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1.  No evidence that selection has been less effective at removing deleterious mutations in Europeans than in Africans 
Nature genetics  2015;47(2):126-131.
Non-African populations have experienced size reductions in the time since their split from West Africans, leading to the hypothesis that natural selection to remove weakly deleterious mutations has been less effective in the history of non-Africans. To test this hypothesis, we measured the per-genome accumulation of non-synonymous substitutions across diverse pairs of populations. We find no evidence for a higher load of deleterious mutations in non-Africans. However, we detect significant differences among more divergent populations, as archaic Denisovans have accumulated non-synonymous mutations faster than either modern humans or Neanderthals. To reconcile these findings with patterns that have been interpreted as evidence of less effective removal of deleterious mutations in non-Africans than in West Africans, we use simulations to show that the observed patterns are not likely to reflect changes in the effectiveness of selection after the populations split, and instead are likely to be driven by other population genetic factors.
PMCID: PMC4310772  PMID: 25581429
2.  A Re-Appraisal of the Early Andean Human Remains from Lauricocha in Peru 
PLoS ONE  2015;10(6):e0127141.
The discovery of human remains from the Lauricocha cave in the Central Andean highlands in the 1960’s provided the first direct evidence for human presence in the high altitude Andes. The skeletons found at this site were ascribed to the Early to Middle Holocene and represented the oldest known population of Western South America, and thus were used in several studies addressing the early population history of the continent. However, later excavations at Lauricocha led to doubts regarding the antiquity of the site. Here, we provide new dating, craniometric, and genetic evidence for this iconic site. We obtained new radiocarbon dates, generated complete mitochondrial genomes and nuclear SNP data from five individuals, and re-analyzed the human remains of Lauricocha to revise the initial morphological and craniometric analysis conducted in the 1960’s. We show that Lauricocha was indeed occupied in the Early to Middle Holocene but the temporal spread of dates we obtained from the human remains show that they do not qualify as a single contemporaneous population. However, the genetic results from five of the individuals fall within the spectrum of genetic diversity observed in pre-Columbian and modern Native Central American populations.
PMCID: PMC4464891  PMID: 26061688
3.  Leveraging population admixture to explain missing heritability of complex traits 
Nature genetics  2014;46(12):1356-1362.
Despite recent progress on estimating the heritability explained by genotyped SNPs (hg2), a large gap between hg2 and estimates of total narrow-sense heritability (h2) remains. Explanations for this gap include rare variants, or upward bias in family-based estimates of h2 due to shared environment or epistasis. We estimate h2 from unrelated individuals in admixed populations by first estimating the heritability explained by local ancestry (hγ2). We show that hγ2 = 2FSTCθ(1−θ)h2, where FSTC measures frequency differences between populations at causal loci and θ is the genome-wide ancestry proportion. Our approach is not susceptible to biases caused by epistasis or shared environment. We examined 21,497 African Americans from three cohorts, analyzing 13 phenotypes. For height and BMI, we obtained h2 estimates of 0.55 ± 0.09 and 0.23 ± 0.06, respectively, which are larger than estimates of hg2 in these and other data, but smaller than family-based estimates of h2.
PMCID: PMC4244251  PMID: 25383972
4.  Ancestry Informative Marker Panels for African Americans Based on Subsets of Commercially Available SNP Arrays 
Genetic epidemiology  2011;35(1):80-83.
Admixture mapping is a widely used method for localizing disease genes in African Americans. Most current methods for inferring ancestry at each locus in the genome use a few thousand single nucleotide polymorphisms (SNPs) that are very different in frequency between West Africans and European Americans, and that are required to not be in linkage disequilibrium in the ancestral populations. Modern SNP arrays provide data on hundreds of thousands of SNPs per sample, and to use these to infer ancestry, using many of the standard methods, it is necessary to choose subsets of the SNPs for analysis. Here we present panels of about 4,300 ancestry informative markers (AIMs) that are subsets respectively of SNPs on the Illumina 1 M, Illumina 650, Illumina 610, Affymetrix 6.0 and Affymetrix 5.0 arrays. To validate the usefulness of these panels, we applied them to samples that are different from the ones used to select the SNPs. The panels provide about 80% of the maximum information about African or European ancestry, even with up to 10% missing data.
PMCID: PMC4386999  PMID: 21181899
ancestry informative markers; admixture mapping; African American disease studies
5.  Non-crossover gene conversions show strong GC bias and unexpected clustering in humans 
eLife  null;4:e04637.
