Available online at www.sciencedirect.com
ScienceDirect Ancient humans and the origin of modern humans Janet Kelso and Kay Pru¨fer Recent advances in sequencing technologies and molecular methods have facilitated the sequencing of DNA from ancient human remains which has, in turn, provided unprecedented insight into human history. Within the past 4 years the genomes of Neandertals and Denisovans, as well as the genomes of at least two early modern humans, have been sequenced. These sequences showed that there have been several episodes of admixture between modern and archaic groups; including admixture from Neandertals into modern human populations outside of Africa, and admixture from Denisovans into modern human populations in Oceania. Recent results indicate that some of these introgressed regions may have been advantageous for modern humans as they expanded into new regions outside of Africa. Addresses Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, 04103 Leipzig, Germany Corresponding author: Kelso, Janet ([email protected])
Current Opinion in Genetics & Development 2014, 29:133–138 This review comes from a themed issue on Genetics of human origin Edited by Aida M. Andre´s and Katja Nowick
We review here advances in the sequencing and analysis of ancient genomes with a focus on archaic human forms and early modern humans older than 12 000 years — a date corresponding with the end of the Paleolithic period. While studies of single genomic loci have yielded information about specific traits in archaic humans, we focus here only on those individuals for which genome-wide sequence data is available, as such data are suitable for studying population history and admixture patterns. We discuss the challenges associated with generating ancient human genome sequences, describe the genomes that have been sequenced, and highlight the insights into modern human history and demography that have been obtained from the analysis of these genomes.
Sequencing DNA from ancient remains The DNA extracted from ancient remains has a number of properties that distinguish it from modern DNA, and which lead to very specific challenges. It has been shown that the concentration of endogenous DNA in bone decreases over time with the result that the majority of samples do not contain appreciable amounts of endogenous DNA [11,12]. A major challenge is therefore to identify bones with a sufficient amount of endogenous DNA for sequencing.
http://dx.doi.org/10.1016/j.gde.2014.09.004 0959-437X/# 2014 Published by Elsevier Ltd.
Introduction In recent years a growing number of insights into the molecular origins of modern humans have been obtained through the analysis of DNA sequence data. While early analyses focused on using single loci and informative markers to reconstruct human population histories and movements [1–5], high throughput sequencing has made possible the sequencing of whole mitochondrial and nuclear genomes from multiple organisms including humans and non-human primates [6–10]. These same sequencing technologies have revolutionized the field of ancient DNA. Whole mitochondrial and nuclear genome sequences of early modern humans as well as the genomes of now extinct human forms including the Neandertals have been sequenced and analyzed, and have yielded a number of key insights into human history. www.sciencedirect.com
Even when a sample with endogenous DNA is identified, the extracted DNA is generally mixed with large quantities of microbial contamination and the endogenous molecules are typically short (0.5
Altai
%
Vindija
3-6%
Africa
Mezmaiskaya N.I.
1.5-2.1% 0.5
-8.
0%
Potential unknown hominin
Current Opinion in Genetics & Development
Tentative model of gene flow events between human groups in the late Pleistocene. The direction of gene flow is indicated by the red arrows and the estimated magnitude by the percentages given with each arrow. The tree and timing of gene flow are not drawn to scale. (Figure modified from Pru¨fer et al. [29]. Current Opinion in Genetics & Development 2014, 29:133–138
www.sciencedirect.com
Ancient humans and the origin of modern humans Kelso and Pru¨fer 137
Functional implications Genomic features that are unique to modern humans and differ from archaic humans and other apes are of particular interest since these may underlie modern human-specific traits. The Neandertal and Denisovan genome sequences have been used to make a catalog of those genomic sequence changes that have risen to high frequency or reached fixation in modern humans. While a full characterization of the phenotypic impact of these changes is ongoing, the list provides several interesting candidates with roles in the cell cycle and skeletal morphology. The impact of Neandertal and Denisovan introgression on human phenotypes has begun to be explored by a number of groups. When modern humans expanded out of Africa they were likely subjected to selective pressures to adapt to these new environments. Since Neandertals and Denisovans inhabited Europe and Western Asia for an extended time before the arrival of modern humans, they may have carried alleles that conveyed an advantage in these environments. If these alleles entered the modern human population by admixture, they are expected to rise to high frequency in populations where they provide an advantage. Alleles that entered modern humans from Neandertals and Denisovans and that have risen to high frequency in some human groups have been identified. These include loci involved in immunity [50,51], altitude adaptation [52], skin and hair physiology [53,54], and metabolism [55]. Genome-wide maps of Neandertal introgression has shown that large regions of the genomes of present-day non-Africans are devoid of Neandertal ancestry [54,56]. These regions are enriched in genes that have their highest expression in testes, suggesting that these devoid regions are due to strong negative selection on some Neandertal alleles, or to hybrid incompatibility between modern and archaic humans — consistent with the prediction of extensive incompatibility proposed by Currat and Excoffier [48].
