Genetic analysis of completely sequenced disease-associated MHC haplotypes identifies shuffling of segments in recent human history.
Genetic analysis of completely sequenced disease-associated MHC haplotypes identifies shuffling of segments in recent human history.
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DOI：
10.1371/journal.pgen.0020009
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发表时间：
2006-01
期刊：
影响因子：
4.5
通讯作者：
Beck, Stephan
中科院分区：
文献类型：
--
作者：
Traherne, James A.;Horton, Roger;Roberts, Anne N.;Miretti, MarcosM.;Hurles, Matthew E.;Stewart, C. Andrew;Ashurst, Jennifer L.;Atrazhev, Alexey M.;Coggill, Penny;Palmer, Sophie;Almeida, Jeff;Sims, Sarah;Wilming, Laurens G.;Rogers, Jane;de Jong, Pieter J.;Carrington, Mary;Elliott, John F.;Sawcer, Stephen;Todd, John A.;Trowsdale, John;Beck, Stephan
主要组织相容性复合体（MHC）被认为是与人类常见疾病相关的最重要的遗传区域之一。在鉴定赋予疾病易感性的MHC基因方面的进展需要对整个复合体的序列变异有更多的了解。然而，人类基因组的高度重复和多态性区域，如MHC，对于一些全基因组分析方法来说有些难处理。为了解决这个问题，我们正在采用细菌人工染色体（BAC）克隆策略，对来自血缘细胞系的整个MHC单倍型进行测序，作为MHC单倍型计划的一部分。在这里，我们提出了4.25 Mb的人类单倍型QBL（HLA-A26-B18-Cw 5-DR 3-DQ 2），并将其与MHC参考单倍型和第二单倍型，考克斯（HLA-A1-B8-Cw 7-DR 3-DQ 2），共享相同的HLA-DRB 1，-DQA 1，和-DQB 1等位基因进行比较。我们已经定义了所有三种单倍型的完整基因、剪接变体和序列变异内容，包括超过259个注释位点和超过20，000个单核苷酸多态性（SNP）。某些编码序列在不同的单倍型之间差异显着，使其成为功能和疾病相关性研究的候选者。两个DR 3单倍型的分析允许划定的共享序列之间的两个HLA II类相关的单倍型不同的疾病协会和鉴定的至少一个网站介导的原始重组事件。除了一个158 kb的片段包含HLA-DRB 1、-DQA 1和-DQB 1基因，并且显示出非常有限的多态性，与血统认同和相对较近的共同祖先（<3，400代）相容之外，整个MHC的变异水平与其他HLA不同的单倍型相似。这些结果表明，这两个DR 3单倍型的差异性疾病协会是由于这个中央158 kb片段以外的序列变异，并通过重组的祖先块改组是一个潜在的机制，从而某些DR-DQ等位基因组合，这大概有有利的免疫功能，可以跨单倍型和人群传播。参与人类免疫系统的一组基因包含在6号染色体的一个令人惊讶的短片段中，该染色体长期以来被认为是与疾病易感性相关的最重要的基因组区域。辨别在疾病中起作用的实际基因已经被证明是困难的，主要是因为该区域包含许多基因，并且也是基因组中遗传变异最多的区域。在这个变化的丛林中，这里报道的研究已经确定并表征了两个个体共享的一个离散片段，该片段几乎没有变化多态性沙漠。在极端变异的背景下，这一片段的保存表明了早期人类历史上的古老起源和遗传交换。这些观察结果在进化方面很重要，因为它们揭示了一种潜在的机制，即与有利的免疫功能相关的某些遗传片段在人群中传播。从医学角度来看，这也可以解释不同种族背景的人患疾病的风险。公众访问这些数据将帮助研究人员找到赋予疾病易感性或抵抗力的特定变体，并如本报告所述，排除对某些疾病具有特异性的区域。
The major histocompatibility complex (MHC) is recognised as one of the most important genetic regions in relation to common human disease. Advancement in identification of MHC genes that confer susceptibility to disease requires greater knowledge of sequence variation across the complex. Highly duplicated and polymorphic regions of the human genome such as the MHC are, however, somewhat refractory to some whole-genome analysis methods. To address this issue, we are employing a bacterial artificial chromosome (BAC) cloning strategy to sequence entire MHC haplotypes from consanguineous cell lines as part of the MHC Haplotype Project. Here we present 4.25 Mb of the human haplotype QBL (HLA-A26-B18-Cw5-DR3-DQ2) and compare it with the MHC reference haplotype and with a second haplotype, COX (HLA-A1-B8-Cw7-DR3-DQ2), that shares the same HLA-DRB1, -DQA1, and -DQB1 alleles. We have defined the complete gene, splice variant, and sequence variation contents of all three haplotypes, comprising over 259 annotated loci and over 20,000 single nucleotide polymorphisms (SNPs). Certain coding sequences vary significantly between different haplotypes, making them candidates for functional and disease-association studies. Analysis of the two DR3 haplotypes allowed delineation of the shared sequence between two HLA class II–related haplotypes differing in disease associations and the identification of at least one of the sites that mediated the original recombination event. The levels of variation across the MHC were similar to those seen for other HLA-disparate haplotypes, except for a 158-kb segment that contained the HLA-DRB1, -DQA1, and -DQB1 genes and showed very limited polymorphism compatible with identity-by-descent and relatively recent common ancestry (<3,400 generations). These results indicate that the differential disease associations of these two DR3 haplotypes are due to sequence variation outside this central 158-kb segment, and that shuffling of ancestral blocks via recombination is a potential mechanism whereby certain DR–DQ allelic combinations, which presumably have favoured immunological functions, can spread across haplotypes and populations. A group of genes involved in the human immune system are contained within a surprisingly short section of Chromosome 6 that has long been recognised as the most important genomic region in relation to disease susceptibility. Discerning the actual genes playing a role in disease has proved difficult mainly because the region contains numerous genes and is also the most genetically variable in the genome. Within this jungle of variation, the research reported here has identified and characterised a discrete segment shared by two individuals that is virtually devoid of variation—a polymorphism desert. The conservation of this segment amongst a background of extreme variation suggests both an ancient origin and genetic exchange in early human history. These observations are important in evolutionary terms as they reveal a potential mechanism whereby certain genetic segments associated with favourable immune functions have spread across human populations. Within medical terms this may also explain contrasting disease risks in people from different ethnic backgrounds. Public access to these data will help researchers find specific variants conferring disease susceptibility or resistance and, as in this report, rule out regions for conveying specificity to certain diseases.
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