Research
Haplotypic analysis of the TNF locus by association efficiency and entropy
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* Corresponding author: Hans Ackerman ackerman@fas.harvard.edu
1 Wellcome Trust for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK
2 Institute of Biological Anthropology, 58 Banbury Road, Oxford, OX2 9QS, UK
3 University Department of Paediatrics, John Radcliffe Hospital, Oxford OX3 9DU, UK
4 MRC Laboratories, Fajara, The Gambia
5 Welcome Trust Research Laboratories and Malaria Project, College of Medicine, University of Malawi, Blantyre, Malawi
6 Current address: Harvard Medical School, 64 Linnaean Street, Cambridge, MA 02138, USA
7 Deceased
Genome Biology 2003, 4:R24 doi:10.1186/gb-2003-4-4-r24
Published: 17 March 2003Abstract
Background
To understand the causal basis of TNF associations with disease, it is necessary to understand the haplotypic structure of this locus. We genotyped 12 single-nucleotide polymorphisms (SNPs) distributed over 4.3 kilobases in 296 healthy, unrelated Gambian and Malawian adults. We generated 592 high-quality haplotypes by integrating family- and population-based reconstruction methods.
Results
We found 32 different haplotypes, of which 13 were shared between the two populations. Both populations were haplotypically diverse (gene diversity = 0.80, Gambia; 0.85, Malawi) and significantly differentiated (p < 10-5 by exact test). More than a quarter of marker pairs showed evidence of intragenic recombination (29% Gambia; 27% Malawi). We applied two new methods of analyzing haplotypic data: association efficiency analysis (AEA), which describes the ability of each SNP to detect every other SNP in a case-control scenario; and the entropy maximization method (EMM), which selects the subset of SNPs that most effectively dissects the underlying haplotypic structure. AEA revealed that many SNPs in TNF are poor markers of each other. The EMM showed that 8 of 12 SNPs (Gambia) and 7 of 12 SNPs (Malawi) are required to describe 95% of the haplotypic diversity.
Conclusions
The TNF locus in the Gambian and Malawi sample is haplotypically diverse and has a rich history of intragenic recombination. As a consequence, a large proportion of TNF SNPs must be typed to detect a disease-modifying SNP at this locus. The most informative subset of SNPs to genotype differs between the two populations.