Publications by authors named "Nick Patterson"

169 Publications

Ethics of DNA research on human remains: five globally applicable guidelines.

Nature 2021 Oct 20. Epub 2021 Oct 20.

Department of Genetics, Harvard Medical School, Boston, MA, USA.

We are a group of archaeologists, anthropologists, curators and geneticists representing diverse global communities and 31 countries. All of us met in a virtual workshop dedicated to ethics in ancient DNA research held in November 2020. There was widespread agreement that globally applicable ethical guidelines are needed, but that recent recommendations grounded in discussion about research on human remains from North America are not always generalizable worldwide. Here we propose the following globally applicable guidelines, taking into consideration diverse contexts. These hold that: (1) researchers must ensure that all regulations were followed in the places where they work and from which the human remains derived; (2) researchers must prepare a detailed plan prior to beginning any study; (3) researchers must minimize damage to human remains; (4) researchers must ensure that data are made available following publication to allow critical re-examination of scientific findings; and (5) researchers must engage with other stakeholders from the beginning of a study and ensure respect and sensitivity to stakeholder perspectives. We commit to adhering to these guidelines and expect they will promote a high ethical standard in DNA research on human remains going forward.
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http://dx.doi.org/10.1038/s41586-021-04008-xDOI Listing
October 2021

COMBINING ANCIENT DNA AND RADIOCARBON DATING DATA TO INCREASE CHRONOLOGICAL ACCURACY.

J Archaeol Sci 2021 Sep 29;133. Epub 2021 Jul 29.

Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

This paper examines how ancient DNA data can enhance radiocarbon dating. Because there is a limit to the number of years that can separate the dates of death of related individuals, the ability to identify relatives through ancient DNA analysis can serve as a constraint on radiocarbon date range estimates. To determine the number of years that can separate related individuals, we modeled maximums derived from biological extremes of human reproduction and death ages and compiled data from historic and genealogical death records. We used these data to jointly study the date ranges of a global dataset of individuals that have been radiocarbon dated and for which ancient DNA analysis identified at least one relative. We found that many of these individuals could have their date uncertainties reduced by building in date of death separation constraints. We examined possible reasons for date discrepancies of related individuals, such as dating of different skeletal elements or wiggles in the radiocarbon curve. We also developed a program, , which researchers can download and use to help refine the radiocarbon date distributions of related individuals. Our research demonstrates that when combined, radiocarbon dating and ancient DNA analysis can provide a refined and richer view of the past.
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http://dx.doi.org/10.1016/j.jas.2021.105452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8415703PMC
September 2021

Assessing the performance of qpAdm: a statistical tool for studying population admixture.

Genetics 2021 04;217(4)

Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA.

qpAdm is a statistical tool for studying the ancestry of populations with histories that involve admixture between two or more source populations. Using qpAdm, it is possible to identify plausible models of admixture that fit the population history of a group of interest and to calculate the relative proportion of ancestry that can be ascribed to each source population in the model. Although qpAdm is widely used in studies of population history of human (and nonhuman) groups, relatively little has been done to assess its performance. We performed a simulation study to assess the behavior of qpAdm under various scenarios in order to identify areas of potential weakness and establish recommended best practices for use. We find that qpAdm is a robust tool that yields accurate results in many cases, including when data coverage is low, there are high rates of missing data or ancient DNA damage, or when diploid calls cannot be made. However, we caution against co-analyzing ancient and present-day data, the inclusion of an extremely large number of reference populations in a single model, and analyzing population histories involving extended periods of gene flow. We provide a user guide suggesting best practices for the use of qpAdm.
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http://dx.doi.org/10.1093/genetics/iyaa045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049561PMC
April 2021

Genetic Ancestry Contributes to Somatic Mutations in Lung Cancers from Admixed Latin American Populations.

