Publications by authors named "Fernando Racimo"

43 Publications

Late Quaternary dynamics of Arctic biota from ancient environmental genomics.

Nature 2021 12 20;600(7887):86-92. Epub 2021 Oct 20.

Center for Environmental Management of Military Lands, Colorado State University, Fort Collins, CO, USA.

During the last glacial-interglacial cycle, Arctic biotas experienced substantial climatic changes, yet the nature, extent and rate of their responses are not fully understood. Here we report a large-scale environmental DNA metagenomic study of ancient plant and mammal communities, analysing 535 permafrost and lake sediment samples from across the Arctic spanning the past 50,000 years. Furthermore, we present 1,541 contemporary plant genome assemblies that were generated as reference sequences. Our study provides several insights into the long-term dynamics of the Arctic biota at the circumpolar and regional scales. Our key findings include: (1) a relatively homogeneous steppe-tundra flora dominated the Arctic during the Last Glacial Maximum, followed by regional divergence of vegetation during the Holocene epoch; (2) certain grazing animals consistently co-occurred in space and time; (3) humans appear to have been a minor factor in driving animal distributions; (4) higher effective precipitation, as well as an increase in the proportion of wetland plants, show negative effects on animal diversity; (5) the persistence of the steppe-tundra vegetation in northern Siberia enabled the late survival of several now-extinct megafauna species, including the woolly mammoth until 3.9 ± 0.2 thousand years ago (ka) and the woolly rhinoceros until 9.8 ± 0.2 ka; and (6) phylogenetic analysis of mammoth environmental DNA reveals a previously unsampled mitochondrial lineage. Our findings highlight the power of ancient environmental metagenomics analyses to advance understanding of population histories and long-term ecological dynamics.
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http://dx.doi.org/10.1038/s41586-021-04016-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8636272PMC
December 2021

Detection of Neanderthal Adaptively Introgressed Genetic Variants That Modulate Reporter Gene Expression in Human Immune Cells.

Mol Biol Evol 2022 01;39(1)

Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA.

Although some variation introgressed from Neanderthals has undergone selective sweeps, little is known about its functional significance. We used a Massively Parallel Reporter Assay (MPRA) to assay 5,353 high-frequency introgressed variants for their ability to modulate the gene expression within 170 bp of endogenous sequence. We identified 2,548 variants in active putative cis-regulatory elements (CREs) and 292 expression-modulating variants (emVars). These emVars are predicted to alter the binding motifs of important immune transcription factors, are enriched for associations with neutrophil and white blood cell count, and are associated with the expression of genes that function in innate immune pathways including inflammatory response and antiviral defense. We combined the MPRA data with other data sets to identify strong candidates to be driver variants of positive selection including an emVar that may contribute to protection against severe COVID-19 response. We endogenously deleted two CREs containing expression-modulation variants linked to immune function, rs11624425 and rs80317430, identifying their primary genic targets as ELMSAN1, and PAN2 and STAT2, respectively, three genes differentially expressed during influenza infection. Overall, we present the first database of experimentally identified expression-modulating Neanderthal-introgressed alleles contributing to potential immune response in modern humans.
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http://dx.doi.org/10.1093/molbev/msab304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8760939PMC
January 2022

Detecting Selection in Multiple Populations by Modeling Ancestral Admixture Components.

Mol Biol Evol 2022 Jan;39(1)

Lundbeck GeoGenetics Centre, Globe Institute, University of Copenhagen, Copenhagen, Denmark.

One of the most powerful and commonly used approaches for detecting local adaptation in the genome is the identification of extreme allele frequency differences between populations. In this article, we present a new maximum likelihood method for finding regions under positive selection. It is based on a Gaussian approximation to allele frequency changes and it incorporates admixture between populations. The method can analyze multiple populations simultaneously and retains power to detect selection signatures specific to ancestry components that are not representative of any extant populations. Using simulated data, we compare our method to related approaches, and show that it is orders of magnitude faster than the state-of-the-art, while retaining similar or higher power for most simulation scenarios. We also apply it to human genomic data and identify loci with extreme genetic differentiation between major geographic groups. Many of the genes identified are previously known selected loci relating to hair pigmentation and morphology, skin, and eye pigmentation. We also identify new candidate regions, including various selected loci in the Native American component of admixed Mexican-Americans. These involve diverse biological functions, such as immunity, fat distribution, food intake, vision, and hair development.
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http://dx.doi.org/10.1093/molbev/msab294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8763095PMC
January 2022

Quantitative Human Paleogenetics: What can Ancient DNA Tell us About Complex Trait Evolution?

