history of copy-number-variable locus for the low-affinity Fcy receptor: mutation rate, autoimmune disease, and the legacy of helminth infection. The American Journal of Human Genetics. 90(6), pp. 973-985. 0002-9297.
| Item Type: | Article |
|---|---|
| Abstract: | Both sequence variation and copy-number variation (CNV) of the genes encoding receptors for immunoglobulin G (Fcg receptors) have been genetically and functionally associated with a number of autoimmune diseases. However, the molecular nature and evolutionary context of this variation is unknown. Here, we describe the structure of the CNV, estimate its mutation rate and diversity, and place it in the context of the known functional alloantigen variation of these genes. Deletion of Fcg receptor IIIB, associated with systemic lupus erythematosus, is a result of independent nonallelic homologous recombination events with a frequency of approximately 0.1%. We also show that pathogen diversity, in particular helminth diversity, has played a critical role in shaping the functional variation at these genes both between mammalian species and between human populations. Positively selected amino acids are involved in the interaction with IgG and include some amino acids that are known polymorphic alloantigens in humans. This supports a genetic contribution to the hygiene hypothesis, which states that past evolution in the context of helminth diversity has left humans with an array of susceptibility alleles for autoimmune disease in the context of a helminth-free environment. This approach shows the link between pathogens and autoimmune disease at the genetic level and provides a strategy for interrogating the genetic variation underlying autoimmunedisease risk and infectious-disease susceptibility. |
| Subjects: |
R Medicine > RC Internal medicine > RC581 Immunologic diseases. Allergy Q Science > QH Natural history > QH426 Genetics > QH438.7 Human genetics |
| Creators: | Machado, Lee, Hardwick, Robert J, Bowdrey, Jennifer, Bogle, Helen, Knowles, Timothy, Sironi, Manuela and Hollox, Edward J |
| Publisher: | University of Chicago Press |
| Northamptonshire and East Midlands: | Health |
| Faculties, Divisions and Institutes: |
University Faculties, Divisions and Research Centres - OLD > Faculty of Health & Society University Faculties, Divisions and Research Centres - OLD > Research Centre > Institute of Health and Wellbeing > Ageing Research Centre Research Centres > Centre for Health Sciences and Services Research Centres > Centre for Physical Activity and Life Sciences |
| Date: | 8 June 2012 |
| Date Type: | Publication |
| Page Range: | pp. 973-985 |
| Journal or Publication Title: | The American Journal of Human Genetics |
| Volume: | 90 |
| Number: | 6 |
| Language: | English |
| DOI: | https://doi.org/10.1016/j.ajhg.2012.04.018 |
| ISSN: | 0002-9297 |
| Status: | Published / Disseminated |
| URI: | http://nectar.northampton.ac.uk/id/eprint/5685 |
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