新晋诺贝尔生理与医学奖Svante Pääbo,何许人也?

2022-10-04 MedSci原创 MedSci原创

Svante Pääbo,2022年度诺贝尔生理与医学奖唯一获得者,超出所有预言者的预料之外,但是他获奖却又是预料之中。他研究的领域是古人类基因组进化,这是非常“冷门&

Svante Pääbo,2022年度诺贝尔生理与医学奖唯一获得者,超出所有预言者的预料之外,但是他获奖却又是预料之中。他研究的领域是古人类基因组进化。2007年,帕博被《时代周刊》评为全世界极具影响力的100人之一。2008 年,又被《New Scientist》评为 8 位年度科学英雄之一。详细见:2022年诺贝尔生理学或医学奖揭晓!古人类基因组和进化基因组开创者Svante Pääbo获奖

古人类基因组进化是非常“冷门”的领域,远远没有肿瘤,心血管免疫,神经系统这样的热门和受关注。如果冷门领域,出现“高引”是极度困难的(越是热门领域,发表的相关文章就越多,被引次数就越高,相反,冷门因为同行专家少,因此被引次数也不会太高),更难是媒体的焦点。

不过,即使是如此冷门,Svante Pääbo的论文仍然被引用高达119938次,2017年以来被引达49887次,H指数为167。在全球顶尖科学家排名中,排在1717位!

Svante Pääbo - Max Planck Institute for Evolutionary ...

一、99%国人不熟悉的领域,实际上年轻时就已是传奇

国人对Svante Pääbo熟悉,可能更多的源自中国一位年青的大咖——付巧妹,她是Svante Pääbo弟子,2019年“科学探索奖”获奖者,获得《2020年度中国科学十大进展》,详细见:https://www.medsci.cn/article/show_article.do?id=dab120e754e8, 主要内容是古基因组揭示近万年来中国人群的演化与迁徙历史,文章发表在Science上,合作者其中也有Svante Pääbo。事实上,付巧妹作为他的学生时,就以第一作者身份发表过3篇Nature文章,确实是名师出高徒。而Svante Pääbo在CNS三大主刊上发表的文章近80篇,而作为主要通讯作者就超过50篇!

Svante Pääbo个人经历也很传奇,1955年出生于瑞典,1986年瑞典Uppsala大学博士毕业,博士期间就发表Cell和Nature!1986年去加州大学伯克利分校,跟随进化生物学先驱Allan Wilson 做博士后,在博士后期间,发表4篇Nature和Cell,1990年博士后毕业。在博士后期间,Pääbo 开始开发研究尼安德特人 DNA 的方法,这项工作持续了几十年。博士后毕业就到德国Munich大学普通生物学任全职教授(C4)。1997年任德国马普古人类进化研究所主任。

二、父子双获诺贝尔奖,你不知道的Svante Pääbo家庭!

1955年4月20日,斯万特·帕博出生于瑞典斯德哥尔摩,他的父亲是苏恩·伯格斯特龙(Sune Bergström),因前列腺素和相关物质的发现获得1982年诺贝尔生理学与医学奖。他的母亲是化学家凯琳·帕博(Karin Pbo),不过据传Svante Pääbo是私生子。

真是印证了中国一句话:虎父无犬子!详细见:121年诺贝尔生理或医学奖汇总(1901-2022)

Svante Pääbo对于生物化学的痴迷,正是受到父亲和化学家母亲的影响,尽管父亲永远 " 只在周六出现 ",也一点不妨碍他对父亲的崇拜。对于Svante Pääbo来说,工作就像游戏,总是充满着无尽的乐趣。

其实,Svante Pääbo还有一个知名的兄弟,著名的瑞典企业家Rurik Bergström。

三、Svante Pääbo是谦和、有趣且执着的科学家

2014年,帕博出版了自己的学术自传《尼安德特人》。作为该书译者,国际肿瘤基因组协作组(ICGC)协调人、中国科普作家协会副秘书长夏志在接受媒体采访时形容道,帕博待人谦和,“唯独对科学问题,他寸步不让”。

在Svante Pääbo获奖的消息传出后,一位了解他的研究者在网络上说道:" 我一直在给我的学生讲述帕博的故事,因为他在年轻的时候就一直保持着广泛的兴趣,比如古埃及学——而当下的学生总被告诫这是浪费时间,要尽早找到专注领域——虽然在很长的一段时间里,这看起来只是让他能够用象形文字标注自己的实验器材,而不必担心被人偷走。"

" 但正是这无用功让他成为了今天的他:第一个从木乃伊中提取到 DNA 的人,以及,一整个领域的创造者。"

四、古基因组学研究难在哪里?

Pääbo 的开创性研究产生了一门全新的科学学科:古基因组学(paleogenomics)。他的研究通过揭示所有现存人类与已灭绝原始人类之间的基因差异,为探索是什么使我们成为独一无二的人类提供了基础。

Svante Pääbo 的开创性研究完成了一件看似不可能的事情:对已经灭绝的尼安德特人(Neanderthal)的基因组进行测序。他还发现了一种此前不为人知的原始人类:丹尼索瓦人(Denisova)。重要的是,Pääbo 还发现,在大约 7 万年前人类离开非洲后,基因从这些现已灭绝的原始人类身上转移到了智人身上。这种古老的基因流动在今天仍与人类存在生理上的关联,例如影响我们的免疫系统对感染的反应。

