欣闻母校学子组成的年轻科研团队又在Cell上发表重磅封面文章，探讨北极熊与棕熊在进化上开始分化（趋异）的年代，此前他们曾在Nature上发文介绍大熊猫基因组测序及组装。

这说明“后生可畏”，不管是博士生还是本科生，学生哥只要有较高的科研起点、较先进的科研平台和较优秀的科研导师，完全可以做出具有世界先进水平的科研成果！

他们所拥有的较高科研起点是功能基因组学，较先进科研平台是高通量全基因组测序，较优秀导师是华大基因研究院享有国际声誉的导师群。

我的科研课题常常与功能基因组学发生联系，因此也很关注国际上该领域的最新研究进展。同时，我对生物分子进化有着浓厚兴趣，尤其对北极熊、大熊猫等珍稀动物的起源与演化研究结果非常好奇。另外，研究涉及的肥胖及代谢疾病的相关内容正是我目前的研究领域。

这篇文章经过国际顶尖学者审查通过，其科学意义和研究水平不容置疑，但我特别想知道他们研究的创新点究竟在哪里。于是，我找来了2012年分别发表在Science和PNAS上的两篇类似的文章，然后跟这篇2014年发表在Cell上的文章对比，看看三者在研究目的和意义、材料与方法、结果和结论上有何异同，这样其创新点就一目了然了！

首先来看研究目的和意义，Science论文是单纯研究北极熊、棕熊、黑熊的分化年代，尤其关注线粒体基因组与细胞核基因组的序列数据一致性，而Cell和PNAS文章不仅研究北极熊的演化，而且把研究焦点集中于其对海洋动物性高脂饮食的适应性基因变异，有助于了解人类肥胖性代谢疾病的成因及探索其解决方案。

其次，从材料与方法来看，Science和PNAS文章都以北极熊、棕熊和黑熊样本为研究材料，其中Science文章使用了45个动物样本，PNAS文章使用了5个动物样本，而Cell文章仅分析了北极熊（79个）与棕熊（10个）样本。三者都采用细胞核基因组测序法，但只有PNAS和Cell文章是深度测序，而Science文章仅针对14个基因位点的9116个核苷酸进行选择性测序。

从结果和结论来看，Science文章认为北极熊与棕熊约在60（33.8-93.4）万年前分化。PNAS文章认为北极熊与棕熊在400万年前至500万年前就开始独立进化，而50万年前北极气候的巨变导致北极熊的快速适应。Cell文章认为北极熊与棕熊的分化年代为47.9万年前至34.3万年前。这些通过细胞核基因组测序对分化年代的估计都远远早于此前通过线粒体基因组测序估计的11.1万年前至16.6万年前。之所以用线粒体基因组估计的分化年代要晚于用细胞核基因组估计的分化年代，是因为北极熊与棕熊在分化后曾发生过杂交，结果使来自棕熊的线粒体混入北极熊后代的细胞质中。由化石估计的北极熊与棕熊的分化年代更是在年代上相差极大的80万年前至15万年前。

最后来看Cell得出有关脂肪组织发育与脂肪代谢基因的结果和结论，在心肌病及血管病相关的16个基因中，有9个基因受到正向选择，也即发生了有益的功能性基因突变，其中最典型的是编码所谓“坏胆固醇”的低密度脂蛋白（LDL）主要蛋白质成分的APOB基因。另外，Cell文章还解析了北极熊白色皮毛源于两个相关基因（LYST和AIM1）的变异。PNAS文章则关注了FTO、PLTP、CPT1B和ACSL6等肥胖相关基因的变异，同时也关注了EDNRB和TRMP1等毛色相关基因的变异。Science文章则未关注任何代谢相关基因。