Although the past decade has seen tremendous progress in our understanding of fine-scale recombination, little is known about non-crossover (NCO) gene conversion. We report the first genome-wide study of NCO events in humans. Using SNP array data from 98 meioses, we identified 103 sites affected by NCO, of which 50/52 were confirmed in sequence data. Overlap with double strand break (DSB) hotspots indicates that most of the events are likely of meiotic origin. We estimate that a site is involved in a NCO at a rate of 5.9 × 10−6/bp/generation, consistent with sperm-typing studies, and infer that tract lengths span at least an order of magnitude. Observed NCO events show strong allelic bias at heterozygous AT/GC SNPs, with 68% (58–78%) transmitting GC alleles (p = 5 × 10−4). Strikingly, in 4 of 15 regions with resequencing data, multiple disjoint NCO tracts cluster in close proximity (∼20–30 kb), a phenomenon not previously seen in mammals.
eLife digest
The genetic information inside our cells is stored in the form of chromosomes, which are carefully packaged strands of DNA. Most human cells contain a pair of each chromosome: one inherited from the mother and another from the father. Typically, when a human cell divides, it duplicates all of its chromosomes and then places one copy of each into the two new cells.
However, a different process—known as ‘meiosis’—occurs when a human cell divides to make the cells involved in sexual reproduction (i.e., egg cells in females and sperm cells in males). First, the cell duplicates all of its chromosomes as before, but then it pairs the chromosomes originally from the mother with the equivalent chromosomes from the father. These paired chromosomes then swap sections of DNA. Next, the cell divides, and the resulting cells divide again; this produces four new cells that each contain a single, unique copy of every chromosome.
In the process of swapping sections of DNA between chromosomes, the DNA molecule inside the chromosome is broken and different sections of DNA are then joined together. This can occur by one of two methods: ‘crossover events’ that produce a final chromosome made up of long sequences from each of the contributing chromosomes; and ‘non-crossover events’, where only a small section of DNA is swapped between the chromosomes.
Research has tended to focus on DNA breaks and crossover events. Now, Williams et al. have looked at the genetic sequences transmitted by both parents to 49 humans—revealing information about a total of 98 meioses—and scoured them for evidence of non-crossover events. In addition to finding 103 sites where these events occurred, Williams et al. discovered that non-crossover events are more frequent around sites where crossover events also have a higher frequency. This suggests that the mechanism that initiates non-crossover events is shared with crossovers, and that non-crossover events primarily occur during meiosis. Unexpectedly, in some areas non-crossover events were found close to each other in ‘clusters’, which had not previously been seen in humans.
Non-crossover events will only produce an observable change if the chromosomes involved have differences in the sequence of the DNA section that is swapped between them. The number of such variable genetic positions that non-crossover events affect in a generation is roughly the same number as the number of newly generated random mutations to the DNA sequence in a generation. Examining the DNA sequences transferred during non-crossover events also shows that two different types of DNA bases (cytosine and guanine) are more likely to be transmitted by a non-crossover event than are the other two bases (adenine and thymine). This bias indicates that non-crossover events are an important factor in driving genome evolution. In the future, sequencing the entire genome—the total genetic material—of many different people could provide further insights into non-crossover events in humans.
PMCID: PMC4404656  PMID: 25806687
recombination; non-crossover; gene conversion; GC-bias; complex crossover; haplotypes; human
6.  Ancient human genomes suggest three ancestral populations for present-day Europeans 
Lazaridis, Iosif | Patterson, Nick | Mittnik, Alissa | Renaud, Gabriel | Mallick, Swapan | Kirsanow, Karola | Sudmant, Peter H. | Schraiber, Joshua G. | Castellano, Sergi | Lipson, Mark | Berger, Bonnie | Economou, Christos | Bollongino, Ruth | Fu, Qiaomei | Bos, Kirsten I. | Nordenfelt, Susanne | Li, Heng | de Filippo, Cesare | Prüfer, Kay | Sawyer, Susanna | Posth, Cosimo | Haak, Wolfgang | Hallgren, Fredrik | Fornander, Elin | Rohland, Nadin | Delsate, Dominique | Francken, Michael | Guinet, Jean-Michel | Wahl, Joachim | Ayodo, George | Babiker, Hamza A. | Bailliet, Graciela | Balanovska, Elena | Balanovsky, Oleg | Barrantes, Ramiro | Bedoya, Gabriel | Ben-Ami, Haim | Bene, Judit | Berrada, Fouad | Bravi, Claudio M. | Brisighelli, Francesca | Busby, George B. J. | Cali, Francesco | Churnosov, Mikhail | Cole, David E. C. | Corach, Daniel | Damba, Larissa | van Driem, George | Dryomov, Stanislav | Dugoujon, Jean-Michel | Fedorova, Sardana A. | Romero, Irene Gallego | Gubina, Marina | Hammer, Michael | Henn, Brenna M. | Hervig, Tor | Hodoglugil, Ugur | Jha, Aashish R. | Karachanak-Yankova, Sena | Khusainova, Rita | Khusnutdinova, Elza | Kittles, Rick | Kivisild, Toomas | Klitz, William | Kučinskas, Vaidutis | Kushniarevich, Alena | Laredj, Leila | Litvinov, Sergey | Loukidis, Theologos | Mahley, Robert W. | Melegh, Béla | Metspalu, Ene | Molina, Julio | Mountain, Joanna | Näkkäläjärvi, Klemetti | Nesheva, Desislava | Nyambo, Thomas | Osipova, Ludmila | Parik, Jüri | Platonov, Fedor | Posukh, Olga | Romano, Valentino | Rothhammer, Francisco | Rudan, Igor | Ruizbakiev, Ruslan | Sahakyan, Hovhannes | Sajantila, Antti | Salas, Antonio | Starikovskaya, Elena B. | Tarekegn, Ayele | Toncheva, Draga | Turdikulova, Shahlo | Uktveryte, Ingrida | Utevska, Olga | Vasquez, René | Villena, Mercedes | Voevoda, Mikhail | Winkler, Cheryl | Yepiskoposyan, Levon | Zalloua, Pierre | Zemunik, Tatijana | Cooper, Alan | Capelli, Cristian | Thomas, Mark G. | Ruiz-Linares, Andres | Tishkoff, Sarah A. | Singh, Lalji | Thangaraj, Kumarasamy | Villems, Richard | Comas, David | Sukernik, Rem | Metspalu, Mait | Meyer, Matthias | Eichler, Evan E. | Burger, Joachim | Slatkin, Montgomery | Pääbo, Svante | Kelso, Janet | Reich, David | Krause, Johannes
Nature  2014;513(7518):409-413.
