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Editorial overview: Genetics of human evolution: The genetics of human origins
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ScienceDirect Editorialoverview:Geneticsofhuman evolution:The genetics of human origins Aida M Andre´s and Katja Nowick Current Opinion in Genetics & Development 2014, 29:v–vii For a complete overview see the Issue http://dx.doi.org/10.1016/j.gde.2014.11.001 0959-437X/# 2014 Elsevier Ltd. All rights reserved.
Aida M Andre´s Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, 04103 Leipzig, Germany e-mail: [email protected] Aida Andre´s is a Group Leader at the Max Planck Institute for Evolutionary Anthropology in Leizpig. Her team investigates how natural selection has influenced the evolution of humans and other primates. They focus on the effects of positive and balancing selection in shaping genetic and phenotypic diversity, and in the conservation of selective pressures across populations and species.
Katja Nowick TFome Research Group, Bioinformatics Group, Interdisciplinary Center for Bioinformatics, Department of Computer Science, University of Leipzig, Ha¨rtelstrasse 16-18, 04107 Leipzig, Germany e-mail: [email protected] Katja Nowick is a group leader at the University of Leipzig, affiliated with the Faculties for Computer Science and Medicine. Using a combination of computational and wet-lab approaches, her team investigates human molecular evolution with a main interest in understanding how genomic differences lead to functional and phenotypic differences. Her focus is on the evolution of gene regulatory differences between humans and non-human primates.
This is an exciting time for those interested in human evolution. Nextgeneration sequencing technologies have dramatically changed the amount, quality, and quantity of genetic data that can be investigated to better understand our genome and its evolution. For the first time genomic information is not limited to a single genome per species, but to dozens, hundreds, or even thousands of genomes from a single population or species. In fact, it is not even limited to the genomes of extant individuals or species. Genome-wide polymorphism catalogs such as the 1000 Genomes project are complemented by datasets that combine genetic and phenotypic information, and by genome-wide functional datasets such as from the ENCODE project. While this data is publicly available, genome sequencing is now even possible in individual labs, allowing researchers to produce inhouse the data they need to answer their question of interest. Together with new analytical approaches and methods, genome-wide data has had great impact on our understanding of human evolution. This issue is dedicated to review the most recent advances in this field.
The demography and adaptations of human populations Archaic genomics had a great influence in our changing views about the evolution of our species. Modern humans are a relatively young species, but a number of extinct human forms exist. Their genomes are now becoming available, together with the genomes of a growing number of ancient modern humans. As Kelso and Pru¨fer discuss, genome sequences of archaic humans have resulted in the discovery of an unknown human group (the Denisovans) based solely on the DNA isolated from ancient bones and have revealed a rich history of interbreeding between human groups. Of particular interest are gene flow events from Neanderthals to non-Africans (Sousa, Peischl and Excoffier), from Denisovans to Oceanians (Dugan and Stoneking), and possibly from unknown archaic forms to certain African groups (Tishkoff). By contributing novel alleles to existing variation in humans, introgression events have influenced the demography and evolution of modern humans. Anatomically modern humans originated in the African continent. Campbell, Hirbo, Townsend and Tishkoff review the complex genetics of African populations, which is characterized not only by high levels of genetic diversity, but also by extensive population structure and large migration events often accompanied by subsequent admixture. Studying the genomes of Africans is important to understand the demographic history of early modern humans and extant African populations, as well as the genetics and disease susceptibility of the large African diaspora in the New World.