在职业生涯早期,Svante Pääbo 就被利用现代遗传学方法研究尼安德特人 DNA 的可能性所吸引。然而,他很快就意识到了极端技术的挑战,因为 DNA 会随着时间的推移被化学修饰并降解成短片段。经过几千年后,只剩下微量的 DNA,而剩下的 DNA 被细菌和当代人类的 DNA 大量污染,这迫使科学家们也必须学习如何挑选出这些基因。同时,它很容易被负责处理它的科学家的 DNA 污染,因此很难区分古代基因和现代基因。

测序已经灭绝的古人类,其难度简直令人无法想象。借用作家伊丽莎白 · 科尔伯特的话来说,就像:" 试图把一部经过碎纸机粉碎、与昨天的垃圾混合在一起、正在垃圾填埋场腐烂的曼哈顿电话簿,重新组合在一起。"

五、遇恩师,获研究突破

读博期间,帕博接触到了DNA克隆的技术,产生了利用这一技术研究古人类,尤其是研究木乃伊DNA的念头。

1984年,帕博成功地从一个死去两千多年的木乃伊身上提取到了DNA,并分析了其中的一小段,其结果发表在东德科学院主办的学术期刊《古代》(Das Altertum)上。然而,当时的主流科学界鲜有人阅读这个杂志,无人注意到这一研究。虽有些沮丧,帕博继续践行自己的想法,尝试在细菌中克隆从木乃伊身上提出来的DNA。

1984年11月,当帕博想办法测序克隆出来的木乃伊DNA时,加州大学伯克利分校的一个实验室报告了他们从一匹斑驴(quagga)的皮肤上提取出DNA并进行克隆,其结果发表在《自然》(Nature)上。斑驴是一种生活在非洲南部的动物,已经在1883年灭绝。也就是说,在帕博尝试利用DNA克隆技术研究古代人类时,也有一群科学家做类似的事情。与年轻的博士研究生帕博不同,该研究的负责人阿兰·威尔森(Allan Wilson)是当时最负盛名的进化生物学家之一,也是“走出非洲”的现代人起源理论的主要建构者。1987年,威尔森和其学生通过对全球现代人样品线粒体DNA的研究,提出现代人“所有的线粒体DNA都追溯到同一个女人”,而这个女人可能生活在二十万年前的非洲,“线粒体夏娃”的假说对现代人起源的研究产生了深远的影响。

1985年4月18日,帕博的论文“对古代埃及木乃伊DNA的分子克隆”(Molecular cloning of Ancient Egyptian mummy DNA)登上《自然》封面,引发学界轰动,很多主流科学媒体都给予了报道。

1986年,帕博拿到了自己的博士学位,随后来到瑞士苏黎世大学的分子生物学研究所做博士后研究,后在英国皇家癌症研究基金(Imperial Cancer Research Fund,现为伦敦癌症研究所)短暂工作了一段时间。

1987年,帕博开始跟随 Allan Wilson 在加州大学伯克利分校做博士后做研究。作为进化生物学领域先驱 Allan Wilson 的博士后学生,Pääbo 开始开发研究尼安德特人 DNA 的方法,这项工作持续了几十年。当时,扩增特定DNA片段的聚合酶连锁反应(Polymerase chain reaction,PCR)技术刚刚兴起。在PCR技术的帮助下,帕博从威尔森实验室剩余的斑驴样品中提取出DNA并进行分析,测序的结果显示与1985年发表的结果相似。这意味着,古DNA的测序不仅可以更高效地进行,而且实验的结果能够被重复验证。

在研究从佛罗里达州发掘出来的一个7000年前的美洲土著的大脑时,帕博提取了一些DNA,并修复了一段看似不同寻常的线粒体DNA序列的片段,却发现它们此前在美洲土著人身上没有出现过,而只在亚洲人身上存在。经过两次独立的实验,结果依然如此。帕博很快意识到,这可能是现今的人的DNA污染造成的。结果确实如此。现代DNA污染是古人类以及其他古生物研究一个普遍性的问题,尤其是在古人类研究中,即便是现代人皮肤上的一丁点颗粒都有可能毁掉最后的结果。

受威尔森等人工作的鼓舞,帕博决定向《自然》投稿。1985年4月18日,帕博的论文“对古代埃及木乃伊DNA的分子克隆”(Molecular cloning of Ancient Egyptian mummy DNA)登上《自然》封面,引发学界轰动,很多主流科学媒体都给予了报道。

六、重新开始,着眼于线粒体DNA

他决定分析来自尼安德特人线粒体的 DNA——细胞中含有自身 DNA 的细胞器。线粒体基因组较小,仅包含细胞内一小部分遗传信息,但它存在成千上万的拷贝,增加了成功的机会。

通过他的改良方法,Pääbo 成功地从一块 4 万年的骨头中测序了线粒体 DNA 的一个区域。因此,我们第一次获得了来自已灭绝的原始人类基因序列。与当代人类和黑猩猩的比较表明,尼安德特人在基因上是不同的。

Pääbo 的努力是有效的,他成功完成了看似不可能的任务,并在 2010 年发表了第一个尼安德特人基因组序列。比较分析表明,尼安德特人和智人最近的共同祖先生活在大约 80 万年前。

 

图片

图 2:A. Pääbo 从已灭绝的原始人类骨骼标本中提取 DNA。他首先从德国的尼安德特获得了一块骨头碎片,尼安德特人就是因此命名的。后来,他使用了来自西伯利亚南部丹尼索瓦洞穴(Denisova Cave)的一根指骨,丹尼索瓦人就是在这里命名的。B.显示智人和已灭绝原始人类之间的进化和关系的系统发育树。系统发育树还说明了 Pääbo 发现的基因流动。

七、尼安德特人灭绝了,为什么现代人存活并继续繁衍到今天?是幸运还是背后的基因组?