We sequenced the genomes of a ~7,000 year old farmer from Germany and eight ~8,000 year old hunter-gatherers from Luxembourg and Sweden. We analyzed these and other ancient genomes1–4 with 2,345 contemporary humans to show that most present Europeans derive from at least three highly differentiated populations: West European Hunter-Gatherers (WHG), who contributed ancestry to all Europeans but not to Near Easterners; Ancient North Eurasians (ANE) related to Upper Paleolithic Siberians3, who contributed to both Europeans and Near Easterners; and Early European Farmers (EEF), who were mainly of Near Eastern origin but also harbored WHG-related ancestry. We model these populations’ deep relationships and show that EEF had ~44% ancestry from a “Basal Eurasian” population that split prior to the diversification of other non-African lineages.
PMCID: PMC4170574  PMID: 25230663
7.  Gibbon genome and the fast karyotype evolution of small apes 
Carbone, Lucia | Harris, R. Alan | Gnerre, Sante | Veeramah, Krishna R. | Lorente-Galdos, Belen | Huddleston, John | Meyer, Thomas J. | Herrero, Javier | Roos, Christian | Aken, Bronwen | Anaclerio, Fabio | Archidiacono, Nicoletta | Baker, Carl | Barrell, Daniel | Batzer, Mark A. | Beal, Kathryn | Blancher, Antoine | Bohrson, Craig L. | Brameier, Markus | Campbell, Michael S. | Capozzi, Oronzo | Casola, Claudio | Chiatante, Giorgia | Cree, Andrew | Damert, Annette | de Jong, Pieter J. | Dumas, Laura | Fernandez-Callejo, Marcos | Flicek, Paul | Fuchs, Nina V. | Gut, Marta | Gut, Ivo | Hahn, Matthew W. | Hernandez-Rodriguez, Jessica | Hillier, LaDeana W. | Hubley, Robert | Ianc, Bianca | Izsvák, Zsuzsanna | Jablonski, Nina G. | Johnstone, Laurel M. | Karimpour-Fard, Anis | Konkel, Miriam K. | Kostka, Dennis | Lazar, Nathan H. | Lee, Sandra L. | Lewis, Lora R. | Liu, Yue | Locke, Devin P. | Mallick, Swapan | Mendez, Fernando L. | Muffato, Matthieu | Nazareth, Lynne V. | Nevonen, Kimberly A. | O,Bleness, Majesta | Ochis, Cornelia | Odom, Duncan T. | Pollard, Katherine S. | Quilez, Javier | Reich, David | Rocchi, Mariano | Schumann, Gerald G. | Searle, Stephen | Sikela, James M. | Skollar, Gabriella | Smit, Arian | Sonmez, Kemal | Hallers, Boudewijn ten | Terhune, Elizabeth | Thomas, Gregg W.C. | Ullmer, Brygg | Ventura, Mario | Walker, Jerilyn A. | Wall, Jeffrey D. | Walter, Lutz | Ward, Michelle C. | Wheelan, Sarah J. | Whelan, Christopher W. | White, Simon | Wilhelm, Larry J. | Woerner, August E. | Yandell, Mark | Zhu, Baoli | Hammer, Michael F. | Marques-Bonet, Tomas | Eichler, Evan E. | Fulton, Lucinda | Fronick, Catrina | Muzny, Donna M. | Warren, Wesley C. | Worley, Kim C. | Rogers, Jeffrey | Wilson, Richard K. | Gibbs, Richard A.
Nature  2014;513(7517):195-201.
Gibbons are small arboreal apes that display an accelerated rate of evolutionary chromosomal rearrangement and occupy a key node in the primate phylogeny between Old World monkeys and great apes. Here we present the assembly and analysis of a northern white-cheeked gibbon (Nomascus leucogenys) genome. We describe the propensity for a gibbon-specific retrotransposon (LAVA) to insert into chromosome segregation genes and alter transcription by providing a premature termination site, suggesting a possible molecular mechanism for the genome plasticity of the gibbon lineage. We further show that the gibbon genera (Nomascus, Hylobates, Hoolock and Symphalangus) experienced a near-instantaneous radiation ~5 million years ago, coincident with major geographical changes in Southeast Asia that caused cycles of habitat compression and expansion. Finally, we identify signatures of positive selection in genes important for forelimb development (TBX5) and connective tissues (COL1A1) that may have been involved in the adaptation of gibbons to their arboreal habitat.
