Haplotyping for Environmental Genomics

描述(由申请人提供)： 环境基因组计划的目标之一是开发一个框架 用于评估由于环境的相互作用而导致的个人疾病风险 暴露和遗传易感性。在山上的一个研究项目中 西奈儿童环境健康中心的研究人员已经 基因功能多态与遗传易感性的关系 对氧磷酶-1(PON1)基因与母亲所生子女的神经发育 暴露在有机磷农药下。对氧磷酶基因包括单个 启动子中的单核苷酸多态(SNPs)影响 酶的表达，以及编码区的SNP影响 不同底物的酶比活力光谱。如果一个 个体对这两类多态都是杂合的，完整的 了解基因对酶活性的影响不需要 不仅有SNP数据，还有单倍型。单倍型有时可以 通过等位基因特异性聚合酶链式反应(PCR)确定，通常 包括沿着更长的基因行走。调查人员建议改为 开发一种可靠的等位基因富集法，可用于 使用标准引物和读数进行高通量基因分型。 由于浓缩将在聚合酶链式反应之前进行，因此单倍型可能是 延伸到分离的DNA分子的全长，不仅包括 单基因，但随机重复的基因家族成员，如 对氧磷酶-1、-2和-3；细胞色素P450基因家族和 组织相容性基因。这种方法可能揭示单倍型特有的效应 这表明有必要研究额外的多态的生物化学 处于连锁不平衡状态。他们将把这种方法应用于PON和CYP3A 家人。其他研究包括：(1)列举其他 多态基因和基因家族在遗传多样性研究中的重要作用 基因-环境相互作用；(2)确定哪些基因、种群、 以及包括单倍型分析在内的基因-环境相互作用 改进研究设计；以及(3)确定潜在人群 未来的分子流行病学研究。

DESCRIPTION (provided by applicant): One of the goals of the Environmental Genome Project is to develop a framework for assessing individual risk of disease due to the interplay of environmental exposure and genetic susceptibility. In one research Project in the Mount Sinai Children's Environmental Health Center, the researchers have been investigating the relationship between functional polymorphisms in the paraoxonase-1 (PON1) gene and neurodevelopment in children born to mothers exposed to organophosphate pesticides. The paraoxonase gene includes single nucleotide polymorphisms (SNPs) in the promoter affecting the level of expression of the enzyme, as well as a SNP in the coding region affecting the spectrum of specific activity of the enzyme with different substrates. If an individual is heterozygous for both classes of polymorphisms, a complete understanding of the effect of genotype on enzymatic activity requires not only the SNP data, but also the haplotypes. Haplotypes can sometimes be determined by using allele-specific polymerase chain reaction (PCR), often involving walking along longer genes. The investigators propose instead to develop a robust allele-enrichment procedure that may be used prior to carrying out high throughput genotyping using standard primers and readouts. Because the enrichment will take place before PCR, the haplotype may be extended over the full length of isolated DNA molecules to include not only single genes, but tandomly-repeated members of gene families, such as paraoxonase-1, -2, and -3; cytochrome P450 gene families and histocompatibility genes. Such a method may reveal haplotype-specific effects that point to the need to study the biochemistry of additional polymorphisms in linkage disequilibrium. They will apply the method to the PON and CYP3A families. Additional studies include: (1) enumeration of additional polymorphic genes and gene families of importance in studies of gene-environment interactions; (2) determination for which genes, populations, and gene-environment interactions that inclusion of haplotype analysis will improve the study design; and (3) identification of potential populations for future molecular epidemiologic studies.