nuclear genome sequences of middle Pleistocene humans may therefore be within reach.
Acknowledgements JK and KP acknowledge financial support from the Max Planck Society. JK is supported by the Deutsche Forschungsgemeinschaft DFG-SFB 1052/1: ‘Obesity mechanisms’ (project A02).
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: of special interest of outstanding interest 1.
Cann RL, Stoneking M, Wilson AC: Mitochondrial DNA and human evolution. Nature 1987, 325:31-36.
2.
Garrigan D, Hammer MF: Reconstructing human origins in the genomic era. Nat Rev Genet 2006, 7:669-680.
3.
Hammer MF: A recent common ancestry for human Y chromosomes. Nature 1995, 378:376-378.
4.
Underhill PA et al.: Y chromosome sequence variation and the history of human populations. Nat Genet 2000, 26:358-361.
5.
Harding RM et al.: Archaic African and Asian lineages in the genetic ancestry of modern humans. Am J Hum Genet 1997, 60:772-789.
6.
Chimpanzee S, Analysis C: Initial sequence of the chimpanzee genome and comparison with the human genome. Nature 2005, 437:69-87.
7.
Lander ES et al.: Initial sequencing and analysis of the human genome. Nature 2001, 409:860-921.
8.
Scally A et al.: Insights into hominid evolution from the gorilla genome sequence. Nature 2012, 483:169-175.
9.
Locke DP et al.: Comparative and demographic analysis of orang-utan genomes. Nature 2011, 469:529-533.
10. Pru¨fer K et al.: The bonobo genome compared with the chimpanzee and human genomes. Nature 2012, 486:527-531. 11. Hofreiter M et al.: Ancient DNA. Nat Rev Genet 2001, 2:353-359. 12. Ho¨ss M et al.: DNA damage and DNA sequence retrieval from ancient tissues. Nucleic Acids Res 1996, 24:1304-1307. 13. Briggs AW et al.: Patterns of damage in genomic DNA sequences from a Neandertal. Proc Natl Acad Sci U S A 2007, 104:14616-14621. 14. Sawyer S et al.: Temporal patterns of nucleotide misincorporations and DNA fragmentation in ancient DNA. PLOS ONE 2012, 7:pe34131. 15. Lindahl T: Instability and decay of the primary structure of DNA. Nature 1993, 362:709-715.
