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Showing papers by "Carlos Bustamante published in 2013"


Journal ArticleDOI
Javier Prado-Martinez1, Peter H. Sudmant2, Jeffrey M. Kidd3, Jeffrey M. Kidd4, Heng Li5, Joanna L. Kelley3, Belen Lorente-Galdos1, Krishna R. Veeramah6, August E. Woerner6, Timothy D. O’Connor2, Gabriel Santpere1, Alex Cagan7, Christoph Theunert7, Ferran Casals1, Hafid Laayouni1, Kasper Munch8, Asger Hobolth8, Anders E. Halager8, Maika Malig2, Jessica Hernandez-Rodriguez1, Irene Hernando-Herraez1, Kay Prüfer7, Marc Pybus1, Laurel Johnstone6, Michael Lachmann7, Can Alkan9, Dorina Twigg4, Natalia Petit1, Carl Baker2, Fereydoun Hormozdiari2, Marcos Fernandez-Callejo1, Marc Dabad1, Michael L. Wilson10, Laurie S. Stevison11, Cristina Camprubí12, Tiago Carvalho1, Aurora Ruiz-Herrera12, Laura Vives2, Marta Melé1, Teresa Abello, Ivanela Kondova13, Ronald E. Bontrop13, Anne E. Pusey14, Felix Lankester15, John Kiyang, Richard A. Bergl, Elizabeth V. Lonsdorf16, Simon Myers17, Mario Ventura18, Pascal Gagneux19, David Comas1, Hans R. Siegismund20, Julie Blanc, Lidia Agueda-Calpena, Marta Gut, Lucinda Fulton21, Sarah A. Tishkoff22, James C. Mullikin23, Richard K. Wilson21, Ivo Gut, Mary Katherine Gonder24, Oliver A. Ryder, Beatrice H. Hahn22, Arcadi Navarro25, Arcadi Navarro1, Joshua M. Akey2, Jaume Bertranpetit1, David Reich5, Thomas Mailund8, Mikkel H. Schierup8, Christina Hvilsom20, Christina Hvilsom26, Aida M. Andrés7, Jeffrey D. Wall11, Carlos Bustamante3, Michael F. Hammer6, Evan E. Eichler27, Evan E. Eichler2, Tomas Marques-Bonet25, Tomas Marques-Bonet1 
25 Jul 2013-Nature
TL;DR: This comprehensive catalogue of great ape genome diversity provides a framework for understanding evolution and a resource for more effective management of wild and captive great ape populations.
Abstract: Most great ape genetic variation remains uncharacterized; however, its study is critical for understanding population history, recombination, selection and susceptibility to disease. Here we sequence to high coverage a total of 79 wild- and captive-born individuals representing all six great ape species and seven subspecies and report 88.8 million single nucleotide polymorphisms. Our analysis provides support for genetically distinct populations within each species, signals of gene flow, and the split of common chimpanzees into two distinct groups: Nigeria-Cameroon/western and central/eastern populations. We find extensive inbreeding in almost all wild populations, with eastern gorillas being the most extreme. Inferred effective population sizes have varied radically over time in different lineages and this appears to have a profound effect on the genetic diversity at, or close to, genes in almost all species. We discover and assign 1,982 loss-of-function variants throughout the human and great ape lineages, determining that the rate of gene loss has not been different in the human branch compared to other internal branches in the great ape phylogeny. This comprehensive catalogue of great ape genome diversity provides a framework for understanding evolution and a resource for more effective management of wild and captive great ape populations.

807 citations


Journal ArticleDOI
TL;DR: RFMix, a powerful discriminative modeling approach that is faster and more accurate than existing methods and capable of learning from the admixed samples themselves to boost performance and autocorrect phasing errors, is presented.
Abstract: Local-ancestry inference is an important step in the genetic analysis of fully sequenced human genomes. Current methods can only detect continental-level ancestry (i.e., European versus African versus Asian) accurately even when using millions of markers. Here, we present RFMix, a powerful discriminative modeling approach that is faster (∼30×) and more accurate than existing methods. We accomplish this by using a conditional random field parameterized by random forests trained on reference panels. RFMix is capable of learning from the admixed samples themselves to boost performance and autocorrect phasing errors. RFMix shows high sensitivity and specificity in simulated Hispanics/Latinos and African Americans and admixed Europeans, Africans, and Asians. Finally, we demonstrate that African Americans in HapMap contain modest (but nonzero) levels of Native American ancestry (∼0.4%).

