Written by: Zachary Loudermilk Bhatia
Edited by: Ryan Lee
Edited by: Ryan Lee
Homo Sapiens is the only species of human alive on Earth in the modern day; however, this was not always the case. 200,000 - 30,000 years ago, multiple species of hominids existed in different parts of the world, including the species Homo Neanderthalensis throughout much of modern-day Europe and Asia (Tattersall 1999). Palaeontological classification via comparison of morphological differences as well as genomic analyses estimate that H. Neanderthalensis and H. Sapiens shared a common ancestor 500,000 years ago (Tattersall 2006). H. Neanderthalensis had a very distinct set of morphological traits, including and not limited to a flared rib cage and a retreating, angular midface and forehead. Palaeontologists and anthropologists have long concluded that “no significant integration of the [H. Neanderthalensis and H. Sapiens] populations ever took place” due to morphological differences indicating incompatibilities in mate recognition (Tattersall 2006). However, the defining separation between H. Neanderthalensis and H. Sapiens has been challenged by modern genomic anthropology.
Single-nucleotide polymorphisms (SNPs), or a substitution mutation in a single base pair of a strand of DNA, can be tracked in mitochondrial DNA (mtDNA) and nonrecombinant Y chromosome segments because these DNA regions are inherited from one parent independently of the other. SNPs at specific locations in mtDNA and nonrecombinant Y chromosomal DNA are used to determine the ancestral and geographic lineage of modern H. Sapiens populations (Underhill 2007). Because specific SNPs appear in a high frequency amongst the members of a geographic population of modern humans’ mtDNA sequences, these SNPs can be used to infer evolutionary history and the migration pattern of behaviourally modern humans as they emigrated around the world. In effect, an individual’s maternal lineage can be estimated by observing which of a specific set of SNPs are present in their mtDNA, and a male’s paternal lineage can be estimated by observing the SNPs present in their nonrecombinant Y chromosomal DNA (Underhill 2007).
The Out-of-Africa model (OOA) of the dispersal of H. Sapiens across the globe is supported by the differences in SNPs between human haplogroups in the modern day. A haplogroup refers to all individuals who share the same, specific SNPs and genetic lineage on either their maternal or paternal side. According to OOA, anatomically modern H. Sapiens evolved in Eastern Africa 200,000 years ago from the species Homo Heidelbergensis; these early humans emigrated to Eurasia, Australia, Oceania, and the Americas (Wilshaw 2017). H. Heidelbergensis was dispersed across much of Africa and Eurasia between 600,000 and 200,000 years ago, and is theorised to be the ancestor of both H. Sapiens and H. Neanderthalensis (Wilshaw 2017). OOA posits that behaviourally modern H. Sapiens outcompeted and replaced all other hominid species, including H. Neanderthalensis as they emigrated out of Africa between 100,000 and 30,000 years ago (Tattersall 1999; Zeberg & Pääbo 2021).
Oligoadenylate Synthetase (OAS) is an important immunological enzyme that is produced in response to a RNA virus infection (Choi 2015). The human OAS (hOAS) proteins hOAS1, hOAS2, and hOAS3 all activate an enzyme called RNase L in response to different species of antigens; RNase L degrades viral RNA (Choi 2015). In H. Sapiens as well as H. Neanderthalensis, the genetic loci responsible for the translation of hOAS proteins are found on chromosome 12 (Zeberg & Pääbo 2021). There are 64 OAS haplotypes found in populations of modern humans, eight of which share a 75,000 nucleotide base sequence with H. Neanderthalensis DNA recovered from 50,000-120,000 year old Neanderthal fossils found in Siberia and Croatia (Zeberg & Pääbo 2021). It is highly unlikely for a DNA sequence of this size to remain unaffected and unchanged in a population for 500,000 years (P = 8.2e-9), meaning that the neanderthal oligoadenylate synthetase (nOAS) haplotype present in modern humans entered the H. Sapiens gene pool through interbreeding with H. Neanderthalensis around 60,000-50,000 years ago (Zeberg & Pääbo 2021).
