Publications by authors named "Priya Moorjani"

27 Publications

  • Page 1 of 1

Mutational Signatures: From Methods to Mechanisms.

Annu Rev Biomed Data Sci 2021 07 11;4:189-206. Epub 2021 May 11.

National Center of Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland 20894, USA; email:

Mutations are the driving force of evolution, yet they underlie many diseases, in particular, cancer. They are thought to arise from a combination of stochastic errors in DNA processing, naturally occurring DNA damage (e.g., the spontaneous deamination of methylated CpG sites), replication errors, and dysregulation of DNA repair mechanisms. High-throughput sequencing has made it possible to generate large datasets to study mutational processes in health and disease. Since the emergence of the first mutational process studies in 2012, this field is gaining increasing attention and has already accumulated a host of computational approaches and biomedical applications.
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http://dx.doi.org/10.1146/annurev-biodatasci-122320-120920DOI Listing
July 2021

Association Between Episodic Memory and Genetic Risk Factors for Alzheimer's Disease in South Asians from the Longitudinal Aging Study in India-Diagnostic Assessment of Dementia (LASI-DAD).

J Am Geriatr Soc 2020 08;68 Suppl 3:S45-S53

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA.

Background/objectives: Genetic factors play an important role in Alzheimer's disease (AD) and cognitive aging. However, it is unclear whether risk loci identified in European ancestry (EA) populations have similar effects in other groups, such as South Asians.

Design: We investigated the allelic distribution and cognitive associations of 56 known AD risk single-nucleotide polymorphisms (SNPs) identified from three EA genome-wide association studies (EA-GWASs) in a South Asian population. Single SNP and genetic risk score (GRS) associations with measures of episodic memory were assessed.

Setting: The Diagnostic Assessment of Dementia for the Longitudinal Aging Study in India (LASI-DAD).

Participants: A total of 906 LASI-DAD participants from diverse states in India.

Measurements: Participants were genotyped using the Illumina Global Screening Array and imputed with 1000G Phase 3v5. Cognitive measures included total learning and delayed word recall.

Results: Although only a few SNPs were significantly associated with memory scores (P < .05), effect estimates from the EA-GWAS and the LASI-DAD showed moderate correlation (0.35-0.88) in the expected direction. GRSs were also associated with memory scores, although percentage variation explained was small (0.1%-0.6%).

Conclusions: Discrepancies in allele frequencies and cognitive association results suggest that genetic factors found predominantly through EA-GWASs may play a limited role in South Asians. However, the extent of differences in the genetic architecture of AD and cognition in EA and South Asians remains uncertain. There is also a critical need to perform a more comprehensive assessment of the mutational spectrum of South Asia to identify novel genetic variants associated with AD and cognition in this population. J Am Geriatr Soc 68:S45-S53, 2020.
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http://dx.doi.org/10.1111/jgs.16735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507858PMC
August 2020

A comparison of humans and baboons suggests germline mutation rates do not track cell divisions.

PLoS Biol 2020 08 17;18(8):e3000838. Epub 2020 Aug 17.

Department of Systems Biology, Columbia University, New York, New York, United States of America.

In humans, most germline mutations are inherited from the father. This observation has been widely interpreted as reflecting the replication errors that accrue during spermatogenesis. If so, the male bias in mutation should be substantially lower in a closely related species with similar rates of spermatogonial stem cell divisions but a shorter mean age of reproduction. To test this hypothesis, we resequenced two 3-4 generation nuclear families (totaling 29 individuals) of olive baboons (Papio anubis), who reproduce at approximately 10 years of age on average, and analyzed the data in parallel with three 3-generation human pedigrees (26 individuals). We estimated a mutation rate per generation in baboons of 0.57×10-8 per base pair, approximately half that of humans. Strikingly, however, the degree of male bias in germline mutations is approximately 4:1, similar to that of humans-indeed, a similar male bias is seen across mammals that reproduce months, years, or decades after birth. These results mirror the finding in humans that the male mutation bias is stable with parental ages and cast further doubt on the assumption that germline mutations track cell divisions. Our mutation rate estimates for baboons raise a further puzzle, suggesting a divergence time between apes and Old World monkeys of 65 million years, too old to be consistent with the fossil record; reconciling them now requires not only a slowdown of the mutation rate per generation in humans but also in baboons.
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http://dx.doi.org/10.1371/journal.pbio.3000838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467331PMC
August 2020

Evolution of the mutation rate across primates.