Front Genet 2021 4;12:703541. Epub 2021 Aug 4.

Lundbeck Foundation GeoGenetics Centre, GLOBE Institute, University of Copenhagen, Copenhagen, Denmark.

Genetic association data from national biobanks and large-scale association studies have provided new prospects for understanding the genetic evolution of complex traits and diseases in humans. In turn, genomes from ancient human archaeological remains are now easier than ever to obtain, and provide a direct window into changes in frequencies of trait-associated alleles in the past. This has generated a new wave of studies aiming to analyse the genetic component of traits in historic and prehistoric times using ancient DNA, and to determine whether any such traits were subject to natural selection. In humans, however, issues about the portability and robustness of complex trait inference across different populations are particularly concerning when predictions are extended to individuals that died thousands of years ago, and for which little, if any, phenotypic validation is possible. In this review, we discuss the advantages of incorporating ancient genomes into studies of trait-associated variants, the need for models that can better accommodate ancient genomes into quantitative genetic frameworks, and the existing limits to inferences about complex trait evolution, particularly with respect to past populations.
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http://dx.doi.org/10.3389/fgene.2021.703541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371751PMC
August 2021

Detecting adaptive introgression in human evolution using convolutional neural networks.

Elife 2021 05 25;10. Epub 2021 May 25.

Lundbeck GeoGenetics Centre, Globe Institute, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Studies in a variety of species have shown evidence for positively selected variants introduced into a population via introgression from another, distantly related population-a process known as adaptive introgression. However, there are few explicit frameworks for jointly modelling introgression and positive selection, in order to detect these variants using genomic sequence data. Here, we develop an approach based on convolutional neural networks (CNNs). CNNs do not require the specification of an analytical model of allele frequency dynamics and have outperformed alternative methods for classification and parameter estimation tasks in various areas of population genetics. Thus, they are potentially well suited to the identification of adaptive introgression. Using simulations, we trained CNNs on genotype matrices derived from genomes sampled from the donor population, the recipient population and a related non-introgressed population, in order to distinguish regions of the genome evolving under adaptive introgression from those evolving neutrally or experiencing selective sweeps. Our CNN architecture exhibits 95% accuracy on simulated data, even when the genomes are unphased, and accuracy decreases only moderately in the presence of heterosis. As a proof of concept, we applied our trained CNNs to human genomic datasets-both phased and unphased-to detect candidates for adaptive introgression that shaped our evolutionary history.
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http://dx.doi.org/10.7554/eLife.64669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192126PMC
May 2021

Population genomics of the Viking world.

Nature 2020 09 16;585(7825):390-396. Epub 2020 Sep 16.

NTNU University Museum, Department of Archaeology and Cultural History, Trondheim, Norway.

The maritime expansion of Scandinavian populations during the Viking Age (about AD 750-1050) was a far-flung transformation in world history. Here we sequenced the genomes of 442 humans from archaeological sites across Europe and Greenland (to a median depth of about 1×) to understand the global influence of this expansion. We find the Viking period involved gene flow into Scandinavia from the south and east. We observe genetic structure within Scandinavia, with diversity hotspots in the south and restricted gene flow within Scandinavia. We find evidence for a major influx of Danish ancestry into England; a Swedish influx into the Baltic; and Norwegian influx into Ireland, Iceland and Greenland. Additionally, we see substantial ancestry from elsewhere in Europe entering Scandinavia during the Viking Age. Our ancient DNA analysis also revealed that a Viking expedition included close family members. By comparing with modern populations, we find that pigmentation-associated loci have undergone strong population differentiation during the past millennium, and trace positively selected loci-including the lactase-persistence allele of LCT and alleles of ANKA that are associated with the immune response-in detail. We conclude that the Viking diaspora was characterized by substantial transregional engagement: distinct populations influenced the genomic makeup of different regions of Europe, and Scandinavia experienced increased contact with the rest of the continent.
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http://dx.doi.org/10.1038/s41586-020-2688-8DOI Listing
September 2020

A community-maintained standard library of population genetic models.

Elife 2020 06 23;9. Epub 2020 Jun 23.

Department of Biology and Institute of Ecology and Evolution, University of Oregon, Eugene, United States.

