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Unlocking the Past on the “Bases” of Ancient DNA
Leading Edge
Select Unlocking the Past on the ‘‘Bases’’ of Ancient DNA Fossils of archaic hominins hold more secrets to the history of human evolution than we could possibly have imagined. The finding that DNA can still persist in some fossil records, and, more importantly, be successfully extracted, amplified, and sequenced, came with a big promise: to help answer long-standing questions about the evolutionary origins of modern humans, their patterns of migration and interactions with their closest relatives—the Neanderthals—with whom we now know they coexisted in Europe over thousands of years. Thanks to many years of research into ancient DNA and important technical advances in high-throughput sequencing that allowed the sequencing of the complete genome of a Neanderthal woman from the Altai Mountains in Siberia (Pru¨fer et al., 2014), we know now that there’s a little bit of Neanderthal in everyone whose roots are outside Africa. But how do these small portions of archaic DNA affect people today? Further insights into Neanderthal genetic contributions and their relevance were offered by two subsequent studies (Vernot and Akey, 2014; Sankararaman et al., 2014). For instance, some Neanderthal-derived alleles
Archaeological site (Atapuerca, Spain). Image from iStock.com/ Roger De Marfa`.
may have conferred an evolutionary advantage to modern humans, by helping them cope with environments outside Africa. However, there were also fitness costs to interbreeding, as other variants appear to confer risk for disease. On the flip side, both studies also reported regions in our genomes that were depleted of Neanderthal lineages. For instance, a genomic region including a locus involved in speech and language, FOXP2, has the tendency to have fewer Neanderthal alleles, as reported by Vernot and Akey. This also seems to be the case for the X chromosome and genes active in testes, as reported by Sankararaman et al., further suggesting that some Neanderthal variants may be deleterious and perhaps reduced fertility in hybrids. Yet, the functional contribution of our surviving Neanderthal DNA has not been well established. In a recent study, Tony Capra and colleagues take a closer look into how the Neanderthal legacy influences health-related human traits (Simonti et al., 2016). By combining genotyping data with electronic health records from 28,000 hospital patients of European ancestry, Simonti et al., discovered associations of Neanderthal alleles with a range of clinically relevant phenotypes, such as the risk of depression or immunological and dermatological medical conditions. All together, these studies provide a catalog of introgressed Neanderthal variants. However, considerably less is known about the contribution of the Denisovans, an archaic hominid form that diverged from the Neanderthals approximately 400,000 years ago. While modern non-Africans contain 1.5%–4% of Neanderthal-inherited DNA, significant contributions of the Denisovans appear to be exclusive to Oceanic and mainland Asian populations (Meyer et al., 2012). To provide a more comprehensive picture into the Denisovan genetic contribution, Vernot et al. analyzed the whole-genome of nearly 1,500 modern humans, along with 35 newly sequenced genomes from individuals from the Melanesian islands. While Melanasian individuals have both Neanderthal and Denisovan ancestry, most other non-African populations retained only Neanderthal DNA (Vernot et al., 2016). Further, the authors developed methods to recover and classify archaic variants allowing the reconstruction of a map of archaic sequences. They used the results to show that whereas multiple Neanderthal populations probably bred on multiple occasions with different non-African populations, Denisovans may have bred only once. Although these studies convincingly demonstrate gene flow from both Neanderthals and Denisovans into non-African modern humans, evidence for a reverse flow of genetic information was not forthcoming. Now, by analyzing the genomes of a Neanderthal and a Denisovan from the Altai Mountains in Siberia, together with the genomic sequences from two Neanderthals from Spain and Croatia, Sergi Castellano and colleagues find evidence of gene flow from modern humans into Neanderthals from the Altai Mountains, but not into the Denisovans (Kuhlwilm et al., 2016). Evidence for admixture Cell 166, July 14, 2016 ª 2016 Published by Elsevier Inc. 259