PMCID: PMC4249732  PMID: 25209798
8.  Modification of Multiple Sclerosis Phenotypes by African Ancestry at HLA 
Archives of neurology  2009;66(2):226-233.
In those with multiple sclerosis (MS), African American individuals have a more severe disease course, an older age at onset, and more often have clinical manifestations restricted to the optic nerves and spinal cord (opticospinal MS) than white persons.
To determine whether genetic variation influences clinical MS patterns.
Retrospective multicenter cohort study.
Six hundred seventy-three African American and 717 white patients with MS.
Main Outcome Measures
Patients with MS were geno-typed for HLA-DRB1 and HLA-DQB1 alleles. The proportion of European ancestry at HLA was estimated by genotyping single-nucleotide polymorphisms with known significant frequency differences in West African and European populations. These genotypes were correlated with the opticospinal disease phenotype, disability measures, and age at onset.
Subjects with DRB1*15 alleles were twice as likely to have typical MS rather than opticospinal MS (P = .001). Of the subjects with opticospinal MS or a history of recurrent transverse myelitis who were seropositive for anti–aquaporin 4 antibodies (approximately 5%), none carried DRB1*15 alleles (P = .008). Independently of DRB1* 15, African ancestry at HLA correlated with disability as measured by the Multiple Sclerosis Severity Score (P < .001) andriskof cane dependency (hazard ratio, 1.36; P < .001); DRB1*15 alleles were associated with a 2.1-year earlier age at onset (P < .001).
These data indicate that the role of HLA in MS is not limited to disease susceptibility but that genes embedded in this locus also influence clinical outcomes.
PMCID: PMC4334456  PMID: 19204159
9.  Genetic history of an archaic hominin group from Denisova Cave in Siberia 
Nature  2010;468(7327):1053-1060.
Using DNA extracted from a finger bone found in Denisova Cave in southern Siberia, we have sequenced the genome of an archaic hominin to about 1.9-fold coverage. This individual is from a group that shares a common origin with Neanderthals. This population was not involved in the putative gene flow from Neanderthals into Eurasians; however, the data suggest that it contributed 4–6% of its genetic material to the genomes of present-day Melanesians. We designate this hominin population ‘Denisovans’ and suggest that it may have been widespread in Asia during the Late Pleistocene epoch. A tooth found in Denisova Cave carries a mitochondrial genome highly similar to that of the finger bone. This tooth shares no derived morphological features with Neanderthals or modern humans, further indicating that Denisovans have an evolutionary history distinct from Neanderthals and modern humans.
PMCID: PMC4306417  PMID: 21179161
10.  Is the Observed Association Between Dairy Intake and Fibroids in African Americans Explained by Genetic Ancestry? 
American Journal of Epidemiology  2013;178(7):1114-1119.
Uterine leiomyomata are a major source of gynecological morbidity and are 2–3 times more prevalent in African Americans than European Americans. In an earlier report, we found that dairy intake was inversely associated with uterine leiomyomata among African Americans. Because African Americans are more likely to have lactose intolerance and avoid dairy products, the observed association might have been confounded by genetic ancestry. This report reevaluates the dairy-uterine leiomyomata association after accounting for genetic ancestry among 1,968 cases and 2,183 noncases from the Black Women's Health Study (1997–2007). Dairy intake was estimated by using food frequency questionnaires in 1995 and 2001. Percent European ancestry was estimated by using a panel of ancestry informative markers. Incidence rate ratios and 95% confidence intervals were estimated by using Cox regression, with adjustment for potential confounders and percent European ancestry. Incidence rate ratios comparing 1, 2, 3, and ≥4 servings/day with <1 serving/day of dairy products were 0.95 (95% confidence interval (CI): 0.85, 1.06), 0.75 (95% CI: 0.61, 0.92), 0.77 (95% CI: 0.57, 1.04), and 0.59 (95% CI: 0.41, 0.86), respectively (Ptrend = 0.0003). These effect estimates were similar to those obtained without control for ancestry. The findings suggest that the observed inverse association between dairy consumption and uterine leiomyomata in African Americans is not explained by percent European ancestry.
PMCID: PMC3857926  PMID: 23825169
African Americans; dairy products; genetic ancestry; leiomyoma; prospective studies
11.  The landscape of Neandertal ancestry in present-day humans 
Nature  2014;507(7492):354-357.