Svante Pääbo认为,不仅仅是尼安德特人灭绝了,丹尼索瓦人也灭绝了,弗洛勒斯人也灭绝了。在距今4万年以后,就没有其他形式的人类存在了。这和现代人类的行为是有关系的,而不是偶然发生的。

1、语言基因,人类最大的优势

现代人类与古人类区别之一是语言,人类有语言基因?

Svante Pääbo发现了FOXP2的基因,将人类身上FOXP2特有的两种突变放在小鼠身上,观察小鼠的变化,发现这个蛋白质看上去有可能与人类的语言能力相关。这是这个蛋白质的功能之一。

把在老鼠体内引入这两个突变后,老鼠发出的声音跟以前不太一样了,而且它学习的速度在提高。因此,我们能够在一定程度上通过研究老鼠理解人类身上的变化,当然,这个过程很复杂,毕竟实验的对象是老鼠而不是人类。

不过,从尼安德特人的基因组来看,我们知道尼安德特人拥有这两个突变,但是影响语言或发音的因素可能有很多,我们目前并不是都很清楚。因此,我们并不知道这两个基因突变到底会对尼安德特人产生什么样的影响。详细见:美国研究显示女人话多与Foxp2蛋白质相关

2、高海拔人类的优势背后的秘密

EPAS1 基因的丹尼索瓦版本,它赋予了高海拔地区生存的优势,并且在当今的藏人中很常见。

EPAS1被称为“超级铁人”基因突变,它帮助红细胞有效地利用氧气,能够很快的适应了高海拔地区的生活,一直在寻找源头,有可能是杰尼索瓦人与智人结合,然后才传给现代人的。详细见:Nature:藏族人群适应高原因气候的关键基因EPAS1

3、具有尼安德特人血统的人出现严重 COVID-19 症状的可能性更高

2020 年,他发表了证据表明具有尼安德特人血统的人出现严重 COVID-19 症状的可能性更高。这种遗传风险变体位于3号染色体上的一个由许多基因组成的区域。在它的附近有几个编码免疫系统中受体的基因。其中的一种受体---CCR5---被HIV病毒用来感染白细胞。Zeberg发现携带这种COVID-19遗传风险变体的人有较少的CCR5受体。这促使他去测试这些人是否也有较低的感染HIV的风险。通过分析来自三个主要生物库(FinnGen、英国生物库和密歇根基因组计划)的患者数据,他发现这种COVID-19遗传风险变体的携带者感染HIV的风险降低了27%。Zeberg说,“这表明一种基因变体可以既是好消息又是坏消息:如果一个人感染了COVID-19,那就是坏消息,但是它让人免受HIV感染艾滋病毒,这是好消息。”详细见:新研究:导致新冠症状变严重的基因,可以防止感染艾滋病

4、最新论文:TKTL1一个氨基酸突变带来现代人大脑的优势!

尼安德特人(Homo neanderthalensis),是一种20万年前活跃在欧洲地区的古人类,他们从12万年前开始统治着整个欧洲、亚洲西部以及非洲北部,但令人惊讶的是,大约在3.5万年前,尼安德特人的生活范围却开始快速缩小,最终在约3万年前彻底灭绝。

值得注意的是,距今3.5万年前,正是智人(Homo sapiens),也就是我们现代人类,来到欧洲的时间。因此,我们不难推测——尼安德特人的消失,与智人有脱不开的干系。

2022年9月9日,Svante Pääbo发现TKTL1蛋白上一个氨基酸的差异,让我们人类比尼安德特人具有了显著优势,增加了大脑神经细胞的产生,这可能是现代人类与已灭绝的其他古代人类之间的认知差异的基础,这项研究也发表在Science 上。

对比结果显示,现代人类的 TKTL1 基因中编码了一种独特氨基酸替代。尼安德特人和猿类中 TKTL1 基因中的赖氨酸(Lysine)在人类中被替换为了精氨酸(Arginine)。正因为这一变化,从而促进新皮质神经元的增殖。

图片
在人类中,TKTL1 基因编码转酮醇酶样蛋白1,这是一种参与生成乙酰辅酶A的代谢途径的酶,乙酰辅酶A用于脂肪酸生成。而基底放射状神经胶质细胞(bRG)需要大量脂肪酸,因此,现代人类的 TKTL1 基因促进了 bRG 的增殖。这种机制可能代表了古代人类和现代人类之间大脑进化的一个关键驱动因素。详细见:Science:TKTL1基因一个氨基酸的改变,让人类大脑胜过尼安德特人?

这些成果见证了人类进化的神奇!

八、Svante Pääbo代表性研究论文(仅摘录发表在CNS主刊上的论文)

1

Pääbo, S., Weber, F., Kämpe, O., Schaffner, W., & Peterson, P. (1983). Association between transplantation antigens and a viral membrane protein synthesized from a mammalian expression vector. Cell, 33(2), 445-453.
DOI    BibTeX   Endnote   

2

Pääbo, S. (1985). Molecular cloning of ancient Egyptian mummy DNA. Nature, 314, 644-645.
DOI    BibTeX   Endnote   

3

Andersson, M., Pääbo, S., Nilsson, T., & Peterson, P. A. (1985). Impaired intracellular transport of class I MHC antigens as a possible means for adenoviruses to evade immune surveillance. Cell, 43(1), 215-222.
DOI    BibTeX   Endnote   

