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HLA-NET is a network targeted to the study of Human leukocyte antigen (HLA) from a populational point of view. The network was initiated by COST Action BM0803[1] in January 2009. Currently HLA-NET activities are being coordinated by a subcommittee of the scientific committee of the European Federation for Immunogenetics.

The project

HLA-NET defined guidelines[2] for the description of HLA typings concerning both the characterisation of the sample (including anthropological information) and the reporting of the typing data (including technical details to avoid misuse in the future). The guidelines also include rules for the validation of samples and suggests minimal requirements for data analysis. The HLA-NET portal provides an interface to software implementing these guidelines.

The genetic system

Structure of the HLA region

Medical relevance

Particularities of HLA data

HLA-NET guidelines

Population description

HLA-NET main recommendations for population characterization have been published.[2] Most notably, outdated racial/ethnical and meaningless terms have to be replaced by an acceptable terminology to describe populations (i.e. geographical and cultural criteria). An electronic population questionnaire for field studies is available on the HLA-NET portal.

Obtaining and reporting data

HLA-NET defined standards for producing high quality data for HLA genotyping and proposed guidelines for reporting typing ambiguities. A best suitable format for optimal allelic and haplotypic HLA frequency estimations, based on the list of allele pairs that account for the genotyping information, has been published.[2] Other formats that allow to express ambiguities without simplifying the data can also be used.

Validation of data sets

Samples are used to provide allele frequency estimates for populations. For HLA loci, the presence of ambiguities and that of putative recessive-like undetected alleles[3] require the assumption of Hardy-Weinberg. HLA-NET explicitly requests that frequency estimates, for alleles or haplotypes, be validated by checking their conformity with Hardy-Weinberg expectations. If Hardy-Weinberg equilibrium is rejected then the frequencies can not be taken as representative of the population. The causes for deviation should be looked for [2] and, if possible, addressed. In any case, non Hardy-Weinberg frequencies should never be used as valid population estimates.

Data analysis

HLA-NET results

Besides the guidelines above, the HLA-NET network made a contributions in the following areas

HLA map of Europe

The most fine grained map of HLA distribution in the pan-European region is a result of cooperation with the AHPD – Analysis of HLA Populations Data – component of the International Histocompatibility Workshops. Besides the well-known pan-European gradients,[4] originally reported by Cavalli-Sforza, local differentiations emerge, most notably the Alps appear as a genetic barrier to gene flow across Europe.[5][6]

Usability of registry data

Registries have moderate to huge data sets, but the recruitment often is not performed in such a way that registry data can be considered as representative of the population. However, under certain conditions, it is possible to assess if a given registry might be used as a population sample or not. Undergoing work is being conducted to formalise the constraints and the procedures required to use registry data as a proxy to population samples.[7]

Assessing natural selection at regional and local levels

Analyses of ambiguous data


  1. Action page on COST official site
  2. 2.0 2.1 2.2 2.3 Sanchez-Mazas, A.; Vidan-Jeras, B.; Nunes, J. M.; Fischer, G.; Little, A.-M.; Bekmane, U.; Buhler, S.; Buus, S. et al. (1 December 2012). "Strategies to work with HLA data in human populations for histocompatibility, clinical transplantation, epidemiology and population genetics: HLA-NET methodological recommendations". International Journal of Immunogenetics 39 (6): 459–476. doi:10.1111/j.1744-313X.2012.01113.x. PMID 22533604. PMC 3533781. 
  3. Nunes, JM; Riccio, ME; Tiercy, JM; Sanchez-Mazas, A (Jun 2011). "Allele frequency estimation from ambiguous data: using resampling schema in validating frequency estimates and in selective neutrality testing.". Human Biology 83 (3): 437–47. doi:10.3378/027.083.0307. PMID 21740157. 
  4. Piazza, L. Luca Cavalli-Sforza, Paolo Menozzi, Alberto (1996). The history and geography of human genes (Abridged paperback ed.). Princeton, N.J.: Princeton University Press. ISBN 0691029059. 
  5. Buhler, S; Nunes, JM; Nicoloso, G; Tiercy, J-M; Sanchez-Mazas, A (2012). "The Heterogeneous HLA Genetic Makeup of the Swiss Population". PLoS ONE 7 (7): e41400. doi:10.1371/journal.pone.0041400. ISSN 1932-6203. PMID 22848484. Bibcode2012PLoSO...741400B. 
  6. Buhler, S.; Megarbane, A.; Lefranc, G.; Tiercy, J.-M.; Sanchez-Mazas, A. (2006). "HLA-C molecular characterization of a Lebanese population and genetic structure of 39 populations from Europe to India-Pakistan". Tissue Antigens 68 (1): 44–57. doi:10.1111/j.1399-0039.2006.00621.x. PMID 16774539. 
  7. Constantia Voniatis Papaioannou!; Alicia Sanchez-Mazas (April 2013). "Anthropological aspects of BMD Registries". EFI Newsletter - Issue 70. Retrieved 7 June 2013. 

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