Curr Opin Genet Dev 2020 06 4;62:58-64. Epub 2020 Jul 4.

Department of Molecular and Cell Biology, University of California, Berkeley, CA, United States; Center for Computational Biology, University of California, Berkeley, CA, United States. Electronic address:

Germline mutations are the source of all heritable variation. In the past few years, whole genome sequencing has allowed direct and comprehensive surveys of mutation patterns in humans and other species. These studies have documented substantial variation in both mutation rates and spectra across primates, the causes of which remain unclear. Here, we review what is currently known about mutation rates in primates, highlight the factors proposed to explain the variation across species, and discuss some implications of these findings on our understanding of the chronology of primate evolution and the process of mutagenesis.
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http://dx.doi.org/10.1016/j.gde.2020.05.028DOI Listing
June 2020

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

Overlooked roles of DNA damage and maternal age in generating human germline mutations.

Proc Natl Acad Sci U S A 2019 05 24;116(19):9491-9500. Epub 2019 Apr 24.

Department of Biological Sciences, Columbia University, New York, NY 10027;

The textbook view that most germline mutations in mammals arise from replication errors is indirectly supported by the fact that there are both more mutations and more cell divisions in the male than in the female germline. When analyzing large de novo mutation datasets in humans, we find multiple lines of evidence that call that view into question. Notably, despite the drastic increase in the ratio of male to female germ cell divisions after the onset of spermatogenesis, even young fathers contribute three times more mutations than young mothers, and this ratio barely increases with parental age. This surprising finding points to a substantial contribution of damage-induced mutations. Indeed, C-to-G transversions and CpG transitions, which together constitute over one-fourth of all base substitution mutations, show genomic distributions and sex-specific age dependencies indicative of double-strand break repair and methylation-associated damage, respectively. Moreover, we find evidence that maternal age at conception influences the mutation rate both because of the accumulation of damage in oocytes and potentially through an influence on the number of postzygotic mutations in the embryo. These findings reveal underappreciated roles of DNA damage and maternal age in the genesis of human germline mutations.
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http://dx.doi.org/10.1073/pnas.1901259116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511033PMC
May 2019

The promise of discovering population-specific disease-associated genes in South Asia.

Nat Genet 2017 Sep 17;49(9):1403-1407. Epub 2017 Jul 17.

CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India.

The more than 1.5 billion people who live in South Asia are correctly viewed not as a single large population but as many small endogamous groups. We assembled genome-wide data from over 2,800 individuals from over 260 distinct South Asian groups. We identified 81 unique groups, 14 of which had estimated census sizes of more than 1 million, that descend from founder events more extreme than those in Ashkenazi Jews and Finns, both of which have high rates of recessive disease due to founder events. We identified multiple examples of recessive diseases in South Asia that are the result of such founder events. This study highlights an underappreciated opportunity for decreasing disease burden among South Asians through discovery of and testing for recessive disease-associated genes.
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http://dx.doi.org/10.1038/ng.3917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5675555PMC
September 2017

Human Germline Mutation and the Erratic Evolutionary Clock.

PLoS Biol 2016 Oct 19;14(10):e2000744. Epub 2016 Oct 19.

Department of Biological Sciences, Columbia University, New York, New York, United States of America.

Our understanding of the chronology of human evolution relies on the "molecular clock" provided by the steady accumulation of substitutions on an evolutionary lineage. Recent analyses of human pedigrees have called this understanding into question by revealing unexpectedly low germline mutation rates, which imply that substitutions accrue more slowly than previously believed. Translating mutation rates estimated from pedigrees into substitution rates is not as straightforward as it may seem, however. We dissect the steps involved, emphasizing that dating evolutionary events requires not "a mutation rate" but a precise characterization of how mutations accumulate in development in males and females-knowledge that remains elusive.
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http://dx.doi.org/10.1371/journal.pbio.2000744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070741PMC
October 2016

Variation in the molecular clock of primates.

Proc Natl Acad Sci U S A 2016 09 6;113(38):10607-12. Epub 2016 Sep 6.