4

Pääbo, S., Bhat, B. M., Wold, W. S., & Peterson, P. A. (1987). A short sequence in the COOH-terminus makes an adenovirus membrane glycoprotein a resident of the endoplasmic reticulum. Cell, 50(2), 311-317.
DOI    BibTeX   Endnote   

5

Pääbo, S., & Wilson, A. C. (1988). Polymerase chain reaction reveals cloning artefacts. Nature, 334, 387-388.
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6

Thomas, R. H., Schaffner, W., Wilson, A. C., & Pääbo, S. (1989). DNA phylogeny of the extinct marsupial wolf. Nature, 340, 465-467.
DOI    BibTeX   Endnote   

7

Thomas, R. H., Pääbo, S., & Wilson, A. C. (1990). Chance marsupial relationships (Reply). Nature, 345, 394.
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8

Pääbo, S., Thomas, W. K., Whitfield, K. M., Kumazawa, Y., & Wilson, A. C. (1991). Rearrangements of mitochondrial transfer RNA genes in marsupials. Journal of Molecular Evolution, 33(5), 426-430.
DOI    BibTeX   Endnote   

9

Ward, R., Frazier, B., Dew-Jager, K., & Pääbo, S. (1991). Extensive mitochondrial diversity within a single Amerindian tribe. Proceedings of the National Academy of Sciences of the United States of America, 88(19), 8720-8724.
BibTeX   Endnote    

10

Höss, M., Kohn, M., Pääbo, S., Knauer, F., & Schröder, W. (1992). Excrement analysis by PCR. Nature, 359, 199.
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11

Schliewen, U., Fricke, H., Schartl, M., Epplen, J., & Pääbo, S. (1993). Which home for coelacanth? Nature, 363, 405.
DOI    BibTeX   Endnote   

12

Schliewen, U. K., Tautz, D., & Pääbo, S. (1994). Sympatric speciation suggested by monophyly of crater lake cichlids. Nature, 368(6472), 629-632.
DOI    BibTeX   Endnote   

13

Handt, O., Richards, M., Trommsdorff, M., Kilger, C., Simanainen, J., Georgiev, O., Bauer, K., Stone, A., Hedges, R., Schaffner, W., Utermann, G., Sykes, B., & Pääbo, S. (1994). Molecular genetic analyses of the Tyrolean Ice Man. Science, 264(5166), 1775-1778.
DOI    BibTeX   Endnote   

14

Höss, M., Pääbo, S., & Vereshchagin, N. (1994). Mammoth DNA sequences. Nature, 370(6488), 333.
DOI    BibTeX   Endnote   

15

Zischler, H., Hoss, M., Handt, O., von Haeseler, A., van der Kuyl, A., Goudsmit, J., & Pääbo, S. (1995). Detecting dinosaur DNA. Science, 268(5214), 1192-1193.
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16

Pääbo, S. (1995). The Y chromosome and the origin of all of us (men). Science, 268(5214), 1141-1142.
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17

Yokobori, S.-I., & Pääbo, S. (1995). tRNA editing in metazoans. Nature, 377(6549), 490.
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18

Zischler, H., Geisert, H., von Haeseler, A., & Pääbo, S. (1995). A nuclear 'fossil' of the mitochondrial D-loop and the origin of modern humans. Nature, 378(6556), 489-492.
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Tishkoff, S. A., Dietzsch, E., Speed, W., Pakstis, A. J., Kidd, J. R., Cheung, K., Bonné-Tamir, B., Santachiara-Benerecetti, A. S., Moral, P., Krings, M., Pääbo, S., Watson, E., Risch, N., Jenkins, T., & Kidd, K. K. (1996). Global patterns of linkage disequilibrium at the CD4 locus and modern human origins. Science, 271(5254), 1380-1387.
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20

Börner, G. V., & Pääbo, S. (1996). Evolutionary fixation of RNA editing. Nature, 383, 225.
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21

Poinar, H. N., Höss, M., Bada, J. L., & Pääbo, S. (1996). Amino acid racemization and the preservation of ancient DNA. Science, 272(5263), 864-866.
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22

Cooper, A., Poinar, H. N., Pääbo, S., Radovcic, J., Debénath, A., Caparros, M., Barroso-Ruiz, C., Bertranpetit, J., Nielsen-Marsh, C., Hedges, R. E. M., & Sykes, B. (1997). Neandertal genetics. Science, 277(5329), 1021-1025.
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23

Poinar, H. N., Hofreiter, M., Spaulding, W. G., Martin, P. S., Stankiewicz, A. B., Bland, H., Evershed, R. P., Possnert, G., & Pääbo, S. (1998). Molecular coproscopy: Dung and diet of the extinct ground sloth Nothrotheriops shastensis. Science, 281(5375), 402-406.
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24

Pääbo, S. (1999). Agriculture: Neolithic genetic engineering (News and Views). Nature, 398, 194-195.
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25

Kaessmann, H., Wiebe, V., & Pääbo, S. (1999). Extensive nuclear DNA sequence diversity among chimpanzees. Science, 286(5442), 1159-1162.
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26

Ingman, M., Kaessmann, H., Pääbo, S., & Gyllenstein, U. (2000). Mitochondrial genome variation and the origin of modern humans. Nature, 408, 708-713.
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27

Pääbo, S. (2001). The human genome and our view of ourselves. Science, 291(5507), 1219-1220.
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28

Poinar, H. N., Kuch, M., & Pääbo, S. (2001). Molecular analyses of oral polio vaccine samples. Science, 292(5517), 743-744.
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29