Cancer Discov 2021 03 2;11(3):591-598. Epub 2020 Dec 2.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Inherited lung cancer risk, particularly in nonsmokers, is poorly understood. Genomic and ancestry analysis of 1,153 lung cancers from Latin America revealed striking associations between Native American ancestry and their somatic landscape, including tumor mutational burden, and specific driver mutations in , and . A local Native American ancestry risk score was more strongly correlated with mutation frequency compared with global ancestry correlation, suggesting that germline genetics (rather than environmental exposure) underlie these disparities. SIGNIFICANCE: The frequency of somatic and mutations in lung cancer varies by ethnicity, but we do not understand why. Our study suggests that the variation in and mutation frequency is associated with genetic ancestry and suggests further studies to identify germline alleles that underpin this association...
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http://dx.doi.org/10.1158/2159-8290.CD-20-1165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933062PMC
March 2021

miqoGraph: fitting admixture graphs using mixed-integer quadratic optimization.

Bioinformatics 2021 08;37(16):2488-2490

Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA.

Summary: Admixture graphs represent the genetic relationship between a set of populations through splits, drift and admixture. In this article, we present the Julia package miqoGraph, which uses mixed-integer quadratic optimization to fit topology, drift lengths and admixture proportions simultaneously. Through applications of miqoGraph to both simulated and real data, we show that integer optimization can greatly speed up and automate what is usually an arduous manual process.

Availability And Implementation: https://github.com/juliayyan/PhylogeneticTrees.jl.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btaa988DOI Listing
August 2021

Two genetic variants explain the association of European ancestry with multiple sclerosis risk in African-Americans.

Sci Rep 2020 10 9;10(1):16902. Epub 2020 Oct 9.

Department of Genetics, Harvard Medical School, New Research Building, Boston, MA, 02115, USA.

Epidemiological studies have suggested differences in the rate of multiple sclerosis (MS) in individuals of European ancestry compared to African ancestry, motivating genetic scans to identify variants that could contribute to such patterns. In a whole-genome scan in 899 African-American cases and 1155 African-American controls, we confirm that African-Americans who inherit segments of the genome of European ancestry at a chromosome 1 locus are at increased risk for MS [logarithm of odds (LOD) = 9.8], although the signal weakens when adding an additional 406 cases, reflecting heterogeneity in the two sets of cases [logarithm of odds (LOD) = 2.7]. The association in the 899 individuals can be fully explained by two variants previously associated with MS in European ancestry individuals. These variants tag a MS susceptibility haplotype associated with decreased CD58 gene expression (odds ratio of 1.37; frequency of 84% in Europeans and 22% in West Africans for the tagging variant) as well as another haplotype near the FCRL3 gene (odds ratio of 1.07; frequency of 49% in Europeans and 8% in West Africans). Controlling for all other genetic and environmental factors, the two variants predict a 1.44-fold higher rate of MS in European-Americans compared to African-Americans.
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http://dx.doi.org/10.1038/s41598-020-74035-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547691PMC
October 2020

ContamLD: estimation of ancient nuclear DNA contamination using breakdown of linkage disequilibrium.

Genome Biol 2020 08 10;21(1):199. Epub 2020 Aug 10.

Department of Genetics, New Research Building, Harvard Medical School, 77 Ave. Louis Pasteur, Boston, MA, 02115, USA.

We report a method called ContamLD for estimating autosomal ancient DNA (aDNA) contamination by measuring the breakdown of linkage disequilibrium in a sequenced individual due to the introduction of contaminant DNA. ContamLD leverages the idea that contaminants should have haplotypes uncorrelated to those of the studied individual. Using simulated data, we confirm that ContamLD accurately infers contamination rates with low standard errors: for example, less than 1.5% standard error in cases with less than 10% contamination and 500,000 sequences covering SNPs. This method is optimized for application to aDNA, taking advantage of characteristic aDNA damage patterns to provide calibrated contamination estimates, and is available at https://github.com/nathan-nakatsuka/ContamLD .
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http://dx.doi.org/10.1186/s13059-020-02111-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418405PMC
August 2020

Liability threshold modeling of case-control status and family history of disease increases association power.

Nat Genet 2020 05 20;52(5):541-547. Epub 2020 Apr 20.

Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Family history of disease can provide valuable information in case-control association studies, but it is currently unclear how to best combine case-control status and family history of disease. We developed an association method based on posterior mean genetic liabilities under a liability threshold model, conditional on case-control status and family history (LT-FH). Analyzing 12 diseases from the UK Biobank (average N = 350,000) we compared LT-FH to genome-wide association without using family history (GWAS) and a previous proxy-based method incorporating family history (GWAX). LT-FH was 63% (standard error (s.e.) 6%) more powerful than GWAS and 36% (s.e. 4%) more powerful than the trait-specific maximum of GWAS and GWAX, based on the number of independent genome-wide-significant loci across all diseases (for example, 690 loci for LT-FH versus 423 for GWAS); relative improvements were similar when applying BOLT-LMM to GWAS, GWAX and LT-FH phenotypes. Thus, LT-FH greatly increases association power when family history of disease is available.
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http://dx.doi.org/10.1038/s41588-020-0613-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210076PMC
May 2020

The spread of steppe and Iranian-related ancestry in the islands of the western Mediterranean.

Nat Ecol Evol 2020 03 24;4(3):334-345. Epub 2020 Feb 24.

Instituto Internacional de Investigaciones Prehistóricas de Cantabria, Universidad de Cantabria-Gobierno de Cantabria-Banco Santander, Santander, Spain.

Steppe-pastoralist-related ancestry reached Central Europe by at least 2500 BC, whereas Iranian farmer-related ancestry was present in Aegean Europe by at least 1900 BC. However, the spread of these ancestries into the western Mediterranean, where they have contributed to many populations that live today, remains poorly understood. Here, we generated genome-wide ancient-DNA data from the Balearic Islands, Sicily and Sardinia, increasing the number of individuals with reported data from 5 to 66. The oldest individual from the Balearic Islands (~2400 BC) carried ancestry from steppe pastoralists that probably derived from west-to-east migration from Iberia, although two later Balearic individuals had less ancestry from steppe pastoralists. In Sicily, steppe pastoralist ancestry arrived by ~2200 BC, in part from Iberia; Iranian-related ancestry arrived by the mid-second millennium BC, contemporary to its previously documented spread to the Aegean; and there was large-scale population replacement after the Bronze Age. In Sardinia, nearly all ancestry derived from the island's early farmers until the first millennium BC, with the exception of an outlier from the third millennium BC, who had primarily North African ancestry and who-along with an approximately contemporary Iberian-documents widespread Africa-to-Europe gene flow in the Chalcolithic. Major immigration into Sardinia began in the first millennium BC and, at present, no more than 56-62% of Sardinian ancestry is from its first farmers. This value is lower than previous estimates, highlighting that Sardinia, similar to every other region in Europe, has been a stage for major movement and mixtures of people.
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http://dx.doi.org/10.1038/s41559-020-1102-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080320PMC
March 2020

Ancient West African foragers in the context of African population history.

Nature 2020 01 22;577(7792):665-670. Epub 2020 Jan 22.

UCL Genetics Institute, University College London, London, UK.

Our knowledge of ancient human population structure in sub-Saharan Africa, particularly prior to the advent of food production, remains limited. Here we report genome-wide DNA data from four children-two of whom were buried approximately 8,000 years ago and two 3,000 years ago-from Shum Laka (Cameroon), one of the earliest known archaeological sites within the probable homeland of the Bantu language group. One individual carried the deeply divergent Y chromosome haplogroup A00, which today is found almost exclusively in the same region. However, the genome-wide ancestry profiles of all four individuals are most similar to those of present-day hunter-gatherers from western Central Africa, which implies that populations in western Cameroon today-as well as speakers of Bantu languages from across the continent-are not descended substantially from the population represented by these four people. We infer an Africa-wide phylogeny that features widespread admixture and three prominent radiations, including one that gave rise to at least four major lineages deep in the history of modern humans.
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http://dx.doi.org/10.1038/s41586-020-1929-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8386425PMC
January 2020

Genomic architecture and introgression shape a butterfly radiation.

Science 2019 11;366(6465):594-599

Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA.

We used 20 de novo genome assemblies to probe the speciation history and architecture of gene flow in rapidly radiating butterflies. Our tests to distinguish incomplete lineage sorting from introgression indicate that gene flow has obscured several ancient phylogenetic relationships in this group over large swathes of the genome. Introgressed loci are underrepresented in low-recombination and gene-rich regions, consistent with the purging of foreign alleles more tightly linked to incompatibility loci. Here, we identify a hitherto unknown inversion that traps a color pattern switch locus. We infer that this inversion was transferred between lineages by introgression and is convergent with a similar rearrangement in another part of the genus. These multiple de novo genome sequences enable improved understanding of the importance of introgression and selective processes in adaptive radiation.
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http://dx.doi.org/10.1126/science.aaw2090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197882PMC
November 2019

Correction to: African evolutionary history inferred from whole genome sequence data of 44 indigenous African populations.

