Department of Zoology, University of Oxford, 11a Mansfield Road, Oxford, OX1 3SZ, UK.
BMC Evol Biol. 2020 Oct 19;20(1):134. doi: 10.1186/s12862-020-01696-3.
Two gerbil species, sand rat (Psammomys obesus) and Mongolian jird (Meriones unguiculatus), can become obese and show signs of metabolic dysregulation when maintained on standard laboratory diets. The genetic basis of this phenotype is unknown. Recently, genome sequencing has uncovered very unusual regions of high guanine and cytosine (GC) content scattered across the sand rat genome, most likely generated by extreme and localized biased gene conversion. A key pancreatic transcription factor PDX1 is encoded by a gene in the most extreme GC-rich region, is remarkably divergent and exhibits altered biochemical properties. Here, we ask if gerbils have proteins in addition to PDX1 that are aberrantly divergent in amino acid sequence, whether they have also become divergent due to GC-biased nucleotide changes, and whether these proteins could plausibly be connected to metabolic dysfunction exhibited by gerbils.
We analyzed ~ 10,000 proteins with 1-to-1 orthologues in human and rodents and identified 50 proteins that accumulated unusually high levels of amino acid change in the sand rat and 41 in Mongolian jird. We show that more than half of the aberrantly divergent proteins are associated with GC biased nucleotide change and many are in previously defined high GC regions. We highlight four aberrantly divergent gerbil proteins, PDX1, INSR, MEDAG and SPP1, that may plausibly be associated with dietary metabolism.
We show that through the course of gerbil evolution, many aberrantly divergent proteins have accumulated in the gerbil lineage, and GC-biased nucleotide substitution rather than positive selection is the likely cause of extreme divergence in more than half of these. Some proteins carry putatively deleterious changes that could be associated with metabolic and physiological phenotypes observed in some gerbil species. We propose that these animals provide a useful model to study the 'tug-of-war' between natural selection and the excessive accumulation of deleterious substitutions mutations through biased gene conversion.
沙鼠（Psammomys obesus）和蒙古仓鼠（Meriones unguiculatus）这两种沙鼠物种在以标准实验室饮食维持时会肥胖并出现代谢失调的迹象。这种表型的遗传基础尚不清楚。最近，基因组测序揭示了沙鼠基因组中散布着非常不寻常的高鸟嘌呤和胞嘧啶（GC）含量区域，这些区域很可能是由极端和局部的偏向基因转换产生的。胰腺转录因子 PDX1 由 GC 含量最丰富的区域中的一个基因编码，其高度分化，表现出改变的生化特性。在这里，我们想问沙鼠除了 PDX1 之外，是否还有其他氨基酸序列异常分化的蛋白质，它们是否也因为 GC 偏向的核苷酸变化而变得分化，以及这些蛋白质是否可能与沙鼠表现出的代谢功能障碍有关。
我们分析了大约 10000 种具有人类和啮齿动物 1:1 直系同源物的蛋白质，在沙鼠和蒙古仓鼠中发现了 50 种蛋白质积累了异常高水平的氨基酸变化。我们表明，超过一半的异常分化蛋白与 GC 偏向的核苷酸变化有关，许多蛋白都在之前定义的高 GC 区域。我们重点介绍了四个异常分化的沙鼠蛋白，PDX1、INSR、MEDAG 和 SPP1，它们可能与饮食代谢有关。
我们表明，在沙鼠进化过程中，许多异常分化的蛋白在沙鼠谱系中积累，而 GC 偏向的核苷酸取代而不是正选择可能是这些蛋白中一半以上极度分化的原因。一些蛋白携带潜在的有害变化，这些变化可能与一些沙鼠物种中观察到的代谢和生理表型有关。我们提出，这些动物为研究自然选择和偏向基因转换导致的有害突变过度积累之间的“拉锯战”提供了一个有用的模型。
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