Enard, W., Khaitovich, P., Klose, J., Zöllner, S., Heißig, F., Giavalisco, P., Nieselt-Struwe, K., Muchmore, E., Varki, A., Ravid, R., Doxiadis, G. M., Bontrop, R. E., & Pääbo, S. (2002). Intra- and interspecific variation in primate gene expression patterns. Science, 296(5566), 340-343.
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30

Enard, W., Przeworski, M., Fisher, S. E., Lai, C. S. L., Wiebe, V., Kitano, T., Monaco, A. P., & Pääbo, S. (2002). Molecular evolution of FOXP2, a gene involved in speech and language. Nature, 418(6900), 869-872.
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31

Pääbo, S. (2003). The mosaic that is our genome. Nature, 421(6921), 409-412.
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32

Jänicke-Després, V. R., Buckler, E. S., Smith, B. D., Gilbert, M. T. P., Cooper, A., Doebley, J., & Pääbo, S. (2003). Early allelic selection in maize as revealed by ancient DNA. Science, 302(5648), 1206-1208.
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33

The international Chimpanzee Chromosome 22 Consortium, Watanabe, H., Fujiyama, A., Hattory, M., Taylor, T. D., Toyoda, A., Kuroki, Y., Noguchi, H., BenKahla, A., Lehrach, H., Sudbrak, R., Kube, M., Taenzer, S., Galgoczy, P., Platzer, M., Scharfe, M., Nordsiek, G., Blöcker, H., Hellmann, I., Khaitovich, P., Pääbo, S., Reinhardt, R., Zheng, H.-J., Zhang, X.-L., Zhu, G.-F., Wang, B.-F., Fu, G., Ren, S.-X., Zhao, G.-P., Chen, Z., Lee, Y.-S., Cheong, J.-E., Choi, S.-H., Wu, K.-M., Liu, T.-T., Hsiao, K.-J., Tsai, S.-F., Kim, C.-G., Oota, S., Kitano, T., Kohora, Y., Saitou, N., Park, H.-S., Wang, S.-Y., Yaspo, M.-L., & Sakaki, Y. (2004). DNA sequence and comparative analysis of chimpanzee chromosome 22. Nature, 429, 382-388.
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34

Khaitovich, P., Hellmann, I., Enard, W., Nowick, K., Leinweber, M., Franz, H., Weiss, G., Lachmann, M., & Pääbo, S. (2005). Parallel patterns of evolution in the genomes and transcriptomes of humans and chimpanzees. Science, 309(5742), 1850-1854.
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35

Krause, J., Dear, P. H., Pollack, J. L., Slatkin, M., Spriggs, H., Barnes, I., Lister, A. M., Ebersberger, I., Pääbo, S., & Hofreiter, M. (2006). Multiplex amplification of the mammoth mitochondrial genome and the evolution of Elephantidae. Nature, 439(7077), 724-727.
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36

Noonan, J. P., Hofreiter, M., Smith, D., Priest, J. R., Rohland, N., Rabeder, G., Krause, J., Detter, J. C., Pääbo, S., & Rubin, E. M. (2005). Genomic sequencing of Pleistocene cave bears. Science, 309(5734), 597-599.
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37

The Chimpanzee Sequencing and Analysis Consortium, Mikkelsen, T. S., Hillier, L. W., Eichler, E. E., Zody, M. C., Jaffe, D. B., Yang, S.-P., Enard, W., Hellmann, I., Lindblad-Toh, K., Altheide, T. K., Archidiacono, N., Bork, P., Butler, J., Chang, J. L., Cheng, Z., Chinwalla, A. T., de Jong, P., Delehaunty, K. D., Fronick, C. C., Fulton, L. L., Gilad, Y., Glusman, G., Gnerre, S., Graves, T. A., Hayakawa, T., Hayden, K. E., Huang, X., Ji, H., Kent, W. J., King, M.-C., Kulbokasl, E. J., Lee, M. K., Liu, G., Lopez-Otin, C., Makova, K. D., Man, O., Mardis, E. R., Mauceli, E., Miner, T. L., Nash, W. E., Nelson, J. O., Pääbo, S., Patterson, N. J., Pohl, C. S., Pollard, K. S., Prüfer, K., Puente, X. S., Reich, D., Rocchi, M., Rosenbloom, K., Ruvolo, M., Richter, D. J., Schaffner, S. F., Smit, A. F. A., Smith, S. M., Suyama, M., Taylor, J., Torrents, D., Tuzun, E., Varki, A., Velasco, G., Ventura, M., Wallis, J. W., Wendl, M. C., Wilson, R. K., Lander, E. S., & Waterston, R. H. (2005). Initial sequence of the chimpanzee genome and comparison with the human genome. Nature, 437(7055), 69-87.
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38

Cheng, Z., Ventura, M., She, X., Khaitovich, P., Graves, T. A., Osoegawa, K., Church, D., de Jong, P., Wilson, R. K., Pääbo, S., Rocchi, M., & Eichler, E. E. (2005). A genome-wide comparison of recent chimpanzee and human segmental duplications. Nature, 437(7055), 88-93.
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39

Noonan, J. P., Coop, G., Kudaravalli, S., Smith, D., Krause, J., Alessi, J., Chen, J., Platt, D., Pääbo, S., Pritchard, J. K., & Rubin, E. M. (2006). Sequencing and analysis of Neanderthal genomic DNA. Science, 314, 1113-1118.
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40

Green, R. E., Krause, J., Ptak, S. E., Briggs, A. W., Ronan, M. T., Simons, J. F., Du, L., Egholm, M., Rothberg, J. M., Paunovic, M., & Pääbo, S. (2006). Analysis of one million base pairs of Neanderthal DNA. Nature, 444, 330-336.
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41