between modern and archaic hominids provides important clues to the migration history of modern humans; however, very little is known about the genetic composition of the early modern humans who arrived in Europe approximately 45,000 years ago and lived there even when Europe was covered in ice during the last glacial period. Recent work from Johannes Krause, Svante Pa¨a¨bo, David Reich, and colleagues now addresses this question (Fu et al., 2016). By assembling and analyzing genome-wide data from 51 modern humans who lived in Eurasia 45,000–7,000 years ago, Fu et al. offer important insights into the complex population history of preNeolithic Europe. While there is no evidence that the earliest modern humans significantly contributed to the present-day European gene pool, it appears that European populations from around 37,000 years ago onward share some ancestry with current Europeans (Fu et al., 2016). How did Neanderthal ancestry change in modern humans over this time? Fu et al. also tackle this question and estimate a decline of Neanderthal-derived alleles during this period, which appears to have been driven by natural selection against Neanderthal DNA. Collectively, these studies provide a glimpse into the incredibly fast-paced field of paleogenomics. But this hasn’t always been the case. Working with ancient DNA is not without challenges, and for a long time the field had endured more failures than successes. Not only do DNA sequences from ancient sources show base damage and fragmentation into short pieces, but the majority of DNA recovered from many specimens is actually of microbial origin. Furthermore, contamination with modern human DNA (derived from human handling during excavations or in museums) is also very common. In addition to working under strict clean laboratory conditions, appropriate sequencing and computational methods are also required to correct and mitigate biases and ensure that the identification of bona fide archaic sequences is accurate (Pa¨a¨bo, 2014). How contemporary humans originated is a fascinating question that embraces all of us, regardless of ethnicity or culture. Ancient genomes have provided priceless snapshots into our history, and, like all exciting research subjects, answering one question generates many more interesting avenues for investigations. One obvious open question is what exactly sets us apart from earlier and archaic hominins. How did they live, behave, and communicate? Did they have the ability for critical thinking? Maybe the immense curiosity about our ancestry is one of the many things that makes us humans.
Pru¨fer, K., Racimo, F., Patterson, N., Jay, F., Sankararaman, S., Sawyer, S., Heinze, A., Renaud, G., Sudmant, P.H., de Filippo, C., et al. (2014). The complete genome sequence of a Neanderthal from the Altai Mountains. Nature 505, 43–49. Sankararaman, S., Mallick, S., Dannemann, M., Pru¨fer, K., Kelso, J., Pa¨a¨bo, S., Patterson, N., and Reich, D. (2014). The genomic landscape of Neanderthal ancestry in present-day humans. Nature 507, 354–357. Simonti, C.N., Vernot, B., Bastarache, L., Bottinger, E., Carrell, D.S., Chisholm, R.L., Crosslin, D.R., Hebbring, S.J., Jarvik, G.P., Kullo, I.J., et al. (2016). The phenotypic legacy of admixture between modern humans and Neandertals. Science 351, 737–741. Vernot, B., and Akey, J.M. (2014). Resurrecting surviving Neandertal lineages from modern human genomes. Science 343, 1017–1021. Vernot, B., Tucci, S., Kelso, J., Schraiber, J.G., Wolf, A.B., Gittelman, R.M., Dannemann, M., Grote, S., McCoy, R.C., Norton, H., et al. (2016). Excavating Neandertal and Denisovan DNA from the genomes of Melanesian individuals. Science 352, 235–239.
Marta Koch
REFERENCES Fu, Q., Posth, C., Hajdinjak, M., Petr, M., Mallick, S., Fernandes, D., Furtwa¨ngler, A., Haak, W., Meyer, M., Mittnik, A., et al. (2016). The genetic history of Ice Age Europe. Nature 534, 200–205. Kuhlwilm, M., Gronau, I., Hubisz, M.J., de Filippo, C., Prado-Martinez, J., Kircher, M., Fu, Q., Burbano, H.A., Lalueza-Fox, C., de la Rasilla, M., et al. (2016). Ancient gene flow from early modern humans into Eastern Neanderthals. Nature 530, 429–433. Meyer, M., Kircher, M., Gansauge, M.T., Li, H., Racimo, F., Mallick, S., Schraiber, J.G., Jay, F., Pru¨fer, K., de Filippo, C., et al. (2012). A high-coverage genome sequence from an archaic Denisovan individual. Science 338, 222–226. Pa¨a¨bo, S. (2014). Neanderthal Man: In Search of Lost Genomes (Basic Books).