The explosion in population genomic data demands ever more complex modes of analysis, and increasingly, these analyses depend on sophisticated simulations. Recent advances in population genetic simulation have made it possible to simulate large and complex models, but specifying such models for a particular simulation engine remains a difficult and error-prone task. Computational genetics researchers currently re-implement simulation models independently, leading to inconsistency and duplication of effort. This situation presents a major barrier to empirical researchers seeking to use simulations for power analyses of upcoming studies or sanity checks on existing genomic data. Population genetics, as a field, also lacks standard benchmarks by which new tools for inference might be measured. Here, we describe a new resource, stdpopsim, that attempts to rectify this situation. Stdpopsim is a community-driven open source project, which provides easy access to a growing catalog of published simulation models from a range of organisms and supports multiple simulation engine backends. This resource is available as a well-documented python library with a simple command-line interface. We share some examples demonstrating how stdpopsim can be used to systematically compare demographic inference methods, and we encourage a broader community of developers to contribute to this growing resource.
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http://dx.doi.org/10.7554/eLife.54967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438115PMC
June 2020

The dental proteome of Homo antecessor.

Nature 2020 04 1;580(7802):235-238. Epub 2020 Apr 1.

Evolutionary Genomics Section, Globe Institute, University of Copenhagen, Copenhagen, Denmark.

The phylogenetic relationships between hominins of the Early Pleistocene epoch in Eurasia, such as Homo antecessor, and hominins that appear later in the fossil record during the Middle Pleistocene epoch, such as Homo sapiens, are highly debated. For the oldest remains, the molecular study of these relationships is hindered by the degradation of ancient DNA. However, recent research has demonstrated that the analysis of ancient proteins can address this challenge. Here we present the dental enamel proteomes of H. antecessor from Atapuerca (Spain) and Homo erectus from Dmanisi (Georgia), two key fossil assemblages that have a central role in models of Pleistocene hominin morphology, dispersal and divergence. We provide evidence that H. antecessor is a close sister lineage to subsequent Middle and Late Pleistocene hominins, including modern humans, Neanderthals and Denisovans. This placement implies that the modern-like face of H. antecessor-that is, similar to that of modern humans-may have a considerably deep ancestry in the genus Homo, and that the cranial morphology of Neanderthals represents a derived form. By recovering AMELY-specific peptide sequences, we also conclude that the H. antecessor molar fragment from Atapuerca that we analysed belonged to a male individual. Finally, these H. antecessor and H. erectus fossils preserve evidence of enamel proteome phosphorylation and proteolytic digestion that occurred in vivo during tooth formation. Our results provide important insights into the evolutionary relationships between H. antecessor and other hominin groups, and pave the way for future studies using enamel proteomes to investigate hominin biology across the existence of the genus Homo.
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http://dx.doi.org/10.1038/s41586-020-2153-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582224PMC
April 2020

The spatiotemporal spread of human migrations during the European Holocene.

Proc Natl Acad Sci U S A 2020 04 1;117(16):8989-9000. Epub 2020 Apr 1.

Department of Archaeology, University of Cambridge, Cambridge CB2 1TN, United Kingdom.

The European continent was subject to two major migrations of peoples during the Holocene: the northwestward movement of Anatolian farmer populations during the Neolithic and the westward movement of Yamnaya steppe peoples during the Bronze Age. These movements changed the genetic composition of the continent's inhabitants. The Holocene was also characterized by major changes in vegetation composition, which altered the environment occupied by the original hunter-gatherer populations. We aim to test to what extent vegetation change through time is associated with changes in population composition as a consequence of these migrations, or with changes in climate. Using ancient DNA in combination with geostatistical techniques, we produce detailed maps of ancient population movements, which allow us to visualize how these migrations unfolded through time and space. We find that the spread of Neolithic farmer ancestry had a two-pronged wavefront, in agreement with similar findings on the cultural spread of farming from radiocarbon-dated archaeological sites. This movement, however, did not have a strong association with changes in the vegetational landscape. In contrast, the Yamnaya migration speed was at least twice as fast and coincided with a reduction in the amount of broad-leaf forest and an increase in the amount of pasture and natural grasslands in the continent. We demonstrate the utility of integrating ancient genomes with archaeometric datasets in a spatiotemporal statistical framework, which we foresee will enable future studies of ancient populations' movements, and their putative effects on local fauna and flora.
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http://dx.doi.org/10.1073/pnas.1920051117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183159PMC
April 2020

Beyond broad strokes: sociocultural insights from the study of ancient genomes.

Nat Rev Genet 2020 06 3;21(6):355-366. Epub 2020 Mar 3.

