Comparative Genomics Group
实验室概况 导师简介 研究方向 最新进展 团队成员


 

用恒河猴做外群进行大脑表达基因在人类中的适应性进化研究

  在这项研究中,用生物信息的办法,选择猕猴做外群,我们进行了2,633个人类大脑表达基因在人和黑猩猩中的进化分析. 研究发现了47个基因在人类进化中受到了达尔文自然选择,而且大脑里高表达基因在人类中的进化速率也高于在黑猩猩中的. 通过比较分析,还发现用人类近缘物种猕猴做外群进行人类进化研究要优于用小鼠这个远缘物种.
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Detecting lineage-specific adaptive evolution of brain-expressed genes in human using rhesus macaque as outgroup
In this project, we conducted phylogeny-based analyses of 2,633 human brain-expressed genes using rhesus macaque as outgroup using bioinformatic tools, and identified 47 candidate genes showing strong evidence of positive selection in the human lineage. We observed that genes with maximal expression in the brain showed higher evolutionary rate in human than in chimpanzee. We also found that rhesus macaque performed much better than mouse as outgroup in identifying lineage-specific selection in humans because it is phylogenetically much closer to human/chimp.
The paper of this work is published in "Genomics".

 

宿兵实验室发现人类大脑特有的基因剪切体

在真核生物基因组中,基因的选择性剪切(alternative splicing)是非常普遍的现象。在人类基因组中,至少有一半以上的基因存在选择性剪切。因此,在进化过程中,基因的选择性剪切是产生新蛋白质和新功能的重要机制之一。宿兵研究员的实验室最近通过对一个在中枢神经系统发挥作用的丝氨酸蛋白酶基因-neuropsin (又称KLK8) 的研究发现,该基因在人类大脑中存在一个表达丰度很高的新的剪切体。这种剪切体在人类的近亲黑猩猩和黄猩猩(orangutan)以及其他非人灵长类中却没有表达,是一个人类大脑中特异表达的剪切体。通过物种间的序列比较分析和细胞水平报告基因的实验,他们发现在人类neuropsin基因内涵子中的一个点突变导致了新的剪切体的产生。他们将黑猩猩neurospin基因的相应位置突变为人类的序列后,黑猩猩的基因在报告基因的实验中也会表达人类特有的新剪切体,从而证明这一在人类进化中产生并在人群中固定下来的突变是导致人类大脑中产生neuropsin基因新剪切体的根本原因。本项研究表明,在人类起源中,基因剪切的变化可能是导致人脑中产生新的蛋白质进而出现新功能的重要机制之一。这一研究成果发表于国际知名刊物《Human Mutation》。(http://www3.interscience.wiley.com/cgi-bin/abstract/114250882/ABSTRACT, May 8, 2007)。英国《新科学家》(New Scientist)杂志对这一研究成果进行了报道 (http://www.newscientist.com/channel/life/mg19426035.100-gene-variant-may-be-responsible-for-human-learning.html, May 12, 2007)

The First Human-Specific Splice Variant Is Discovered by Bing Su’s Research Group

In eukaryotic genome, alternative splicing is a versatile form of genetic control whereby a common pre- mRNA is processed into multiple mRNA isoforms differing in their precise combination of exon sequences. A recent study suggested that more than 55% of human genes are alternatively spliced. More scientists accept that this is also one potentially important mechanism for creation of new proteins during evolution.
Led by Dr. Bing Su of the Chinese Academy of Sciences in Kunming, China, a new study showed that a certain form ?(type II) of neuropsin (KLK8), a protein that plays a role in learning and memory, is expressed only in the central nervous systems of humans and that it originated less than 5 million years ago. By comparative sequence analysis and in vitro splicing assay, they found one fixed site T in human is not only necessary but also sufficient for type II expression .This work demonstrate a molecular mechanism for the creation of novel proteins through alternative splicing in the central nervous system during human evolution.
New Scientist Magazine also reports this research work..

http://www.newscientist.com/channel/life/mg19426035.100-gene-variant-may-be-responsible-for-human-learning.html, May 12, 2007)

 

 