www.sciencedirect.com
Current Opinion in Genetics & Development 2014, 29:v–vii
vi Genetics of human evolution
Out of Africa, human demography was dominated by population growth, range expansions, and the colonization of a vast diversity of environments. Demographic modeling is essential to understand these processes. Sousa, Peischl and Excoffier argue that incorporating the geographic component of individuals, in geographically explicit models, substantially improves inferences of human demography and of its effects in genetic variation. This is important because, as Lohmueller discusses, the demographic history of populations influences the accumulation of functional variation, including the proportion of deleterious alleles. He reviews and reconciles recent apparently contrasting observations about the effects that demography has in the per-population accumulation of deleterious alleles and in the per-individual genetic load. Some geographic areas have been colonized in particularly interesting ways, and genetics may hold the key to understand these events. One example is East Asia and Oceania, where colonization of a number of islands involved a series of migration events. Duggan and Stoneking review how modern and ancient DNA, more comprehensive sampling of populations, and novel analysis methods are enlightening the demographic history and relationships of these populations. The relatively fast colonization of a myriad of different environments, in particular out of Africa, was accompanied by a strong pressure for novel genetic adaptations. Jeong and Di Rienzo discuss our present knowledge about how populations adapted to these novel, local environments. Adaptation happens not only (and perhaps not mostly) through strong, positive selection on single new alleles, and the authors highlight the role of soft sweeps, polygenic adaptation, and convergent adaptation in human populations. Throughout human evolution, individuals have constantly been subject to a variety of selective pressures. Siddle and Quintana-Murci argue that exposure to pathogens likely represents one of the strongest among them, with immune-related genes being enriched for diverse signatures of positive selection. It is possible, and intriguing, that these selective forces may also influence present-day susceptibility to immune-related diseases. Immune-related functions are also frequently targets of balancing selection. Key, Teixeira, de Filippo and Andre´s review recent growing evidence that balancing selection is an important selective force in humans, maintaining advantageous genetic polymorphisms for millions of years and resulting in the presence of advantageous phenotypic diversity within populations. Understanding human evolutionary history also holds great potential for better understanding the origin and causes of human diseases. As Rodrı´guez, Marigorta and Current Opinion in Genetics & Development 2014, 29:v–vii
Navarro explain, because natural selection favors reproduction over old-age health, some diseases (e.g. civilization diseases) may be the result of adaptations to ancient environments. The authors call for combining insights from evolutionary medicine (which studies why an ailment existed) and medical genomics (which studies how diseases appear and how they progress within an organism), and provide a first demonstration that GWAS studies can be utilized to evaluate the fitness effect of a disease. Human evolution is not only biological, but also cultural and linguistic. Pakendorf describes the parallelisms between linguistics and genetics, and how their combined analysis helps decipher the history of populations. Interestingly, while linguistic and genetic relationships between populations largely agree, in certain populations language is not a barrier to migration and gene flow, and individual mobility influences language evolution. In addition, culture itself may have imposed selective pressures on some genes, for instance on genes involved in general language processing, lighter skin pigmentation in high latitudes, pain tolerance or diet, as well as in many other examples detailed in the review by Ross and Richerson.
Towards functional genomics of human adaptations Genomic data has allowed great progress not only in identifying parts of the genome that have changed during human evolution, but also in terms of investigating and interpreting how these genomic differences manifest in functional or phenotypic differences. Important sources of phenotypic changes are genes that are human specific. According to Zhang and Long there are about 300 human specific protein-coding genes, many of which seem to be implicated in brain functions, testis functions (male reproduction), and diseases (cancer). There are also numerous human specific non-protein coding genes (Perdomo-Sabogal, Kanton, Walter and Nowick). A further source for human specific traits are DNA sequences that are present in other species but have dramatically increased in substitution rates in the human lineage, so-called Human Accelerated Regions (HARs). These regions include many non-protein coding genes as well, but also non-coding regions (Pollard and Hubisz), which can play an important role in gene expression regulation. Pollard and Hubisz provide new data on the timing of evolutionary events that generated HARs and HARs that are unique to modern humans or even specific to certain human populations. Besides sequence differences, also expression differences play an essential role in driving phenotypic diversity. Pai and Gilad compare the impact that cis and trans sequence changes, as well as epigenetic changes, www.sciencedirect.com
Editorial overview Andre´s and Nowick vii