Cell 166, July 14, 2016 261
Select Unlocking the Past on the ‘‘Bases’’ of Ancient DNA Fossils of archaic hominins hold more secrets to the history of human evolution than we could possibly have imagined. The finding that DNA can still persist in some fossil records, and, more importantly, be successfully extracted, amplified, and sequenced, came with a big promise: to help answer long-standing questions about the evolutionary origins of modern humans, their patterns of migration and interactions with their closest relatives—the Neanderthals—with whom we now know they coexisted in Europe over thousands of years. Thanks to many years of research into ancient DNA and important technical advances in high-throughput sequencing that allowed the sequencing of the complete genome of a Neanderthal woman from the Altai Mountains in Siberia (Pru¨fer et al., 2014), we know now that there’s a little bit of Neanderthal in everyone whose roots are outside Africa. But how do these small portions of archaic DNA affect people today? Further insights into Neanderthal genetic contributions and their relevance were offered by two subsequent studies (Vernot and Akey, 2014; Sankararaman et al., 2014). For instance, some Neanderthal-derived alleles
Archaeological site (Atapuerca, Spain). Image from iStock.com/ Roger De Marfa`.
may have conferred an evolutionary advantage to modern humans, by helping them cope with environments outside Africa. However, there were also fitness costs to interbreeding, as other variants appear to confer risk for disease. On the flip side, both studies also reported regions in our genomes that were depleted of Neanderthal lineages. For instance, a genomic region including a locus involved in speech and language, FOXP2, has the tendency to have fewer Neanderthal alleles, as reported by Vernot and Akey. This also seems to be the case for the X chromosome and genes active in testes, as reported by Sankararaman et al., further suggesting that some Neanderthal variants may be deleterious and perhaps reduced fertility in hybrids. Yet, the functional contribution of our surviving Neanderthal DNA has not been well established. In a recent study, Tony Capra and colleagues take a closer look into how the Neanderthal legacy influences health-related human traits (Simonti et al., 2016). By combining genotyping data with electronic health records from 28,000 hospital patients of European ancestry, Simonti et al., discovered associations of Neanderthal alleles with a range of clinically relevant phenotypes, such as the risk of depression or immunological and dermatological medical conditions. All together, these studies provide a catalog of introgressed Neanderthal variants. However, considerably less is known about the contribution of the Denisovans, an archaic hominid form that diverged from the Neanderthals approximately 400,000 years ago. While modern non-Africans contain 1.5%–4% of Neanderthal-inherited DNA, significant contributions of the Denisovans appear to be exclusive to Oceanic and mainland Asian populations (Meyer et al., 2012). To provide a more comprehensive picture into the Denisovan genetic contribution, Vernot et al. analyzed the whole-genome of nearly 1,500 modern humans, along with 35 newly sequenced genomes from individuals from the Melanesian islands. While Melanasian individuals have both Neanderthal and Denisovan ancestry, most other non-African populations retained only Neanderthal DNA (Vernot et al., 2016). Further, the authors developed methods to recover and classify archaic variants allowing the reconstruction of a map of archaic sequences. They used the results to show that whereas multiple Neanderthal populations probably bred on multiple occasions with different non-African populations, Denisovans may have bred only once. Although these studies convincingly demonstrate gene flow from both Neanderthals and Denisovans into non-African modern humans, evidence for a reverse flow of genetic information was not forthcoming. Now, by analyzing the genomes of a Neanderthal and a Denisovan from the Altai Mountains in Siberia, together with the genomic sequences from two Neanderthals from Spain and Croatia, Sergi Castellano and colleagues find evidence of gene flow from modern humans into Neanderthals from the Altai Mountains, but not into the Denisovans (Kuhlwilm et al., 2016). Evidence for admixture Cell 166, July 14, 2016 ª 2016 Published by Elsevier Inc. 259