综上所述，Cell文章的创新点在于引入了基因的功能分析，比如适应高脂饮食的基因和皮毛变白的基因，而且与PNAS文章所关注的基因完全不同，其研究结果对了解及治疗人类疾病有启发。那么，是不是Science文章无法进行这类分析（数据挖掘）呢？其实并非如此，可能它仅仅关注熊类动物的起源与进化研究，而没有考虑进行生物信息学分析。尽管针对全基因组测序所获得的数据，研究人员都可以通过同源性比较发现基因突变及其位置，但却并不能解释这样的突变就能导致这样的功能。遗憾的是，Cell和PNAS文章也未能做到这一点，仅仅针对人类及小鼠同源基因进行了关联比较，有待今后进一步开展研究，将基因的某个（些）突变与蛋白质的某种（些）功能联系起来。

附：

Science论文题目和摘要

Nuclear Genomic Sequences Reveal that Polar Bears Are an Old and Distinct Bear Lineage

Hailer F. et al.

Recent studies have shown that the polar bear matriline (mitochondrial DNA) evolved from a brown bear lineage since the late Pleistocene, potentially indicating rapid speciation and adaption to arctic conditions. Here, we present a high-resolution data set from multiple independent loci across the nuclear genomes of a broad sample of polar, brown, and black bears. Bayesian coalescent analyses place polar bears outside the brown bear clade and date the divergence much earlier, in the middle Pleistocene, about 600 (338 to 934) thousand years ago. This provides more time for polar bear evolution and confirms previous suggestions that polar bears carry introgressed brown bear mitochondrial DNA due to past hybridization. Our results highlight that multilocus genomic analyses are crucial for an accurate understanding of evolutionary history.

PNAS论文题目和摘要

Polar and brown bear genomes reveal ancient admixture and demographic footprints of past climate change

Miller W. et al.

Polar bears (PBs) are superbly adapted to the extreme Arctic environment and have become emblematic of the threat to biodiversity from global climate change. Their divergence from the lower-latitude brown bear provides a textbook example of rapid evolution of distinct phenotypes. However, limited mitochondrial and nuclear DNA evidence conflicts in the timing of PB origin as well as placement of the species within versus sister to the brown bear lineage. We gathered extensive genomic sequence data from contemporary polar, brown, and American black bear samples, in addition to a 130,000- to 110,000-y old PB, to examine this problem from a genome-wide perspective. Nuclear DNA markers reflect a species tree consistent with expectation, showing polar and brown bears to be sister species. However, for the enigmatic brown bears native to Alaska’s Alexander Archipelago, we estimate that not only their mitochondrial genome, but also 5–10% of their nuclear genome, is most closely related to PBs, indicating ancient admixture between the two species. Explicit admixture analyses are consistent with ancient splits among PBs, brown bears and black bears that were later followed by occasional admixture. We also provide paleodemographic estimates that suggest bear evolution has tracked key climate events, and that PB in particular experienced a prolonged and dramatic decline in its effective population size during the last ca. 500,000 years. We demonstrate that brown bears and PBs have had sufficiently independent evolutionary histories over the last 4–5 million years to leave imprints in the PB nuclear genome that likely are associated with ecological adaptation to the Arctic environment.

Cell论文题目和摘要

Liu S. et al.

Population Genomics Reveal Recent Speciation and Rapid Evolutionary Adaptation in Polar Bears

Polar bears are uniquely adapted to life in the High Arctic and have undergone drastic physiological changes in response to Arctic climates and a hyperlipid diet of primarily marine mammal prey. We analyzed 89 complete genomes of polar bear and brown bear using population genomic modeling and show that the species diverged only 479–343 thousand years BP. We find that genes on the polar bear lineage have been under stronger positive selection than in brown bears; nine of the top 16 genes under strong positive selection are associated with cardiomyopathy and vascular disease, implying important reorganization of the cardiovascular system. One of the genes showing the strongest evidence of selection, APOB, encodes the primary lipoprotein component of low-density lipoprotein (LDL); functional mutations in APOB may explain how polar bears are able to cope with life-long elevated LDL levels that are associated with high risk of heart disease in humans.

Science.pdf    PNAS-2012-Miller-E2382-90.pdf    Cell-2014-Liu.pdf

雪人（范晓萱）

阿莲（戴军）