segmental duplications, and alternative splicing have had in modifying the expression landscape in humans. While cis-changes are more frequent in evolution, each single change in trans can in principle have a higher impact on the phenotypes, because it might affect the expression of hundreds to thousands of genes. A review on the role of gene regulatory factors that act in trans, like transcription factors (TFs) and long-non-coding RNAs, can be found in the work of Perdomo-Sabogal, Kanton, Walter and Nowick. They describe examples of human specific TFs and lncRNAs and TFs and lncRNAs that have changed between archaic and modern humans, or that show signatures of positive selection in modern humans. Siepel and Arbiza on the other hand focus on cis-changes and discuss new statistical tests for identifying TF binding sites that have evolved under positive selection in humans. Their work suggests that adaptive substitutions in cis-regulatory elements between humans and chimpanzees are at least as common as changes in protein-coding genes. One of the most intriguing human specific traits is the larger human brain and the cognitive skills associated with it. Several papers review recent progress in understanding how the human brain evolved. Somel, Rohlfs and Liu give a comprehensive overview of phenotypic differences between human and chimpanzee brains and discuss seemingly contradictory results obtained in recent studies on differential expression in primate brains. How is it possible that on the one hand human brain gene expression seems to be highly conserved or evolve neutrally by mostly cis-changes, but on the other hand it shows accelerated evolution with marked differences in TF genes? One step further in bridging the gap from genomic to phenotypic differences comes from the review by Fontenot and Konopka. Focusing on the evolution of cognitive skills in humans, they discuss the power of co-expression networks to gain insights into functional relationships of genes. They also explore how studies on humans with cognitive disorders can
www.sciencedirect.com
aid in deciphering the molecular basis of cognition. Several other reviews in this issue also discuss the impact of genetic changes on the evolution of the human brain, such as human-specific genes (Zhang and Long), HARs (Pollard and Hubisz), and gene regulatory factors (Perdomo-Sabogal, Kanton, Walter and Nowick). A major question is how to move from cataloguing genomic changes to comprehending how these changes contribute to the evolution of human phenotypes. To this end, appropriate model systems are important to demonstrate the functional impact of genomic changes. As Enard explains, given that an assay is available, the function of ancestral and derived alleles can be compared in model systems. Humanized mice can for example provide insights into the evolution of genes and regulatory elements and into how they affect synapse densities or brain size. However, the mouse has limitations for studying some aspects of human evolution, as for example epistasis can potentially lead to artefacts or no effects in mice. To investigate functional changes in a human or primate genomic background, cell lines such as re-programmable induced pluripotent stem cells (Pai and Gilad, Pollard and Hubisz, Fontenot and Konopka), or organoids (Somel, Rohlfs and Liu) hold great potential. Further opportunities represent transgenic primates (not discussed here but e.g. in work of Erika Sazaki). Together, the reviews in this issue provide a global view about how different lines of research are helping us draw a more accurate picture of how humans came to be. Still, many questions remain open, which can only be answered combining different types of data and using a multidisciplinary approach. This includes integrating information that ranges from the detection of genetic changes, the investigation of why and how they persist in the genome, to the determination of their functional consequences. We hope researchers of different disciplines will work even closer together to explore and reveal the complex and fascinating evolution of our species.
Current Opinion in Genetics & Development 2014, 29:v–vii
ScienceDirect Editorialoverview:Geneticsofhuman evolution:The genetics of human origins Aida M Andre´s and Katja Nowick Current Opinion in Genetics & Development 2014, 29:v–vii For a complete overview see the Issue http://dx.doi.org/10.1016/j.gde.2014.11.001 0959-437X/# 2014 Elsevier Ltd. All rights reserved.
Aida M Andre´s Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, 04103 Leipzig, Germany e-mail: [email protected] Aida Andre´s is a Group Leader at the Max Planck Institute for Evolutionary Anthropology in Leizpig. Her team investigates how natural selection has influenced the evolution of humans and other primates. They focus on the effects of positive and balancing selection in shaping genetic and phenotypic diversity, and in the conservation of selective pressures across populations and species.
Katja Nowick TFome Research Group, Bioinformatics Group, Interdisciplinary Center for Bioinformatics, Department of Computer Science, University of Leipzig, Ha¨rtelstrasse 16-18, 04107 Leipzig, Germany e-mail: [email protected] Katja Nowick is a group leader at the University of Leipzig, affiliated with the Faculties for Computer Science and Medicine. Using a combination of computational and wet-lab approaches, her team investigates human molecular evolution with a main interest in understanding how genomic differences lead to functional and phenotypic differences. Her focus is on the evolution of gene regulatory differences between humans and non-human primates.
This is an exciting time for those interested in human evolution. Nextgeneration sequencing technologies have dramatically changed the amount, quality, and quantity of genetic data that can be investigated to better understand our genome and its evolution. For the first time genomic information is not limited to a single genome per species, but to dozens, hundreds, or even thousands of genomes from a single population or species. In fact, it is not even limited to the genomes of extant individuals or species. Genome-wide polymorphism catalogs such as the 1000 Genomes project are complemented by datasets that combine genetic and phenotypic information, and by genome-wide functional datasets such as from the ENCODE project. While this data is publicly available, genome sequencing is now even possible in individual labs, allowing researchers to produce inhouse the data they need to answer their question of interest. Together with new analytical approaches and methods, genome-wide data has had great impact on our understanding of human evolution. This issue is dedicated to review the most recent advances in this field.