between modern and archaic hominids provides important clues to the migration history of modern humans; however, very little is known about the genetic composition of the early modern humans who arrived in Europe approximately 45,000 years ago and lived there even when Europe was covered in ice during the last glacial period. Recent work from Johannes Krause, Svante Pa¨a¨bo, David Reich, and colleagues now addresses this question (Fu et al., 2016). By assembling and analyzing genome-wide data from 51 modern humans who lived in Eurasia 45,000–7,000 years ago, Fu et al. offer important insights into the complex population history of preNeolithic Europe. While there is no evidence that the earliest modern humans significantly contributed to the present-day European gene pool, it appears that European populations from around 37,000 years ago onward share some ancestry with current Europeans (Fu et al., 2016). How did Neanderthal ancestry change in modern humans over this time? Fu et al. also tackle this question and estimate a decline of Neanderthal-derived alleles during this period, which appears to have been driven by natural selection against Neanderthal DNA. Collectively, these studies provide a glimpse into the incredibly fast-paced field of paleogenomics. But this hasn’t always been the case. Working with ancient DNA is not without challenges, and for a long time the field had endured more failures than successes. Not only do DNA sequences from ancient sources show base damage and fragmentation into short pieces, but the majority of DNA recovered from many specimens is actually of microbial origin. Furthermore, contamination with modern human DNA (derived from human handling during excavations or in museums) is also very common. In addition to working under strict clean laboratory conditions, appropriate sequencing and computational methods are also required to correct and mitigate biases and ensure that the identification of bona fide archaic sequences is accurate (Pa¨a¨bo, 2014). How contemporary humans originated is a fascinating question that embraces all of us, regardless of ethnicity or culture. Ancient genomes have provided priceless snapshots into our history, and, like all exciting research subjects, answering one question generates many more interesting avenues for investigations. One obvious open question is what exactly sets us apart from earlier and archaic hominins. How did they live, behave, and communicate? Did they have the ability for critical thinking? Maybe the immense curiosity about our ancestry is one of the many things that makes us humans.
Pru¨fer, K., Racimo, F., Patterson, N., Jay, F., Sankararaman, S., Sawyer, S., Heinze, A., Renaud, G., Sudmant, P.H., de Filippo, C., et al. (2014). The complete genome sequence of a Neanderthal from the Altai Mountains. Nature 505, 43–49. Sankararaman, S., Mallick, S., Dannemann, M., Pru¨fer, K., Kelso, J., Pa¨a¨bo, S., Patterson, N., and Reich, D. (2014). The genomic landscape of Neanderthal ancestry in present-day humans. Nature 507, 354–357. Simonti, C.N., Vernot, B., Bastarache, L., Bottinger, E., Carrell, D.S., Chisholm, R.L., Crosslin, D.R., Hebbring, S.J., Jarvik, G.P., Kullo, I.J., et al. (2016). The phenotypic legacy of admixture between modern humans and Neandertals. Science 351, 737–741. Vernot, B., and Akey, J.M. (2014). Resurrecting surviving Neandertal lineages from modern human genomes. Science 343, 1017–1021. Vernot, B., Tucci, S., Kelso, J., Schraiber, J.G., Wolf, A.B., Gittelman, R.M., Dannemann, M., Grote, S., McCoy, R.C., Norton, H., et al. (2016). Excavating Neandertal and Denisovan DNA from the genomes of Melanesian individuals. Science 352, 235–239.
Marta Koch
REFERENCES Fu, Q., Posth, C., Hajdinjak, M., Petr, M., Mallick, S., Fernandes, D., Furtwa¨ngler, A., Haak, W., Meyer, M., Mittnik, A., et al. (2016). The genetic history of Ice Age Europe. Nature 534, 200–205. Kuhlwilm, M., Gronau, I., Hubisz, M.J., de Filippo, C., Prado-Martinez, J., Kircher, M., Fu, Q., Burbano, H.A., Lalueza-Fox, C., de la Rasilla, M., et al. (2016). Ancient gene flow from early modern humans into Eastern Neanderthals. Nature 530, 429–433. Meyer, M., Kircher, M., Gansauge, M.T., Li, H., Racimo, F., Mallick, S., Schraiber, J.G., Jay, F., Pru¨fer, K., de Filippo, C., et al. (2012). A high-coverage genome sequence from an archaic Denisovan individual. Science 338, 222–226. Pa¨a¨bo, S. (2014). Neanderthal Man: In Search of Lost Genomes (Basic Books).
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