653 citations


Journal ArticleDOI
TL;DR: It is demonstrated that the ancestral components in admixed genomes can be traced back to distinct sub-continental source populations with far greater resolution than previously thought, even when limited pre-Columbian Caribbean haplotypes have survived.
Abstract: The Caribbean basin is home to some of the most complex interactions in recent history among previously diverged human populations. Here, we investigate the population genetic history of this region by characterizing patterns of genome-wide variation among 330 individuals from three of the Greater Antilles (Cuba, Puerto Rico, Hispaniola), two mainland (Honduras, Colombia), and three Native South American (Yukpa, Bari, and Warao) populations. We combine these data with a unique database of genomic variation in over 3,000 individuals from diverse European, African, and Native American populations. We use local ancestry inference and tract length distributions to test different demographic scenarios for the pre- and post-colonial history of the region. We develop a novel ancestry-specific PCA (ASPCA) method to reconstruct the sub-continental origin of Native American, European, and African haplotypes from admixed genomes. We find that the most likely source of the indigenous ancestry in Caribbean islanders is a Native South American component shared among inland Amazonian tribes, Central America, and the Yucatan peninsula, suggesting extensive gene flow across the Caribbean in pre-Columbian times. We find evidence of two pulses of African migration. The first pulse—which today is reflected by shorter, older ancestry tracts—consists of a genetic component more similar to coastal West African regions involved in early stages of the trans-Atlantic slave trade. The second pulse—reflected by longer, younger tracts—is more similar to present-day West-Central African populations, supporting historical records of later transatlantic deportation. Surprisingly, we also identify a Latino-specific European component that has significantly diverged from its parental Iberian source populations, presumably as a result of small European founder population size. We demonstrate that the ancestral components in admixed genomes can be traced back to distinct sub-continental source populations with far greater resolution than previously thought, even when limited pre-Columbian Caribbean haplotypes have survived.

312 citations


Journal ArticleDOI
TL;DR: The whole-genome capture approach makes it less costly to sequence aDNA from specimens containing very low levels of endogenous DNA, enabling the analysis of larger numbers of samples, increasing resolution in population genetic analyses.
Abstract: Most ancient specimens contain very low levels of endogenous DNA, precluding the shotgun sequencing of many interesting samples because of cost. Ancient DNA (aDNA) libraries often contain <1% endogenous DNA, with the majority of sequencing capacity taken up by environmental DNA. Here we present a capture-based method for enriching the endogenous component of aDNA sequencing libraries. By using biotinylated RNA baits transcribed from genomic DNA libraries, we are able to capture DNA fragments from across the human genome. We demonstrate this method on libraries created from four Iron Age and Bronze Age human teeth from Bulgaria, as well as bone samples from seven Peruvian mummies and a Bronze Age hair sample from Denmark. Prior to capture, shotgun sequencing of these libraries yielded an average of 1.2% of reads mapping to the human genome (including duplicates). After capture, this fraction increased substantially, with up to 59% of reads mapped to human and enrichment ranging from 6- to 159-fold. Furthermore, we maintained coverage of the majority of regions sequenced in the precapture library. Intersection with the 1000 Genomes Project reference panel yielded an average of 50,723 SNPs (range 3,062–147,243) for the postcapture libraries sequenced with 1 million reads, compared with 13,280 SNPs (range 217–73,266) for the precapture libraries, increasing resolution in population genetic analyses. Our whole-genome capture approach makes it less costly to sequence aDNA from specimens containing very low levels of endogenous DNA, enabling the analysis of larger numbers of samples.

284 citations


Journal ArticleDOI
02 Aug 2013-Science
TL;DR: The findings suggest that, contrary to previous claims, male lineages do not coalesce significantly more recently than female lineages.
Abstract: The Y chromosome and the mitochondrial genome have been used to estimate when the common patrilineal and matrilineal ancestors of humans lived. We sequenced the genomes of 69 males from nine populations, including two in which we find basal branches of the Y-chromosome tree. We identify ancient phylogenetic structure within African haplogroups and resolve a long-standing ambiguity deep within the tree. Applying equivalent methodologies to the Y chromosome and the mitochondrial genome, we estimate the time to the most recent common ancestor (T(MRCA)) of the Y chromosome to be 120 to 156 thousand years and the mitochondrial genome T(MRCA) to be 99 to 148 thousand years. Our findings suggest that, contrary to previous claims, male lineages do not coalesce significantly more recently than female lineages.