The demography and adaptations of human populations Archaic genomics had a great influence in our changing views about the evolution of our species. Modern humans are a relatively young species, but a number of extinct human forms exist. Their genomes are now becoming available, together with the genomes of a growing number of ancient modern humans. As Kelso and Pru¨fer discuss, genome sequences of archaic humans have resulted in the discovery of an unknown human group (the Denisovans) based solely on the DNA isolated from ancient bones and have revealed a rich history of interbreeding between human groups. Of particular interest are gene flow events from Neanderthals to non-Africans (Sousa, Peischl and Excoffier), from Denisovans to Oceanians (Dugan and Stoneking), and possibly from unknown archaic forms to certain African groups (Tishkoff). By contributing novel alleles to existing variation in humans, introgression events have influenced the demography and evolution of modern humans. Anatomically modern humans originated in the African continent. Campbell, Hirbo, Townsend and Tishkoff review the complex genetics of African populations, which is characterized not only by high levels of genetic diversity, but also by extensive population structure and large migration events often accompanied by subsequent admixture. Studying the genomes of Africans is important to understand the demographic history of early modern humans and extant African populations, as well as the genetics and disease susceptibility of the large African diaspora in the New World.
www.sciencedirect.com
Current Opinion in Genetics & Development 2014, 29:v–vii
vi Genetics of human evolution
Out of Africa, human demography was dominated by population growth, range expansions, and the colonization of a vast diversity of environments. Demographic modeling is essential to understand these processes. Sousa, Peischl and Excoffier argue that incorporating the geographic component of individuals, in geographically explicit models, substantially improves inferences of human demography and of its effects in genetic variation. This is important because, as Lohmueller discusses, the demographic history of populations influences the accumulation of functional variation, including the proportion of deleterious alleles. He reviews and reconciles recent apparently contrasting observations about the effects that demography has in the per-population accumulation of deleterious alleles and in the per-individual genetic load. Some geographic areas have been colonized in particularly interesting ways, and genetics may hold the key to understand these events. One example is East Asia and Oceania, where colonization of a number of islands involved a series of migration events. Duggan and Stoneking review how modern and ancient DNA, more comprehensive sampling of populations, and novel analysis methods are enlightening the demographic history and relationships of these populations. The relatively fast colonization of a myriad of different environments, in particular out of Africa, was accompanied by a strong pressure for novel genetic adaptations. Jeong and Di Rienzo discuss our present knowledge about how populations adapted to these novel, local environments. Adaptation happens not only (and perhaps not mostly) through strong, positive selection on single new alleles, and the authors highlight the role of soft sweeps, polygenic adaptation, and convergent adaptation in human populations. Throughout human evolution, individuals have constantly been subject to a variety of selective pressures. Siddle and Quintana-Murci argue that exposure to pathogens likely represents one of the strongest among them, with immune-related genes being enriched for diverse signatures of positive selection. It is possible, and intriguing, that these selective forces may also influence present-day susceptibility to immune-related diseases. Immune-related functions are also frequently targets of balancing selection. Key, Teixeira, de Filippo and Andre´s review recent growing evidence that balancing selection is an important selective force in humans, maintaining advantageous genetic polymorphisms for millions of years and resulting in the presence of advantageous phenotypic diversity within populations. Understanding human evolutionary history also holds great potential for better understanding the origin and causes of human diseases. As Rodrı´guez, Marigorta and Current Opinion in Genetics & Development 2014, 29:v–vii
Navarro explain, because natural selection favors reproduction over old-age health, some diseases (e.g. civilization diseases) may be the result of adaptations to ancient environments. The authors call for combining insights from evolutionary medicine (which studies why an ailment existed) and medical genomics (which studies how diseases appear and how they progress within an organism), and provide a first demonstration that GWAS studies can be utilized to evaluate the fitness effect of a disease. Human evolution is not only biological, but also cultural and linguistic. Pakendorf describes the parallelisms between linguistics and genetics, and how their combined analysis helps decipher the history of populations. Interestingly, while linguistic and genetic relationships between populations largely agree, in certain populations language is not a barrier to migration and gene flow, and individual mobility influences language evolution. In addition, culture itself may have imposed selective pressures on some genes, for instance on genes involved in general language processing, lighter skin pigmentation in high latitudes, pain tolerance or diet, as well as in many other examples detailed in the review by Ross and Richerson.