宿兵实验室发现快速进化的灵长类microRNA

microRNA是近年发现的在基因组中广泛存在的一类小的、非编码基因。它通过与mRNA中特定的互补位点结合来调节蛋白编码基因的表达和翻译,从而参与发育的精细调控等一系列重要的生命过程。目前,绝大多数已知的microRNA在序列上都很保守,表明其承担着重要的生物学功能。然而,基因组中也可能存在快速进化的microRNA, 并在新的表型和功能的产生中发挥作用。
我所宿兵研究员的实验室最近通过对灵长类代表物种的研究,发现了一个快速进化的microRNA家族。这个家族位于X染色体上,并在睾丸中优势表达。在灵长类的进化过程中,这个家族不断通过基因重复产生新的拷贝,且拷贝数在灵长类物种间存在差异。同时,这个家族的microRNA序列变异的速度明显高于基因组中已知microRNA基因的平均水平,从而导致一些物种特异的microRNA基因的产生。以前的很多研究表明,在灵长类的进化中,与雄性生殖相关的蛋白编码基因由于受到很强的选择,进化速度很快。宿兵研究员实验室的研究结果证实,除蛋白编码基因以外,microRNA基因也会受到达尔文正选择的影响,发生快速的进化。这一研究结果将为我们更为全面地了解非蛋白编码基因的进化模式及其在功能进化中的作用提供崭新的视角。研究结果发表于基因组学国际知名刊物《Genome Research》 (http://www.genome.org/papbyrecent.shtml)。

The First Human-Specific Splice Variant Is Discovered by Bing Su’s Research Group

In eukaryotic genome, alternative splicing is a versatile form of genetic control whereby a common pre- mRNA is processed into multiple mRNA isoforms differing in their precise combination of exon sequences. A recent study suggested that more than 55% of human genes are alternatively spliced. More scientists accept that this is also one potentially important mechanism for creation of new proteins during evolution.
Led by Dr. Bing Su of the Chinese Academy of Sciences in Kunming, China, a new study showed that a certain form ?(type II) of neuropsin (KLK8), a protein that plays a role in learning and memory, is expressed only in the central nervous systems of humans and that it originated less than 5 million years ago. By comparative sequence analysis and in vitro splicing assay, they found one fixed site T in human is not only necessary but also sufficient for type II expression .This work demonstrate a molecular mechanism for the creation of novel proteins through alternative splicing in the central nervous system during human evolution.
New Scientist Magazine also reports this research work..

http://www.newscientist.com/channel/life/mg19426035.100-gene-variant-may-be-responsible-for-human-learning.html, May 12, 2007)?

 

 

垂体腺苷环化酶激活肽(PACAP)在人类起源中的加速进化

  PACAP在中枢神经系统丰富表达,参与神经系统发育调控和神经信号传导。在脊椎动物中,PACAP的氨基酸序列非常保守,具有很强的功能限制。然而,我们在对人和非人灵长类PACAP前体基因的研究中发现,该基因在人类起源过程中经历了异常快速的进化。尽管PACAP本身的序列很保守,但PACAP前体蛋白在人类中产生了很多的氨基酸变异,其变异速率是其他哺乳动物的7倍以上。同时,通过基因结构域的分析,我们推测在人类的大脑中可能产生了一个新的神经肽,参与人类高级认知的起源,论文发表于《 Genetics 》。 <文章下载>《Science》报道连接: http://sciencenow.sciencemag.org/cgi/content/full/2005/420/4

Accelerated Evolution of the Pituitary Adenylate Cyclase-Activating Polypeptide Precursor Gene During Human Origin
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide abundantly expressed in the central nervous system, and involved in regulating neurogenesis and neuronal signal transduction. The amino acid sequence of PACAP is extremely conserved across vertebrate species, indicating a strong functional constraint during the course of evolution. However, through comparative sequence analysis, we demonstrated that the PACAP precursor gene underwent an accelerated evolution in the human lineage since the divergence from chimpanzees, and the amino acid substitution rate in humans is at least seven times faster than in other mammal species resulting from strong Darwinian positive selection. Eleven human-specific amino acid changes were identified in the PACAP precursors which are conserved from murine to African apes. Protein structural analysis suggested that a putative novel neuropeptide might have originated during human evolution and functioned in the human brain. Our data suggested that the PACAP precursor gene underwent adaptive changes during human origin and may contribute to the formation of human cognition. This research is published in the《Genetics》170:801-806(2005)。 <Download>
《Science》news report: http://sciencenow.sciencemag.org/cgi/content/full/2005/420/4

