Pharmacogenetic Variation in Neanderthals and Denisovans and Implications for Human Health and Response to Medications.
Pharmacogenetic Variation in Neanderthals and Denisovans and Implications for Human Health and Response to Medications.
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DOI：
10.1093/gbe/evad222
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发表时间：
2023-12-01
影响因子：
3.3
通讯作者：
Claw, Katrina G.
中科院分区：
文献类型：
--
作者：
Wroblewski, Tadeusz H.;Witt, Kelsey E.;Lee, Seung-been;Malhi, Ripan S.;Peede, David;Huerta-Sanchez, Emilia;Villanea, Fernando A.;Claw, Katrina G.
现代人类携带尼安德特人和丹尼索瓦人（古代）基因组元素，这些基因组元素是人类基因库的一部分，影响着活着的个体的生命和健康。古DNA的影响可能在药物基因中特别明显，这些基因负责处理外源物质，如食物，污染物和药物，因为这些基因可能与不断变化的环境影响有关，当现代人遇到新环境时，有益的变异可能被保留下来。然而，古代祖先对现代人类药物基因的健康影响和贡献仍然没有得到充分研究。在这里，我们探讨了11个关键的细胞色素P450基因（CYP450）参与75%的所有药物代谢反应在三个尼安德特人和一个丹尼索瓦人的个人，并检查古代基因渗入现代人群。我们推断这11个CYP450基因在古代个体中的代谢效率，并发现相对于现代人类变体的重要预测表型差异。我们在每个基因中确定了古人类和现代人类之间共享的几个单核苷酸变体，包括古CYP 450基因中的一些潜在功能改变突变，这可能导致携带这些变体的活人代谢改变。我们还发现了几个古老的CYP450基因的变体，这些变体是古老人类特有的，还有一个基因CYP2B6，它显示了只在尼安德特人和现代非洲人中发现的基因重复的证据。最后，我们强调CYP2A6，CYP2C9和CYP2J2，这些基因显示了古代基因渗入现代人类的证据，并解释了现代人群中等位基因频率的进化假说。
Modern humans carry both Neanderthal and Denisovan (archaic) genome elements that are part of the human gene pool and affect the life and health of living individuals. The impact of archaic DNA may be particularly evident in pharmacogenes—genes responsible for the processing of exogenous substances such as food, pollutants, and medications—as these can relate to changing environmental effects, and beneficial variants may have been retained as modern humans encountered new environments. However, the health implications and contribution of archaic ancestry in pharmacogenes of modern humans remain understudied. Here, we explore 11 key cytochrome P450 genes (CYP450) involved in 75% of all drug metabolizing reactions in three Neanderthal and one Denisovan individuals and examine archaic introgression in modern human populations. We infer the metabolizing efficiency of these 11 CYP450 genes in archaic individuals and find important predicted phenotypic differences relative to modern human variants. We identify several single nucleotide variants shared between archaic and modern humans in each gene, including some potentially function-altering mutations in archaic CYP450 genes, which may result in altered metabolism in living people carrying these variants. We also identified several variants in the archaic CYP450 genes that are novel and unique to archaic humans as well as one gene, CYP2B6, that shows evidence for a gene duplication found only in Neanderthals and modern Africans. Finally, we highlight CYP2A6, CYP2C9, and CYP2J2, genes which show evidence for archaic introgression into modern humans and posit evolutionary hypotheses that explain their allele frequencies in modern populations.
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DOI：
10.3109/00498254.2012.685777
发表时间：
2012-11
期刊：
Xenobiotica; the fate of foreign compounds in biological systems
影响因子：
--
作者：
Desta Z;Moaddel R;Ogburn ET;Xu C;Ramamoorthy A;Venkata SL;Sanghvi M;Goldberg ME;Torjman MC;Wainer IW
通讯作者：
Wainer IW
影响因子：
2.8
作者：
Haeggstrom, Sigrid;Ingelman-Sundberg, Magnus;Paabo, Svante;Zeberg, Hugo
通讯作者：
Zeberg, Hugo
通过适应本地来进行全球：对最近的人类适应的评论。
DOI：
10.1126/science.aaf5098
发表时间：
2016-10-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Fan S;Hansen ME;Lo Y;Tishkoff SA
通讯作者：
Tishkoff SA
影响因子：
3.5
作者：
Chen, L.;Li, J. H.;Florez, J. C.
通讯作者：
Florez, J. C.
影响因子：
64.5
作者：
Browning SR;Browning BL;Zhou Y;Tucci S;Akey JM
通讯作者：
Akey JM