Division of Human Genetics, Center for Molecular Medicine, Jichi Medical University, Yakushiji, Shimotsuke, Tochigi, Japan.
Hum Genet. 2013 Feb;132(2):201-17. doi: 10.1007/s00439-012-1240-9. Epub 2012 Oct 31.
Accumulation of visceral fat increases cardiovascular mortality in industrialized societies. However, during the evolution of the modern human, visceral fat may have acted as energy storage facility to survive in times of famine. Therefore, past natural selection might contribute to shaping the variation of visceral fat accumulation in present populations. Here, we report that the gene encoding tribbles homolog 2 (TRIB2) influenced visceral fat accumulation and was operated by recent positive natural selection in East Asians. Our candidate gene association analysis on 11 metabolic traits of 5,810 East Asians revealed that rs1057001, a T/A transversion polymorphism in 3'untranslated region (UTR) of TRIB2, was strongly associated with visceral fat area (VFA) and waist circumference adjusted for body mass index (P = 2.7 × 10(-6) and P = 9.0 × 10(-6), respectively). rs1057001 was in absolute linkage disequilibrium with a conserved insertion-deletion polymorphism in the 3'UTR and was associated with allelic imbalance of TRIB2 transcript levels in adipose tissues. rs1057001 showed high degree of interpopulation variation of the allele frequency; the low-VFA-associated A allele was found with high frequencies in East Asians. Haplotypes containing the rs1057001 A allele exhibited a signature of a selective sweep, which may have occurred 16,546-27,827 years ago in East Asians. Given the predominance of the thrifty gene hypothesis, it is surprising that the apparently non-thrifty allele was selectively favored in the evolution of modern humans. Environmental/physiological factors other than famine would be needed to explain the non-neutral evolution of TRIB2 in East Asians.
内脏脂肪的积累会增加工业化社会的心血管死亡率。然而，在现代人类的进化过程中，内脏脂肪可能充当了能量储存设施，以在饥荒时期生存。因此，过去的自然选择可能有助于塑造现代人类中内脏脂肪积累的变异。在这里，我们报告编码 tribbles 同源物 2（TRIB2）的基因影响内脏脂肪积累，并且在东亚人群中受到近期正选择的作用。我们对 5810 名东亚人的 11 项代谢特征进行候选基因关联分析，发现 TRIB2 的 3'UTR 中 T/A 颠换多态性 rs1057001 与内脏脂肪面积（VFA）和体重指数调整后的腰围强烈相关（P=2.7×10(-6)和 P=9.0×10(-6)）。rs1057001 与 3'UTR 中的保守插入缺失多态性完全连锁，并与脂肪组织中 TRIB2 转录本水平的等位基因不平衡相关。rs1057001 显示出等位基因频率在不同人群之间的高度变异；低 VFA 相关的 A 等位基因在东亚人群中出现的频率较高。含有 rs1057001 A 等位基因的单倍型表现出选择清除的特征，这可能发生在 16546-27827 年前的东亚人群中。鉴于节俭基因假说的盛行，令人惊讶的是，在现代人类的进化过程中，明显非节俭的等位基因受到了选择的青睐。需要环境/生理因素来解释 TRIB2 在东亚人群中的非中性进化，而不仅仅是饥荒。