Analyses of Neandertal genomes have revealed that Neandertals have contributed genetic variants to modern humans1–2. The antiquity of Neandertal gene flow into modern humans means that regions that derive from Neandertals in any one human today are usually less than a hundred kilobases in size. However, Neandertal haplotypes are also distinctive enough that several studies have been able to detect Neandertal ancestry at specific loci1,3–8. Here, we have systematically inferred Neandertal haplotypes in the genomes of 1,004 present-day humans12. Regions that harbor a high frequency of Neandertal alleles in modern humans are enriched for genes affecting keratin filaments suggesting that Neandertal alleles may have helped modern humans adapt to non-African environments. Neandertal alleles also continue to shape human biology, as we identify multiple Neandertal-derived alleles that confer risk for disease. We also identify regions of millions of base pairs that are nearly devoid of Neandertal ancestry and enriched in genes, implying selection to remove genetic material derived from Neandertals. Neandertal ancestry is significantly reduced in genes specifically expressed in testis, and there is an approximately 5-fold reduction of Neandertal ancestry on chromosome X, which is known to harbor a disproportionate fraction of male hybrid sterility genes20–22. These results suggest that part of the reduction in Neandertal ancestry near genes is due to Neandertal alleles that reduced fertility in males when moved to a modern human genetic background.
PMCID: PMC4072735  PMID: 24476815
12.  Reconstructing Austronesian population history in Island Southeast Asia 
Nature Communications  2014;5:4689.
Austronesian languages are spread across half the globe, from Easter Island to Madagascar. Evidence from linguistics and archaeology indicates that the ‘Austronesian expansion,’ which began 4,000–5,000 years ago, likely had roots in Taiwan, but the ancestry of present-day Austronesian-speaking populations remains controversial. Here, we analyse genome-wide data from 56 populations using new methods for tracing ancestral gene flow, focusing primarily on Island Southeast Asia. We show that all sampled Austronesian groups harbour ancestry that is more closely related to aboriginal Taiwanese than to any present-day mainland population. Surprisingly, western Island Southeast Asian populations have also inherited ancestry from a source nested within the variation of present-day populations speaking Austro-Asiatic languages, which have historically been nearly exclusive to the mainland. Thus, either there was once a substantial Austro-Asiatic presence in Island Southeast Asia, or Austronesian speakers migrated to and through the mainland, admixing there before continuing to western Indonesia.
Populations speaking Austronesian languages are numerous and widespread, but their history remains controversial. Here, the authors analyse genetic data from Southeast Asia and show that all populations harbour ancestry most closely related to aboriginal Taiwanese, while some also contain a component closest to Austro-Asiatic speakers.
PMCID: PMC4143916  PMID: 25137359
13.  The complete genome sequence of a Neandertal from the Altai Mountains 
Nature  2013;505(7481):43-49.
We present a high-quality genome sequence of a Neandertal woman from Siberia. We show that her parents were related at the level of half siblings and that mating among close relatives was common among her recent ancestors. We also sequenced the genome of a Neandertal from the Caucasus to low coverage. An analysis of the relationships and population history of available archaic genomes and 25 present-day human genomes shows that several gene flow events occurred among Neandertals, Denisovans and early modern humans, possibly including gene flow into Denisovans from an unknown archaic group. Thus, interbreeding, albeit of low magnitude, occurred among many hominin groups in the Late Pleistocene. In addition, the high quality Neandertal genome allows us to establish a definitive list of substitutions that became fixed in modern humans after their separation from the ancestors of Neandertals and Denisovans.
PMCID: PMC4031459  PMID: 24352235
14.  Analysis of Latino populations from GALA and MEC studies reveals genomic loci with biased local ancestry estimation 
Bioinformatics  2013;29(11):1407-1415.
Motivation: Local ancestry analysis of genotype data from recently admixed populations (e.g. Latinos, African Americans) provides key insights into population history and disease genetics. Although methods for local ancestry inference have been extensively validated in simulations (under many unrealistic assumptions), no empirical study of local ancestry accuracy in Latinos exists to date. Hence, interpreting findings that rely on local ancestry in Latinos is challenging.
Results: Here, we use 489 nuclear families from the mainland USA, Puerto Rico and Mexico in conjunction with 3204 unrelated Latinos from the Multiethnic Cohort study to provide the first empirical characterization of local ancestry inference accuracy in Latinos. Our approach for identifying errors does not rely on simulations but on the observation that local ancestry in families follows Mendelian inheritance. We measure the rate of local ancestry assignments that lead to Mendelian inconsistencies in local ancestry in trios (MILANC), which provides a lower bound on errors in the local ancestry estimates. We show that MILANC rates observed in simulations underestimate the rate observed in real data, and that MILANC varies substantially across the genome. Second, across a wide range of methods, we observe that loci with large deviations in local ancestry also show enrichment in MILANC rates. Therefore, local ancestry estimates at such loci should be interpreted with caution. Finally, we reconstruct ancestral haplotype panels to be used as reference panels in local ancestry inference and show that ancestry inference is significantly improved by incoroprating these reference panels.
Availability and implementation: We provide the reconstructed reference panels together with the maps of MILANC rates as a public resource for researchers analyzing local ancestry in Latinos at
Supplementary information: Supplementary data are available at Bioinformatics online.
