生物谷报道：生活在大城市里的人与世世代代生活在封闭区域的人相比，其聪明程度的差距可能正在拉大。美国华人科学家，芝加哥大学助教Bruce T. Lahn（中文译为蓝田）吃惊地发现：人类大脑中的一组“人性基因Humanness”仍在以超乎寻常的速度进化！这一组基因决定前人类的脑容量以及智力的进化和发育。由于这组基因的进化与人所处的社会的文明活动有关，大脑的加速进化还可能带来一些社会后果———可能会导致不同社会中的人种间的智力发展不平衡。这一组基因是通过对大量的高等生物的基因组比较筛选出的候选基因。
The foreground shows brain images of human, macaque monkey, rat, and mouse (from top to bottom), as well as the phylogenetic relationship among these four taxa. The background shows DNA sequences. Brain complexity has increased dramatically in primates relative to rodents, and the increase is particularly pronounced in the lineage leading to humans. At the molecular level, genes involved in nervous system function also show accelerated rates of evolution in primates, especially in the lineage leading to humans. Thus, the dramatic phenotypic evolution of the brain in the origin of Homo sapiens is correlated with salient molecular evolution.
Cover image, Cell, December 29, 2004; illustrator, Sean Gould. See also Dorus, S., Vallender, E.J., Evans, P.D., Anderson, J.R., Gilbert, S.L., Mahowald, M., Wyckoff, G.J., Malcom, C.M., and Lahn, B.T. 2004. Cell 119:1027–1040.
这一研究结果刊登在今日美国出版的Science杂志上，由华裔科学家蓝田领导的研究小组的新发现有可能引发人类学家激烈的争论。蓝田同一课题的两篇论文同时发表在一期Science杂志上，实属罕见，这两篇论文分别介绍了人脑中两个正在高速进化的“人性基因Humanness”，以证明人类大脑仍在高速进化。其中一个名为ASPM的基因在距今5800年前才出现；另一个名为Mi-crocephalin的基因是距今37000年前出现的。此前，人类学家认为20万年前现代人出现之后，人类进化就“定型”了，蓝田等人的研究可能引起人类学家对现代人进化速度的重新关注。科学家认为，这两个“新基因”可能决定人脑的容量，进而可能影响到人类的智力水平。为此Science同一期还发表了两篇述评，见附文。
据蓝田的博士后项鹏介绍，从1998年开始，蓝田通过对全基因组范围内与神经系统有关的两百多个基因的系统性研究，并对人类、猴子、大鼠和小鼠进行比较，发现灵长类（人、猴）的神经系统基因的进化速度比啮齿类（老鼠等）高出30%；而在灵长类中，神经系统基因的进化速度尤其迅速。2004年同样一篇阶段性成果发表在Cell上。
科学家推测，这两个“新基因”的出现可能与农耕、语言、文字等人类文明活动的出现有关，这似乎表明了人类基因进化随着社会文明的不断发展而推进，两者之间存在一种因果关系。另一方面，由于人类文明发展速度不平衡，一些落后地区的人大脑中“人性基因”的进化速度可能较为缓慢。
美国科学家８日说，基因分析表明，直到现在为止人类的大脑一直在快速进化过程中，而且这种进化与人类文明的兴起有密切联系。
早先的化石和基因证据表明，人类和黑猩猩在约６００万年前由共同的祖先“分家”，此后人类祖先的大脑快速进化，并产生了较高级的认知功能，直至距今约２０万年前现代智人出现为止。在人们的习惯观念中，现代人类大脑在生理上已经“定型”了。
由芝加哥大学科学家蓝田博士领导的一个研究小组，对人类体内管理脑容量大小的两个基因的演变进行分析。他们共搜集了世界各地５９个民族、１０００多人的基因样本，并发现这两个基因都正在进化中，现代人的大脑没有“定型”。
蓝田解释说，这种进化并不是同时发生在整个种群中，而是一个漫长的选择过程。极少数个体率先发生基因变异，出现新的单模态，而基因的新单模态使这些个体获得生存和繁衍的优势，然后在整个种群中传播。
研究人员发现，这两种对大脑发育至关重要的基因在自然选择的压力下以超乎寻常的速度进化。７０％的现代人小脑症基因的单模态，是距今３．７万年前首次出现的；而３０％现代人异常纺锤型小脑畸形症相关基因的单模态，是在５８００年前首次出现。两种形态的出现都大大晚于２０万年前出现的现代人类。
研究人员说，这些新近出现的基因变异，在时间上与人类文明的兴起有密切联系。人类历史上首次出现复杂工具制造、艺术、音乐等是在５万年前，而人类最古老的文明——美索不达米亚文明在公元前７０００年兴起。
他们猜测，文明的出现使人类面临的环境更加复杂，也加快了选择的过程，因此优势的基因单模态能很快传播。
蓝田说，人类大脑的容量和复杂度仍然在快速进化中，现代人类面临的环境变化更快，也需要更复杂的技能，而人脑将继续通过适应性选择来进化，跟上变化的环境。生物谷专家认为蓝田博士的研究使人类从分子水平对人类的进化作了新的阐述，是分子进化学的研究上的里程碑式的研究，从分子角度揭示了高等生物，尤其是人类进化之谜。
本期Science上的两篇蓝田博士文章及两篇评论
Microcephalin, a Gene Regulating Brain Size, Continues to Evolve Adaptively in Humans
Patrick D. Evans, Sandra L. Gilbert, Nitzan Mekel-Bobrov, Eric J. Vallender, Jeffrey R. Anderson, Leila M. Vaez-Azizi, Sarah A. Tishkoff, Richard R. Hudson, and Bruce T. Lahn
Science 9 September 2005: 1717-1720