 

痛觉相关基因MrgX2的适应性进化

  MrgX2是一个在外周神经系统的感觉神经元特异表达的G蛋白偶联受体。我们对人类和非人灵长类MrgX2的分子进化研究表明,在人类这一进化支上产生了较多的改变氨基酸序列的变异,其错义突变速率远高于同义突变速率。进一步分析表明,达尔文正向选择是导致人类蛋白序列变化加快的主要原因。蛋白质二级机构分析表明,人类特异的氨基酸变异大多分布于细胞膜外的结构域中,从而可能改变受体/配体的相互作用。人类MrgX2的适应性变异可能是人类进化过程产生的对痛觉感受的一种保护性机制。论文发表于《 Gene 》<文章下载>

Adaptive evolution of MRGX2, a human sensory neuron specific gene involved in nociception
MRGX2, a G-protein-coupled receptor, is specifically expressed in the sensory neurons of the human peripheral nervous system and involved in nociception. Here, we studied DNA polymorphism patterns and evolution of the MRGX2 gene in world-wide human populations and the representative nonhuman primate species. Our results demonstrated that MRGX2 had undergone adaptive changes in the path of human evolution, which were likely caused by Darwinian positive selection. The patterns of DNA sequence polymorphisms in human populations showed an excess of derived substitutions, which against the expectation of neutral evolution, implying that the adaptive evolution of MRGX2 in humans was a relatively recent event. The reconstructed secondary structure of the human MRGX2 revealed that three of the four human-specific amino acid substitutions were located in the extra-cellular domains. Such critical substitutions may alter the interactions between MRGX2 protein and its ligand, thus, potentially led to adaptive changes of the pain-perception-related nervous system during human evolution. This research is published in the 《 Gene 》<Download>

 

人类小脑症基因的分子进化研究

  小脑症基因(microcephalin)是调控人类大脑发育的关键基因之一。前人的研究表明,该基因突变失活以后,会引发人类原发性小脑症,病人的脑容量仅有正常人的三分之一到四分之一,相当于早期类人猿的脑容量。我们通过对人类和十二种代表性灵长类动物(包括非洲大猿、亚洲小猿和旧大陆猴等)小脑症基因DNA一级序列的比较研究,发现小脑症基因在人群中存在较为丰富的多态性。在对来自亚洲,非洲和欧洲人群的分析中,他们共发现了15个蛋白质序列变异。中性检验和分子系统学分析显示,人群中小脑症基因丰富的多态性可能是新石器时期以来人群的迅速增长和达尔文正向选择两种力量共同作用的结果。通过对小脑症基因在灵长类中突变模式的分析,我们还发现,该基因在从小猿到大猿的进化过程中可能受到较强的达尔文正向选择的作用,从而参与大猿起源过程中大脑容量的急剧增加(由90毫升到300毫升)。因此,我们的研究结果表明,小脑症基因在灵长类演化和人类的起源过程中,尤其是大脑的演化过程中,可能是一个重要的参与者。该研究将为了解灵长类进化中大脑容量增大的分子机制和人类起源的遗传学基础提供有益的信息。论文发表于 《 Human Molecular Genetics 》 (2004年第13卷第11期) <文章下载>

Molecular evolution of microcephalin, a gene determining human brain size
Microcephalin gene is one of the major players in regulating human brain development. It was reported that truncated mutations in this gene can cause primary microcephaly in humans with a brain size comparable with that of early hominids. We studied the molecular evolution of microcephalin by sequencing the coding region of microcephalin gene in humans and 12 representative non-human primate species covering great apes, lesser apes, Old World monkeys and New World monkeys. Our results showed that microcephalin is highly polymorphic in human populations. We observed 22 substitutions in the coding region of microcephalin gene in human populations, with 15 of them causing amino acid changes. The neutrality tests and phylogenetic analysis indicated that the rich sequence variations of microcephalin in humans are likely caused by the combination of recent population expansion and Darwinian positive selection. The synonymous/non-synonymous analyses in primates revealed positive selection on microcephalin during the origin of the last common ancestor of humans and great apes, which coincides with the drastic brain enlargement from lesser apes to great apes (from 90ml to 300ml). The codon-based neutrality test also indicated the signal of positive selection on five individual amino acid sites of microcephalin, which may contribute to brain enlargement during primate evolution and human origin. This research is published in the 《Human Molecular Genetics》13:1131-1137(2004)。 <Download>