The SNPs that distinguish the Neanderthal haplotypes from modern human haplotypes also improve the function of Oligoadenylate Synthetase to exceed hOAS. The nOAS1 protein differs from hOAS1 via one SNP; this slight change in protein structure allows nOAS1 to splice and process viral RNA at a higher frequency than hOAS1 (Sams 2016; Zeberg & Pääbo 2021). RNA viruses that nOAS1 activity defends against include West Nile virus, Hepatitis C, and SARS-CoV-2. Conversely, nOAS3 expression is reduced in the neanderthal haplotype when compared to the hOAS3 haplotype when exposed to single-stranded RNA viruses such as influenza (Sams 2016). A possible explanation is that a high cost of maintaining the functionality of all three OAS exists, and the nOAS defenses were positively selected for in response to the profile of antigens H. Neanderthalensis faced. Despite this, evolutionary processes have positively selected for the nOAS haplotypes over the hOAS haplotype variants. 20,000 years ago, the nOAS haplotype was expressed in less than 10% of individuals. Today, more than 30% of individuals in Eurasia express the nOAS haplotype (Zeberg & Pääbo 2021).
The existence of a neanderthal genetic profile in modern humans provides evidence that H. Neanderthalensis was not as genetically distinct from H. Sapiens as many longstanding palaeontological beliefs claim; these two species interbred between 60,000 and 50,000 years ago. Around the same time, the Y chromosomal haplogroups representing all modern humans without direct lineage in sub-Saharan Africa separated from the haplogroups present in sub-Saharan Africans; similarly, the mtDNA haplogroups representing the majority of modern humans without direct lineage in sub-Saharan Africa separated from mtDNA haplogroups still present in modern sub-Saharan Africans (Underhill 2007); the C, DE, and F paternal haplogroups as well as the M and N mtDNA haplogroups are representative of the majority of modern humans living outside of sub-Saharan Africa (Underhill 2007). The SNPs differentiating haplogroups C, DE, and F from sub-Saharan African paternal haplogroups, as well as the SNPs differentiating haplogroups M and N from sub-Saharan African maternal haplogroups, may entered the H. Sapiens gene pool through inheritance from H. Neanderthalensis.
The initial 20,000 years following the emigration of behaviourally modern H. Sapiens out of Africa introduced archaic humans of at least two species to one another. In addition, this genomic evidence shines some light on the case of the Lagar Velho cave child, the controversial 24,000 year old fossil remains of a hominid who has been classified as both H. Neanderthalensis and H. Sapiens (Tattersall 1999); the possibility of interbreeding between the two species of humans offers the alternative explanation that H. Neanderthalensis did not “die off” but rapidly transitioned into H. Sapiens.
References
Choi, U. Y., Kang, J.-S., Hwang, Y. S., & Kim, Y.-J. (2015). Oligoadenylate synthase-like (OASL) proteins: Dual functions and associations with diseases. Experimental & Molecular Medicine, 47(3), Article 3. https://doi.org/10.1038/emm.2014.110
Hardy, J., Pittman, A., Myers, A., Gwinn-Hardy, K., Fung, H. C., de Silva, R., Hutton, M., & Duckworth, J. (2005). Evidence suggesting that Homo neanderthalensis contributed the H2 MAPT haplotype to Homo sapiens. Biochemical Society Transactions, 33(4), 582–585. https://doi.org/10.1042/BST0330582
Mortazavi, S. A. R., Kaveh-Ahangar, K., Mortazavi, S. M. J., Firoozi, D., & Haghani, M. (2021). How Our Neanderthal Genes Affect the COVID-19 Mortality: Iran and Mongolia, Two Countries with the Same SARS-CoV-2 Mutation Cluster but Different Mortality Rates. Journal of Biomedical Physics & Engineering, 11(1), 109–114. https://doi.org/10.31661/jbpe.v0i0.2010-1218
Sams, A. J., Dumaine, A., Nédélec, Y., Yotova, V., Alfieri, C., Tanner, J. E., Messer, P. W., & Barreiro, L. B. (2016). Adaptively introgressed Neandertal haplotype at the OAS locus functionally impacts innate immune responses in humans. Genome Biology, 17(1), 246. https://doi.org/10.1186/s13059-016-1098-6
Stoneking, M., & Soodyall, H. (1996). Human evolution and the mitochondrial genome. Current Opinion in Genetics & Development, 6(6), 731–736. https://doi.org/10.1016/S0959-437X(96)80028-1
Tattersall, I., & Schwartz, J. H. (1999). Hominids and hybrids: The place of Neanderthals in human evolution. Proceedings of the National Academy of Sciences, 96(13), 7117–7119. https://doi.org/10.1073/pnas.96.13.7117