Prabhakar, S., Noonan, J. P., Pääbo, S., & Rubin, E. M. (2006). Accelerated evolution of conserved noncoding sequences in humans. Science, 314, 786-786.
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42

Weber, M., Hellmann, I., Stadler, M. B., Ramos, L., Pääbo, S., Rebhan, M., & Schübeler, D. (2007). Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nature Genetics, 39(4), 457-466.
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43

Krause, J., Orlando, L., Serre, D., Viola, B., Prüfer, K., Richards, M. P., Hublin, J.-J., Hänni, C., Derevianko, A. P., & Pääbo, S. (2007). Neanderthals in central Asia and Siberia. Nature, 449(7164), 902-904.
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44

Green, R. E., Malaspinas, A.-S., Krause, J., Briggs, A. W., Johnson, P. L. F., Uhler, C., Meyer, M., Good, J. M., Maricic, T., Stenzel, U., Prüfer, K., Siebauer, M., Burbano, H. A., Ronan, M. T., Rothberg, J. M., Egholm, M., Rudan, P., Brajkovic, D., Kucan, Z., Gusic, I., Wikström, M., Laakkonen, L., Kelso, J., Slatkin, M., & Pääbo, S. (2008). A complete Neandertal mitochondrial genome sequence determined by high-throughput sequencing. Cell, 134(3), 416-426.
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45

Enard, W., Gehre, S., Hammerschmidt, K., Hölter, S. M., Blass, T., Somel, M., Brückner, M. K., Schreiweis, C., Winter, C., Sohr, R., Becker, L., Wiebe, V., Nickel, B., Müller, U., Groszer, M., Adler, T., Aguilar, A., Bolle, I., Calzada-Wack, J., Dalke, C., Erhardt, N., Favor, J., Fuchs, H., Gailus-Durner, V., Hans, W., Hölzlwimmer, G., Javaheri, A., Kalaydjiev, S., Kallnik, M., Kling, E., Kunder, S., Moßbrugger, I., Naton, B., Racz, I., Rathkolb, B., Rozman, J., Schrewe, A., Busch, D. H., Graw, J., Ivandic, B., Klingenspor, M., Klopstock, T., Ollert, M., Quintanilla-Martinez, L., Schulz, H., Wolf, E., Wurst, W., Zimmer, A., Fisher, S. E., Morgenstern, R., Arendt, T., Hrabé de Angelis, M., Fischer, J., Schwarz, J., & Pääbo, S. (2009). A humanized version of Foxp2 affects cortico-basal ganglia circuits in mice. Cell, 137(5), 961-971.
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46

Briggs, A. W., Good, J. M., Green, R. E., Krause, J., Maricic, T., Stenzel, U., Lalueza-Fox, C., Rudan, P., Brajkovic, D., Kucan, Z., Gusic, I., Schmitz, R. W., Doronichev, V. B., Golovanova, L. V., de la Rasilla, M., Fortea, J., Rosas, A., & Pääbo, S. (2009). Targeted retrieval and analysis of five Neandertal mtDNA genomes. Science, 325(5938), 318-321.
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47

Krause, J., Fu, Q., Good, J. M., Viola, B., Shunkov, M. V., Derevianko, A. P., & Pääbo, S. (2010). The complete mitochondrial DNA genome of an unknown hominin from southern Siberia. Nature, 464(7290), 894-897.
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48

Burbano, H. A., Hodges, E., Green, R. E., Briggs, A. W., Krause, J., Meyer, M., Good, J. M., Maricic, T., Johnson, P. L. F., Xuan, Z., Rooks, M., Bhattacharjee, A., Brizuela, L., Albert, F. W., Rasilla, M. d. l., Fortea, J., Rosas, A., Lachmann, M., Hannon, G. J., & Pääbo, S. (2010). Targeted investigation of the Neandertal genome by array-based sequence capture. Science, 328(5979), 723-725.
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49

Green, R. E., Krause, J., Briggs, A. W., Maricic, T., Stenzel, U., Kircher, M., Patterson, N., Li, H., Zhai, W., Fritz, M.-H.-Y., Hansen, N. F., Durand, E. Y., Malaspinas, A.-S., Jensen, J. D., Marques-Bonet, T., Alkan, C., Prüfer, K., Meyer, M., Burbano, H. A., Good, J. M., Schultz, R., Aximu-Petri, A., Butthoff, A., Höber, B., Höffner, B., Siegemund, M., Weihmann, A., Nusbaum, C., Lander, E. S., Russ, C., Novod, N., Affourtit, J., Egholm, M., Verna, C., Rudan, P., Brajkovic, D., Kucan, Z., Gusic, I., Doronichev, V. B., Golovanova, L. V., Lalueza-Fox, C., Rasilla, M. d. l., Fortea, J., Rosas, A., Schmitz, R. W., Johnson, P. L. F., Eichler, E. E., Falush, D., Birney, E., Mullikin, J. C., Slatkin, M., Nielsen, R., Kelso, J., Lachmann, M., Reich, D., & Pääbo, S. (2010). A draft sequence of the Neandertal genome. Science, 328(5979), 710-722.
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50

Reich, D., Green, R. E., Kircher, M., Krause, J., Patterson, N., Durand, E. Y., Viola, B., Briggs, A. W., Stenzel, U., Johnson, P. L. F., Maricic, T., Good, J. M., Marques-Bonet, T., Alkan, C., Fu, Q., Mallick, S., Li, H., Meyer, M., Eichler, E. E., Stoneking, M., Richards, M., Talamo, S., Shunkov, M. V., Derevianko, A. P., Hublin, J.-J., Kelso, J., Slatkin, M., & Pääbo, S. (2010). Genetic history of an archaic hominin group from Denisova Cave in Siberia. Nature, 468(7327), 1053-1060.
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51