Institute of Evolutionary Biology, CSIC-Universitat Pompeu Fabra, Barcelona, Spain.

In the field of human history, ancient DNA has provided answers to long-standing debates about major movements of people and has begun to inform on other important facets of the human experience. The field is now moving from mostly large-scale supraregional studies to a more local perspective, shedding light on socioeconomic processes, inheritance rules, marriage practices and technological diffusion. In this Review, we summarize recent studies showcasing these types of insights, focusing on methods used to infer sociocultural aspects of human behaviour. This approach often involves working across disciplines - such as anthropology, archaeology, linguistics and genetics - that have until recently evolved in separation. Multidisciplinary dialogue is important for an integrated reconstruction of human history, which can yield extraordinary insights about past societies, reproductive behaviours and even lifestyle habits that would not be possible to obtain otherwise.
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http://dx.doi.org/10.1038/s41576-020-0218-zDOI Listing
June 2020

Identifying loci under positive selection in complex population histories.

Genome Res 2019 09 30;29(9):1506-1520. Epub 2019 Jul 30.

Lundbeck GeoGenetics Centre, The Globe Institute, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 1350, Denmark.

Detailed modeling of a species' history is of prime importance for understanding how natural selection operates over time. Most methods designed to detect positive selection along sequenced genomes, however, use simplified representations of past histories as null models of genetic drift. Here, we present the first method that can detect signatures of strong local adaptation across the genome using arbitrarily complex admixture graphs, which are typically used to describe the history of past divergence and admixture events among any number of populations. The method-called graph-aware retrieval of selective sweeps ()-has good power to detect loci in the genome with strong evidence for past selective sweeps and can also identify which branch of the graph was most affected by the sweep. As evidence of its utility, we apply the method to bovine, codfish, and human population genomic data containing panels of multiple populations related in complex ways. We find new candidate genes for important adaptive functions, including immunity and metabolism in understudied human populations, as well as muscle mass, milk production, and tameness in specific bovine breeds. We are also able to pinpoint the emergence of large regions of differentiation owing to inversions in the history of Atlantic codfish.
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http://dx.doi.org/10.1101/gr.246777.118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724678PMC
September 2019

Human Disease Variation in the Light of Population Genomics.

Cell 2019 03;177(1):115-131

Department of Zoology, University of Cambridge, Cambridge CB2 3EJ, UK; Lundbeck Foundation GeoGenetics Centre, Natural History Museum of Denmark, University of Copenhagen, 1350 Copenhagen, Denmark. Electronic address:

Identifying the causes of similarities and differences in genetic disease prevalence among humans is central to understanding disease etiology. While present-day humans are not strongly differentiated, vast amounts of genomic data now make it possible to study subtle patterns of genetic variation. This allows us to trace our genomic history thousands of years into the past and its implications for the distribution of disease-associated variants today. Genomic analyses have shown that demographic processes shaped the distribution and frequency of disease-associated variants over time. Furthermore, local adaptation to new environmental conditions-including pathogens-has generated strong patterns of differentiation at particular loci. Researchers are also beginning to uncover the genetic architecture of complex diseases, affected by many variants of small effect. The field of population genomics thus holds great potential for providing further insights into the evolution of human disease.
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http://dx.doi.org/10.1016/j.cell.2019.01.052DOI Listing
March 2019

Reduced signal for polygenic adaptation of height in UK Biobank.

Elife 2019 03 21;8. Epub 2019 Mar 21.

Center for Population Biology, University of California, Davis, Davis, United States.

Several recent papers have reported strong signals of selection on European polygenic height scores. These analyses used height effect estimates from the GIANT consortium and replication studies. Here, we describe a new analysis based on the the UK Biobank (UKB), a large, independent dataset. We find that the signals of selection using UKB effect estimates are strongly attenuated or absent. We also provide evidence that previous analyses were confounded by population stratification. Therefore, the conclusion of strong polygenic adaptation now lacks support. Moreover, these discrepancies highlight (1) that methods for correcting for population stratification in GWAS may not always be sufficient for polygenic trait analyses, and (2) that claims of differences in polygenic scores between populations should be treated with caution until these issues are better understood.

Editorial Note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).
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http://dx.doi.org/10.7554/eLife.39725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428572PMC
March 2019

Early human dispersals within the Americas.

Science 2018 12 8;362(6419). Epub 2018 Nov 8.

Canadian Museum of History, Gatineau, Québec K1A 0M8, Canada.