Conclusions Over the past 5 years the sequencing and analysis of archaic genomes have fundamentally changed our understanding of the origins and population history of modern humans. These genomes also provided insights into the inhabitants of Eurasia before the arrival of modern humans, and revealed previously unknown interactions with the arriving modern humans. Among the most exciting results was the identification of a new human group, the Denisovans, based solely on genetic evidence. Recent advances in DNA extraction and library preparation made it possible to sequence the mitochondrial genome of a 400 000-year old individual. The www.sciencedirect.com
16. Orlando L et al.: Recalibrating Equus evolution using the genome sequence of an early Middle Pleistocene horse. Nature 2013, 499:74-78. The authors extracted and sequenced DNA from a 700 000 year old horse found in permafrost in Yukon, Canada. This was the first study to show that the sequencing and analysis of middle Pleistocene genomes was technically feasible and provided information about the population history of modern horses. 17. Meyer M et al.: A mitochondrial genome sequence of a hominin from Sima de los Huesos. Nature 2014, 505:403-406. Mitochondrial DNA was extracted and sequenced from a 400 000 year old hominin bone from Sima de los Huesos. The authors demonstrated that DNA can be obtained from middle Pleistocene human bones found in non-permafrost conditions, opening up the possibility that nuclear genome sequences from older hominin forms may be accessible. 18. Dabney J et al.: Complete mitochondrial genome sequence of a Middle Pleistocene cave bear reconstructed from ultrashort Current Opinion in Genetics & Development 2014, 29:133–138
138 Genetics of human origin
DNA fragments. Proc Natl Acad Sci U S A 2013, 110: 15758-15763. 19. Wall JD, Kim SK: Inconsistencies in Neanderthal genomic DNA sequences. PLoS Genet 2007, 3:1862-1866. 20. Green RE et al.: The Neandertal genome and ancient DNA authenticity. EMBO J 2009, 28:2494-2502. 21. Green RE et al.: A draft sequence of the Neandertal genome. Science 2010, 328:710-722. 22. Fu Q et al.: A revised timescale for human evolution based on ancient mitochondrial genomes. Curr Biol 2013, 23:553-559. 23. Ginolhac A et al.: mapDamage: testing for damage patterns in ancient DNA sequences. Bioinformatics 2011, 27:2153-2155. 24. Skoglund P et al.: Separating endogenous ancient DNA from modern day contamination in a Siberian Neandertal. Proc Natl Acad Sci U S A 2014, 111:2229-2234. 25. Hublin JJ: Out of Africa: modern human origins special feature: the origin of Neandertals. Proc Natl Acad Sci U S A 2009, 106:16022-16027. 26. Krings M et al.: Neandertal DNA sequences and the origin of modern humans. Cell 1997, 90:19-30. 27. Green RE et al.: A complete Neandertal mitochondrial genome sequence determined by high-throughput sequencing. Cell 2008, 134:416-426. 28. Meyer M et al.: A high-coverage genome sequence from an archaic Denisovan individual. Science 2012, 338:222-226. The authors developed a new method to prepare single-stranded DNA sequencing libraries from ancient DNA and used this to sequence to high coverage the nuclear genome of a new human group that were called ‘Denisovans’. 29. Pru¨fer K et al.: The complete genome sequence of a Neanderthal from the Altai Mountains. Nature 2014, 505:43-49. The authors sequenced the genome of a Neandertal from the Altai mountains. This is the first high coverage genome of a Neandertal individual and it was used together with the Denisovan genome sequence to show that admixture between archaic humans was common. 30. Castellano S et al.: Patterns of coding variation in the complete exomes of three Neandertals. Proc Natl Acad Sci U S A 2014, 111:6666-6671.
40. Reich D et al.: Genetic history of an archaic hominin group from Denisova Cave in Siberia. Nature 2010, 468:1053-1060. 41. Li H, Durbin R: Inference of human population history from individual whole-genome sequences. Nature 2011, 475:493496. 42. Kong A et al.: Rate of de novo mutations and the importance of father’s age to disease risk. Nature 2012, 488:471-475. 43. Scally A, Durbin R: Revising the human mutation rate: implications for understanding human evolution. Nat Rev Genet 2012, 13:745-753. 44. Langergraber KE et al.: Generation times in wild chimpanzees and gorillas suggest earlier divergence times in great ape and human evolution. Proc Natl Acad Sci U S A 2012, 109:1571615721. 45. Eriksson A, Manica A: Effect of ancient population structure on the degree of polymorphism shared between modern human populations and ancient hominins. Proc Natl Acad Sci U S A 2012, 109:13956-13960. 46. Sankararaman S et al.: The date of interbreeding between Neandertals and Modern humans. PLoS Genet 2012, 8. 47. Yang MA et al.: Ancient structure in Africa unlikely to explain Neanderthal and non-African genetic similarity. Mol Biol Evol 2012, 29:2987-2995. 48. Currat M, Excoffier L: Strong reproductive isolation between humans and Neanderthals inferred from observed patterns of introgression. Proc Natl Acad Sci U S A 2011, 108:15129-15134. 49. Skoglund P, Jakobsson M: Archaic human ancestry in East Asia. Proc Natl Acad Sci U S A 2011, 108:18301-18306. 50. Abi-Rached L et al.: The shaping of modern human immune systems by multiregional admixture with archaic humans. Science 2011, 334:89-94. 51. Mendez FL, Watkins JC, Hammer MF: Neandertal origin of genetic variation at the cluster of OAS immunity genes. Mol Biol Evol 2013, 30:798-801.