Brawand, D., Soumillon, M., Necsulea, A., Julien, P., Csárdi, G., Harrigan, P., Weier, M., Liechti, A., Aximu-Petri, A., Kircher, M., Albert, F. W., Zeller, U., Khaitovich, P., Grützner, F., Bergmann, S., Nielsen, R., Pääbo, S., & Kaessmann, H. (2011). The evolution of gene expression levels in mammalian organs. Nature, 478(7369), 343-348.
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52

Prüfer, K., Munch, K., Hellmann, I., Akagi, K., Miller, J. R., Walenz, B., Koren, S., Sutton, G., Kodira, C., Winer, R., Knight, J. R., Mullikin, J. C., Meader, S. J., Ponting, C. P., Lunter, G., Higashino, S., Hobolth, A., Dutheil, J., Karakoç, E., Alkan, C., Sajjadian, S., Catacchio, C. R., Ventura, M., Marques-Bonet, T., Eichler, E. E., André, C., Atencia, R., Mugisha, L., Junhold, J., Patterson, N., Siebauer, M., Good, J. M., Fischer, A., Ptak, S. E., Lachmann, M., Symer, D. E., Mailund, T., Schierup, M. H., Andrés, A. M., Kelso, J., & Pääbo, S. (2012). The bonobo genome compared with the chimpanzee and human genomes. Nature, 486(7404), 527-531.
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53

Meyer, M., Kircher, M., Gansauge, M.-T., Li, H., Racimo, F., Mallick, S., Schraiber, J. G., Jay, F., Prüfer, K., Filippo, C. d., Sudmant, P. H., Alkan, C., Fu, Q., Do, R., Rohland, N., Tandon, A., Siebauer, M., Green, R. E., Bryc, K., Briggs, A. W., Stenzel, U., Dabney, J., Shendure, J., Kitzman, J., Hammer, M. F., Shunkov, M. V., Derevianko, A. P., Patterson, N., Andrés, A. M., Eichler, E. E., Slatkin, M., Reich, D., Kelso, J., & Pääbo, S. (2012). A high-coverage genome sequence from an archaic Denisovan individual. Science, 338(6104), 222-226.
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54

Thalmann, O., Shapiro, B., Cui, P., Schuenemann, V. J., Sawyer, S., Greenfield, D. L., Germonpré, M. B., Sablin, M. V., López-Giráldez, F., Domingo-Roura, X., Napierala, H., Uerpmann, H.-P., Loponte, D. M., Acosta, A. A., Giemsch, L., Schmitz, R. W., Worthington, B., Buikstra, J. E., Druzhkova, A., Graphodatsky, A. S., Ovodov, N. D., Wahlberg, N., Freedman, A. H., Schweizer, R. M., Koepfli, K.-P., Leonard, J. A., Meyer, M., Krause, J., Pääbo, S., Green, R. E., & Wayne, R. K. (2013). Complete mitochondrial genomes of ancient canids suggest a European origin of domestic dogs. Science, 342(6160), 871-874.
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55

The SIGMA Type 2 Diabetes Consortium, including authors, Prüfer, K., Sawyer, S., Stenzel, U., Kelso, J., Pääbo, S., & and others (2014). Sequence variants in SLC16A11 are a common risk factor for type 2 diabetes in Mexico. Nature, 506, 97-101.
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56

Prüfer, K., Racimo, F., Patterson, N., Jay, F., Sankararaman, S., Sawyer, S., Heinze, A., Renaud, G., Sudmant, P. H., de Filippo, C., Li, H., Mallick, S., Dannemann, M., Fu, Q., Kircher, M., Kuhlwilm, M., Lachmann, M., Meyer, M., Ongyerth, M., Siebauer, M. F., Theunert, C., Tandon, A., Moorjani, P., Pickrell, J., Mullikin, J. C., Vohr, S. H., Green, R. E., Hellmann, I., Johnson, P. L. F., Blanche, H., Cann, H., Kitzman, J. O., Shendure, J., Eichler, E. E., Lein, E. S., Bakken, T. E., Golovanova, L. V., Doronichev, V. B., Shunkov, M. V., Derevianko, A. P., Viola, B., Slatkin, M., Reich, D., Kelso, J., & Pääbo, S. (2014). The complete genome sequence of a Neanderthal from the Altai Mountains. Nature, 505(7481), 43-49.
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57

Meyer, M., Fu, Q., Ayinuer-Petri, A., Glocke, I., Nickel, B., Arsuaga, J.-L., Martínez, I., Gracia, A., de Castro, J. M. B., Carbonell, E., & Pääbo, S. (2014). A mitochondrial genome sequence of a hominin from Sima de los Huesos. Nature, 505(7483), 403-406.
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58

Sankararaman, S., Mallick, S., Dannemann, M., Prüfer, K., Kelso, J., Pääbo, S., Patterson, N., & Reich, D. (2014). The genomic landscape of Neanderthal ancestry in present-day humans. Nature, 507(7492), 354-357.
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59

Pääbo, S. (2014). The human condition: A molecular approach (Review). Cell, 157(1), 216-226.
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60

Gokhman, D., Lavi, E., Prüfer, K., Fraga, M. F., Riancho, J. A., Kelso, J., Pääbo, S., Meshorer, E., & Carmel, L. (2014). Reconstructing the DNA methylation maps of the Neandertal and the Denisovan. Science, 344(6183), 523-527.
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61