Department of Biological Sciences, Columbia University, New York, NY 10027; Department of Systems Biology, Columbia University, New York, NY 10027

Events in primate evolution are often dated by assuming a constant rate of substitution per unit time, but the validity of this assumption remains unclear. Among mammals, it is well known that there exists substantial variation in yearly substitution rates. Such variation is to be expected from differences in life history traits, suggesting it should also be found among primates. Motivated by these considerations, we analyze whole genomes from 10 primate species, including Old World Monkeys (OWMs), New World Monkeys (NWMs), and apes, focusing on putatively neutral autosomal sites and controlling for possible effects of biased gene conversion and methylation at CpG sites. We find that substitution rates are up to 64% higher in lineages leading from the hominoid-NWM ancestor to NWMs than to apes. Within apes, rates are ∼2% higher in chimpanzees and ∼7% higher in the gorilla than in humans. Substitution types subject to biased gene conversion show no more variation among species than those not subject to it. Not all mutation types behave similarly, however; in particular, transitions at CpG sites exhibit a more clocklike behavior than do other types, presumably because of their nonreplicative origin. Thus, not only the total rate, but also the mutational spectrum, varies among primates. This finding suggests that events in primate evolution are most reliably dated using CpG transitions. Taking this approach, we estimate the human and chimpanzee divergence time is 12.1 million years,​ and the human and gorilla divergence time is 15.1 million years​.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5035889PMC
http://dx.doi.org/10.1073/pnas.1600374113DOI Listing
September 2016

A genetic method for dating ancient genomes provides a direct estimate of human generation interval in the last 45,000 years.

Proc Natl Acad Sci U S A 2016 May 2;113(20):5652-7. Epub 2016 May 2.

Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142; Department of Genetics, Harvard Medical School, Boston, MA 02115; Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115

The study of human evolution has been revolutionized by inferences from ancient DNA analyses. Key to these studies is the reliable estimation of the age of ancient specimens. High-resolution age estimates can often be obtained using radiocarbon dating, and, while precise and powerful, this method has some biases, making it of interest to directly use genetic data to infer a date for samples that have been sequenced. Here, we report a genetic method that uses the recombination clock. The idea is that an ancient genome has evolved less than the genomes of present-day individuals and thus has experienced fewer recombination events since the common ancestor. To implement this idea, we take advantage of the insight that all non-Africans have a common heritage of Neanderthal gene flow into their ancestors. Thus, we can estimate the date since Neanderthal admixture for present-day and ancient samples simultaneously and use the difference as a direct estimate of the ancient specimen's age. We apply our method to date five Upper Paleolithic Eurasian genomes with radiocarbon dates between 12,000 and 45,000 y ago and show an excellent correlation of the genetic and (14)C dates. By considering the slope of the correlation between the genetic dates, which are in units of generations, and the (14)C dates, which are in units of years, we infer that the mean generation interval in humans over this period has been 26-30 y. Extensions of this methodology that use older shared events may be applicable for dating beyond the radiocarbon frontier.
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http://dx.doi.org/10.1073/pnas.1514696113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878468PMC
May 2016

Genome sequence of a 45,000-year-old modern human from western Siberia.

Nature 2014 Oct;514(7523):445-9

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

We present the high-quality genome sequence of a ∼45,000-year-old modern human male from Siberia. This individual derives from a population that lived before-or simultaneously with-the separation of the populations in western and eastern Eurasia and carries a similar amount of Neanderthal ancestry as present-day Eurasians. However, the genomic segments of Neanderthal ancestry are substantially longer than those observed in present-day individuals, indicating that Neanderthal gene flow into the ancestors of this individual occurred 7,000-13,000 years before he lived. We estimate an autosomal mutation rate of 0.4 × 10(-9) to 0.6 × 10(-9) per site per year, a Y chromosomal mutation rate of 0.7 × 10(-9) to 0.9 × 10(-9) per site per year based on the additional substitutions that have occurred in present-day non-Africans compared to this genome, and a mitochondrial mutation rate of 1.8 × 10(-8) to 3.2 × 10(-8) per site per year based on the age of the bone.
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http://dx.doi.org/10.1038/nature13810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4753769PMC
October 2014

Cross-disorder genome-wide analyses suggest a complex genetic relationship between Tourette's syndrome and OCD.

Am J Psychiatry 2015 Jan 31;172(1):82-93. Epub 2014 Oct 31.