PMCID: PMC3661056  PMID: 23572411
15.  Ancient DNA reveals key stages in the formation of Central European mitochondrial genetic diversity 
Science (New York, N.Y.)  2013;342(6155):257-261.
The processes which shaped modern European mitochondrial DNA (mtDNA) variation remain unclear. The initial peopling by Palaeolithic hunter-gatherers ~42kyrs ago and the immigration of Neolithic farmers into Europe ~8kyrs ago appear to have played important roles, but do not explain present-day mtDNA diversity. We generated mtDNA profiles of 364 individuals from prehistoric cultures in Central Europe to perform a chronological study, spanning the Early Neolithic to the Early Bronze Age (5,500–1,550 cal BC). We use this transect through time to identify four marked shifts in genetic composition during the Neolithic period, revealing a key role for Late Neolithic cultures in shaping modern Central European genetic diversity.
PMCID: PMC4039305  PMID: 24115443
16.  Great ape genetic diversity and population history 
Prado-Martinez, Javier | Sudmant, Peter H. | Kidd, Jeffrey M. | Li, Heng | Kelley, Joanna L. | Lorente-Galdos, Belen | Veeramah, Krishna R. | Woerner, August E. | O’Connor, Timothy D. | Santpere, Gabriel | Cagan, Alexander | Theunert, Christoph | Casals, Ferran | Laayouni, Hafid | Munch, Kasper | Hobolth, Asger | Halager, Anders E. | Malig, Maika | Hernandez-Rodriguez, Jessica | Hernando-Herraez, Irene | Prüfer, Kay | Pybus, Marc | Johnstone, Laurel | Lachmann, Michael | Alkan, Can | Twigg, Dorina | Petit, Natalia | Baker, Carl | Hormozdiari, Fereydoun | Fernandez-Callejo, Marcos | Dabad, Marc | Wilson, Michael L. | Stevison, Laurie | Camprubí, Cristina | Carvalho, Tiago | Ruiz-Herrera, Aurora | Vives, Laura | Mele, Marta | Abello, Teresa | Kondova, Ivanela | Bontrop, Ronald E. | Pusey, Anne | Lankester, Felix | Kiyang, John A. | Bergl, Richard A. | Lonsdorf, Elizabeth | Myers, Simon | Ventura, Mario | Gagneux, Pascal | Comas, David | Siegismund, Hans | Blanc, Julie | Agueda-Calpena, Lidia | Gut, Marta | Fulton, Lucinda | Tishkoff, Sarah A. | Mullikin, James C. | Wilson, Richard K. | Gut, Ivo G. | Gonder, Mary Katherine | Ryder, Oliver A. | Hahn, Beatrice H. | Navarro, Arcadi | Akey, Joshua M. | Bertranpetit, Jaume | Reich, David | Mailund, Thomas | Schierup, Mikkel H. | Hvilsom, Christina | Andrés, Aida M. | Wall, Jeffrey D. | Bustamante, Carlos D. | Hammer, Michael F. | Eichler, Evan E. | Marques-Bonet, Tomas
Nature  2013;499(7459):471-475.
PMCID: PMC3822165  PMID: 23823723
17.  Riluzole for relapse prevention following intravenous ketamine in treatment-resistant depression: a pilot randomized, placebo-controlled continuation trial 
The N-methyl-d-aspartate (NMDA) glutamate receptor antagonist ketamine may have rapid, albeit transient, antidepressant properties. This study in patients with treatment-resistant major depression (TRD) aimed to (1) replicate the acute efficacy of single-dose intravenous (i.v.) ketamine; (2) test the efficacy of the glutamate-modulating agent riluzole in preventing post-ketamine relapse ; and (3) examine whether pretreatment with lamotrigine would attenuate ketamine’s psychotomimetic effects and enhance its antidepressant activity. Twenty-six medication-free patients received open-label i.v. ketamine (0.5 mg/kg over 40 min). Two hours prior to infusion, patients were randomized to lamotrigine (300 mg) or placebo. Seventeen patients (65%) met response criterion (≥50% reduction from baseline on the Montgomery–Asberg Depression Rating Scale) 24 h following ketamine. Lamotrigine failed to attenuate the mild, transient side-effects associated with ketamine and did not enhance its antidepressant effects. Fourteen patients (54%) met response criterion 72 h following ketamine and proceeded to participate in a 32-d, randomized, double-blind, placebo-controlled, flexible-dose continuation trial of riluzole (100–200 mg/d). The main outcome measure was time-to-relapse. An interim analysis found no significant differences in time-to-relapse between riluzole and placebo groups [log-rank χ2 = 0.17, d.f. = 1, p = 0.68], with 80% of patients relapsing on riluzole vs. 50% on placebo. The trial was thus stopped for futility. This pilot study showed that a sub-anaesthetic dose of i.v. ketamine is well-tolerated in TRD, and may have rapid and sustained antidepressant properties. Riluzole did not prevent relapse in the first month following ketamine. Further investigation of relapse prevention strategies post-ketamine is necessary.
PMCID: PMC3883127  PMID: 19288975
Ketamine; lamotrigine; major depression; riluzole; treatment resistance
18.  African Ancestry and Genetic Risk for Uterine Leiomyomata 
American Journal of Epidemiology  2012;176(12):1159-1168.