31. Briggs AW et al.: Targeted retrieval and analysis of five Neandertal mtDNA genomes. Science 2009, 325:318-321.
52. Huerta-Sanchez E et al.: Altitude adaptation in Tibetans caused by introgression of Denisovan-like DNA. Nature 2014, 512:194197 http://dx.doi.org/10.1038/nature13408. The authors show that the functionally important allele of the EPAS1 gene in Tibetans is introgressed from Denisovans.
32. Briggs AW et al.: Primer extension capture: targeted sequence retrieval from heavily degraded DNA sources. J Vis Exp 2009:1573.
53. Ding Q et al.: Neanderthal introgression at Chromosome 3p21.31 was under positive natural selection in east Asians. Mol Biol Evol 2014, 31:683-695.
33. Maricic T, Whitten M, Paabo S: Multiplexed DNA sequence capture of mitochondrial genomes using PCR products. PLoS ONE 2010, 5:e14004.
54. Sankararaman S et al.: The genomic landscape of Neanderthal ancestry in present-day humans. Nature 2014, 507:354-357. A genome-wide map of the Neandertal alleles in present-day non-Africans was constructed using the Neandertal genome sequence and the sequences of multiple present-day non-Africans. Neandertal ancestry was shown to be non-uniform in its distribution with Neandertal alleles more common in regions of the genome that are not near genes and other functional elements. Functional analyses demonstrated that extensive deserts of Neandertal ancestry on the X chromosome and showed that these deserts are are particularly enriched for genes with their highest expression in testes.
34. Krause J et al.: The complete mitochondrial DNA genome of an unknown hominin from southern Siberia. Nature 2010, 464:894897. 35. Krause J et al.: A complete mtDNA genome of an early modern human from Kostenki, Russia. Curr Biol 2010, 20:231-236. 36. Fu Q et al.: DNA analysis of an early modern human from Tianyuan Cave, China. Proc Natl Acad Sci U S A 2013, 110: 2223-2227. 37. Raghavan M et al.: Upper Palaeolithic Siberian genome reveals dual ancestry of native Americans. Nature 2014, 505:87-91. The first full nuclear genome sequence of an early modern human from Siberia was used to gain insights into the ancestry of native Americans. 38. Fu Q et al.: The complete genome sequence of a 45,000-yearold modern human from western Siberia. Nature: (in press). 39. Rasmussen M et al.: The genome of a Late Pleistocene human from a Clovis burial site in western Montana. Nature 2014, 506:225-229.
Current Opinion in Genetics & Development 2014, 29:133–138
55. Khrameeva EE et al.: Neanderthal ancestry drives evolution of lipid catabolism in contemporary Europeans. Nat Commun 2014, 5:3584. 56. Vernot B, Akey JM: Resurrecting surviving Neandertal lineages from modern human genomes. Science 2014, 343:1017-1021. A genome-wide map of the Neandertal alleles in present-day non-Africans was constructed using the sequences of 665 present-day humans. The authors inferred a second Neandertal introgression into the ancestors of Asians based on differences in Neandertal ancestry between presentday Asians and Europeans. The gene FOXP2 was shown to be in a desert of Neandertal ancestry suggesting that Neandertal alleles in this region may have been under negative selection.
