Development of SNP catalog toward to disease mapping by sequence determination of the HLA haplotypes

对许多mhc相关疾病缺乏合理的解释。对几种人类和灵长类单倍型的MHC区域（编码单元或完整contigs）进行测序，可以分析整个片段的单核苷酸变异（SNV）。我们证明了MI-IC-I的多样性并不局限于抗原/TCR结合位点，而是扩散到周围的片段。确凿的数据表明，这种搭便车的多样性，在大多数其他基因组位点被净化选择所消除，在MHC中持续存在，可能是因为不断产生和维持物种特异性多样等位基因库的强烈生物激励。大量hvSNV的存在证明了这一点，这让人想起这样一个事实，即大多数MHC多样性是从头产生的，而不是像最初认为的那样是跨物种遗传的结果。这一结果最终使MHC与大量种群和进化遗传学数据一致，这些数据坚定地得出结论，即我们物种的起源出现了一个狭窄的瓶颈，这与跨物种假设所要求的等位基因从一个物种大量流向另一个物种的事实不一致。此外，这种抗感染的适应性似乎对邻近的基因座造成了损害，因为HLA-B周围基因最丰富和多态性的片段也是大多数MHC-I疾病的定位位点。最后，这一观察结果并不局限于MHC I类区域，因为它扩展到其他MHC疾病关联，甚至可能扩展到更广泛的基因组。

A plausible explanation for many MHC-linked diseases is lacking. Sequencing of the MHC region (coding units or full contigs) in several human and primate single haplotypes allowed an analysis of Single Nucleotide Variations (SNV) across this entire segment. We demonstrate that the MI-IC-I diversity is not limited to the antigen/TCR binding sites but spreads to surrounding segments. Corroborating data suggests that this hitchhiking diversity, otherwise eliminated by purifying selection in most other genomic sites, has perdured within the MHC perhaps because of the strong biological incentive for constant generation and maintenance of a species-specific diverse allelic repertoire. This was evidenced by the existence of a large reservoir of hvSNV, reminiscent of the fact that most of MHC diversity is de novo generated and not as the result of their trans-species inheritance as initially thought.This result finally puts the MHC in line with the bulk of population and evolutionary genetics data which firmly conclude that a narrow bottleneck has occurred at the origin of our species, -a fact inconsistent with massive flow of alleles from one species to the next as required by the trans-species postulate.Moreover, this fitness in fighting infections seems to have taken its toll on neighboring loci, as the most gene-rich and polymorphic segment around HLA-B is also where most MHC-I diseases are mapped to.Finally, this observation is not limited to the MHC class I region as it extends to the other MHC-disease associations and perhaps to the wider genome.