From the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston; the Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Mass.; the Department of Psychiatry, University of California, San Francisco; the Department of Neurology, Massachusetts General Hospital, Boston; the Division of Cognitive and Behavioral Neurology, Brigham and Women's Hospital, Boston; the Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston; Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago; the Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam; the Department of Preventive Medicine, Division of Biostatistics, Keck School of Medicine, University of Southern California, Los Angeles; the Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Md.; the Genomic and Bioinformatic Unit, Filarete Foundation, Milan, Italy; the Department of Health Sciences, Graduate School of Nephrology, University of Milan, Milan; the Toronto Western Research Institute, University Health Network, Toronto; Hospital for Sick Children, Toronto; Università Vita-Salute San Raffaele, Milan; the Herman Dana Division of Child and Adolescent Psychiatry, Hadassah-Hebrew University Medical Center, Jerusalem; Universidad de Antioquia, Universidad Pontificia Bolivariana, Medellín, Colombia; the Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore; the Department of Psychiatry, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; the Child Study Center and the Department of Psychiatry, Yale University School of Medicine, New Haven, Conn.; the Department of Psychiatry, University of São Paulo Medical School, São Paulo, Brazil; North Shore-Long Island Jewish Medical Center and North Shore-Lo

Objective: Obsessive-compulsive disorder (OCD) and Tourette's syndrome are highly heritable neurodevelopmental disorders that are thought to share genetic risk factors. However, the identification of definitive susceptibility genes for these etiologically complex disorders remains elusive. The authors report a combined genome-wide association study (GWAS) of Tourette's syndrome and OCD.

Method: The authors conducted a GWAS in 2,723 cases (1,310 with OCD, 834 with Tourette's syndrome, 579 with OCD plus Tourette's syndrome/chronic tics), 5,667 ancestry-matched controls, and 290 OCD parent-child trios. GWAS summary statistics were examined for enrichment of functional variants associated with gene expression levels in brain regions. Polygenic score analyses were conducted to investigate the genetic architecture within and across the two disorders.

Results: Although no individual single-nucleotide polymorphisms (SNPs) achieved genome-wide significance, the GWAS signals were enriched for SNPs strongly associated with variations in brain gene expression levels (expression quantitative loci, or eQTLs), suggesting the presence of true functional variants that contribute to risk of these disorders. Polygenic score analyses identified a significant polygenic component for OCD (p=2×10(-4)), predicting 3.2% of the phenotypic variance in an independent data set. In contrast, Tourette's syndrome had a smaller, nonsignificant polygenic component, predicting only 0.6% of the phenotypic variance (p=0.06). No significant polygenic signal was detected across the two disorders, although the sample is likely underpowered to detect a modest shared signal. Furthermore, the OCD polygenic signal was significantly attenuated when cases with both OCD and co-occurring Tourette's syndrome/chronic tics were included in the analysis (p=0.01).

Conclusions: Previous work has shown that Tourette's syndrome and OCD have some degree of shared genetic variation. However, the data from this study suggest that there are also distinct components to the genetic architectures of these two disorders. Furthermore, OCD with co-occurring Tourette's syndrome/chronic tics may have different underlying genetic susceptibility compared with OCD alone.
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http://dx.doi.org/10.1176/appi.ajp.2014.13101306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4282594PMC
January 2015

Reconstructing Austronesian population history in Island Southeast Asia.

Nat Commun 2014 Aug 19;5:4689. Epub 2014 Aug 19.

1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.

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.
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http://dx.doi.org/10.1038/ncomms5689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143916PMC
August 2014

The complete genome sequence of a Neanderthal from the Altai Mountains.

Nature 2014 Jan 18;505(7481):43-9. Epub 2013 Dec 18.

Fondation Jean Dausset, Centre d'Étude du Polymorphisme Humain (CEPH), 75010 Paris, France.

We present a high-quality genome sequence of a Neanderthal 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 Neanderthal 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 Neanderthals, 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 Neanderthal genome allows us to establish a definitive list of substitutions that became fixed in modern humans after their separation from the ancestors of Neanderthals and Denisovans.
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http://dx.doi.org/10.1038/nature12886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031459PMC
January 2014

Genetic evidence for recent population mixture in India.

Am J Hum Genet 2013 Sep 8;93(3):422-38. Epub 2013 Aug 8.