 

Neuropsin基因选择性剪切(alternative splicing)的进化研究

  Neuropsin是一种主要在大脑海马区表达的丝氨酸蛋白酶。对小鼠的研究发现该基因同学习和记忆的功能调节以及大脑的发育相关。在人脑中,Neuropsin基因表达两种RNA(Type I 和TypeII)。其中,TypeII是小鼠中没有的。在人的胚胎中,TypeI和TypeII两种剪切方式都有表达,且丰度相似。在成人脑中,TypeII成为优势表达的剪切方式,TypeI仅有少量表达。我们测定了主要灵长类代表物种的Neurospin基因的序列。发现在新大陆和旧大陆猴中,TypeII特异的第3外显子存在1-2个碱基的插缺,从而将导致TypeII读码框的改变;但在小猿和大猿中没有发现插缺。因此,我们推测,TypeII起源于人猿超科(Hominoid)的祖先距今约1千8百万年前。这种新的Neuropsin基因的剪切方式的产生,可能对灵长类大脑功能的演化产生影响。我们进一步分析了Neuropsin两种剪切产物在人和非人灵长类大脑中的表达情况。结果显示,TypeII 只在人的大脑中表达。在检测的猕猴、滇金丝猴和长臂猿的大脑中只表达Type-I。因此,TypeII 在大脑中发挥生物学功能可能比1千8百万年更要晚近。论文发表于《Molecular Biology and Evolution》(2004年21卷2111-2114)。<文章下载>

Recent origin of a hominoid-specific splice form of neuropsin
In this project, we investigated the origin of type II splicing form of neuropsin, a secreted-type serine protease involved in learning and memory. Using comparative sequence analysis, we found that only the hominoid species (humans and apes) have the intact open reading frame of the type II splice form. RT-PCR experiment detected abundant expression of the type II form in the frontal lobe of the adult human brain, but not in lesser apes and Old World monkeys, indicating that the type II form of neuropsin only became functional in recent time, and it might contribute to the progressive change of cognitive abilities during primate evolution.
This work was published in “MBE”. <Download>


东亚现代人史前迁徙的遗传学研究

东亚现代人的史前迁徙一直是人类学界颇多争议的问题之一。 以前的遗传学研究揭示了东亚南方和北方人群在遗传背景上存在一定的差异,但如何解释这种遗传差异以及它同东亚现代人史前迁徙路线的关系是大家争论的焦点。采用父系遗传的 Y 染色体的遗传标记,我们对 40 个东亚南北方代表群体 , 共 2332 个男性个体进行了系统的比较分析。研究结果表明,南方群体的 Y 染色体单倍型较北方群体更为丰富,并存在南方群体特有的单倍型,而北方群体仅有部分南方群体具有的 Y 染色体单倍型。据此,我们的研究结论是,东亚南方群体是祖先群体,北方群体是在约 2.5 - 3 万年以前从南方迁移到北方的。换言之,由非洲起源的东亚现代人最早到达东亚的南部,他们最初的迁徙路线是由南向北。该项研究结果最近发表于美国人类遗传学杂志( American Journal of Human Genetics , 77:408–419 , 2005 )。<文章下载>

The previous studies suggested there had the genetic divergence between the north and the south East Asian. The prehistoric peopling of East Asia by modern humans remains controversial with respect to early population migrations. Here, we present a systematic sampling and genetic screening of an East Asian–specific Y-chromosome haplogroup (O3-M122) in 2,332 individuals from diverse East Asian populations. Our results indicate that the O3-M122 lineage is dominant in East Asian populations, with an average frequency of 44.3%. The microsatellite data show that the O3-M122 haplotypes in southern East Asia are more diverse than those in northern East Asia, suggesting a southern origin of the O3-M122 mutation. It was estimated that the early northward migration of the O3-M122 lineages in East Asia occurred ~25,000–30,000 years ago, consistent with the fossil records of modern humans in East Asia. This research is published in the《American Journal of Human Genetics 77:408–419 (2005) Download

