Guo Zhen, Hood Leroy, Malkki Mari, Petersdorf Effie W
Division of Clinical Research, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA.
Proc Natl Acad Sci U S A. 2006 May 2;103(18):6964-9. doi: 10.1073/pnas.0602286103. Epub 2006 Apr 21.
Haplotypes are a powerful tool for identifying the genetic basis of common complex diseases. Disease-association mapping requires molecular methods for haplotyping biallelic SNP variation and highly complex polymorphisms. We developed a method for phasing HLA-A, HLA-B, and HLA-DRB1 alleles on chromosome 6 in unrelated individuals. This method uses the highly polymorphic HLA-B locus to discriminate the two HLA haplotypes in heterozygous individuals and its ideal location 1.4 Mbp telomeric to HLA-DRB1 and 1.2 Mbp centromeric to HLA-A to capture 2-Mbp-long genomic DNA. Genomic DNA representing a single HLA-B-captured haplotype is genotyped for HLA-A and HLA-DRB1 alleles and linkage to HLA-B is established. Proof of principle was established in a large blinded study of phase-known samples. Availability of an efficient method for MHC haplotype phase determination will facilitate the mapping of causative MHC-resident genes in many human diseases and has the potential to be broadened to other polymorphic gene complexes.
单倍型是识别常见复杂疾病遗传基础的有力工具。疾病关联图谱绘制需要用于对双等位基因SNP变异和高度复杂多态性进行单倍型分型的分子方法。我们开发了一种在无关个体中对6号染色体上的HLA - A、HLA - B和HLA - DRB1等位基因进行定相的方法。该方法利用高度多态的HLA - B基因座来区分杂合个体中的两种HLA单倍型，其理想位置是在HLA - DRB1端粒方向1.4 Mbp处以及HLA - A着丝粒方向1.2 Mbp处，以捕获2 Mbp长的基因组DNA。对代表单个HLA - B捕获单倍型的基因组DNA进行HLA - A和HLA - DRB1等位基因基因分型，并建立与HLA - B的连锁关系。在一项对已知定相样本的大型盲法研究中确立了原理证明。一种有效的MHC单倍型定相测定方法将有助于在许多人类疾病中对致病的MHC驻留基因进行图谱绘制，并且有可能扩展到其他多态基因复合体。