Zeberg, H., & Pääbo, S. (2021). A genomic region associated with protection against severe COVID-19 is inherited from Neandertals. Proceedings of the National Academy of Sciences, 118(9). https://doi.org/10.1073/pnas.2026309118
Single-nucleotide polymorphisms (SNPs), or a substitution mutation in a single base pair of a strand of DNA, can be tracked in mitochondrial DNA (mtDNA) and nonrecombinant Y chromosome segments because these DNA regions are inherited from one parent independently of the other. SNPs at specific locations in mtDNA and nonrecombinant Y chromosomal DNA are used to determine the ancestral and geographic lineage of modern H. Sapiens populations (Underhill 2007). Because specific SNPs appear in a high frequency amongst the members of a geographic population of modern humans’ mtDNA sequences, these SNPs can be used to infer evolutionary history and the migration pattern of behaviourally modern humans as they emigrated around the world. In effect, an individual’s maternal lineage can be estimated by observing which of a specific set of SNPs are present in their mtDNA, and a male’s paternal lineage can be estimated by observing the SNPs present in their nonrecombinant Y chromosomal DNA (Underhill 2007).
The Out-of-Africa model (OOA) of the dispersal of H. Sapiens across the globe is supported by the differences in SNPs between human haplogroups in the modern day. A haplogroup refers to all individuals who share the same, specific SNPs and genetic lineage on either their maternal or paternal side. According to OOA, anatomically modern H. Sapiens evolved in Eastern Africa 200,000 years ago from the species Homo Heidelbergensis; these early humans emigrated to Eurasia, Australia, Oceania, and the Americas (Wilshaw 2017). H. Heidelbergensis was dispersed across much of Africa and Eurasia between 600,000 and 200,000 years ago, and is theorised to be the ancestor of both H. Sapiens and H. Neanderthalensis (Wilshaw 2017). OOA posits that behaviourally modern H. Sapiens outcompeted and replaced all other hominid species, including H. Neanderthalensis as they emigrated out of Africa between 100,000 and 30,000 years ago (Tattersall 1999; Zeberg & Pääbo 2021).
Oligoadenylate Synthetase (OAS) is an important immunological enzyme that is produced in response to a RNA virus infection (Choi 2015). The human OAS (hOAS) proteins hOAS1, hOAS2, and hOAS3 all activate an enzyme called RNase L in response to different species of antigens; RNase L degrades viral RNA (Choi 2015). In H. Sapiens as well as H. Neanderthalensis, the genetic loci responsible for the translation of hOAS proteins are found on chromosome 12 (Zeberg & Pääbo 2021). There are 64 OAS haplotypes found in populations of modern humans, eight of which share a 75,000 nucleotide base sequence with H. Neanderthalensis DNA recovered from 50,000-120,000 year old Neanderthal fossils found in Siberia and Croatia (Zeberg & Pääbo 2021). It is highly unlikely for a DNA sequence of this size to remain unaffected and unchanged in a population for 500,000 years (P = 8.2e-9), meaning that the neanderthal oligoadenylate synthetase (nOAS) haplotype present in modern humans entered the H. Sapiens gene pool through interbreeding with H. Neanderthalensis around 60,000-50,000 years ago (Zeberg & Pääbo 2021).
The SNPs that distinguish the Neanderthal haplotypes from modern human haplotypes also improve the function of Oligoadenylate Synthetase to exceed hOAS. The nOAS1 protein differs from hOAS1 via one SNP; this slight change in protein structure allows nOAS1 to splice and process viral RNA at a higher frequency than hOAS1 (Sams 2016; Zeberg & Pääbo 2021). RNA viruses that nOAS1 activity defends against include West Nile virus, Hepatitis C, and SARS-CoV-2. Conversely, nOAS3 expression is reduced in the neanderthal haplotype when compared to the hOAS3 haplotype when exposed to single-stranded RNA viruses such as influenza (Sams 2016). A possible explanation is that a high cost of maintaining the functionality of all three OAS exists, and the nOAS defenses were positively selected for in response to the profile of antigens H. Neanderthalensis faced. Despite this, evolutionary processes have positively selected for the nOAS haplotypes over the hOAS haplotype variants. 20,000 years ago, the nOAS haplotype was expressed in less than 10% of individuals. Today, more than 30% of individuals in Eurasia express the nOAS haplotype (Zeberg & Pääbo 2021).