224 citations


Journal ArticleDOI
TL;DR: Theobroma cacao L. cultivar Matina 1-6 belongs to the most cultivated cacao type and the availability of its genome sequence and methods for identifying genes responsible for important cacao traits will aid cacao researchers and breeders as discussed by the authors.
Abstract: Background Theobroma cacao L. cultivar Matina 1-6 belongs to the most cultivated cacao type. The availability of its genome sequence and methods for identifying genes responsible for important cacao traits will aid cacao researchers and breeders.

222 citations


Journal ArticleDOI
TL;DR: A fine-scale genetic map is constructed from patterns of linkage disequilibrium assessed using high-throughput sequence data from 51 free-ranging dogs to show that biased gene conversion is a plausible mechanism by which the high CpG content of the dog genome could have occurred.
Abstract: The identification of the H3K4 trimethylase, PRDM9, as the gene responsible for recombination hotspot localization has provided considerable insight into the mechanisms by which recombination is initiated in mammals. However, uniquely amongst mammals, canids appear to lack a functional version of PRDM9 and may therefore provide a model for understanding recombination that occurs in the absence of PRDM9, and thus how PRDM9 functions to shape the recombination landscape. We have constructed a fine-scale genetic map from patterns of linkage disequilibrium assessed using high-throughput sequence data from 51 free-ranging dogs, Canis lupus familiaris. While broad-scale properties of recombination appear similar to other mammalian species, our fine-scale estimates indicate that canine highly elevated recombination rates are observed in the vicinity of CpG rich regions including gene promoter regions, but show little association with H3K4 trimethylation marks identified in spermatocytes. By comparison to genomic data from the Andean fox, Lycalopex culpaeus, we show that biased gene conversion is a plausible mechanism by which the high CpG content of the dog genome could have occurred.

207 citations


Journal ArticleDOI
TL;DR: The source of genetic diversity in southern Europe has important biomedical implications and it is found that most disease risk alleles from genome-wide association studies follow expected patterns of divergence between Europe and North Africa, with the principal exception of multiple sclerosis.
Abstract: Human genetic diversity in southern Europe is higher than in other regions of the continent. This difference has been attributed to postglacial expansions, the demic diffusion of agriculture from the Near East, and gene flow from Africa. Using SNP data from 2,099 individuals in 43 populations, we show that estimates of recent shared ancestry between Europe and Africa are substantially increased when gene flow from North Africans, rather than Sub-Saharan Africans, is considered. The gradient of North African ancestry accounts for previous observations of low levels of sharing with Sub-Saharan Africa and is independent of recent gene flow from the Near East. The source of genetic diversity in southern Europe has important biomedical implications; we find that most disease risk alleles from genome-wide association studies follow expected patterns of divergence between Europe and North Africa, with the principal exception of multiple sclerosis.

182 citations


Journal ArticleDOI
TL;DR: The 1000 Genomes Project provides a unique opportunity for improving our understanding of population genetic history by providing over a hundred sequenced low coverage genomes and exomes from Colombian (CLM), Mexican-American (MXL), and Puerto Rican (PUR) populations.
Abstract: There is great scientific and popular interest in understanding the genetic history of populations in the Americas. We wish to understand when different regions of the continent were inhabited, where settlers came from, and how current inhabitants relate genetically to earlier populations. Recent studies unraveled parts of the genetic history of the continent using genotyping arrays and uniparental markers. The 1000 Genomes Project provides a unique opportunity for improving our understanding of population genetic history by providing over a hundred sequenced low coverage genomes and exomes from Colombian (CLM), Mexican-American (MXL), and Puerto Rican (PUR) populations. Here, we explore the genomic contributions of African, European, and especially Native American ancestry to these populations. Estimated Native American ancestry is in MXL, in CLM, and in PUR. Native American ancestry in PUR is most closely related to populations surrounding the Orinoco River basin, confirming the Southern America ancestry of the Taino people of the Caribbean. We present new methods to estimate the allele frequencies in the Native American fraction of the populations, and model their distribution using a demographic model for three ancestral Native American populations. These ancestral populations likely split in close succession: the most likely scenario, based on a peopling of the Americas thousand years ago (kya), supports that the MXL Ancestors split kya, with a subsequent split of the ancestors to CLM and PUR kya. The model also features effective populations of in Mexico, in Colombia, and in Puerto Rico. Modeling Identity-by-descent (IBD) and ancestry tract length, we show that post-contact populations also differ markedly in their effective sizes and migration patterns, with Puerto Rico showing the smallest effective size and the earlier migration from Europe. Finally, we compare IBD and ancestry assignments to find evidence for relatedness among European founders to the three populations.

