Genetic variation in an individual human exome.
Genetic variation in an individual human exome.
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DOI：
10.1371/journal.pgen.1000160
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发表时间：
2008-08-15
期刊：
影响因子：
4.5
通讯作者：
Venter, J. Craig
中科院分区：
文献类型：
--
作者：
Ng, Pauline C.;Levy, Samuel;Huang, Jiaqi;Stockwell, Timothy B.;Walenz, Brian P.;Li, Kelvin;Axelrod, Nelson;Busam, Dana A.;Strausberg, Robert L.;Venter, J. Craig
人们对人体的差异有很大的兴趣，因为这可能会阐明对一个人的表型的贡献，从而使个性化的基因组学在这里。一个基因组，因为认为外显子体具有大部分功能变异，所以我们对影响个人基因组的蛋白质编码部分的约1200个变体进行了分析在该个体中，〜10,400个非象征性的单核苷酸多态性（NSSNP），其中约15-20％在人口中很少见〜700个编码实例，大约一半的长度往往是三个的长度，这会导致相应蛋白质中的氨基酸插入/缺失，而不是引入框架也经常出现在基因的末端，因此，indel会导致框架，在基因中的替代开始或停止位点仍然可以用来制作功能蛋白。 12,500个非专利的编码变体对一组变体的变体最有可能对其蛋白质的功能产生重大影响。个性化基因组学的状态。我们将发现非SNP变体。变化。
表征个体的功能变化是迈向个性化医学时代的重要一步。 J. Craig Venter的遗传变异，重点是基因编码部分的变异，这被认为对一个人的物理化妆有显着贡献调查约为12,500个非专业编码变体，通过采用多种生物信息学方法，我们将潜在的表型变体的数量减少了约8倍。与任何已知的表型有关；在人口中，由于在未来几年中，通过全基因组关联研究来阐明与常见变异的表型关联，因此随着个性化基因组的测序，解释个性化基因组的能力将变得更加普遍。我们在这项研究中提出了范式，以追求许多个体基因组蛋白质编码变体的研究。
There is much interest in characterizing the variation in a human individual, because this may elucidate what contributes significantly to a person's phenotype, thereby enabling personalized genomics. We focus here on the variants in a person's ‘exome,’ which is the set of exons in a genome, because the exome is believed to harbor much of the functional variation. We provide an analysis of the ∼12,500 variants that affect the protein coding portion of an individual's genome. We identified ∼10,400 nonsynonymous single nucleotide polymorphisms (nsSNPs) in this individual, of which ∼15–20% are rare in the human population. We predict ∼1,500 nsSNPs affect protein function and these tend be heterozygous, rare, or novel. Of the ∼700 coding indels, approximately half tend to have lengths that are a multiple of three, which causes insertions/deletions of amino acids in the corresponding protein, rather than introducing frameshifts. Coding indels also occur frequently at the termini of genes, so even if an indel causes a frameshift, an alternative start or stop site in the gene can still be used to make a functional protein. In summary, we reduced the set of ∼12,500 nonsilent coding variants by ∼8-fold to a set of variants that are most likely to have major effects on their proteins' functions. This is our first glimpse of an individual's exome and a snapshot of the current state of personalized genomics. The majority of coding variants in this individual are common and appear to be functionally neutral. Our results also indicate that some variants can be used to improve the current NCBI human reference genome. As more genomes are sequenced, many rare variants and non-SNP variants will be discovered. We present an approach to analyze the coding variation in humans by proposing multiple bioinformatic methods to hone in on possible functional variation. Characterizing the functional variation in an individual is an important step towards the era of personalized medicine. Protein-coding exons are thought to be especially enriched in functional variation. In 2007, we published the genome sequence of J. Craig Venter. Here we analyze the genetic variation of J. Craig Venter's exome, focusing on variation in the coding portion of genes, which is thought to contribute significantly to a person's physical make-up. We survey ∼12,500 nonsilent coding variants and, by applying multiple bioinformatic approaches, we reduce the number of potential phenotypic variants by ∼8-fold. Our analysis provides a snapshot of the current state of personalized genomics. We find that <1% of variants are linked to any known phenotypes; this demonstrates the dearth of scientific knowledge for phenotype-genotype associations. However, ∼80% of an individual's nonsynonymous variants are commonly found in the human population and, because phenotypic associations to common variants will be elucidated via genome-wide association studies over the next few years, the capability to interpret personalized genomes will expand and evolve. As sequencing of individual genomes becomes more prevalent, the bioinformatic approaches we present in this study can be used as a paradigm to pursue the study of protein-coding variants for the genomes of many individuals.
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