Lazaridis, I., Patterson, N., Mittnik, A., Renaud, G., Mallick, S., Kirsanow, K., Sudmant, P. H., Schraiber, J. G., Castellano, S., Lipson, M., Berger, B., Economou, C., Bollongino, R., Fu, Q., Bos, K. I., Nordenfelt, S., Li, H., de Filippo, C., Prüfer, K., Sawyer, S., Posth, C., Haak, W., Hallgren, F., Fornander, E., Rohland, N., Delsate, D., Francken, M., Guinet, J.-M., Wahl, J., Ayodo, G., Babiker, H. A., Bailliet, G., Balanovska, E., Balanovsky, O., Barrantes, R., Bedoya, G., Ben-Ami, H., Bene, J., Berrada, F., Bravi, C. M., Brisighelli, F., Busby, G. B. J., Cali, F., Churnosov, M., Cole, D. E. C., Corach, D., Damba, L., van Driem, G., Dryomov, S., Dugoujon, J.-M., Fedorova, S. A., Romero, I. G., Gubina, M., Hammer, M., Henn, B. M., Hervig, T., Hodoglugil, U., Jha, A. R., Karachanak-Yankova, S., Khusainova, R., Khusnutdinova, E., Kittles, R., Kivisild, T., Klitz, W., Kucinskas, V., Kushniarevich, A., Laredj, L., Litvinov, S., Loukidis, T., Mahley, R. W., Melegh, B., Metspalu, E., Molina, J., Mountain, J., Näkkäläjärvi, K., Nesheva, D., Nyambo, T., Osipova, L., Parik, J., Platonov, F., Posukh, O., Romano, V., Rothhammer, F., Rudan, I., Ruizbakiev, R., Sahakyan, H., Sajantila, A., Salas, A., Starikovskaya, E. B., Tarekegn, A., Toncheva, D., Turdikulova, S., Uktveryte, I., Utevska, O., Vasquez, R., Villena, M., Voevoda, M., Winkler, C. A., Yepiskoposyan, L., Zalloua, P., Zemunik, T., Cooper, A., Capelli, C., Thomas, M. G., Ruiz-Linares, A., Tishkoff, S. A., Singh, L., Thangaraj, K., Villems, R., Comas, D., Sukernik, R., Metspalu, M., Meyer, M., Eichler, E. E., Burger, J., Slatkin, M., Pääbo, S., Kelso, J., Reich, D., & Krause, J. (2014). Ancient human genomes suggest three ancestral populations for present-day Europeans. Nature, 513(7518), 409-413.
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Fu, Q., Li, H., Moorjani, P., Jay, F., Slepchenko, S. M., Bondarev, A. A., Johnson, P. L. F., Ayinuer-Petri, A., Prüfer, K., de Filippo, C., Meyer, M., Zwyns, N., Salazar García, D. C., Kuzmin, Y. V., Keates, S. G., Kosintsev, P. A., Razhev, D. I., Richards, M. P., Peristov, N. V., Lachmann, M., Douka, K., Higham, T. F. G., Slatkin, M., Hublin, J.-J., Reich, D., Kelso, J., Viola, B., & Pääbo, S. (2014). Genome sequence of a 45,000-year-old modern human from western Siberia. Nature, 514(7523), 445-449.
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63

Florio, M., Albert, M., Taverna, E., Namba, T., Brandl, H., Lewitus, E., Haffner, C., Sykes, A., Wong, F. K., Peters, J., Guhr, E., Klemroth, S., Prüfer, K., Kelso, J., Naumann, R., Nüsslein, I., Dahl, A., Lachmann, R., Pääbo, S., & Huttner, W. B. (2015). Human-specific gene ARHGAP11B promotes basal progenitor amplification and neocortex expansion. Science, 347(6229), 1465-1470.
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Benazzi, S., Slon, V., Talamo, S., Negrino, F., Peresani, M., Bailey, S. E., Sawyer, S., Panetta, D., Vicino, G., Starnini, E., Mannino, M. A., Salvadori, P. A., Meyer, M., Pääbo, S., & Hublin, J.-J. (2015). The makers of the Protoaurignacian and implications for Neandertal extinction. Science, 348(6236), 793-796.
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参考资料:

https://www.eva.mpg.de/genetics/staff/paabo/

https://mp.weixin.qq.com/s/G4JtzDq62QuK319Dylrv8A

https://mp.weixin.qq.com/s/T3lMLTeL2e-F_Tf23NGGJQ

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    2022-11-12 ms7000000025362926

    基础研究非常重要

    0

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    2022-10-10 0348

    好文字

    0

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    2022-10-09 weigq

    绝大部分人缺乏的是兴趣。

    0

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    2022-10-07 风雨无阻308

    基础研究非常重要

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    2022-10-04 病毒猎手

    牛人的后代也是牛人

    0

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梅斯锐评:由2019年诺贝尔生理与医学奖想到的……,什么是我们应该追求的方向?!

作者:梅斯医学全体编辑2019年诺贝尔生理学与医学奖终于落地了,霍华德-休斯医学研究所的William G. Kaelin Jr、弗朗西斯-克里克研究所的Sir Peter J. Ratcliffe和约翰斯霍普金斯的Gregg L. Semenza因揭示细胞感知和适应氧气供应的机制而获得此奖。诺贝尔奖预测一直是热门话题,尤其是科睿唯安公司(Clarivate Analytics),每年都在诺奖前宣