177 citations


Journal ArticleDOI
TL;DR: The RootReader2D as mentioned in this paper is a custom phenotyping platform designed to capture images of whole root systems, and novel software tools were developed to process and analyse these images.
Abstract: High-throughput phenotyping of root systems requires a combination of specialized techniques and adaptable plant growth, root imaging and software tools. A custom phenotyping platform was designed to capture images of whole root systems, and novel software tools were developed to process and analyse these images. The platform and its components are adaptable to a wide range root phenotyping studies using diverse growth systems (hydroponics, paper pouches, gel and soil) involving several plant species, including, but not limited to, rice, maize, sorghum, tomato and Arabidopsis. The RootReader2D software tool is free and publicly available and was designed with both user-guided and automated features that increase flexibility and enhance efficiency when measuring root growth traits from specific roots or entire root systems during large-scale phenotyping studies. To demonstrate the unique capabilities and high-throughput capacity of this phenotyping platform for studying root systems, genome-wide association studies on rice (Oryza sativa) and maize (Zea mays) root growth were performed and root traits related to aluminium (Al) tolerance were analysed on the parents of the maize nested association mapping (NAM) population.

173 citations


Journal ArticleDOI
TL;DR: Analysis of the core genome suggested that among 73 genes present in all isolates of S. mutans but absent in other species of the mutans taxonomic group, the majority can be associated with metabolic processes that could have contributed to the successful adaptation of the species to its new niche, the human mouth, and with the dietary changes that accompanied the onset of human agriculture.
Abstract: Streptococcus mutans is widely recognized as one of the key etiological agents of human dental caries. Despite its role in this important disease, our present knowledge of gene content variability across the species and its relationship to adaptation is minimal. Estimates of its demographic history are not available. In this study, we generated genome sequences of 57 S. mutans isolates, as well as representative strains of the most closely related species to S. mutans (S. ratti, S. macaccae, and S. criceti), to identify the overall structure and potential adaptive features of the dispensable and core components of the genome. We also performed population genetic analyses on the core genome of the species aimed at understanding the demographic history, and impact of selection shaping its genetic variation. The maximum gene content divergence among strains was approximately 23%, with the majority of strains diverging by 5–15%. The core genome consisted of 1,490 genes and the pan-genome approximately 3,296. Maximum likelihood analysis of the synonymous site frequency spectrum (SFS) suggested that the S. mutans population started expanding exponentially approximately 10,000 years ago (95% confidence interval [CI]: 3,268–14,344 years ago), coincidental with the onset of human agriculture. Analysis of the replacement SFS indicated that a majority of these substitutions are under strong negative selection, and the remainder evolved neutrally. A set of 14 genes was identified as being under positive selection, most of which were involved in either sugar metabolism or acid tolerance. Analysis of the core genome suggested that among 73 genes present in all isolates of S. mutans but absent in other species of the mutans taxonomic group, the majority can be associated with metabolic processes that could have contributed to the successful adaptation of S. mutans to its new niche, the human mouth, and with the dietary changes that accompanied the origin of agriculture.

Posted Content
TL;DR: The genomic contributions of African, European, and especially Native American ancestry to these populations are explored and identity-by-descent (IBD) and ancestry tract length are compared to find evidence for relatedness among European founders to the three populations.
Abstract: There is great scientific and popular interest in understanding the genetic history of populations in the Americas. We wish to understand when different regions of the continent were inhabited, where settlers came from, and how current inhabitants relate genetically to earlier populations. Recent studies unraveled parts of the genetic history of the continent using genotyping arrays and uniparental markers. The 1000 Genomes Project provides a unique opportunity for improving our understanding of population genetic history by providing over a hundred sequenced low coverage genomes and exomes from Colombian (CLM), Mexican-American (MXL), and Puerto Rican (PUR) populations. Here, we explore the genomic contributions of African, European, and Native American ancestry to these populations. Estimated Native American ancestry is 48% in MXL, 25% in CLM, and 13% in PUR. Native American ancestry in PUR is most closely related to populations surrounding the Orinoco River basin, confirming the Southern America ancestry of the Ta\'ino people of the Caribbean. We present new methods to estimate the allele frequencies in the Native American fraction of the populations, and model their distribution using a demographic model for three ancestral Native American populations. These ancestral populations likely split in close succession: the most likely scenario, based on a peopling of the Americas 16 thousand years ago (kya), supports that the MXL Ancestors split 12.2kya, with a subsequent split of the ancestors to CLM and PUR 11.7kya. The model also features effective populations of 62,000 in Mexico, 8,700 in Colombia, and 1,900 in Puerto Rico. Modeling Identity-by-descent and ancestry tract length, we show that post-contact populations differ markedly in their effective sizes and migration patterns, with Puerto Rico showing the smallest effective size and the earlier migration from Europe.

