Detecting signatures of natural selection in the human genome with geographically explicit models

现代测序技术为我们提供了非常庞大的基因数据集，其规模在几年前是难以想象的。由于这些数据集包含了来自全球的人口，因此研究遗传变异的地理分布并试图找到为什么某些变异在某些地方比在其他地方更常见的解释是很有诱惑力的。毕竟，我们很久以前就知道，镰状细胞性贫血是在疟疾流行的地区发现的，因为它可以使人对这种致命疾病产生抵抗力。那么，我们是否可以通过研究它们的地理分布来发现其他受自然选择影响的重要基因变异呢？虽然这种方法听起来很有希望，但它提出了一个问题，即如何区分那些真正反映过去和现在选择的模式，以及那些可能只是偶然出现的模式。在这个项目中，我们建议开发一个种群遗传学框架，这将使我们能够重建解剖学上现代人在全球范围内的传播，同时考虑到过去气候和大陆形状的变化。通过了解人们是如何以及何时到达世界不同地区的，我们将能够区分哪些基因变异的地理分布过于极端，不可能仅仅是偶然的结果，从而成为自然选择的目标。除了在核基因组中寻找被选择的区域外，我们还将考虑线粒体中包含的少量遗传物质，线粒体是我们细胞中充当生化发电厂的小细胞器。线粒体DNA可以说是重建人类历史最广泛使用的信息来源，但这种重建依赖于线粒体DNA没有受到自然选择影响的假设。我们的新框架，加上这个项目将实现的线粒体遗传变异的更好的地理覆盖，将使我们能够测试中立的假设，并找到在未来人类定居历史工作中应该考虑的任何偏差。

Modern sequencing techniques have provided us with very large genetic datasets, on a scale that was hard to imagine only a couple of years ago. As these datasets comprise human populations from the entire globe, it is tempting to look at the geographic distribution of genetic variants and try to find explanations for why some variants are more common in some places rather than others. After all, we have known for a long time that sickle cell anaemia is found in regions where malaria was prevalent, as it can confer resistance to the deadly disease. So, could we find other important genetic variants that have been affected by natural selection by examining their geographic distribution? While this approach sounds promising, it raises the issue of being able to distinguish between those patterns that truly reflect past and present selection, and patterns that might have simply arisen by chance. In this project, we propose to develop a population genetics framework that will allow us to reconstruct the spread of anatomically modern humans around the globe, taking into account past changes in climate and the shape of continents. By knowing how and when people got to different parts of the world, we will then be able to distinguish which genetic variants have geographic distributions too extreme to be the result of mere chance, and thus have been the target of natural selection. Besides looking for regions under selection in the nuclear genome, we will also consider the small amount of genetic material contained in the mitochondria, small organelles that act as the biochemical powerhouses in our cells. Mitochondrial DNA is arguably the most widely used source of information for reconstructing human past history, but such reconstructions rely on the assumption that mitochondrial DNA has not been affected by natural selection. Our new framework, together with a better geographic coverage of mitochondrial genetic variability that will be achieved in this project, will allow us to test the assumption of neutrality and to find any deviation that should be taken into account in future work on human settlement history.