www.sciencedirect.com
ScienceDirect Ancient humans and the origin of modern humans Janet Kelso and Kay Pru¨fer Recent advances in sequencing technologies and molecular methods have facilitated the sequencing of DNA from ancient human remains which has, in turn, provided unprecedented insight into human history. Within the past 4 years the genomes of Neandertals and Denisovans, as well as the genomes of at least two early modern humans, have been sequenced. These sequences showed that there have been several episodes of admixture between modern and archaic groups; including admixture from Neandertals into modern human populations outside of Africa, and admixture from Denisovans into modern human populations in Oceania. Recent results indicate that some of these introgressed regions may have been advantageous for modern humans as they expanded into new regions outside of Africa. Addresses Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, 04103 Leipzig, Germany Corresponding author: Kelso, Janet ([email protected])
Current Opinion in Genetics & Development 2014, 29:133–138 This review comes from a themed issue on Genetics of human origin Edited by Aida M. Andre´s and Katja Nowick
We review here advances in the sequencing and analysis of ancient genomes with a focus on archaic human forms and early modern humans older than 12 000 years — a date corresponding with the end of the Paleolithic period. While studies of single genomic loci have yielded information about specific traits in archaic humans, we focus here only on those individuals for which genome-wide sequence data is available, as such data are suitable for studying population history and admixture patterns. We discuss the challenges associated with generating ancient human genome sequences, describe the genomes that have been sequenced, and highlight the insights into modern human history and demography that have been obtained from the analysis of these genomes.
Sequencing DNA from ancient remains The DNA extracted from ancient remains has a number of properties that distinguish it from modern DNA, and which lead to very specific challenges. It has been shown that the concentration of endogenous DNA in bone decreases over time with the result that the majority of samples do not contain appreciable amounts of endogenous DNA [11,12]. A major challenge is therefore to identify bones with a sufficient amount of endogenous DNA for sequencing.
http://dx.doi.org/10.1016/j.gde.2014.09.004 0959-437X/# 2014 Published by Elsevier Ltd.
Introduction In recent years a growing number of insights into the molecular origins of modern humans have been obtained through the analysis of DNA sequence data. While early analyses focused on using single loci and informative markers to reconstruct human population histories and movements [1–5], high throughput sequencing has made possible the sequencing of whole mitochondrial and nuclear genomes from multiple organisms including humans and non-human primates [6–10]. These same sequencing technologies have revolutionized the field of ancient DNA. Whole mitochondrial and nuclear genome sequences of early modern humans as well as the genomes of now extinct human forms including the Neandertals have been sequenced and analyzed, and have yielded a number of key insights into human history. www.sciencedirect.com
Even when a sample with endogenous DNA is identified, the extracted DNA is generally mixed with large quantities of microbial contamination and the endogenous molecules are typically short (0.5
Altai
%
Vindija
3-6%
Africa
Mezmaiskaya N.I.
1.5-2.1% 0.5
-8.
0%
Potential unknown hominin
Current Opinion in Genetics & Development
Tentative model of gene flow events between human groups in the late Pleistocene. The direction of gene flow is indicated by the red arrows and the estimated magnitude by the percentages given with each arrow. The tree and timing of gene flow are not drawn to scale. (Figure modified from Pru¨fer et al. [29]. Current Opinion in Genetics & Development 2014, 29:133–138
www.sciencedirect.com
Ancient humans and the origin of modern humans Kelso and Pru¨fer 137
Functional implications Genomic features that are unique to modern humans and differ from archaic humans and other apes are of particular interest since these may underlie modern human-specific traits. The Neandertal and Denisovan genome sequences have been used to make a catalog of those genomic sequence changes that have risen to high frequency or reached fixation in modern humans. While a full characterization of the phenotypic impact of these changes is ongoing, the list provides several interesting candidates with roles in the cell cycle and skeletal morphology. The impact of Neandertal and Denisovan introgression on human phenotypes has begun to be explored by a number of groups. When modern humans expanded out of Africa they were likely subjected to selective pressures to adapt to these new environments. Since Neandertals and Denisovans inhabited Europe and Western Asia for an extended time before the arrival of modern humans, they may have carried alleles that conveyed an advantage in these environments. If these alleles entered the modern human population by admixture, they are expected to rise to high frequency in populations where they provide an advantage. Alleles that entered modern humans from Neandertals and Denisovans and that have risen to high frequency in some human groups have been identified. These include loci involved in immunity [50,51], altitude adaptation [52], skin and hair physiology [53,54], and metabolism [55]. Genome-wide maps of Neandertal introgression has shown that large regions of the genomes of present-day non-Africans are devoid of Neandertal ancestry [54,56]. These regions are enriched in genes that have their highest expression in testes, suggesting that these devoid regions are due to strong negative selection on some Neandertal alleles, or to hybrid incompatibility between modern and archaic humans — consistent with the prediction of extensive incompatibility proposed by Currat and Excoffier [48].