Journal ArticleDOI
24 Oct 2013-Cell
TL;DR: Single-molecule analyses reveal that phosphate release is the force-generating step in the ATP-hydrolysis cycle and that ClpXP translocates substrate polypeptides in bursts resulting from highly coordinated conformational changes in two to four ATPase subunits.

Journal ArticleDOI
24 Sep 2013-eLife
TL;DR: Surprisingly, it is found that the forward translocation rate is comparable to the catalysis rate, revealing a linear, non-branched ratchet mechanism for the nucleotide addition cycle in which translocation is one of the rate-limiting steps.
Abstract: During transcription elongation, RNA polymerase has been assumed to attain equilibrium between pre- and post-translocated states rapidly relative to the subsequent catalysis. Under this assumption, recent single-molecule studies proposed a branched Brownian ratchet mechanism that necessitates a putative secondary nucleotide binding site on the enzyme. By challenging individual yeast RNA polymerase II with a nucleosomal barrier, we separately measured the forward and reverse translocation rates. Surprisingly, we found that the forward translocation rate is comparable to the catalysis rate. This finding reveals a linear, non-branched ratchet mechanism for the nucleotide addition cycle in which translocation is one of the rate-limiting steps. We further determined all the major on- and off-pathway kinetic parameters in the elongation cycle. The resulting translocation energy landscape shows that the off-pathway states are favored thermodynamically but not kinetically over the on-pathway states, conferring the enzyme its propensity to pause and furnishing the physical basis for transcriptional regulation. DOI:http://dx.doi.org/10.7554/eLife.00971.001.

Journal ArticleDOI
TL;DR: It is found that genetic risk for type 2 diabetes and pancreatic cancer decreased as humans migrated toward East Asia, and biliary liver cirrhosis, alopecia areata, bladder cancer, inflammatory bowel disease, membranous nephropathy, and vitiligo have undergone genetic risk differentiation.
Abstract: Genetic diversity across different human populations can enhance understanding of the genetic basis of disease. We calculated the genetic risk of 102 diseases in 1,043 unrelated individuals across 51 populations of the Human Genome Diversity Panel. We found that genetic risk for type 2 diabetes and pancreatic cancer decreased as humans migrated toward East Asia. In addition, biliary liver cirrhosis, alopecia areata, bladder cancer, inflammatory bowel disease, membranous nephropathy, systemic lupus erythematosus, systemic sclerosis, ulcerative colitis, and vitiligo have undergone genetic risk differentiation. This analysis represents a large-scale attempt to characterize genetic risk differentiation in the context of migration. We anticipate that our findings will enable detailed analysis pertaining to the driving forces behind genetic risk differentiation.

Journal ArticleDOI
TL;DR: The findings establish the DnaB collar as an autoregulatory hub that controls the ability of the helicase to transition between different functional states in response to both nucleotide and replication initiation/elongation factors.

Journal ArticleDOI
TL;DR: Identification of the mutations responsible for these two early-onset retinal degenerations provides new large animal models for comparative disease studies and evaluation of potential therapeutic approaches for the homologous human diseases.
Abstract: Purpose To identify the causative mutations in two early-onset canine retinal degenerations, crd1 and crd2, segregating in the American Staffordshire terrier and the Pit Bull Terrier breeds, respectively. Methods Retinal morphology of crd1- and crd2-affected dogs was evaluated by light microscopy. DNA was extracted from affected and related unaffected controls. Association analysis was undertaken using the Illumina Canine SNP array and PLINK (crd1 study), or the Affymetrix Version 2 Canine array, the "MAGIC" genotype algorithm, and Fisher's Exact test for association (crd2 study). Positional candidate genes were evaluated for each disease. Results Structural photoreceptor abnormalities were observed in crd1-affected dogs as young as 11-weeks old. Rod and cone inner segment (IS) and outer segments (OS) were abnormal in size, shape, and number. In crd2-affected dogs, rod and cone IS and OS were abnormal as early as 3 weeks of age, progressing with age to severe loss of the OS, and thinning of the outer nuclear layer (ONL) by 12 weeks of age. Genome-wide association study (GWAS) identified association at the telomeric end of CFA3 in crd1-affected dogs and on CFA33 in crd2-affected dogs. Candidate gene evaluation identified a three bases deletion in exon 21 of PDE6B in crd1-affected dogs, and a cytosine insertion in exon 10 of IQCB1 in crd2-affected dogs. Conclusions Identification of the mutations responsible for these two early-onset retinal degenerations provides new large animal models for comparative disease studies and evaluation of potential therapeutic approaches for the homologous human diseases.

