POLYMORPHISMS IN THE TRYPTOPHAN HYDROXYLASE 2 (TPH2) GENE IN RHESUS MONKEYS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。色氨酸羟化酶（TPH）介导色氨酸形成5-羟色胺（5-HT）的第一步。最近，发现了一个脑特异性TPH基因（TPH 2）。在人类中，G1463 A（Arg 441 His）单核苷酸多态性（SNP）与5-HT合成减少和神经精神疾病的易感性有关。为了鉴定恒河猴TPH 2基因相应区域的多态性，并研究其与人类TPH 2变体相比的功能意义，我们研究了235只恒河猴血液中的基因组DNA。通过DNA测序鉴定多态性。结果如下：鉴定了三种连锁的多态性：1）终止密码子下游29 bp处的MboI敏感性A/G SNP; 2）终止密码子下游653 bp处的159 bp插入片段，其是内含子9内连续序列的重复; 3）内含子9中的C/T SNP。应用扩增子大小判别法对203只恒河猴进行了159 bp插入多态性基因分型，其中7只（3.5%）为ins/ins纯合子，64只（31.5%）为杂合子。159 bp插入片段的等位基因频率为19.2%。在一个队列的32个行为和生理特征的猴子的初步基因型-表型调查表明，A/G多态性可能与下丘脑-垂体-肾上腺（HPA）轴功能。队列中唯一的ins/ins纯合子未能显示地塞米松抑制，并且在队列中具有最低的CSF促肾上腺皮质激素释放激素水平。讨论：这三个多态性是连锁不平衡的。初步的基因型-表型相关性暗示了3？UTR多态性和进一步的研究正在进行中。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Tryptophan hydroxylase (TPH) mediates the first step in formation of serotonin (5-HT) from tryptophan. Recently, a brain-specific TPH gene (TPH2) was discovered. In human, a G1463A (Arg441His) single nucleotide polymorphism (SNP) was reported to be associated with decreased 5-HT synthesis and susceptibility to neuropsychiatric disorders. To identify polymorphisms in corresponding regions of the rhesus monkey TPH2 gene, and investigate their functional significance compared to the human TPH2 variant we investigated genomic DNA from blood of 235 rhesus monkeys. Polymorphisms were identified by DNA sequencing. Results: Three linked polymorphisms were identified: 1) an MboI-sensitive A/G SNP 29 bp downstream from the stop codon; 2) a 159-bp insert located 653 bp downstream from the stop codon that is a duplication of a contiguous sequence within intron 9; and 3) a C/T SNP in intron 9. Amplicon size discrimination was used to genotype 203 rhesus monkeys for the 159-bp insertion polymorphism, among which 7 (3.5%) monkeys were ins/ins homozygotes and 64 (31.5%) were heterozygotes. The allele frequency for the 159-bp insert was 19.2%. Preliminary genotype-phenotype investigations in a cohort of 32 behaviorally and physiologically characterized monkeys suggests that the A/G polymorphism may be associated with hypothalamic-pituitary-adrenal (HPA) axis function. The only ins/ins homozygote in the cohort failed to show dexamethasone suppression and had the lowest CSF corticotrophin-releasing hormone levels in the cohort. Discussion: The three identified polymorphisms are in linkage disequilibrium. Preliminary genotype-phenotype correlation implies a potential significance for the 3?-UTR polymorphisms and further studies are in progress.