Rates of uterine leiomyomata (UL) are 2–3 times higher in African Americans than in European Americans. It is unclear whether inherited factors explain the ethnic disparity. To investigate the presence of risk alleles for UL that are highly differentiated in frequency between African Americans and European Americans, the authors conducted an admixture-based genome-wide scan of 2,453 UL cases confirmed by ultrasound or surgery in the Black Women's Health Study (1997–2009), a national prospective cohort study. Controls (n = 2,102) were women who did not report a UL diagnosis through 2009. Mean percentage of European ancestry was significantly lower among cases (20.00%) than among controls (21.63%; age-adjusted mean difference = −1.76%, 95% confidence interval: −2.40, −1.12; P < 0.0001), and the association was stronger in younger cases. Admixture analyses showed suggestive evidence of association at chromosomes 2, 4, and 10. The authors also genotyped a dense set of tag single nucleotide polymorphisms at different loci associated with UL in Japanese women but failed to replicate the associations. This suggests that genetic variation for UL differs in populations with and without African ancestry. The admixture findings further indicate that no single highly differentiated locus is responsible for the ethnic disparity in UL, raising the possibility that multiple variants jointly contribute to the higher incidence of UL in African Americans.
PMCID: PMC3571235  PMID: 23161897
African Americans; African continental ancestry group; European continental ancestry group; female; genetics; leiomyoma; prospective studies; uterine neoplasms
19.  Using population admixture to help complete maps of the human genome 
Nature genetics  2013;45(4):406-414e2.
Tens of millions of base pairs of euchromatic human genome sequence, including many protein-coding genes, have no known location in the human genome. We describe an approach for localizing the human genome's missing pieces by utilizing the patterns of genome sequence variation created by population admixture. We mapped the locations of 70 scaffolds spanning four million base pairs of the human genome's unplaced euchromatic sequence, including more than a dozen protein-coding genes, and identified eight large novel inter-chromosomal segmental duplications. We find that most of these sequences are hidden in the genome's heterochromatin, particularly its pericentromeric regions. Many cryptic, pericentromeric genes are expressed in RNA and have been maintained intact for millions of years while their expression patterns diverged from those of paralogous genes elsewhere in the genome. We describe how knowledge of the locations of these sequences can inform disease association and genome biology studies.
PMCID: PMC3683849  PMID: 23435088
20.  The HLA–DRB1 Shared Epitope Is Associated With Susceptibility to Rheumatoid Arthritis in African Americans Through European Genetic Admixture 
Arthritis and rheumatism  2008;58(2):349-358.
To determine whether shared epitope (SE)–containing HLA–DRB1 alleles are associated with rheumatoid arthritis (RA) in African Americans and whether their presence is associated with higher degrees of global (genome-wide) genetic admixture from the European population.
In this multicenter cohort study, African Americans with early RA and matched control subjects were analyzed. In addition to measurement of serum anti–cyclic citrullinated peptide (anti-CCP) antibodies and HLA–DRB1 genotyping, a panel of >1,200 ancestry-informative markers was analyzed in patients with RA and control subjects, to estimate the proportion of European ancestry.
The frequency of SE-containing HLA–DRB1 alleles was 25.2% in African American patients with RA versus 13.6% in control subjects (P = 0.00005). Of 321 patients with RA, 42.1% had at least 1 SE-containing allele, compared with 25.3% of 166 control subjects (P = 0.0004). The mean estimated percent European ancestry was associated with SE-containing HLA–DRB1 alleles in African Americans, regardless of disease status (RA or control). As reported in RA patients of European ancestry, there was a significant association of the SE with the presence of the anti-CCP antibody: 86 (48.9%) of 176 patients with anti-CCP antibody–positive RA had at least 1 SE allele, compared with 36 (32.7%) of 110 patients with anti-CCP antibody–negative RA (P = 0.01, by chi-square test).
HLA–DRB1 alleles containing the SE are strongly associated with susceptibility to RA in African Americans. The absolute contribution is less than that reported in RA among populations of European ancestry, in which ~50–70% of patients have at least 1 SE allele. As in Europeans with RA, the SE association was strongest in the subset of African American patients with anti-CCP antibodies. The finding of a higher degree of European ancestry among African Americans with SE alleles suggests that a genetic risk factor for RA was introduced into the African American population through admixture, thus making these individuals more susceptible to subsequent environmental or unknown factors that trigger the disease.
PMCID: PMC3726059  PMID: 18240241
21.  Efficient Moment-Based Inference of Admixture Parameters and Sources of Gene Flow 
Molecular Biology and Evolution  2013;30(8):1788-1802.