Journal ArticleDOI
TL;DR: The predominance of small, immature sharks caught in the coastal, artisanal fishery indicates that both species may use the area as a pupping, and possibly a nursery zone during spring and summer, and an increasing trend to land P. eauca, possibly to satisfy the international shark fin trade.

Journal ArticleDOI
23 Oct 2013-PLOS ONE
TL;DR: It is suggested that purifying natural selection, genetic drift, and a complex demographic history are the dominant drivers of genome evolution for the two orang-utan populations.
Abstract: To gain insights into evolutionary forces that have shaped the history of Bornean and Sumatran populations of orang-utans, we compare patterns of variation across more than 11 million single nucleotide polymorphisms found by previous mitochondrial and autosomal genome sequencing of 10 wild-caught orang-utans. Our analysis of the mitochondrial data yields a far more ancient split time between the two populations (~3.4 million years ago) than estimates based on autosomal data (0.4 million years ago), suggesting a complex speciation process with moderate levels of primarily male migration. We find that the distribution of selection coefficients consistent with the observed frequency spectrum of autosomal non-synonymous polymorphisms in orang-utans is similar to the distribution in humans. Our analysis indicates that 35% of genes have evolved under detectable negative selection. Overall, our findings suggest that purifying natural selection, genetic drift, and a complex demographic history are the dominant drivers of genome evolution for the two orang-utan populations.

Journal ArticleDOI
TL;DR: The analysis of 16 whole R1 sequences shows that a set of 19 unique nucleotide substitutions defines the Ashkenazi R1a lineage, indicative of a geographic source of the Levite founder lineage in the Near East and its likely presence among pre-Diaspora Hebrews.
Abstract: Previous Y-chromosome studies have demonstrated that Ashkenazi Levites, members of a paternally inherited Jewish priestly caste, display a distinctive founder event within R1a, the most prevalent Y-chromosome haplogroup in Eastern Europe. Here we report the analysis of 16 whole R1 sequences and show that a set of 19 unique nucleotide substitutions defines the Ashkenazi R1a lineage. While our survey of one of these, M582, in 2,834 R1a samples reveals its absence in 922 Eastern Europeans, we show it is present in all sampled R1a Ashkenazi Levites, as well as in 33.8% of other R1a Ashkenazi Jewish males and 5.9% of 303 R1a Near Eastern males, where it shows considerably higher diversity. Moreover, the M582 lineage also occurs at low frequencies in non-Ashkenazi Jewish populations. In contrast to the previously suggested Eastern European origin for Ashkenazi Levites, the current data are indicative of a geographic source of the Levite founder lineage in the Near East and its likely presence among pre-Diaspora Hebrews.

Journal ArticleDOI
TL;DR: Puerto Rican ethnicity and mixed origin were associated with degree of atopy within US Latino children with asthma and local environment variation, represented by site, was associated withdegree of sensitization.
Abstract: Background Atopy varies by ethnicity, even within Latino groups. This variation might be due to environmental, sociocultural, or genetic factors. Objective We sought to examine risk factors for atopy within a nationwide study of US Latino children with and without asthma. Methods Aeroallergen skin test responses were analyzed in 1830 US Latino subjects. Key determinants of atopy included country/region of origin, generation in the United States, acculturation, genetic ancestry, and site to which subjects migrated. Serial multivariate zero-inflated negative binomial regressions stratified by asthma status examined the association of each key determinant variable with the number of positive skin test responses. In addition, the independent effect of each key variable was determined by including all key variables in the final models. Results In baseline analyses African ancestry was associated with 3 times (95% CI, 1.62-5.57) as many positive skin test responses in asthmatic participants and 3.26 times (95% CI, 1.02-10.39) as many positive skin test responses in control participants. Generation and recruitment site were also associated with atopy in crude models. In final models adjusted for key variables, asthmatic patients of Puerto Rican (exp[β] [95% CI], 1.31 [1.02-1.69]) and mixed (exp[β] [95% CI], 1.27 [1.03-1.56]) ethnicity had a greater probability of positive skin test responses compared with Mexican asthmatic patients. Ancestry associations were abrogated by recruitment site but not region of origin. Conclusions Puerto Rican ethnicity and mixed origin were associated with degree of atopy within US Latino children with asthma. African ancestry was not associated with degree of atopy after adjusting for recruitment site. Local environment variation, represented by site, was associated with degree of sensitization.

