A comprehensively molecular haplotype-resolved genome of a European individual
A comprehensively molecular haplotype-resolved genome of a European individual
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DOI：
10.1101/gr.125047.111
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发表时间：
2011-10-01
期刊：
影响因子：
7
通讯作者：
Hoehe, Margret R.
中科院分区：
文献类型：
--
作者：
Suk, Eun-Kyung;McEwen, Gayle K.;Hoehe, Margret R.
独立确定个体基因组的两种单倍型序列对于将遗传变异与基因组功能、表型和疾病联系起来是至关重要的。为了解决阶段的重要性，我们通过基于Fosmid池的下一代测序生成了迄今为止最完整的单倍型解析基因组“Max Planck One”(MP1)。几乎所有的SNP(>；99%)和80,000个Indels都被分成了高达6.3Mb(N50类似于1Mb)的单倍体序列。分期的完整性允许确定绝大多数基因(81%)的具体分子单倍型对，包括潜在的调节序列，其中90%被发现由两种不同的分子形式组成。159个基因的子集，在顺式或反式构型中具有潜在的严重突变，特别是阶段对基因功能、疾病和个人基因组的临床解释的作用(例如，BRCA1)。含有多种物理和/或功能相关基因和调控元件组合的扩展基因组区域被分解成它们潜在的“单倍体景观”，这可能定义了功能基因组。此外，大多数基因和功能序列都被发现含有个别或罕见的SNPs，这不能仅从种群数据中分阶段进行，强调了分子相变对于表征基因组的分子个体性的重要性。我们的工作为理解分子单倍型的区别对于解决基因、基因组和疾病的(固有的个体)生物学是必不可少的，并为“相敏感”的个人基因组学建立了一个参照点。MP1的S注释的单倍体基因组可以作为公共资源获得。
Independent determination of both haplotype sequences of an individual genome is essential to relate genetic variation to genome function, phenotype, and disease. To address the importance of phase, we have generated the most complete haplotype-resolved genome to date, "Max Planck One'' (MP1), by fosmid pool-based next generation sequencing. Virtually all SNPs (>99%) and 80,000 indels were phased into haploid sequences of up to 6.3 Mb (N50 similar to 1 Mb). The completeness of phasing allowed determination of the concrete molecular haplotype pairs for the vast majority of genes (81%) including potential regulatory sequences, of which >90% were found to be constituted by two different molecular forms. A subset of 159 genes with potentially severe mutations in either cis or trans configurations exemplified in particular the role of phase for gene function, disease, and clinical interpretation of personal genomes (e.g., BRCA1). Extended genomic regions harboring manifold combinations of physically and/or functionally related genes and regulatory elements were resolved into their underlying "haploid landscapes,'' which may define the functional genome. Moreover, the majority of genes and functional sequences were found to contain individual or rare SNPs, which cannot be phased from population data alone, emphasizing the importance of molecular phasing for characterizing a genome in its molecular individuality. Our work provides the foundation to understand that the distinction of molecular haplotypes is essential to resolve the (inherently individual) biology of genes, genomes, and disease, establishing a reference point for "phase-sensitive'' personal genomics. MP1's annotated haploid genomes are available as a public resource.