 

G 蛋白偶联受体基因 CXCR1 的分子进化

人类的嗜中性粒细胞是一类白细胞 , 在细菌感染时形成了早期的防御体系。白细胞介素 -8 (IL-8) 是关键的免疫系统细胞因子之一 , 嗜中性粒细胞对其有高度的反应能力,因为嗜中性粒细胞膜表面分布有丰富的 IL-8 受体 CXCR1 。作为 G 蛋白偶联受体家族成员 , CXCR1 在与细菌感染早期防御相关的信号通路中扮演了重要的角色 . 通过检测全世界范围内主要人群以及五个有代表性的非人灵长类物种 CXCR1 基因的编码区序列,我们发现在人这一进化支出现了蛋白序列的加速进化。进一步的分析显示 CXCR1 蛋白氮末端的受体识别位点在人类进化过程中受到了达尔文正选择作用。研究结果发表在近期的《 Journal of Molecular Evolution 》 , 61:691-696 (2005). <文章下载 >

Molecular Evolution of CXCR1, a G Protein-Coupled Receptor Involved in Signal Transduction of Neutrophils
 Human neutrophils are a type of white blood cell, which forms an early line of defense against bacterial infections. Neutrophils are highly responsive to the chemokine, interleukin-8 (IL-8) due to the abundant distribution of CXCR1, one of the IL-8 receptors on the neutrophil cell surface. As a member of the GPCR family, CXCR1 plays a crucial role in the IL-8 signal transduction pathway in neutrophils. We sequenced the complete coding region of the CXCR1 gene in worldwide human populations and five representative nonhuman primate species.Our results indicate accelerated protein evolution in the human lineage, which was likely caused by Darwinian positive selection. The sliding window analysis and the codon-based neutrality test identified signatures of positive selection at the N-terminal ligand/receptor recognition domain of human CXCR1. This research is published in the 《 Journal of Molecular Evolution 》, 61:691-696 (2005) <Download >

 

 

抗人类艾滋病毒基因 TRIM5 a 在灵长类中的适应性进化

最近的研究表明非人灵长类的 TRIM5α 能有效地阻止 HIV-1 感染人类细胞系。 TRIM5α 也能抑制其它的反转录病毒,因此可能 具有广普的抗反转录病毒感染的作用。 我们在灵长类中的对 TRIM5α 进行了分子进化的分析 。结果表明 TRIM5α 在灵长类中经历了快速进化,其原因可能是达尔文正向选择。 TRIM5α 的 SPRY 结构域可能负责识别入侵病毒的衣壳,这个结构域比基因的其它部分在进化过程中具有更高的错义突变同义突变比率,表明 TRIM5α 的适应性进化可能是灵长类发展抗反转录病毒感染策略的结果。比较 SPRY 结构域中的第 344 位氨基酸( R/Q/P )的替代模式表明,此氨基酸位点可以解释各灵长类物种对 HIV-1 易感性的差异。研究结果发表在近期的《 Gene 》 , 362:109-116 (2005). <文章下载 >

Adaptive evolution of primate TRIM5α, a gene restricting HIV-1 infection

Recent studies showed that nonhuman primate TRIM5α can efficiently block HIV-1 infection in human cell lines. It can also restrict other retroviruses, therefore, suggested as a general defender against retrovirus infection. Here, we present an evolutionary analysis of TRIM5α in primates. Our results demonstrated that TRIM5α has been evolving rapidly in primates, which is likely caused by Darwinian positive selection. The SPRY domain of TRIM5α, which may be responsible for recognition of incoming viral capsids showed higher nonsynonymous/synonymous substitution ratios than the non-SPRY domain, indicating that the adaptive evolution of TRIM5α in primates might be an innate strategy developed in defending retrovirus infection during primate evolution. In addition, the comparative protein sequence analysis suggested that the amino acid substitution pattern at a single site (344R/Q/P) located in the SPRY domain may explain the differences in susceptibilities of HIV-1 infection in diverse primate species. This research is published in the 《Gene》362:109-116 (2005) . <Download >


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