Genetic Adaptation of Fatty-Acid Metabolism: A Human-Specific Haplotype Increasing the Biosynthesis of Long-Chain Omega-3 and Omega-6 Fatty Acids
Genetic Adaptation of Fatty-Acid Metabolism: A Human-Specific Haplotype Increasing the Biosynthesis of Long-Chain Omega-3 and Omega-6 Fatty Acids
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DOI：
10.1016/j.ajhg.2012.03.014
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发表时间：
2012-05-04
影响因子：
9.8
通讯作者：
Gyllensten, Ulf
中科院分区：
文献类型：
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作者：
Ameur, Adam;Enroth, Stefan;Gyllensten, Ulf
Omega-3 和 omega-6 长链多不饱和脂肪酸 (LC-PUFA) 对于人类大脑的发育和功能至关重要。它们可以直接从食物（例如鱼）中获得，也可以由植物油中的前体分子合成。为了确定遗传变异对脂肪酸生物合成的重要性，我们研究了 FADS1 和 FADS2，它们编码脂肪酸转化的限速酶。我们对五个欧洲人群队列的 FADS 区域进行了全基因组基因分型（n = 5,652 人）和靶向重测序（n = 960 人）。我们还分析了来自人类、古人类和更遥远的灵长类动物的可用基因组数据。我们的结果表明，当今人类有两种常见的 FADS 单倍型（由 38.9 kb 上的 28 个紧密相连的 SNP 定义），它们生成 LC-PUFA 的能力存在显着差异。通过靶向重测序检测到的稀有 SNP 没有发现对 FADS 活性的独立影响。在导致现代人类和尼安德特人的谱系分裂之后，出现了更有效的、进化衍生的单倍型，并显示出正选择的证据。这种人类特异性单倍型提高了从前体合成必需长链脂肪酸的效率，从而可能在饮食中长链多不饱和脂肪酸获取有限的环境中提供优势。在现代世界，这种单倍型与生活方式相关的疾病有关，例如冠状动脉疾病。
Omega-3 and omega-6 long-chain polyunsaturated fatty acids (LC-PUFAs) are essential for the development and function of the human brain. They can be obtained directly from food, e.g., fish, or synthesized from precursor molecules found in vegetable oils. To determine the importance of genetic variability to fatty-acid biosynthesis, we studied FADS1 and FADS2, which encode rate-limiting enzymes for fatty-acid conversion. We performed genome-wide genotyping (n = 5,652 individuals) and targeted resequencing (n = 960 individuals) of the FADS region in five European population cohorts. We also analyzed available genomic data from human populations, archaic hominins, and more distant primates. Our results show that present-day humans have two common FADS haplotypes-defined by 28 closely linked SNPs across 38.9 kb-that differ dramatically in their ability to generate LC-PUFAs. No independent effects on FADS activity were seen for rare SNPs detected by targeted resequencing. The more efficient, evolutionarily derived haplotype appeared after the lineage split leading to modern humans and Neanderthals and shows evidence of positive selection. This human-specific haplotype increases the efficiency of synthesizing essential long-chain fatty acids from precursors and thereby might have provided an advantage in environments with limited access to dietary LC-PUFAs. In the modern world, this haplotype has been associated with lifestyle-related diseases, such as coronary artery disease.