nuclear genome sequences of middle Pleistocene humans may therefore be within reach.
Acknowledgements JK and KP acknowledge financial support from the Max Planck Society. JK is supported by the Deutsche Forschungsgemeinschaft DFG-SFB 1052/1: ‘Obesity mechanisms’ (project A02).
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: of special interest of outstanding interest 1.
Cann RL, Stoneking M, Wilson AC: Mitochondrial DNA and human evolution. Nature 1987, 325:31-36.
2.
Garrigan D, Hammer MF: Reconstructing human origins in the genomic era. Nat Rev Genet 2006, 7:669-680.
3.
Hammer MF: A recent common ancestry for human Y chromosomes. Nature 1995, 378:376-378.
4.
Underhill PA et al.: Y chromosome sequence variation and the history of human populations. Nat Genet 2000, 26:358-361.
5.
Harding RM et al.: Archaic African and Asian lineages in the genetic ancestry of modern humans. Am J Hum Genet 1997, 60:772-789.
6.
Chimpanzee S, Analysis C: Initial sequence of the chimpanzee genome and comparison with the human genome. Nature 2005, 437:69-87.
7.
Lander ES et al.: Initial sequencing and analysis of the human genome. Nature 2001, 409:860-921.
8.
Scally A et al.: Insights into hominid evolution from the gorilla genome sequence. Nature 2012, 483:169-175.
9.
Locke DP et al.: Comparative and demographic analysis of orang-utan genomes. Nature 2011, 469:529-533.
10. Pru¨fer K et al.: The bonobo genome compared with the chimpanzee and human genomes. Nature 2012, 486:527-531. 11. Hofreiter M et al.: Ancient DNA. Nat Rev Genet 2001, 2:353-359. 12. Ho¨ss M et al.: DNA damage and DNA sequence retrieval from ancient tissues. Nucleic Acids Res 1996, 24:1304-1307. 13. Briggs AW et al.: Patterns of damage in genomic DNA sequences from a Neandertal. Proc Natl Acad Sci U S A 2007, 104:14616-14621. 14. Sawyer S et al.: Temporal patterns of nucleotide misincorporations and DNA fragmentation in ancient DNA. PLOS ONE 2012, 7:pe34131. 15. Lindahl T: Instability and decay of the primary structure of DNA. Nature 1993, 362:709-715.