Patent
12 Aug 2013
TL;DR: In this article, a novel phasing algorithm harnesses sequencing read information from next generation sequencing technologies to guide and improve local haplotype reconstruction from genotypes by determining correlated occurrences of single nucleotide polymorphisms in genes of a population of individuals.
Abstract: A novel phasing algorithm harnesses sequencing read information from next generation sequencing technologies to guide and improve local haplotype reconstruction from genotypes. Techniques include determining correlated occurrences of single nucleotide polymorphisms (SNPs) in genes of a population of individuals. A plurality of sequences of nucleotide bases in one or more individuals from the populations of individuals is determined based on ultra-high throughput sequencing of a sample from the one or more individuals. Haplotypes included in the population of individuals are determined based on both the correlated occurrences and the plurality of sequences. The inclusion of paired end read data is especially advantageous for the phasing of rare variants, including singletons.


Proceedings ArticleDOI
01 Nov 2013
TL;DR: A web-based tool is developed, PATH-SCAN, which annotates individual genomes and exomes for ClinVar designated pathogenic variants found within the genes from the ACMG guidelines, which will allow individuals or researchers to identify potential risk variants in order to consult physicians or genetic counselors for further evaluation.
Abstract: The American College of Medical Genetics and Genomics (ACMG) recently released guidelines regarding the reporting of incidental findings in sequencing data. Given the availability of Direct to Consumer (DTC) genetic testing and the falling cost of whole exome and genome sequencing, individuals will increasingly have the opportunity to analyze their own genomic data. We have developed a web-based tool, PATH-SCAN, which annotates individual genomes and exomes for ClinVar designated pathogenic variants found within the genes from the ACMG guidelines. Because mutations in these genes predispose individuals to conditions with actionable outcomes, our tool will allow individuals or researchers to identify potential risk variants in order to consult physicians or genetic counselors for further evaluation. Moreover, our tool allows individuals to anonymously submit their pathogenic burden, so that we can crowd source the collection of quantitative information regarding the frequency of these variants. We tested our tool on 1092 publicly available genomes from the 1000 Genomes project, 163 genomes from the Personal Genome Project, and 15 genomes from a clinical genome sequencing research project. Excluding the most commonly seen variant in 1000 Genomes, about 20% of all genomes analyzed had a ClinVar designated pathogenic variant that required further evaluation.

Journal ArticleDOI
TL;DR: Feeding and stable isotope analyses for Bythaelurus canescens individuals were conducted to describe the diet of individuals as well as infer their potential prey species in the community, showing siphonophores and cephalopods as the most important food in the diet.
Abstract: Summary: Feeding and stable isotope analyses for Bythaelurus canescens individuals were conducted to describe the diet of B. canescens as well as infer their potential prey species in the community. Stomach content analysis and mixing models by ratio isotopes composition were used to infer the food habits and calculate the trophic level of the dusky catshark, B. canescens. The results showed siphonophores and cephalopods as the most important food in the diet (67.9 and 20.2%, respectively). Calculated trophic level was 3.9, indicating that B. canescens is a meso-predator in the upper continental slope communities off Chile. By mixing models based on isotope data it can be inferred that the probabilities of the consumption cephalopods and siphonophores would be 36.7 and 15.2%, respectively.