Studies of the peopling of the Americas have focused on the timing and number of initial migrations. Less attention has been paid to the subsequent spread of people within the Americas. We sequenced 15 ancient human genomes spanning from Alaska to Patagonia; six are ≥10,000 years old (up to ~18× coverage). All are most closely related to Native Americans, including those from an Ancient Beringian individual and two morphologically distinct "Paleoamericans." We found evidence of rapid dispersal and early diversification that included previously unknown groups as people moved south. This resulted in multiple independent, geographically uneven migrations, including one that provides clues of a Late Pleistocene Australasian genetic signal, as well as a later Mesoamerican-related expansion. These led to complex and dynamic population histories from North to South America.
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http://dx.doi.org/10.1126/science.aav2621DOI Listing
December 2018

The prehistoric peopling of Southeast Asia.

Science 2018 07;361(6397):88-92

Anthropological and Paleoenvironmental Department, Institute of Archaeology, Hanoi, Vietnam.

The human occupation history of Southeast Asia (SEA) remains heavily debated. Current evidence suggests that SEA was occupied by Hòabìnhian hunter-gatherers until ~4000 years ago, when farming economies developed and expanded, restricting foraging groups to remote habitats. Some argue that agricultural development was indigenous; others favor the "two-layer" hypothesis that posits a southward expansion of farmers giving rise to present-day Southeast Asian genetic diversity. By sequencing 26 ancient human genomes (25 from SEA, 1 Japanese Jōmon), we show that neither interpretation fits the complexity of Southeast Asian history: Both Hòabìnhian hunter-gatherers and East Asian farmers contributed to current Southeast Asian diversity, with further migrations affecting island SEA and Vietnam. Our results help resolve one of the long-standing controversies in Southeast Asian prehistory.
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http://dx.doi.org/10.1126/science.aat3628DOI Listing
July 2018

Something old, something borrowed: admixture and adaptation in human evolution.

Curr Opin Genet Dev 2018 12 9;53:1-8. Epub 2018 Jun 9.

Centre for GeoGenetics, Natural History Museum of Denmark, Copenhagen, Denmark. Electronic address:

The sequencing of ancient DNA from archaic humans-Neanderthals and Denisovans-has revealed that modern and archaic humans interbred at least twice during the Pleistocene. The field of human paleogenomics has now turned its attention towards understanding the nature of this genetic legacy in the gene pool of present-day humans. What exactly did modern humans obtain from interbreeding with Neanderthals and Denisovans? Was the introgressed genetic material beneficial, neutral or maladaptive? Can differences in phenotypes among present-day human populations be explained by archaic human introgression? These questions are of prime importance for our understanding of recent human evolution, but will require careful computational modeling and extensive functional assays before they can be answered in full. Here, we review the recent literature characterizing introgressed DNA and the likely biological consequences for their modern human carriers. We focus particularly on archaic human haplotypes that were beneficial to modern humans as they expanded across the globe, and on ways to understand how populations harboring these haplotypes evolved over time.
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http://dx.doi.org/10.1016/j.gde.2018.05.009DOI Listing
December 2018

Ancient Biomolecules and Evolutionary Inference.

Annu Rev Biochem 2018 06 25;87:1029-1060. Epub 2018 Apr 25.

Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, 1350 Copenhagen, Denmark; email: ,

Over the past three decades, studies of ancient biomolecules-particularly ancient DNA, proteins, and lipids-have revolutionized our understanding of evolutionary history. Though initially fraught with many challenges, today the field stands on firm foundations. Researchers now successfully retrieve nucleotide and amino acid sequences, as well as lipid signatures, from progressively older samples, originating from geographic areas and depositional environments that, until recently, were regarded as hostile to long-term preservation of biomolecules. Sampling frequencies and the spatial and temporal scope of studies have also increased markedly, and with them the size and quality of the data sets generated. This progress has been made possible by continuous technical innovations in analytical methods, enhanced criteria for the selection of ancient samples, integrated experimental methods, and advanced computational approaches. Here, we discuss the history and current state of ancient biomolecule research, its applications to evolutionary inference, and future directions for this young and exciting field.
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http://dx.doi.org/10.1146/annurev-biochem-062917-012002DOI Listing
June 2018

Physiological and Genetic Adaptations to Diving in Sea Nomads.