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

Most Indian groups descend from a mixture of two genetically divergent populations: Ancestral North Indians (ANI) related to Central Asians, Middle Easterners, Caucasians, and Europeans; and Ancestral South Indians (ASI) not closely related to groups outside the subcontinent. The date of mixture is unknown but has implications for understanding Indian history. We report genome-wide data from 73 groups from the Indian subcontinent and analyze linkage disequilibrium to estimate ANI-ASI mixture dates ranging from about 1,900 to 4,200 years ago. In a subset of groups, 100% of the mixture is consistent with having occurred during this period. These results show that India experienced a demographic transformation several thousand years ago, from a region in which major population mixture was common to one in which mixture even between closely related groups became rare because of a shift to endogamy.
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http://dx.doi.org/10.1016/j.ajhg.2013.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3769933PMC
September 2013

Reconstructing Roma history from genome-wide data.

PLoS One 2013 13;8(3):e58633. Epub 2013 Mar 13.

Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.

The Roma people, living throughout Europe and West Asia, are a diverse population linked by the Romani language and culture. Previous linguistic and genetic studies have suggested that the Roma migrated into Europe from South Asia about 1,000-1,500 years ago. Genetic inferences about Roma history have mostly focused on the Y chromosome and mitochondrial DNA. To explore what additional information can be learned from genome-wide data, we analyzed data from six Roma groups that we genotyped at hundreds of thousands of single nucleotide polymorphisms (SNPs). We estimate that the Roma harbor about 80% West Eurasian ancestry-derived from a combination of European and South Asian sources-and that the date of admixture of South Asian and European ancestry was about 850 years before present. We provide evidence for Eastern Europe being a major source of European ancestry, and North-west India being a major source of the South Asian ancestry in the Roma. By computing allele sharing as a measure of linkage disequilibrium, we estimate that the migration of Roma out of the Indian subcontinent was accompanied by a severe founder event, which appears to have been followed by a major demographic expansion after the arrival in Europe.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0058633PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3596272PMC
September 2013

Genome-wide diversity in the levant reveals recent structuring by culture.

PLoS Genet 2013 28;9(2):e1003316. Epub 2013 Feb 28.

Institut de Biologia Evolutiva (CSIC-UPF), Departament de Ciències de la Salut i de la Vida, Universitat Pompeu Fabra, Barcelona, Spain.

The Levant is a region in the Near East with an impressive record of continuous human existence and major cultural developments since the Paleolithic period. Genetic and archeological studies present solid evidence placing the Middle East and the Arabian Peninsula as the first stepping-stone outside Africa. There is, however, little understanding of demographic changes in the Middle East, particularly the Levant, after the first Out-of-Africa expansion and how the Levantine peoples relate genetically to each other and to their neighbors. In this study we analyze more than 500,000 genome-wide SNPs in 1,341 new samples from the Levant and compare them to samples from 48 populations worldwide. Our results show recent genetic stratifications in the Levant are driven by the religious affiliations of the populations within the region. Cultural changes within the last two millennia appear to have facilitated/maintained admixture between culturally similar populations from the Levant, Arabian Peninsula, and Africa. The same cultural changes seem to have resulted in genetic isolation of other groups by limiting admixture with culturally different neighboring populations. Consequently, Levant populations today fall into two main groups: one sharing more genetic characteristics with modern-day Europeans and Central Asians, and the other with closer genetic affinities to other Middle Easterners and Africans. Finally, we identify a putative Levantine ancestral component that diverged from other Middle Easterners ∼23,700-15,500 years ago during the last glacial period, and diverged from Europeans ∼15,900-9,100 years ago between the last glacial warming and the start of the Neolithic.
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http://dx.doi.org/10.1371/journal.pgen.1003316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3585000PMC
June 2013

Inferring admixture histories of human populations using linkage disequilibrium.

Genetics 2013 Apr 14;193(4):1233-54. Epub 2013 Feb 14.

Department of Mathematics and Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

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.
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http://dx.doi.org/10.1534/genetics.112.147330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3606100PMC
April 2013

Ancient admixture in human history.

Genetics 2012 Nov 7;192(3):1065-93. Epub 2012 Sep 7.

Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.