Proceedings ArticleDOI
01 Nov 2013
TL;DR: It is found that imputation is more accurate across both the genome and exome for common variant arrays than the next generation array for all allele frequencies, including rare alleles, and accuracy is substantially improved for rare variants when the same population is included in the reference panel.
Abstract: A striking finding from recent large-scale sequencing efforts is that the vast majority of variants in the human genome are rare and found within single populations or lineages. These observations hold important implications for the design of the next round of disease variant discovery efforts—if genetic variants that influence disease risk follow the same trend, then we expect to see population-specific disease associations that require large samples sizes for detection. To address this challenge, and due to the still prohibitive cost of sequencing large cohorts, researchers have developed a new generation of low-cost genotyping arrays that assay rare variation previously identified from large exome sequencing studies. Genotyping approaches rely not only on directly observing variants, but also on phasing and imputation methods that use publicly available reference panels to infer unobserved variants in a study cohort. Rare variant exome arrays are intentionally enriched for variants likely to be disease causing, and here we assay the ability of the first commercially available rare exome variant array (the Illumina Infinium HumanExome BeadChip) to also tag other potentially damaging variants not molecularly assayed. Using full sequence data from chromosome 22 from the phase I 1000 Genomes Project, we evaluate three methods for imputation (BEAGLE, MaCH-Admix, and SHAPEIT2/IMPUTE2) with the rare exome variant array under varied study panel sizes, reference panel sizes, and LD structures via population differences. We find that imputation is more accurate across both the genome and exome for common variant arrays than the next generation array for all allele frequencies, including rare alleles. We also find that imputation is the least accurate in African populations, and accuracy is substantially improved for rare variants when the same population is included in the reference panel. Depending on the goals of GWAS researchers, our results will aid budget decisions by helping determine whether money is best spent sequencing the genomes of smaller sample sizes, genotyping larger sample sizes with rare and/or common variant arrays and imputing SNPs, or some combination of the two.

Posted Content
TL;DR: It is found that surprisingly, none of the extant wolf lineages from putative domestication centers are more closely related to dogs, and the sampled wolves instead form a sister monophyletic clade, suggesting a re-evaluation of past hypotheses of dog origin is necessary.
Abstract: To identify genetic changes underlying dog domestication and reconstruct their early evolutionary history, we analyzed novel high-quality genome sequences of three gray wolves, one from each of three putative centers of dog domestication, two ancient dog lineages (Basenji and Dingo) and a golden jackal as an outgroup We find dogs and wolves diverged through a dynamic process involving population bottlenecks in both lineages and post-divergence gene flow, which confounds previous inferences of dog origins In dogs, the domestication bottleneck was severe involving a 17 to 49-fold reduction in population size, a much stronger bottleneck than estimated previously from less intensive sequencing efforts A sharp bottleneck in wolves occurred soon after their divergence from dogs, implying that the pool of diversity from which dogs arose was far larger than represented by modern wolf populations Conditional on mutation rate, we narrow the plausible range for the date of initial dog domestication to an interval from 11 to 16 thousand years ago This period predates the rise of agriculture, implying that the earliest dogs arose alongside hunter-gathers rather than agriculturists Regarding the geographic origin of dogs, we find that surprisingly, none of the extant wolf lineages from putative domestication centers are more closely related to dogs, and the sampled wolves instead form a sister monophyletic clade This result, in combination with our finding of dog-wolf admixture during the process of domestication, suggests a re-evaluation of past hypotheses of dog origin is necessary Finally, we also detect signatures of selection, including evidence for selection on genes implicated in morphology, metabolism, and neural development Uniquely, we find support for selective sweeps at regulatory sites suggesting gene regulatory changes played a critical role in dog domestication

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TL;DR: A non-parametric statistical approach was used as an exploratory tool for egg case identification in which six proportional measurements were sufficient to discriminate between species.
Abstract: Descriptions of the egg cases of three catsharks, Asymbolus analis, Asymbolus rubiginosus and Figaro boardmani, are provided from 65 egg cases obtained from fishing surveys carried out on the continental shelf of southern Queensland, Australia. Egg cases of A. analis, A. rubiginosus and F. boardmani have the same basic morphology; they are typically vase-shaped, dorso-ventrally flattened and yellow and brown-tan in colour. The shape of the posterior border in terms of horn length and tendril thickness is the specific characteristic discriminating these three catsharks: enclosed horns in F. boardmani, short horns and tendrils in A. rubiginosus and long, coiled tendrils in A. analis. A non-parametric statistical approach was used as an exploratory tool for egg case identification in which six proportional measurements were sufficient to discriminate between species. Three egg cases of F. boardmani were recovered from the stomachs of three A. rubiginosus, which provided the first evidence of catshark-catshark predator-prey interaction.


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TL;DR: The Prison University Project at San Quentin State Prison as discussed by the authors designed an algebra-level, physics course that is intended to bridge this requirement for prisoners so that they may qualify for direct transfer to a Bachelor's program upon release.