Cell 2018 04;173(3):569-580.e15

Centre for GeoGenetics, University of Copenhagen, Copenhagen 1350, Denmark; Department of Zoology, University of Cambridge, Cambridge, CB2 3EJ, UK; Wellcome Trust, Sanger Institute, Hinxton CB10 1SA, UK. Electronic address:

Understanding the physiology and genetics of human hypoxia tolerance has important medical implications, but this phenomenon has thus far only been investigated in high-altitude human populations. Another system, yet to be explored, is humans who engage in breath-hold diving. The indigenous Bajau people ("Sea Nomads") of Southeast Asia live a subsistence lifestyle based on breath-hold diving and are renowned for their extraordinary breath-holding abilities. However, it is unknown whether this has a genetic basis. Using a comparative genomic study, we show that natural selection on genetic variants in the PDE10A gene have increased spleen size in the Bajau, providing them with a larger reservoir of oxygenated red blood cells. We also find evidence of strong selection specific to the Bajau on BDKRB2, a gene affecting the human diving reflex. Thus, the Bajau, and possibly other diving populations, provide a new opportunity to study human adaptation to hypoxia tolerance. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.cell.2018.03.054DOI Listing
April 2018

Detecting Polygenic Adaptation in Admixture Graphs.

Genetics 2018 04 18;208(4):1565-1584. Epub 2018 Jan 18.

New York Genome Center, New York, New York 10013.

An open question in human evolution is the importance of polygenic adaptation: adaptive changes in the mean of a multifactorial trait due to shifts in allele frequencies across many loci. In recent years, several methods have been developed to detect polygenic adaptation using loci identified in genome-wide association studies (GWAS). Though powerful, these methods suffer from limited interpretability: they can detect which sets of populations have evidence for polygenic adaptation, but are unable to reveal where in the history of multiple populations these processes occurred. To address this, we created a method to detect polygenic adaptation in an admixture graph, which is a representation of the historical divergences and admixture events relating different populations through time. We developed a Markov chain Monte Carlo (MCMC) algorithm to infer branch-specific parameters reflecting the strength of selection in each branch of a graph. Additionally, we developed a set of summary statistics that are fast to compute and can indicate which branches are most likely to have experienced polygenic adaptation. We show via simulations that this method-which we call PolyGraph-has good power to detect polygenic adaptation, and applied it to human population genomic data from around the world. We also provide evidence that variants associated with several traits, including height, educational attainment, and self-reported unibrow, have been influenced by polygenic adaptation in different populations during human evolution.
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http://dx.doi.org/10.1534/genetics.117.300489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5887149PMC
April 2018

Natural Selection on Genes Related to Cardiovascular Health in High-Altitude Adapted Andeans.

Am J Hum Genet 2017 Nov;101(5):752-767

Department of Integrative Biology, University of California, Berkeley, Berkeley, CA 94702, USA; Museum of Natural History, University of Copenhagen, Øster Voldgade 5-7, 1350 Copenhagen, Denmark; Department of Statistics, University of California, Berkeley, Berkeley, CA 94702, USA. Electronic address:

The increase in red blood cell mass (polycythemia) due to the reduced oxygen availability (hypoxia) of residence at high altitude or other conditions is generally thought to be beneficial in terms of increasing tissue oxygen supply. However, the extreme polycythemia and accompanying increased mortality due to heart failure in chronic mountain sickness most likely reduces fitness. Tibetan highlanders have adapted to high altitude, possibly in part via the selection of genetic variants associated with reduced polycythemic response to hypoxia. In contrast, high-altitude-adapted Quechua- and Aymara-speaking inhabitants of the Andean Altiplano are not protected from high-altitude polycythemia in the same way, yet they exhibit other adaptive features for which the genetic underpinnings remain obscure. Here, we used whole-genome sequencing to scan high-altitude Andeans for signals of selection. The genes showing the strongest evidence of selection-including BRINP3, NOS2, and TBX5-are associated with cardiovascular development and function but are not in the response-to-hypoxia pathway. Using association mapping, we demonstrated that the haplotypes under selection are associated with phenotypic variations related to cardiovascular health. We hypothesize that selection in response to hypoxia in Andeans could have vascular effects and could serve to mitigate the deleterious effects of polycythemia rather than reduce polycythemia itself.
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http://dx.doi.org/10.1016/j.ajhg.2017.09.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673686PMC
November 2017

Deeply divergent archaic mitochondrial genome provides lower time boundary for African gene flow into Neanderthals.

Nat Commun 2017 07 4;8:16046. Epub 2017 Jul 4.

Institute for Archaeological Sciences, University of Tübingen, Rümelin Strasse 23, Tübingen 72070, Germany.