Population mixture is an important process in biology. We present a suite of methods for learning about population mixtures, implemented in a software package called ADMIXTOOLS, that support formal tests for whether mixture occurred and make it possible to infer proportions and dates of mixture. We also describe the development of a new single nucleotide polymorphism (SNP) array consisting of 629,433 sites with clearly documented ascertainment that was specifically designed for population genetic analyses and that we genotyped in 934 individuals from 53 diverse populations. To illustrate the methods, we give a number of examples that provide new insights about the history of human admixture. The most striking finding is a clear signal of admixture into northern Europe, with one ancestral population related to present-day Basques and Sardinians and the other related to present-day populations of northeast Asia and the Americas. This likely reflects a history of admixture between Neolithic migrants and the indigenous Mesolithic population of Europe, consistent with recent analyses of ancient bones from Sweden and the sequencing of the genome of the Tyrolean "Iceman."
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http://dx.doi.org/10.1534/genetics.112.145037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3522152PMC
November 2012

Indian Siddis: African descendants with Indian admixture.

Am J Hum Genet 2011 Jul 7;89(1):154-61. Epub 2011 Jul 7.

Centre for Cellular and Molecular Biology, Council of Scientific and Industrial Research, Hyderabad, India.

The Siddis (Afro-Indians) are a tribal population whose members live in coastal Karnataka, Gujarat, and in some parts of Andhra Pradesh. Historical records indicate that the Portuguese brought the Siddis to India from Africa about 300-500 years ago; however, there is little information about their more precise ancestral origins. Here, we perform a genome-wide survey to understand the population history of the Siddis. Using hundreds of thousands of autosomal markers, we show that they have inherited ancestry from Africans, Indians, and possibly Europeans (Portuguese). Additionally, analyses of the uniparental (Y-chromosomal and mitochondrial DNA) markers indicate that the Siddis trace their ancestry to Bantu speakers from sub-Saharan Africa. We estimate that the admixture between the African ancestors of the Siddis and neighboring South Asian groups probably occurred in the past eight generations (∼200 years ago), consistent with historical records.
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http://dx.doi.org/10.1016/j.ajhg.2011.05.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3135801PMC
July 2011

The history of African gene flow into Southern Europeans, Levantines, and Jews.

PLoS Genet 2011 Apr 21;7(4):e1001373. Epub 2011 Apr 21.

Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.

Previous genetic studies have suggested a history of sub-Saharan African gene flow into some West Eurasian populations after the initial dispersal out of Africa that occurred at least 45,000 years ago. However, there has been no accurate characterization of the proportion of mixture, or of its date. We analyze genome-wide polymorphism data from about 40 West Eurasian groups to show that almost all Southern Europeans have inherited 1%-3% African ancestry with an average mixture date of around 55 generations ago, consistent with North African gene flow at the end of the Roman Empire and subsequent Arab migrations. Levantine groups harbor 4%-15% African ancestry with an average mixture date of about 32 generations ago, consistent with close political, economic, and cultural links with Egypt in the late middle ages. We also detect 3%-5% sub-Saharan African ancestry in all eight of the diverse Jewish populations that we analyzed. For the Jewish admixture, we obtain an average estimated date of about 72 generations. This may reflect descent of these groups from a common ancestral population that already had some African ancestry prior to the Jewish Diasporas.
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http://dx.doi.org/10.1371/journal.pgen.1001373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3080861PMC
April 2011

Corticotrophin-releasing hormone type 1 receptor gene (CRHR1) variants predict posttraumatic stress disorder onset and course in pediatric injury patients.

Dis Markers 2011 ;30(2-3):89-99

Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, 23298-0126, USA.

Posttraumatic stress disorder (PTSD) is a common and disabling anxiety disorder that may occur in the aftermath of exposure to potentially traumatic life events. PTSD is moderately heritable, but few specific molecular variants accounting for this heritability have been identified. Genes regulating the hypothalamic-pituitary-adrenal (HPA) axis, such as corticotrophin-releasing hormone type 1 receptor gene (CRHR1), have been implicated in traumatic-stress related phenotypes but have yet to be studied in relation to PTSD. The present study sought to examine the relation between 9 single nucleotide polymorphisms (SNPs) in the CRHR1 gene and posttraumatic stress symptoms in a prospective study of pediatric injury patients (n=103) who were first assessed in the acute aftermath of their injury at the hospital. Results indicated that multiple SNPs were associated with acute symptoms at a univariate level, and after correction for multiple testing, rs12944712 was significantly related to acute PTSD symptoms. Longitudinal latent growth curve analyses suggest that rs12944712 is also related to both acute symptom level and trajectory of symptoms over time. The present study adds support for the role of CRHR1 in the stress response following potentially traumatic event exposure in youth. It should be noted that the sample size in this study was small, and therefore statistical power was low; following, results from this study should be considered preliminary. Although results are not definitive, the findings from this study warrant future replication studies on how variation in this gene relates to response to traumatic event exposure in youth.
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http://dx.doi.org/10.3233/DMA-2011-0761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3722863PMC
August 2011

Panic disorder and serotonergic genes (SLC6A4, HTR1A and HTR2A): Association and interaction with childhood trauma and parenting.