[Abstract] [Full Text] [PDF] [Supporting Online Material]
Ongoing Adaptive Evolution of ASPM, a Brain Size Determinant in Homo sapiens
Nitzan Mekel-Bobrov, Sandra L. Gilbert, Patrick D. Evans, Eric J. Vallender, Jeffrey R. Anderson, Richard R. Hudson, Sarah A. Tishkoff, and Bruce T. Lahn
Science 9 September 2005: 1720-1722
[Abstract] [Full Text] [PDF] [Supporting Online Material]
Are Human Brains Still Evolving? Brain Genes Show Signs of Selection
Michael Balter
Science 9 September 2005: 1662-1663
[Summary] [Full Text] [PDF]
A Human-Specific Gene in Microglia
Toshiyuki Hayakawa, Takashi Angata, Amanda L. Lewis, Tarjei S. Mikkelsen, Nissi M. Varki, and Ajit Varki
Science 9 September 2005: 1693
[Abstract] [Full Text] [PDF] [Supporting Online Material]
国外报道：
Accelerated Evolution of Nervous System Genes in the Descent of Homo sapiens
Thus far, most efforts to study the genetic basis of human brain evolution have focused on one gene (or one gene family) at a time. The ad hoc nature of these studies (and their scarcity) made it difficult to discern broad evolutionary trends. To address whether the evolution of the human brain has left genome-wide genetic imprints, we systematically examined the evolutionary history of more than 200 genes implicated in diverse biological aspects of the human nervous system. Coding sequences of these genes were compared across four mammalian taxa—human, macaque (an Old World monkey), rat, and mouse. For each gene, the nonsynonymous-to-synonymous substitution ratio (Ka/Ks) was calculated separately for primates (based on human-macaque comparison) and for rodents (based on rat-mouse comparison). The Ka/Ks ratio is a measure of protein evolution rate as scaled to neutral mutation rate.
Our analysis showed that, on average, Ka/Ks for nervous system genes is higher in primate than in rodent (by more than 30 percent), indicating that the proteins encoded by these genes have evolved about 30 percent faster in primates. Moreover, when examining only the subset of genes that function predominantly in nervous system development, the primate-rodent disparity in Ka/Ks became even more pronounced (more than 50 percent higher in primates than rodents). By contrast, genes that function primarily in the routine physiology and maintenance of the nervous system showed much less primate-rodent disparity. Within primates, the increase in Ka/Ks is most pronounced in the lineage leading from ancestral primates to humans. These observations argue that the remarkable phenotypic evolution of the human nervous system is correlated with accelerated evolution in the protein-coding regions of the underlying genes, particularly those genes involved in the development of the nervous system. The above trends are the result of a large number of mutations scattered across many nervous system genes.