Ancient DNA is revealing new insights into the genetic relationship between Pleistocene hominins and modern humans. Nuclear DNA indicated Neanderthals as a sister group of Denisovans after diverging from modern humans. However, the closer affinity of the Neanderthal mitochondrial DNA (mtDNA) to modern humans than Denisovans has recently been suggested as the result of gene flow from an African source into Neanderthals before 100,000 years ago. Here we report the complete mtDNA of an archaic femur from the Hohlenstein-Stadel (HST) cave in southwestern Germany. HST carries the deepest divergent mtDNA lineage that splits from other Neanderthals ∼270,000 years ago, providing a lower boundary for the time of the putative mtDNA introgression event. We demonstrate that a complete Neanderthal mtDNA replacement is feasible over this time interval even with minimal hominin introgression. The highly divergent HST branch is indicative of greater mtDNA diversity during the Middle Pleistocene than in later periods.
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http://dx.doi.org/10.1038/ncomms16046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5500885PMC
July 2017

Joint Estimation of Relatedness Coefficients and Allele Frequencies from Ancient Samples.

Genetics 2017 06 10;206(2):1025-1035. Epub 2017 Apr 10.

Department of Integrative Biology, University of California, Berkeley, California 94720.

Here, we develop and test a method to address whether DNA samples sequenced from a group of fossil hominin bone or tooth fragments originate from the same individual or from closely related individuals. Our method assumes low amounts of retrievable DNA, significant levels of sequencing error, and contamination from one or more present-day humans. We develop and implement a maximum likelihood method that estimates levels of contamination, sequencing error rates, and pairwise relatedness coefficients in a set of individuals. We assume that there is no reference panel for the ancient population to provide allele and haplotype frequencies. Our approach makes use of single nucleotide polymorphisms (SNPs) and does not make assumptions about the underlying demographic model. By artificially mating genomes from the 1000 Genomes Project, we determine the numbers of individuals at a given genomic coverage that are required to detect different levels of genetic relatedness with confidence.
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http://dx.doi.org/10.1534/genetics.117.200600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499161PMC
June 2017

Selection in Europeans on Fatty Acid Desaturases Associated with Dietary Changes.

Mol Biol Evol 2017 06;34(6):1307-1318

Departments of Integrative Biology and Statistics, University of California Berkeley, Berkeley, CA.

FADS genes encode fatty acid desaturases that are important for the conversion of short chain polyunsaturated fatty acids (PUFAs) to long chain fatty acids. Prior studies indicate that the FADS genes have been subjected to strong positive selection in Africa, South Asia, Greenland, and Europe. By comparing FADS sequencing data from present-day and Bronze Age (5-3k years ago) Europeans, we identify possible targets of selection in the European population, which suggest that selection has targeted different alleles in the FADS genes in Europe than it has in South Asia or Greenland. The alleles showing the strongest changes in allele frequency since the Bronze Age show associations with expression changes and multiple lipid-related phenotypes. Furthermore, the selected alleles are associated with a decrease in linoleic acid and an increase in arachidonic and eicosapentaenoic acids among Europeans; this is an opposite effect of that observed for selected alleles in Inuit from Greenland. We show that multiple SNPs in the region affect expression levels and PUFA synthesis. Additionally, we find evidence for a gene-environment interaction influencing low-density lipoprotein (LDL) levels between alleles affecting PUFA synthesis and PUFA dietary intake: carriers of the derived allele display lower LDL cholesterol levels with a higher intake of PUFAs. We hypothesize that the selective patterns observed in Europeans were driven by a change in dietary composition of fatty acids following the transition to agriculture, resulting in a lower intake of arachidonic acid and eicosapentaenoic acid, but a higher intake of linoleic acid and α-linolenic acid.
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http://dx.doi.org/10.1093/molbev/msx103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435082PMC
June 2017

Archaic Adaptive Introgression in TBX15/WARS2.

Mol Biol Evol 2017 03;34(3):509-524

Department of Integrative Biology, University of California Berkeley, Berkeley, CA.