Towards functional genomics of human adaptations Genomic data has allowed great progress not only in identifying parts of the genome that have changed during human evolution, but also in terms of investigating and interpreting how these genomic differences manifest in functional or phenotypic differences. Important sources of phenotypic changes are genes that are human specific. According to Zhang and Long there are about 300 human specific protein-coding genes, many of which seem to be implicated in brain functions, testis functions (male reproduction), and diseases (cancer). There are also numerous human specific non-protein coding genes (Perdomo-Sabogal, Kanton, Walter and Nowick). A further source for human specific traits are DNA sequences that are present in other species but have dramatically increased in substitution rates in the human lineage, so-called Human Accelerated Regions (HARs). These regions include many non-protein coding genes as well, but also non-coding regions (Pollard and Hubisz), which can play an important role in gene expression regulation. Pollard and Hubisz provide new data on the timing of evolutionary events that generated HARs and HARs that are unique to modern humans or even specific to certain human populations. Besides sequence differences, also expression differences play an essential role in driving phenotypic diversity. Pai and Gilad compare the impact that cis and trans sequence changes, as well as epigenetic changes, www.sciencedirect.com
Editorial overview Andre´s and Nowick vii
segmental duplications, and alternative splicing have had in modifying the expression landscape in humans. While cis-changes are more frequent in evolution, each single change in trans can in principle have a higher impact on the phenotypes, because it might affect the expression of hundreds to thousands of genes. A review on the role of gene regulatory factors that act in trans, like transcription factors (TFs) and long-non-coding RNAs, can be found in the work of Perdomo-Sabogal, Kanton, Walter and Nowick. They describe examples of human specific TFs and lncRNAs and TFs and lncRNAs that have changed between archaic and modern humans, or that show signatures of positive selection in modern humans. Siepel and Arbiza on the other hand focus on cis-changes and discuss new statistical tests for identifying TF binding sites that have evolved under positive selection in humans. Their work suggests that adaptive substitutions in cis-regulatory elements between humans and chimpanzees are at least as common as changes in protein-coding genes. One of the most intriguing human specific traits is the larger human brain and the cognitive skills associated with it. Several papers review recent progress in understanding how the human brain evolved. Somel, Rohlfs and Liu give a comprehensive overview of phenotypic differences between human and chimpanzee brains and discuss seemingly contradictory results obtained in recent studies on differential expression in primate brains. How is it possible that on the one hand human brain gene expression seems to be highly conserved or evolve neutrally by mostly cis-changes, but on the other hand it shows accelerated evolution with marked differences in TF genes? One step further in bridging the gap from genomic to phenotypic differences comes from the review by Fontenot and Konopka. Focusing on the evolution of cognitive skills in humans, they discuss the power of co-expression networks to gain insights into functional relationships of genes. They also explore how studies on humans with cognitive disorders can
www.sciencedirect.com
aid in deciphering the molecular basis of cognition. Several other reviews in this issue also discuss the impact of genetic changes on the evolution of the human brain, such as human-specific genes (Zhang and Long), HARs (Pollard and Hubisz), and gene regulatory factors (Perdomo-Sabogal, Kanton, Walter and Nowick). A major question is how to move from cataloguing genomic changes to comprehending how these changes contribute to the evolution of human phenotypes. To this end, appropriate model systems are important to demonstrate the functional impact of genomic changes. As Enard explains, given that an assay is available, the function of ancestral and derived alleles can be compared in model systems. Humanized mice can for example provide insights into the evolution of genes and regulatory elements and into how they affect synapse densities or brain size. However, the mouse has limitations for studying some aspects of human evolution, as for example epistasis can potentially lead to artefacts or no effects in mice. To investigate functional changes in a human or primate genomic background, cell lines such as re-programmable induced pluripotent stem cells (Pai and Gilad, Pollard and Hubisz, Fontenot and Konopka), or organoids (Somel, Rohlfs and Liu) hold great potential. Further opportunities represent transgenic primates (not discussed here but e.g. in work of Erika Sazaki). Together, the reviews in this issue provide a global view about how different lines of research are helping us draw a more accurate picture of how humans came to be. Still, many questions remain open, which can only be answered combining different types of data and using a multidisciplinary approach. This includes integrating information that ranges from the detection of genetic changes, the investigation of why and how they persist in the genome, to the determination of their functional consequences. We hope researchers of different disciplines will work even closer together to explore and reveal the complex and fascinating evolution of our species.
Current Opinion in Genetics & Development 2014, 29:v–vii