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

许多与MHC相关的疾病缺乏合理的解释。对几种人类和灵长类动物单倍型的MHC区域（编码单位或完整重叠群）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。确证的数据表明，这种搭便车的多样性，否则消除了纯化选择在大多数其他基因组位点，已经perdur内的MHC可能是因为强大的生物刺激不断产生和维持物种特异性的多样性等位基因库。hvSNV的大量储存证明了这一点，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，而不是最初认为的跨物种遗传的结果。这一结果最终使MHC与大部分人口和进化遗传学数据一致，这些数据坚定地得出结论，即在我们物种的起源处发生了一个狭窄的瓶颈，- 这一事实与跨物种假设所要求的等位基因从一个物种到下一个物种的大量流动不一致。此外，这种对抗感染的适应性似乎已经对邻近的基因座造成了损失，因为HLA-B周围基因最丰富和多态性最高的片段也是大多数MHC-I疾病的定位。最后，这一观察结果并不局限于MHC I类区域，因为它延伸到其它MHC-疾病相关性，并且可能延伸到更广泛的基因组。

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.