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建立一个框架 用于评估由于环境因素的相互作用而导致的个体疾病风险 暴露和遗传易感性。 在一个研究项目中， 西奈儿童环境健康中心，研究人员一直在 研究功能性多态性之间的关系 对氧磷酶-1基因与母亲所生儿童神经发育 接触有机磷杀虫剂 对氧磷酶基因包括单个 启动子中的核苷酸多态性（SNP）影响 该酶的表达，以及编码区中的SNP影响该酶的表达。 酶与不同底物的比活性谱。 如果 个体对于两种类型的多态性都是杂合的， 了解基因型对酶活性的影响不需要 不仅是SNP数据，还有单倍型。 单倍型有时可以 通过使用等位基因特异性聚合酶链反应（PCR）确定，通常 包括沿着更长的基因走沿着。 调查人员建议， 开发一个强大的等位基因富集程序，可以在 使用标准引物和读数进行高通量基因分型。 因为富集将在PCR之前发生，所以单倍型可以是 延伸到分离的DNA分子的全长，不仅包括 单个基因，但基因家族的随机重复成员，如 对氧磷酶-1、-2和-3;细胞色素P450基因家族， 组织相容性基因 这种方法可能揭示单倍型特异性效应 这表明需要研究其他多态性的生物化学， 连锁不平衡。 他们将把这种方法应用于PON和CYP 3A 家庭 其他研究包括：（1）列举其他 多态性基因和基因家族的重要性研究 基因-环境相互作用;（2）确定哪些基因，种群， 以及基因与环境的相互作用，包括单倍型分析将 改进研究设计;（3）识别潜在人群 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.