Genome Biol 2019 Oct 9;20(1):204. Epub 2019 Oct 9.

Department of Genetics, University of Pennsylvania, Philadelphia, PA, 19104, USA.

Following publication of the original article [1], a typographical error in the formula for calculating d in the "Scans for local adaptation" subsection in the Method section, was identified. The correct formula should be.
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http://dx.doi.org/10.1186/s13059-019-1821-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784328PMC
October 2019

An Ancient Harappan Genome Lacks Ancestry from Steppe Pastoralists or Iranian Farmers.

Cell 2019 10 5;179(3):729-735.e10. Epub 2019 Sep 5.

Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address:

We report an ancient genome from the Indus Valley Civilization (IVC). The individual we sequenced fits as a mixture of people related to ancient Iranians (the largest component) and Southeast Asian hunter-gatherers, a unique profile that matches ancient DNA from 11 genetic outliers from sites in Iran and Turkmenistan in cultural communication with the IVC. These individuals had little if any Steppe pastoralist-derived ancestry, showing that it was not ubiquitous in northwest South Asia during the IVC as it is today. The Iranian-related ancestry in the IVC derives from a lineage leading to early Iranian farmers, herders, and hunter-gatherers before their ancestors separated, contradicting the hypothesis that the shared ancestry between early Iranians and South Asians reflects a large-scale spread of western Iranian farmers east. Instead, sampled ancient genomes from the Iranian plateau and IVC descend from different groups of hunter-gatherers who began farming without being connected by substantial movement of people.
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http://dx.doi.org/10.1016/j.cell.2019.08.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800651PMC
October 2019

The formation of human populations in South and Central Asia.

Science 2019 09;365(6457)

Earth Institute, University College Dublin, Dublin 4, Ireland.

By sequencing 523 ancient humans, we show that the primary source of ancestry in modern South Asians is a prehistoric genetic gradient between people related to early hunter-gatherers of Iran and Southeast Asia. After the Indus Valley Civilization's decline, its people mixed with individuals in the southeast to form one of the two main ancestral populations of South Asia, whose direct descendants live in southern India. Simultaneously, they mixed with descendants of Steppe pastoralists who, starting around 4000 years ago, spread via Central Asia to form the other main ancestral population. The Steppe ancestry in South Asia has the same profile as that in Bronze Age Eastern Europe, tracking a movement of people that affected both regions and that likely spread the distinctive features shared between Indo-Iranian and Balto-Slavic languages.
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http://dx.doi.org/10.1126/science.aat7487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822619PMC
September 2019

Ancient DNA from the skeletons of Roopkund Lake reveals Mediterranean migrants in India.

Nat Commun 2019 08 20;10(1):3670. Epub 2019 Aug 20.

CSIR Centre for Cellular and Molecular Biology, Hyderabad, Telangana, 500007, India.

Situated at over 5,000 meters above sea level in the Himalayan Mountains, Roopkund Lake is home to the scattered skeletal remains of several hundred individuals of unknown origin. We report genome-wide ancient DNA for 38 skeletons from Roopkund Lake, and find that they cluster into three distinct groups. A group of 23 individuals have ancestry that falls within the range of variation of present-day South Asians. A further 14 have ancestry typical of the eastern Mediterranean. We also identify one individual with Southeast Asian-related ancestry. Radiocarbon dating indicates that these remains were not deposited simultaneously. Instead, all of the individuals with South Asian-related ancestry date to ~800 CE (but with evidence of being deposited in more than one event), while all other individuals date to ~1800 CE. These differences are also reflected in stable isotope measurements, which reveal a distinct dietary profile for the two main groups.
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http://dx.doi.org/10.1038/s41467-019-11357-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702210PMC
August 2019

Extreme Polygenicity of Complex Traits Is Explained by Negative Selection.