Neurosci Lett 2010 Nov 15;485(1):11-5. Epub 2010 Sep 15.

Anxiety Disorders Program, Hospital de Clínicas de Porto Alegre, Post-Graduate Program in Medical Sciences: Psychiatry, Federal University of Rio Grande do Sul, Luiz Manoel Gonzaga, 630/11, 90470-280 Porto Alegre, RS, Brazil.

Objective: The aim of this study is to evaluate the association between HTR1A, HTR2A and the 5-HTTLPR in panic disorder (PD) patients and controls. In addition, this study also aims to evaluate the interaction between these genes and two environmental factors previously associated with PD: childhood trauma and parental bonding.

Methods: This is a case-control candidate gene association study (107 PD patients and 125 controls). Genes were analyzed using a gene-based test in PLINK followed by single marker association tests and haplotype test only for genes that reached experiment-wide significance in the gene-based test in order to minimize multiple testing. Logistic regression was used to test the relationships between genotype in the additive model, trauma, optimal paternal parenting and optimal maternal parenting and their interactions.

Results: Only HTR1A was associated with PD in gene-based test after correction for multiple tests (p(corrected)=0.027) and one HTR1A haplotype comprising four SNPs was associated with PD (p(corrected)=0.032). In the interaction analysis, no significant gene-environment interaction was found with the genes evaluated.

Conclusion: This study reinforces the association between HTR1A and PD. No major evidence of gene-environment interaction in PD with parenting or trauma was found. Further studies are necessary in order to confirm these findings.
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http://dx.doi.org/10.1016/j.neulet.2010.08.042DOI Listing
November 2010

Complete Khoisan and Bantu genomes from southern Africa.

Nature 2010 Feb;463(7283):943-7

Pennsylvania State University, Center for Comparative Genomics and Bioinformatics, 310 Wartik Lab, University Park, Pennsylvania 16802, USA.

The genetic structure of the indigenous hunter-gatherer peoples of southern Africa, the oldest known lineage of modern human, is important for understanding human diversity. Studies based on mitochondrial and small sets of nuclear markers have shown that these hunter-gatherers, known as Khoisan, San, or Bushmen, are genetically divergent from other humans. However, until now, fully sequenced human genomes have been limited to recently diverged populations. Here we present the complete genome sequences of an indigenous hunter-gatherer from the Kalahari Desert and a Bantu from southern Africa, as well as protein-coding regions from an additional three hunter-gatherers from disparate regions of the Kalahari. We characterize the extent of whole-genome and exome diversity among the five men, reporting 1.3 million novel DNA differences genome-wide, including 13,146 novel amino acid variants. In terms of nucleotide substitutions, the Bushmen seem to be, on average, more different from each other than, for example, a European and an Asian. Observed genomic differences between the hunter-gatherers and others may help to pinpoint genetic adaptations to an agricultural lifestyle. Adding the described variants to current databases will facilitate inclusion of southern Africans in medical research efforts, particularly when family and medical histories can be correlated with genome-wide data.
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http://dx.doi.org/10.1038/nature08795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3890430PMC
February 2010

Preliminary evidence of association between EFHC2, a gene implicated in fear recognition, and harm avoidance.

Neurosci Lett 2009 Mar 19;452(1):84-6. Epub 2009 Jan 19.

Anxiety Disorders Program, Hospital de Clínicas de Porto Alegre, Post-Graduate Program in Medical Sciences: Psychiatry, Federal University of Rio Grande do Sul, Department of Psychiatry, Luiz Manoel Gonzaga 630/11, 90470-280 Porto Alegre, RS, Brazil.