Our study shed light on several long-standing questions regarding the genetic basis of human brain evolution. The first is whether functionally important mutations have occurred predominantly in protein-coding regions or regulatory regions of genes. Our data suggest that changes in coding regions are likely to be important, although this conclusion does not in any way imply that regulatory changes are necessarily less important to brain evolution. The study also asked whether many genes or just a few key genes confer the increase in brain size and structural complexity. The results suggest that a large number of mutations in many genes are probably needed to produce the dramatic structural changes observed in the human brain. Indeed, it can be roughly estimated that there is, on average, an excess of 1–2 nonsynonymous substitutions in primates over rodents for every nervous system gene. When only the developmental subgroup of genes is considered, the excess rises to 3–4 nonsynonymous substitutions per gene in primates over rodents. Thus, thousands of mutations in many hundreds (or possibly even thousands) of genes might have contributed to the evolution of the human brain. The third question addressed by the study is how easily detectable these functionally important mutations are. The results suggest that the human genome (when analyzed in conjunction with the genomes of other species) might contain an abundance of “smoking guns” that are informative about the genetic changes important for the emergence of the human form.
To extend our analysis to the entire genome, we are taking advantage of the growing number of mammalian genomes that have been sequenced. These studies should not only offer additional broad insights but also provide an entry point for identifying individual genes that have played important roles in human evolution.
Candidate “Humanness” Genes
Although they shed broad light on how the human brain evolved at the genetic level, the evolutionary trends described above do not immediately reveal the specific genes (or mutations) that are key to human brain evolution. The second major objective of our research is to use a multistep strategy to identify such genes.
In the first step, we perform large-scale comparisons of genes across multiple species in a manner similar to the comparative study described above. This allows us to identify “outliers” in the genome—i.e., genes exhibiting a rate of evolutionary changes in the human lineage that is significantly greater than that of the other mammalian lineages. In the second step, we compare outlier genes over a much wider range of primate and nonprimate taxa, to confirm the exceptional nature of their accelerated evolution in the human lineage. In the third step, we subject genes with the most interesting evolutionary patterns to polymorphism studies in humans. Through combined analysis of polymorphism data and divergence data—for example, by using the McDonald-Kreitman test—we can discern whether the accelerated evolution in the human lineage is due to positive selection.
Employing the above strategy, we identified a number of candidate genes that might have played a role in the evolution of the human brain (candidate “humanness” genes). In humans, homozygous loss-of-function mutations in two of these genes, ASPM or Microcephalin, cause microcephaly, a congenital developmental defect characterized by severely reduced brain size. Although their brains are smaller, affected subjects have relatively normal brain structure and no overt abnormalities outside of the nervous system. Based on these observations, it was concluded that ASPM and Microcephalin are specific regulators of brain size. The two genes share a similar set of evolutionary properties. First, they show significantly accelerated evolution in primates relative to nonprimate mammals. Second, within primates, this acceleration is most prominent in the lineage leading to humans. Third, comparison of interspecies divergence data with human polymorphism data confirmed that the accelerated evolution in the human lineage is likely due to positive selection. Finally, the accelerated evolution appears to be highly localized within specific regions of these genes, suggesting that positive selection has targeted certain domains of the genes more intensely than others. The above data provide compelling evidence that ASPM and Microcephalin have been the target of strong positive selection during primate evolution, and such selection is most prominent in the human lineage.
Is the Human Brain Still Evolving?