Conclusions Over the past 5 years the sequencing and analysis of archaic genomes have fundamentally changed our understanding of the origins and population history of modern humans. These genomes also provided insights into the inhabitants of Eurasia before the arrival of modern humans, and revealed previously unknown interactions with the arriving modern humans. Among the most exciting results was the identification of a new human group, the Denisovans, based solely on genetic evidence. Recent advances in DNA extraction and library preparation made it possible to sequence the mitochondrial genome of a 400 000-year old individual. The www.sciencedirect.com
16. Orlando L et al.: Recalibrating Equus evolution using the genome sequence of an early Middle Pleistocene horse. Nature 2013, 499:74-78. The authors extracted and sequenced DNA from a 700 000 year old horse found in permafrost in Yukon, Canada. This was the first study to show that the sequencing and analysis of middle Pleistocene genomes was technically feasible and provided information about the population history of modern horses. 17. Meyer M et al.: A mitochondrial genome sequence of a hominin from Sima de los Huesos. Nature 2014, 505:403-406. Mitochondrial DNA was extracted and sequenced from a 400 000 year old hominin bone from Sima de los Huesos. The authors demonstrated that DNA can be obtained from middle Pleistocene human bones found in non-permafrost conditions, opening up the possibility that nuclear genome sequences from older hominin forms may be accessible. 18. Dabney J et al.: Complete mitochondrial genome sequence of a Middle Pleistocene cave bear reconstructed from ultrashort Current Opinion in Genetics & Development 2014, 29:133–138
138 Genetics of human origin
DNA fragments. Proc Natl Acad Sci U S A 2013, 110: 15758-15763. 19. Wall JD, Kim SK: Inconsistencies in Neanderthal genomic DNA sequences. PLoS Genet 2007, 3:1862-1866. 20. Green RE et al.: The Neandertal genome and ancient DNA authenticity. EMBO J 2009, 28:2494-2502. 21. Green RE et al.: A draft sequence of the Neandertal genome. Science 2010, 328:710-722. 22. Fu Q et al.: A revised timescale for human evolution based on ancient mitochondrial genomes. Curr Biol 2013, 23:553-559. 23. Ginolhac A et al.: mapDamage: testing for damage patterns in ancient DNA sequences. Bioinformatics 2011, 27:2153-2155. 24. Skoglund P et al.: Separating endogenous ancient DNA from modern day contamination in a Siberian Neandertal. Proc Natl Acad Sci U S A 2014, 111:2229-2234. 25. Hublin JJ: Out of Africa: modern human origins special feature: the origin of Neandertals. Proc Natl Acad Sci U S A 2009, 106:16022-16027. 26. Krings M et al.: Neandertal DNA sequences and the origin of modern humans. Cell 1997, 90:19-30. 27. Green RE et al.: A complete Neandertal mitochondrial genome sequence determined by high-throughput sequencing. Cell 2008, 134:416-426. 28. Meyer M et al.: A high-coverage genome sequence from an archaic Denisovan individual. Science 2012, 338:222-226. The authors developed a new method to prepare single-stranded DNA sequencing libraries from ancient DNA and used this to sequence to high coverage the nuclear genome of a new human group that were called ‘Denisovans’. 29. Pru¨fer K et al.: The complete genome sequence of a Neanderthal from the Altai Mountains. Nature 2014, 505:43-49. The authors sequenced the genome of a Neandertal from the Altai mountains. This is the first high coverage genome of a Neandertal individual and it was used together with the Denisovan genome sequence to show that admixture between archaic humans was common. 30. Castellano S et al.: Patterns of coding variation in the complete exomes of three Neandertals. Proc Natl Acad Sci U S A 2014, 111:6666-6671.
40. Reich D et al.: Genetic history of an archaic hominin group from Denisova Cave in Siberia. Nature 2010, 468:1053-1060. 41. Li H, Durbin R: Inference of human population history from individual whole-genome sequences. Nature 2011, 475:493496. 42. Kong A et al.: Rate of de novo mutations and the importance of father’s age to disease risk. Nature 2012, 488:471-475. 43. Scally A, Durbin R: Revising the human mutation rate: implications for understanding human evolution. Nat Rev Genet 2012, 13:745-753. 44. Langergraber KE et al.: Generation times in wild chimpanzees and gorillas suggest earlier divergence times in great ape and human evolution. Proc Natl Acad Sci U S A 2012, 109:1571615721. 45. Eriksson A, Manica A: Effect of ancient population structure on the degree of polymorphism shared between modern human populations and ancient hominins. Proc Natl Acad Sci U S A 2012, 109:13956-13960. 46. Sankararaman S et al.: The date of interbreeding between Neandertals and Modern humans. PLoS Genet 2012, 8. 47. Yang MA et al.: Ancient structure in Africa unlikely to explain Neanderthal and non-African genetic similarity. Mol Biol Evol 2012, 29:2987-2995. 48. Currat M, Excoffier L: Strong reproductive isolation between humans and Neanderthals inferred from observed patterns of introgression. Proc Natl Acad Sci U S A 2011, 108:15129-15134. 49. Skoglund P, Jakobsson M: Archaic human ancestry in East Asia. Proc Natl Acad Sci U S A 2011, 108:18301-18306. 50. Abi-Rached L et al.: The shaping of modern human immune systems by multiregional admixture with archaic humans. Science 2011, 334:89-94. 51. Mendez FL, Watkins JC, Hammer MF: Neandertal origin of genetic variation at the cluster of OAS immunity genes. Mol Biol Evol 2013, 30:798-801.