Genetic variation at the EF-hand domain containing 2 gene (EFHC2) locus has been associated with fear recognition in Turner syndrome. The aim of this study was to examine whether EFHC2 variants are associated with non-syndromic anxiety-related traits [harm avoidance (HA) and behavioral inhibition (BI)] and with panic disorder (PD). Our sample comprised 127 PD patients and 132 controls without psychiatric disorder. We genotyped nine SNPs within the EFHC2 locus and used PLINK to perform association analyses. An intronic SNP (rs1562875) was associated with HA (permuted p=0.031) accounting alone for over 3% of variance in this trait. This same SNP was nominally, but not empirically, associated with BI (r(2)=0.022; nominal p=0.022) and PD (OR=2.64; nominal p=0.009). The same association was found in a subsample of only females. In sum, we observed evidence of association between a variant in EFHC2, a gene previously associated with the processing of fear and social threat, and HA. Larger studies are warranted to confirm this association.
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http://dx.doi.org/10.1016/j.neulet.2009.01.036DOI Listing
March 2009

Pharmacogenetic analysis of genes implicated in rodent models of antidepressant response: association of TREK1 and treatment resistance in the STAR(*)D study.

Neuropsychopharmacology 2008 Nov 20;33(12):2810-9. Epub 2008 Feb 20.

Depression Clinical and Research Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Recent rodent models of antidepressant response implicate a novel set of genes in mechanisms of antidepressant action. The authors examined variants in four such genes (KCNK2 (TREK1), SLC18A2 (VMAT2), S100A10, and HDAC5) for association with remission in a large effectiveness trial of antidepressant treatments. Subjects were drawn from the Sequenced Treatment Alternatives to Relieve Depression (STAR(*)D) study, a multicenter, prospective, effectiveness trial in major depressive disorder (MDD). Outpatients with nonpsychotic MDD were initially treated with citalopram for up to 14 weeks; those who did not remit with citalopram were sequentially randomized to a series of next-step treatments, each for up to 12 weeks. Single-nucleotide polymorphisms in four genes were examined for association with remission, defined as a clinician-rated Quick Inventory of Depressive Symptomatology (QIDS-C(16)) score < or =5. Of 1554 participants for whom DNA was available, 565 (36%) reached remission with citalopram treatment. No association with any of the four genes was identified. However, among the 751 who entered next-step treatment, variants in KCNK2 were associated with treatment response (Bonferroni-corrected, gene-based empirical p<0.001). In follow-up analyses, KCNK2 was also associated with effects of similar magnitude for third-step treatment among those with unsatisfactory benefit to both citalopram and one next-step pharmacotherapy (n=225). These findings indicate that genetic variation in KCNK2 may identify individuals at risk for treatment resistance. More broadly, they indicate the utility of animal models in identifying genes for pharmacogenetic studies of antidepressant response.
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http://dx.doi.org/10.1038/npp.2008.6DOI Listing
November 2008

Unexpected diversity displayed in cDNAs expressed by the immune cells of the purple sea urchin, Strongylocentrotus purpuratus.

Physiol Genomics 2006 Jul;26(2):134-44

Department of Biological Sciences, George Washington University, Washington, District of Columbia 20052, USA.

We recently identified a unique family of transcripts, the 185/333 family, that comprise approximately 60% of the mRNAs induced by coelomocytes from the purple sea urchin in response to immunological challenge from lipopolysaccharide. An analysis of 81 full-length cDNAs revealed 67 unique nucleotide sequences encoding 64 different proteins. Diversity of the transcripts was based on 25 sequence blocks, or "elements," which resulted in 22 different element patterns based on their presence or absence. Furthermore, there was a high level of nucleotide variation within elements, including single nucleotide polymorphisms and insertions/deletions, both of which resulted in amino acid sequence variability. The deduced 185/333 proteins contained an NH2-terminal leader, a glycine-rich region with an RGD motif, a histidine-rich region, and a COOH-terminal region. Two 185/333 genes, identified in the partially assembled Strongylocentrotus purpuratus genome, have two exons. The first encoded the leader, and the second encoded the remainder of the predicted protein. Estimates from quantitative PCR indicated that there were approximately 100 alleles in the diploid genome. These results suggested that the purple sea urchin may have mechanisms for generating high levels of diversity in response to immunological challenge that have not been considered previously.
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http://dx.doi.org/10.1152/physiolgenomics.00011.2006DOI Listing
July 2006
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