Am J Hum Genet 2019 09 8;105(3):456-476. Epub 2019 Aug 8.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address:

Complex traits and common diseases are extremely polygenic, their heritability spread across thousands of loci. One possible explanation is that thousands of genes and loci have similarly important biological effects when mutated. However, we hypothesize that for most complex traits, relatively few genes and loci are critical, and negative selection-purging large-effect mutations in these regions-leaves behind common-variant associations in thousands of less critical regions instead. We refer to this phenomenon as flattening. To quantify its effects, we introduce a mathematical definition of polygenicity, the effective number of independently associated SNPs (M), which describes how evenly the heritability of a trait is spread across the genome. We developed a method, stratified LD fourth moments regression (S-LD4M), to estimate M, validating that it produces robust estimates in simulations. Analyzing 33 complex traits (average N = 361k), we determined that heritability is spread ∼4× more evenly among common SNPs than among low-frequency SNPs. This difference, together with evolutionary modeling of new mutations, suggests that complex traits would be orders of magnitude less polygenic if not for the influence of negative selection. We also determined that heritability is spread more evenly within functionally important regions in proportion to their heritability enrichment; functionally important regions do not harbor common SNPs with greatly increased causal effect sizes, due to selective constraint. Our results suggest that for most complex traits, the genes and loci with the most critical biological effects often differ from those with the strongest common-variant associations.
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http://dx.doi.org/10.1016/j.ajhg.2019.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732528PMC
September 2019

African evolutionary history inferred from whole genome sequence data of 44 indigenous African populations.

Genome Biol 2019 04 26;20(1):82. Epub 2019 Apr 26.

Department of Genetics, University of Pennsylvania, Philadelphia, PA, 19104, USA.

Background: Africa is the origin of modern humans within the past 300 thousand years. To infer the complex demographic history of African populations and adaptation to diverse environments, we sequenced the genomes of 92 individuals from 44 indigenous African populations.

Results: Genetic structure analyses indicate that among Africans, genetic ancestry is largely partitioned by geography and language, though we observe mixed ancestry in many individuals, consistent with both short- and long-range migration events followed by admixture. Phylogenetic analysis indicates that the San genetic lineage is basal to all modern human lineages. The San and Niger-Congo, Afroasiatic, and Nilo-Saharan lineages were substantially diverged by 160 kya (thousand years ago). In contrast, the San and Central African rainforest hunter-gatherer (CRHG), Hadza hunter-gatherer, and Sandawe hunter-gatherer lineages were diverged by ~ 120-100 kya. Niger-Congo, Nilo-Saharan, and Afroasiatic lineages diverged more recently by ~ 54-16 kya. Eastern and western CRHG lineages diverged by ~ 50-31 kya, and the western CRHG lineages diverged by ~ 18-12 kya. The San and CRHG populations maintained the largest effective population size compared to other populations prior to 60 kya. Further, we observed signatures of positive selection at genes involved in muscle development, bone synthesis, reproduction, immune function, energy metabolism, and cell signaling, which may contribute to local adaptation of African populations.

Conclusions: We observe high levels of genomic variation between ethnically diverse Africans which is largely correlated with geography and language. Our study indicates ancient population substructure and local adaptation of Africans.
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http://dx.doi.org/10.1186/s13059-019-1679-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485071PMC
April 2019

Polygenic adaptation on height is overestimated due to uncorrected stratification in genome-wide association studies.

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

Department of Biomedical Informatics, Harvard Medical School, Boston, United States.

Genetic predictions of height differ among human populations and these differences have been interpreted as evidence of polygenic adaptation. These differences were first detected using SNPs genome-wide significantly associated with height, and shown to grow stronger when large numbers of sub-significant SNPs were included, leading to excitement about the prospect of analyzing large fractions of the genome to detect polygenic adaptation for multiple traits. Previous studies of height have been based on SNP effect size measurements in the GIANT Consortium meta-analysis. Here we repeat the analyses in the UK Biobank, a much more homogeneously designed study. We show that polygenic adaptation signals based on large numbers of SNPs below genome-wide significance are extremely sensitive to biases due to uncorrected population stratification. More generally, our results imply that typical constructions of polygenic scores are sensitive to population stratification and that population-level differences should be interpreted with caution.