The most salient trend in the evolutionary history of Homo sapiens is the rapid increase of brain size and complexity. Could this trend be continuing even in modern-day humans? To address this question, we focused on the set of candidate “humanness” genes we found through comparative genomics analysis and searched for evidence of ongoing adaptive evolution among present-day humans. We reasoned that if a gene has evolved adaptively in the making of the human species, it may well continue to undergo adaptive evolution even after the emergence of anatomically modern humans. Based on the analysis of human polymorphism patterns, we found evidence that some of these genes are experiencing ongoing positive selection in modern humans, suggesting that the human brain is still evolving actively toward new and more adaptive forms.
Other Research Activities
Within the evolution field, we are also interested in identifying genome-wide patterns. For example, our recent study showed that a strong correlation exists between the fixation probability of nonsynonymous mutations and mutation rate. This highly unexpected finding indicates that the probability by which new mutations are accepted during evolution is affected not only by selection—as postulated by the long-standing theoretical paradigm—but also by mutation rate. The fact that our finding cannot be reconciled with prevailing theories suggests that the current theoretical framework of molecular evolution may need a major revision.
Another research emphasis of my lab is stem cell biology, which includes two broad aims. First, we attempt to understand the molecular mechanisms that render pluripotency to stem cells, or conversely, restricted cellular phenotype to differentiated cells. We are testing the hypothesis that the restriction of cell fate during development is achieved, at least in part, by secluding key regulatory genes from the cell's transcriptional machinery. The second aim of our stem cell research is to explore applications of these cells in therapy. We are using both in vitro and in vivo approaches to develop methods to differentiate stem cells into desired cell types. We are also testing the therapeutic potential of stem cells in animal models. Some of our stem cell work, especially that aimed at therapeutic applications, is done in collaboration with the Center for Stem Cell Biology and Tissue Engineering at Sun Yat-sen University, China.
Finally, our lab is interested in neurogenetics. We recently cloned a mouse gene corresponding to a hypertonia phenotype (i.e., increased muscle tone). Further characterization of the gene showed that it plays a critical role in regulating the homeostasis of GABAA receptors in neurons, probably by modulating the endocytic recycling of GABAA receptors. In mutant mice, GABAA receptor concentration is dramatically reduced, leading to disinhibition of motor neurons (and hence hypertonia). In another project, which combines stem cell biology with neurogenetics, we knocked out a mouse gene that has been suggested by other people's work to play an important role in the development of neural stem cells. Knockout mice showed a severe developmental defect of the nervous system that is likely due to the misregulation of neural stem cells. In a related project, we are developing a set of genetic tools to study the function and fate of neural stem cells in the adult mouse brain.
Grants from the National Institutes of Health, the Burroughs Wellcome Fund, and the Searle Scholars Program provided support for these projects.
Bruce T. Lahn, Ph.D. 简介及实验室，联系方式
University of Chicago
Department of Human Genetics
Cummings Life Sciences Center
920 E. 58th St., 3rd Floor
Chicago, Illinois 60637
Phone: 773-834-4065
Fax: 773-834-8470
support@hominid.uchicago.edu
Bruce T. Lahn博士近年几年的重要论文
Gilbert SL, Dobyns WB, Lahn BT.Genetic links between brain development and brain evolution.
Nat Rev Genet. 2005 Jul;6(7):581-90. Review.
Wyckoff GJ, Malcom CM, Vallender EJ, Lahn BT. A highly unexpected strong correlation between fixation probability of nonsynonymous mutations and mutation rate.
Trends Genet. 2005 Jul;21(7):381-5. Review
Vallender EJ, Pearson NM, Lahn BT. The X chromosome: not just her brother's keeper.
Nat Genet. 2005 Apr;37(4):343-
Dorus S, Vallender EJ, Evans PD, Anderson JR, Gilbert SL, Mahowald M, Wyckoff GJ, Malcom CM, Lahn BT.Accelerated evolution of nervous system genes in the origin of Homo sapiens.
Cell. 2004 Dec 29;119(7):1027-40.
Dorus S, Evans PD, Wyckoff GJ, Choi SS, Lahn BT. Rate of molecular evolution of the seminal protein gene SEMG2 correlates with levels of female promiscuity.
Nat Genet. 2004 Dec;36(12):1326-9