The existence of a neanderthal genetic profile in modern humans provides evidence that H. Neanderthalensis was not as genetically distinct from H. Sapiens as many longstanding palaeontological beliefs claim; these two species interbred between 60,000 and 50,000 years ago. Around the same time, the Y chromosomal haplogroups representing all modern humans without direct lineage in sub-Saharan Africa separated from the haplogroups present in sub-Saharan Africans; similarly, the mtDNA haplogroups representing the majority of modern humans without direct lineage in sub-Saharan Africa separated from mtDNA haplogroups still present in modern sub-Saharan Africans (Underhill 2007); the C, DE, and F paternal haplogroups as well as the M and N mtDNA haplogroups are representative of the majority of modern humans living outside of sub-Saharan Africa (Underhill 2007). The SNPs differentiating haplogroups C, DE, and F from sub-Saharan African paternal haplogroups, as well as the SNPs differentiating haplogroups M and N from sub-Saharan African maternal haplogroups, may entered the H. Sapiens gene pool through inheritance from H. Neanderthalensis.
The initial 20,000 years following the emigration of behaviourally modern H. Sapiens out of Africa introduced archaic humans of at least two species to one another. In addition, this genomic evidence shines some light on the case of the Lagar Velho cave child, the controversial 24,000 year old fossil remains of a hominid who has been classified as both H. Neanderthalensis and H. Sapiens (Tattersall 1999); the possibility of interbreeding between the two species of humans offers the alternative explanation that H. Neanderthalensis did not “die off” but rapidly transitioned into H. Sapiens.
References
Choi, U. Y., Kang, J.-S., Hwang, Y. S., & Kim, Y.-J. (2015). Oligoadenylate synthase-like (OASL) proteins: Dual functions and associations with diseases. Experimental & Molecular Medicine, 47(3), Article 3. https://doi.org/10.1038/emm.2014.110
Hardy, J., Pittman, A., Myers, A., Gwinn-Hardy, K., Fung, H. C., de Silva, R., Hutton, M., & Duckworth, J. (2005). Evidence suggesting that Homo neanderthalensis contributed the H2 MAPT haplotype to Homo sapiens. Biochemical Society Transactions, 33(4), 582–585. https://doi.org/10.1042/BST0330582
Mortazavi, S. A. R., Kaveh-Ahangar, K., Mortazavi, S. M. J., Firoozi, D., & Haghani, M. (2021). How Our Neanderthal Genes Affect the COVID-19 Mortality: Iran and Mongolia, Two Countries with the Same SARS-CoV-2 Mutation Cluster but Different Mortality Rates. Journal of Biomedical Physics & Engineering, 11(1), 109–114. https://doi.org/10.31661/jbpe.v0i0.2010-1218
Sams, A. J., Dumaine, A., Nédélec, Y., Yotova, V., Alfieri, C., Tanner, J. E., Messer, P. W., & Barreiro, L. B. (2016). Adaptively introgressed Neandertal haplotype at the OAS locus functionally impacts innate immune responses in humans. Genome Biology, 17(1), 246. https://doi.org/10.1186/s13059-016-1098-6
Stoneking, M., & Soodyall, H. (1996). Human evolution and the mitochondrial genome. Current Opinion in Genetics & Development, 6(6), 731–736. https://doi.org/10.1016/S0959-437X(96)80028-1
Tattersall, I., & Schwartz, J. H. (1999). Hominids and hybrids: The place of Neanderthals in human evolution. Proceedings of the National Academy of Sciences, 96(13), 7117–7119. https://doi.org/10.1073/pnas.96.13.7117
Zeberg, H., & Pääbo, S. (2021). A genomic region associated with protection against severe COVID-19 is inherited from Neandertals. Proceedings of the National Academy of Sciences, 118(9). https://doi.org/10.1073/pnas.2026309118
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