Human From the Neander Valley

Sharply distinguished by our unique mode of cognition, we humans possess intellectual capacity that are incomparable to most living organisms, and were scientifically named Homo sapiens, which implies “wise man” in Latin. Yet, there was once a species who shared a surprisingly similar appearance with us, and managed to create tools for domestic uses such as sharpened spears to kill animals for food [1]. They are described as our sister species and our distant relative, whose major specimen was first discovered in 1856 in the Neander Valley in Germany. Anthropologists therefore name them Homo neanderthalensis, meaning “human from the Neander Valley” [2].

Spotlight on the Pioneer­ – Svante Pääbo

Paleogenetics is the field of studying the past by recovering and analyzing the preserved genetic material in ancient organisms. Over the last four decades, Prof. Svante Pääbo has revolutionized our understanding of human evolutionary history [3]. As the Director of the Department of Evolutionary Genetics at the Max Planck Institute for Evolutionary Anthropology, Prof. Svante Pääbo was the pioneer who adopted the cutting-edge next-generation sequencing technology in paleogenetics and contributed to overcome the technical obstacles encountered [4]. In 2002, his team published a paper on the evolution of the gene FOXP2, which sparked wide interest in its possible role on the ability of humans to articulate speech and develop language [5, 6]. In 2006, he initiated a project to sequence the entire Neanderthal genome; a draft sequence was eventually published in May 2010 [7]. In March 2010, he identified an extinct human species, Denisovan, which was previously unknown [8]. These contributions have profound influence on our understanding of human evolution and our ancient relatives.

Legacy From Neanderthals in Our DNA

With the three billion-letter Neanderthal genome first sequenced in 2010, it was revealed that Neanderthal DNA is approximately 99.7% identical to modern human DNA [6]. Close phylogenetic relationships between Homo sapiens and Homo neanderthalensis, where the two species shared a common ancestor 400,000 to 700,000 years ago, can be concluded by genomic calculations and fossil record [9-11]. Most striking of all, by looking into the genomes of five present-day humans from different continents, 2% of the non-African modern human genome was proven inherited from Neanderthals, whereas no Neanderthal DNA could be found in the genomes of the two Africans [9]. Despite of the limited sample size, the result seems to support the famous “out-of-Africa” model, a hypothesis which suggests Africa as the single location for the origin of genus Homo. It is believed that the genus Homo migrated out of Africa in a few waves [12]. Modern humans were speculated to have encountered and interbred with the Neanderthals and Denisovans who had left Africa much earlier, when we first spread out of sub-Saharan Africa [12]. The interbreeding hypothesis is now supported by the results of many genetic analyses [13, 14], including the 2% inheritance of Neanderthal DNA exclusively found in non-African genomes in the study above [9].

Not only did we find evidence that reconstructed our genealogy, we also found traits linked to these remnants in our DNA. Published in Nature in September 2020, a genomic segment inherited from Neanderthals on the third chromosome has been identified as a risk locus for respiratory failure after infection of SARS-CoV-2 [15], meaning that the genomic location may contain a version of gene (scientifically termed an allele) associated with an increased risk of severe infection and hospitalization. That allele concerns around 50% and 16% of south Asia and European populations respectively [15]. Scientists posited that the allele could once confer a significant survival advantage on individuals by its ability to elicit a protective immune response against ancient pathogens, so that it was positively selected for in some populations during the course of natural selection [16]. However, the ancient genes may be unfavorable today as the immune response induced could be overly aggressive and potentially fatal in a COVID-19 infection [15].

Our Second Distant Relative – Denisovans

The tree of evolution is continuously being tangled with additional discoveries of human ancestry. Besides the archaic humans Neanderthals, Denisovans lived about 40,000 to 400,000 years ago in Europe and Western Asia [17]. This group of extinct human species was first identified by Prof. Pääbo from the genetic material recovered from a finger bone fragment collected from Denisova Cave in the Altai Mountains of Russia, which gave rise to the name “Denisovans” [18]. Anatomically, Denisovans were speculated to have an elongated face, a wide pelvis, an increased dental arch and lateral cranial expansion [19].

Genetically, there was also evidence of interbreeding between Denisovans, Neanderthals and ancestors of modern humans [11, 20]. Traces of Denisovans can primarily be found nowadays in the genomes of Southeast Asian and Pacific Islander populations, whereas people in other parts of the world contain only a very low or an undetectable amount of Denisovan DNA sequence [17]. Similar to the genetic variations inherited from Neanderthals, genetic variants from Denisovans may also contribute to many of our traits, for example, hair texture, height, sensitivity of smell and immune responses [17].