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.39702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428571PMC
March 2019

The genomic history of the Iberian Peninsula over the past 8000 years.

Science 2019 03;363(6432):1230-1234

Departamento de Prehistoria e Historia Antigua, Universidad Nacional de Educación a Distancia, Valencia, Spain.

We assembled genome-wide data from 271 ancient Iberians, of whom 176 are from the largely unsampled period after 2000 BCE, thereby providing a high-resolution time transect of the Iberian Peninsula. We document high genetic substructure between northwestern and southeastern hunter-gatherers before the spread of farming. We reveal sporadic contacts between Iberia and North Africa by ~2500 BCE and, by ~2000 BCE, the replacement of 40% of Iberia's ancestry and nearly 100% of its Y-chromosomes by people with Steppe ancestry. We show that, in the Iron Age, Steppe ancestry had spread not only into Indo-European-speaking regions but also into non-Indo-European-speaking ones, and we reveal that present-day Basques are best described as a typical Iron Age population without the admixture events that later affected the rest of Iberia. Additionally, we document how, beginning at least in the Roman period, the ancestry of the peninsula was transformed by gene flow from North Africa and the eastern Mediterranean.
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http://dx.doi.org/10.1126/science.aav4040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436108PMC
March 2019

Estimating cross-population genetic correlations of causal effect sizes.

Genet Epidemiol 2019 03 25;43(2):180-188. Epub 2018 Nov 25.

Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts.

Recent studies have examined the genetic correlations of single-nucleotide polymorphism (SNP) effect sizes across pairs of populations to better understand the genetic architectures of complex traits. These studies have estimated ρ g , the cross-population correlation of joint-fit effect sizes at genotyped SNPs. However, the value of ρ g depends both on the cross-population correlation of true causal effect sizes ( ρ b ) and on the similarity in linkage disequilibrium (LD) patterns in the two populations, which drive tagging effects. Here, we derive the value of the ratio ρ g / ρ b as a function of LD in each population. By applying existing methods to obtain estimates of ρ g , we can use this ratio to estimate ρ b . Our estimates of ρ b were equal to 0.55 ( SE = 0.14) between Europeans and East Asians averaged across nine traits in the Genetic Epidemiology Research on Adult Health and Aging data set, 0.54 ( SE = 0.18) between Europeans and South Asians averaged across 13 traits in the UK Biobank data set, and 0.48 ( SE = 0.06) and 0.65 ( SE = 0.09) between Europeans and East Asians in summary statistic data sets for type 2 diabetes and rheumatoid arthritis, respectively. These results implicate substantially different causal genetic architectures across continental populations.
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http://dx.doi.org/10.1002/gepi.22173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375794PMC
March 2019

Reconstructing the Deep Population History of Central and South America.

Cell 2018 11 8;175(5):1185-1197.e22. Epub 2018 Nov 8.

Department of Human Evolution, Max Planck Institute for Evolutionary Anthropology, Leipzig 04103, Germany.

We report genome-wide ancient DNA from 49 individuals forming four parallel time transects in Belize, Brazil, the Central Andes, and the Southern Cone, each dating to at least ∼9,000 years ago. The common ancestral population radiated rapidly from just one of the two early branches that contributed to Native Americans today. We document two previously unappreciated streams of gene flow between North and South America. One affected the Central Andes by ∼4,200 years ago, while the other explains an affinity between the oldest North American genome associated with the Clovis culture and the oldest Central and South Americans from Chile, Brazil, and Belize. However, this was not the primary source for later South Americans, as the other ancient individuals derive from lineages without specific affinity to the Clovis-associated genome, suggesting a population replacement that began at least 9,000 years ago and was followed by substantial population continuity in multiple regions.
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http://dx.doi.org/10.1016/j.cell.2018.10.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6327247PMC
November 2018

Publisher Correction: Ancient DNA from Chalcolithic Israel reveals the role of population mixture in cultural transformation.

Nat Commun 2018 09 20;9(1):3913. Epub 2018 Sep 20.

Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

In the original version of this Article, references in the format 'First author et al.' were inappropriately deleted. These errors have been corrected in the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41467-018-06484-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6147797PMC
September 2018

Detecting genome-wide directional effects of transcription factor binding on polygenic disease risk.

Nat Genet 2018 10 3;50(10):1483-1493. Epub 2018 Sep 3.

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Biological interpretation of genome-wide association study data frequently involves assessing whether SNPs linked to a biological process, for example, binding of a transcription factor, show unsigned enrichment for disease signal. However, signed annotations quantifying whether each SNP allele promotes or hinders the biological process can enable stronger statements about disease mechanism. We introduce a method, signed linkage disequilibrium profile regression, for detecting genome-wide directional effects of signed functional annotations on disease risk. We validate the method via simulations and application to molecular quantitative trait loci in blood, recovering known transcriptional regulators. We apply the method to expression quantitative trait loci in 48 Genotype-Tissue Expression tissues, identifying 651 transcription factor-tissue associations including 30 with robust evidence of tissue specificity. We apply the method to 46 diseases and complex traits (average n = 290 K), identifying 77 annotation-trait associations representing 12 independent transcription factor-trait associations, and characterize the underlying transcriptional programs using gene-set enrichment analyses. Our results implicate new causal disease genes and new disease mechanisms.
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http://dx.doi.org/10.1038/s41588-018-0196-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202062PMC
October 2018

Ancient DNA from Chalcolithic Israel reveals the role of population mixture in cultural transformation.

Nat Commun 2018 08 20;9(1):3336. Epub 2018 Aug 20.

Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA.

The material culture of the Late Chalcolithic period in the southern Levant (4500-3900/3800 BCE) is qualitatively distinct from previous and subsequent periods. Here, to test the hypothesis that the advent and decline of this culture was influenced by movements of people, we generated genome-wide ancient DNA from 22 individuals from Peqi'in Cave, Israel. These individuals were part of a homogeneous population that can be modeled as deriving ~57% of its ancestry from groups related to those of the local Levant Neolithic, ~17% from groups related to those of the Iran Chalcolithic, and ~26% from groups related to those of the Anatolian Neolithic. The Peqi'in population also appears to have contributed differently to later Bronze Age groups, one of which we show cannot plausibly have descended from the same population as that of Peqi'in Cave. These results provide an example of how population movements propelled cultural changes in the deep past.
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http://dx.doi.org/10.1038/s41467-018-05649-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6102297PMC
August 2018

No evidence for unknown archaic ancestry in South Asia.

Nat Genet 2018 05;50(5):632-633

Department of Genetics, Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1038/s41588-018-0097-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433599PMC
May 2018

Reconstructing the genetic history of late Neanderthals.

Nature 2018 03 21;555(7698):652-656. Epub 2018 Mar 21.

Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, D-04103 Leipzig, Germany.

Although it has previously been shown that Neanderthals contributed DNA to modern humans, not much is known about the genetic diversity of Neanderthals or the relationship between late Neanderthal populations at the time at which their last interactions with early modern humans occurred and before they eventually disappeared. Our ability to retrieve DNA from a larger number of Neanderthal individuals has been limited by poor preservation of endogenous DNA and contamination of Neanderthal skeletal remains by large amounts of microbial and present-day human DNA. Here we use hypochlorite treatment of as little as 9 mg of bone or tooth powder to generate between 1- and 2.7-fold genomic coverage of five Neanderthals who lived around 39,000 to 47,000 years ago (that is, late Neanderthals), thereby doubling the number of Neanderthals for which genome sequences are available. Genetic similarity among late Neanderthals is well predicted by their geographical location, and comparison to the genome of an older Neanderthal from the Caucasus indicates that a population turnover is likely to have occurred, either in the Caucasus or throughout Europe, towards the end of Neanderthal history. We find that the bulk of Neanderthal gene flow into early modern humans originated from one or more source populations that diverged from the Neanderthals that were studied here at least 70,000 years ago, but after they split from a previously sequenced Neanderthal from Siberia around 150,000 years ago. Although four of the Neanderthals studied here post-date the putative arrival of early modern humans into Europe, we do not detect any recent gene flow from early modern humans in their ancestry.
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http://dx.doi.org/10.1038/nature26151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485383PMC
March 2018
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