31. Briggs AW et al.: Targeted retrieval and analysis of five Neandertal mtDNA genomes. Science 2009, 325:318-321.
52. Huerta-Sanchez E et al.: Altitude adaptation in Tibetans caused by introgression of Denisovan-like DNA. Nature 2014, 512:194197 http://dx.doi.org/10.1038/nature13408. The authors show that the functionally important allele of the EPAS1 gene in Tibetans is introgressed from Denisovans.
32. Briggs AW et al.: Primer extension capture: targeted sequence retrieval from heavily degraded DNA sources. J Vis Exp 2009:1573.
53. Ding Q et al.: Neanderthal introgression at Chromosome 3p21.31 was under positive natural selection in east Asians. Mol Biol Evol 2014, 31:683-695.
33. Maricic T, Whitten M, Paabo S: Multiplexed DNA sequence capture of mitochondrial genomes using PCR products. PLoS ONE 2010, 5:e14004.
54. Sankararaman S et al.: The genomic landscape of Neanderthal ancestry in present-day humans. Nature 2014, 507:354-357. A genome-wide map of the Neandertal alleles in present-day non-Africans was constructed using the Neandertal genome sequence and the sequences of multiple present-day non-Africans. Neandertal ancestry was shown to be non-uniform in its distribution with Neandertal alleles more common in regions of the genome that are not near genes and other functional elements. Functional analyses demonstrated that extensive deserts of Neandertal ancestry on the X chromosome and showed that these deserts are are particularly enriched for genes with their highest expression in testes.
34. Krause J et al.: The complete mitochondrial DNA genome of an unknown hominin from southern Siberia. Nature 2010, 464:894897. 35. Krause J et al.: A complete mtDNA genome of an early modern human from Kostenki, Russia. Curr Biol 2010, 20:231-236. 36. Fu Q et al.: DNA analysis of an early modern human from Tianyuan Cave, China. Proc Natl Acad Sci U S A 2013, 110: 2223-2227. 37. Raghavan M et al.: Upper Palaeolithic Siberian genome reveals dual ancestry of native Americans. Nature 2014, 505:87-91. The first full nuclear genome sequence of an early modern human from Siberia was used to gain insights into the ancestry of native Americans. 38. Fu Q et al.: The complete genome sequence of a 45,000-yearold modern human from western Siberia. Nature: (in press). 39. Rasmussen M et al.: The genome of a Late Pleistocene human from a Clovis burial site in western Montana. Nature 2014, 506:225-229.
Current Opinion in Genetics & Development 2014, 29:133–138
55. Khrameeva EE et al.: Neanderthal ancestry drives evolution of lipid catabolism in contemporary Europeans. Nat Commun 2014, 5:3584. 56. Vernot B, Akey JM: Resurrecting surviving Neandertal lineages from modern human genomes. Science 2014, 343:1017-1021. A genome-wide map of the Neandertal alleles in present-day non-Africans was constructed using the sequences of 665 present-day humans. The authors inferred a second Neandertal introgression into the ancestors of Asians based on differences in Neandertal ancestry between presentday Asians and Europeans. The gene FOXP2 was shown to be in a desert of Neandertal ancestry suggesting that Neandertal alleles in this region may have been under negative selection.
www.sciencedirect.com