The Quest to Answer the Unanswered

The rise of human ancient DNA research not only feeds our mere curiosity, but also provides us new insights on how the course of evolution shapes human into the creature we are today; or in other words, what makes humans human. The fascinating findings on human adaptation and disease susceptibility through time also reveal many intriguing facts about ourselves, not least, to be aware that there is so much we do not know. How many of you would like to follow the footsteps of Prof. Pääbo?

References:

[1] Williams, F. L., Trinkaus, E., & Tuttle, R. H. (2020, February 6). Neanderthal. Encyclopedia Britannica. Retrieved from https://www.britannica.com/topic/Neanderthal
[2] Dorey, F. (2020, December 3). Homo neanderthalensis – The Neanderthals. Retrieved from https://australian.museum/learn/science/human-evolution/homo-neanderthalensis
[3] Zagorski, N. (2006). Profile of Svante Pääbo. Proceedings of the National Academy of Sciences of the United States of America, 103(37), 13575-13577. doi:10.1073/pnas.0606596103
[4] Stiller, M., Green, R. E., Ronan, M., Simons, J. F., Du, L., He, W., … Pääbo, S. (2006). Patterns of nucleotide misincorporations during enzymatic amplification and direct large-scale sequencing of ancient DNA. Proceedings of the National Academy of Sciences of the United States of America, 103(37), 13578–13584. doi:10.1073/pnas.0605327103
[5] Enard, W., Przeworski, M., Fisher, S. E., Lai, C. S. L., Wiebe, V., Kitano, T., … Pääbo, S. (2002). Molecular evolution of FOXP2, a gene involved in speech and language. Nature, 418(6900), 869–872. doi:10.1038/nature01025
[6] Hunter P. (2019). The riddle of speech: After FOXP2 dominated research on the origins of speech, other candidate genes have recently emerged. EMBO reports, 20(2), e47618. doi:10.15252/embr.201847618
[7] Green, R. E., Krause, J., Briggs, A. W., Maricic, T., Stenzel, U., Kircher, M., … Pääbo, S. (2010). A draft sequence of the Neandertal genome. Science, 328(5979), 710–722. doi:10.1126/science.1188021
[8] 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. doi:10.1038/nature08976
[9] National Human Genome Research Institute. (2010). Complete Neanderthal Genome Sequenced. Retrieved from https://www.genome.gov/27539119/2010-release-complete-neanderthal-genome-sequenced
[10] Stringer, C. (2016). The origin and evolution of Homo sapiens. Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 371(1698), 20150237. doi:10.1098/rstb.2015.0237
[11] Prüfer, K., Racimo, F., Patterson, N., Jay, F., Sankararaman, S., Sawyer, S., … Pääbo, S. (2014). The complete genome sequence of a Neanderthal from the Altai Mountains. Nature, 505(7481), 43–49. doi:10.1038/nature12886
[12] Sanders, M. F., & Bowman, J. L. (2019). Genetic analysis: an integrated approach (3rd ed.). New York, NY: Pearson Education.
[13] Sankararaman, S., Patterson, N., Li, H., Pääbo, S., & Reich, D. (2012). The date of interbreeding between Neandertals and modern humans. PLoS genetics, 8(10), e1002947. doi:10.1371/journal.pgen.1002947
[14] Wall, J. D., Lohmueller, K. E., & Plagnol, V. (2009). Detecting ancient admixture and estimating demographic parameters in multiple human populations. Molecular Biology and Evolution, 26(8), 1823–1827. doi:10.1093/molbev/msp096
[15] Zeberg, H., & Pääbo, S. (2020). The major genetic risk factor for severe COVID-19 is inherited from Neanderthals. Nature, 587(7835), 610–612. doi:10.1038/s41586-020-2818-3
[16] Luo, Y. (2020). Neanderthal DNA highlights complexity of COVID risk factors. Nature, 587(7835), 552–553. doi:10.1038/d41586-020-02957-3
[17] U.S. National Library of Medicine (2020). What does it mean to have Neanderthal or Denisovan DNA?. Retrieved from https://medlineplus.gov/genetics/understanding/dtcgenetictesting/neanderthaldna
[18] Warren, M. (2018). Mum’s a Neanderthal, Dad’s a Denisovan: First discovery of an ancient-human hybrid. Nature, 560(7719), 417–418. doi:10.1038/d41586-018-06004-0
[19] Gokhman, D., Mishol, N., de Manuel, M., de Juan, D., Shuqrun, J., Meshorer, E., … Carmel, L. (2019). Reconstructing Denisovan Anatomy Using DNA Methylation Maps. Cell, 179(1), 180–192.e10. doi:10.1016/j.cell.2019.08.035
[20] Slon, V., Mafessoni, F., Vernot, B., de Filippo, C., Grote, S., Viola, B., … Pääbo, S. (2018). The genome of the offspring of a Neanderthal mother and a Denisovan father. Nature, 561(7721), 113–116. doi:10.1038/s41586-018-0455-x