The recent explosion in available genetic data has led to significant advances in understanding the demographic histories of and relationships among human populations. It is still a challenge, however, to infer reliable parameter values for complicated models involving many populations. Here, we present MixMapper, an efficient, interactive method for constructing phylogenetic trees including admixture events using single nucleotide polymorphism (SNP) genotype data. MixMapper implements a novel two-phase approach to admixture inference using moment statistics, first building an unadmixed scaffold tree and then adding admixed populations by solving systems of equations that express allele frequency divergences in terms of mixture parameters. Importantly, all features of the model, including topology, sources of gene flow, branch lengths, and mixture proportions, are optimized automatically from the data and include estimates of statistical uncertainty. MixMapper also uses a new method to express branch lengths in easily interpretable drift units. We apply MixMapper to recently published data for Human Genome Diversity Cell Line Panel individuals genotyped on a SNP array designed especially for use in population genetics studies, obtaining confident results for 30 populations, 20 of them admixed. Notably, we confirm a signal of ancient admixture in European populations—including previously undetected admixture in Sardinians and Basques—involving a proportion of 20–40% ancient northern Eurasian ancestry.
PMCID: PMC3708505  PMID: 23709261
admixture; human populations; genetic drift; moment statistics
Science (New York, N.Y.)  2012;338(6104):222-226.
We present a DNA library preparation method that has allowed us to reconstruct a high coverage (30X) genome sequence of a Denisovan, an extinct relative of Neandertals. The quality of this genome allows a direct estimation of Denisovan heterozygosity indicating that genetic diversity in these archaic hominins was extremely low. It also allows tentative dating of the specimen on the basis of “missing evolution” in its genome, detailed measurements of Denisovan and Neandertal admixture into present-day human populations, and the generation of a near-complete catalog of genetic changes that swept to high frequency in modern humans since their divergence from Denisovans.
PMCID: PMC3617501  PMID: 22936568
23.  Reconstructing Native American Population History 
Nature  2012;488(7411):370-374.
The peopling of the Americas has been the subject of extensive genetic, archaeological and linguistic research; however, central questions remain unresolved1–5. One contentious issue is whether the settlement occurred via a single6–8 or multiple streams of migration from Siberia9–15. The pattern of dispersals within the Americas is also poorly understood. To address these questions at higher resolution than was previously possible, we assembled data from 52 Native American and 17 Siberian groups genotyped at 364,470 single nucleotide polymorphisms. We show that Native Americans descend from at least three streams of Asian gene flow. Most descend entirely from a single ancestral population that we call “First American”. However, speakers of Eskimo-Aleut languages from the Arctic inherit almost half their ancestry from a second stream of Asian gene flow, and the Na-Dene-speaking Chipewyan from Canada inherit roughly one-tenth of their ancestry from a third stream. We show that the initial peopling followed a southward expansion facilitated by the coast, with sequential population splits and little gene flow after divergence, especially in South America. A major exception is in Chibchan-speakers on both sides of the Panama Isthmus, who have ancestry from both North and South America.
PMCID: PMC3615710  PMID: 22801491
24.  A direct characterization of human mutation based on microsatellites 
Nature genetics  2012;44(10):1161-1165.
Mutations are the raw material of evolution, but have been difficult to study directly. We report the largest study of new mutations to date: 2,058 germline changes discovered by analyzing 85,289 Icelanders at 2,477 microsatellites. The paternal-to-maternal mutation rate ratio is 3.3, and the rate in fathers doubles from age 20 to 58 whereas there is no association with age in mothers. Longer microsatellite alleles are more mutagenic and tend to decrease in length, whereas the opposite is seen for shorter alleles. We use these empirical observations to build a model that we apply to individuals for whom we have both genome sequence and microsatellite data, allowing us to estimate key parameters of evolution without calibration to the fossil record. We infer that the sequence mutation rate is 1.4–2.3×10−8 per base pair per generation (90% credible interval), and that human-chimpanzee speciation occurred 3.7–6.6 million years ago.
PMCID: PMC3459271  PMID: 22922873
25.  Inferring Admixture Histories of Human Populations Using Linkage Disequilibrium 
Genetics  2013;193(4):1233-1254.
Long-range migrations and the resulting admixtures between populations have been important forces shaping human genetic diversity. Most existing methods for detecting and reconstructing historical admixture events are based on allele frequency divergences or patterns of ancestry segments in chromosomes of admixed individuals. An emerging new approach harnesses the exponential decay of admixture-induced linkage disequilibrium (LD) as a function of genetic distance. Here, we comprehensively develop LD-based inference into a versatile tool for investigating admixture. We present a new weighted LD statistic that can be used to infer mixture proportions as well as dates with fewer constraints on reference populations than previous methods. We define an LD-based three-population test for admixture and identify scenarios in which it can detect admixture events that previous formal tests cannot. We further show that we can uncover phylogenetic relationships among populations by comparing weighted LD curves obtained using a suite of references. Finally, we describe several improvements to the computation and fitting of weighted LD curves that greatly increase the robustness and speed of the calculations. We implement all of these advances in a software package, ALDER, which we validate in simulations and apply to test for admixture among all populations from the Human Genome Diversity Project (HGDP), highlighting insights into the admixture history of Central African Pygmies, Sardinians, and Japanese.
PMCID: PMC3606100  PMID: 23410830
admixture; linkage disequilibrium

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