A recent study conducted the first genome-wide scan for selection in Inuit from Greenland using single nucleotide polymorphism chip data. Here, we report that selection in the region with the second most extreme signal of positive selection in Greenlandic Inuit favored a deeply divergent haplotype that is closely related to the sequence in the Denisovan genome, and was likely introgressed from an archaic population. The region contains two genes, WARS2 and TBX15, and has previously been associated with adipose tissue differentiation and body-fat distribution in humans. We show that the adaptively introgressed allele has been under selection in a much larger geographic region than just Greenland. Furthermore, it is associated with changes in expression of WARS2 and TBX15 in multiple tissues including the adrenal gland and subcutaneous adipose tissue, and with regional DNA methylation changes in TBX15.
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http://dx.doi.org/10.1093/molbev/msw283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5430617PMC
March 2017

Correction: Joint Estimation of Contamination, Error and Demography for Nuclear DNA from Ancient Humans.

PLoS Genet 2016 Nov 8;12(11):e1006444. Epub 2016 Nov 8.

[This corrects the article DOI: 10.1371/journal.pgen.1005972.].
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http://dx.doi.org/10.1371/journal.pgen.1006444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5100944PMC
November 2016

Signatures of Archaic Adaptive Introgression in Present-Day Human Populations.

Mol Biol Evol 2017 02;34(2):296-317

School of Natural Sciences, University of California Merced, Merced, CA.

Comparisons of DNA from archaic and modern humans show that these groups interbred, and in some cases received an evolutionary advantage from doing so. This process-adaptive introgression-may lead to a faster rate of adaptation than is predicted from models with mutation and selection alone. Within the last couple of years, a series of studies have identified regions of the genome that are likely examples of adaptive introgression. In many cases, once a region was ascertained as being introgressed, commonly used statistics based on both haplotype as well as allele frequency information were employed to test for positive selection. Introgression by itself, however, changes both the haplotype structure and the distribution of allele frequencies, thus confounding traditional tests for detecting positive selection. Therefore, patterns generated by introgression alone may lead to false inferences of positive selection. Here we explore models involving both introgression and positive selection to investigate the behavior of various statistics under adaptive introgression. In particular, we find that the number and allelic frequencies of sites that are uniquely shared between archaic humans and specific present-day populations are particularly useful for detecting adaptive introgression. We then examine the 1000 Genomes dataset to characterize the landscape of uniquely shared archaic alleles in human populations. Finally, we identify regions that were likely subject to adaptive introgression and discuss some of the most promising candidate genes located in these regions.
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http://dx.doi.org/10.1093/molbev/msw216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5400396PMC
February 2017

A genomic history of Aboriginal Australia.

Nature 2016 Oct 21;538(7624):207-214. Epub 2016 Sep 21.

Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, Øster Voldgade 5-7, 1350 Copenhagen, Denmark.

The population history of Aboriginal Australians remains largely uncharacterized. Here we generate high-coverage genomes for 83 Aboriginal Australians (speakers of Pama-Nyungan languages) and 25 Papuans from the New Guinea Highlands. We find that Papuan and Aboriginal Australian ancestors diversified 25-40 thousand years ago (kya), suggesting pre-Holocene population structure in the ancient continent of Sahul (Australia, New Guinea and Tasmania). However, all of the studied Aboriginal Australians descend from a single founding population that differentiated ~10-32 kya. We infer a population expansion in northeast Australia during the Holocene epoch (past 10,000 years) associated with limited gene flow from this region to the rest of Australia, consistent with the spread of the Pama-Nyungan languages. We estimate that Aboriginal Australians and Papuans diverged from Eurasians 51-72 kya, following a single out-of-Africa dispersal, and subsequently admixed with archaic populations. Finally, we report evidence of selection in Aboriginal Australians potentially associated with living in the desert.
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http://dx.doi.org/10.1038/nature18299DOI Listing
October 2016

The Simons Genome Diversity Project: 300 genomes from 142 diverse populations.

Nature 2016 Oct 21;538(7624):201-206. Epub 2016 Sep 21.

Department of Zoology, University of Oxford, Oxford OX1 3PS, UK.

Here we report the Simons Genome Diversity Project data set: high quality genomes from 300 individuals from 142 diverse populations. These genomes include at least 5.8 million base pairs that are not present in the human reference genome. Our analysis reveals key features of the landscape of human genome variation, including that the rate of accumulation of mutations has accelerated by about 5% in non-Africans compared to Africans since divergence. We show that the ancestors of some pairs of present-day human populations were substantially separated by 100,000 years ago, well before the archaeologically attested onset of behavioural modernity. We also demonstrate that indigenous Australians, New Guineans and Andamanese do not derive substantial ancestry from an early dispersal of modern humans; instead, their modern human ancestry is consistent with coming from the same source as that of other non-Africans.
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http://dx.doi.org/10.1038/nature18964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161557PMC
October 2016
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