Genetic clustering algorithms, implemented in programs such as STRUCTURE and ADMIXTURE, have been used extensively in the characterisation of individuals and populations based on genetic data. A ...successful example is the reconstruction of the genetic history of African Americans as a product of recent admixture between highly differentiated populations. Histories can also be reconstructed using the same procedure for groups that do not have admixture in their recent history, where recent genetic drift is strong or that deviate in other ways from the underlying inference model. Unfortunately, such histories can be misleading. We have implemented an approach, badMIXTURE, to assess the goodness of fit of the model using the ancestry "palettes" estimated by CHROMOPAINTER and apply it to both simulated data and real case studies. Combining these complementary analyses with additional methods that are designed to test specific hypotheses allows a richer and more robust analysis of recent demographic history.
The advent of genome-wide dense variation data provides an opportunity to investigate ancestry in unprecedented detail, but presents new statistical challenges. We propose a novel inference framework ...that aims to efficiently capture information on population structure provided by patterns of haplotype similarity. Each individual in a sample is considered in turn as a recipient, whose chromosomes are reconstructed using chunks of DNA donated by the other individuals. Results of this "chromosome painting" can be summarized as a "coancestry matrix," which directly reveals key information about ancestral relationships among individuals. If markers are viewed as independent, we show that this matrix almost completely captures the information used by both standard Principal Components Analysis (PCA) and model-based approaches such as STRUCTURE in a unified manner. Furthermore, when markers are in linkage disequilibrium, the matrix combines information across successive markers to increase the ability to discern fine-scale population structure using PCA. In parallel, we have developed an efficient model-based approach to identify discrete populations using this matrix, which offers advantages over PCA in terms of interpretability and over existing clustering algorithms in terms of speed, number of separable populations, and sensitivity to subtle population structure. We analyse Human Genome Diversity Panel data for 938 individuals and 641,000 markers, and we identify 226 populations reflecting differences on continental, regional, local, and family scales. We present multiple lines of evidence that, while many methods capture similar information among strongly differentiated groups, more subtle population structure in human populations is consistently present at a much finer level than currently available geographic labels and is only captured by the haplotype-based approach. The software used for this article, ChromoPainter and fineSTRUCTURE, is available from http://www.paintmychromosomes.com/.
Phase‐change materials (PCMs) are seeing tremendous interest for their use in reconfigurable photonic devices; however, the most common PCMs exhibit a large absorption loss in one or both states. ...Here, Sb2S3 and Sb2Se3 are demonstrated as a class of low loss, reversible alternatives to the standard commercially available chalcogenide PCMs. A contrast of refractive index of Δn = 0.60 for Sb2S3 and Δn = 0.77 for Sb2Se3 is reported, while maintaining very low losses (k < 10−5) in the telecommunications C‐band at 1550 nm. With a stronger absorption in the visible spectrum, Sb2Se3 allows for reversible optical switching using conventional visible wavelength lasers. Here, a stable switching endurance of better than 4000 cycles is demonstrated. To deal with the essentially zero intrinsic absorption losses, a new figure of merit (FOM) is introduced taking into account the measured waveguide losses when integrating these materials onto a standard silicon photonics platform. The FOM of 29 rad phase shift per dB of loss for Sb2Se3 outperforms Ge2Sb2Te5 by two orders of magnitude and paves the way for on‐chip programmable phase control. These truly low‐loss switchable materials open up new directions in programmable integrated photonic circuits, switchable metasurfaces, and nanophotonic devices.
New optical phase‐change materials are demonstrated, with the ability to realize on‐chip programmable phase control with very low optical losses. The chalcogenides Sb2S3 and Sb2Se3 exhibit a large refractive index contrast between their crystalline and amorphous phases. With reversible switching over thousands of cycles and easy integration with silicon, these materials pave the way for low‐loss reconfigurable and programmable nanophotonics.
Investigate whether acute workload (1 week total distance) and chronic workload (4-week average acute workload) predict injury in elite rugby league players.
Data were collected from 53 elite players ...over two rugby league seasons. The 'acute:chronic workload ratio' was calculated by dividing acute workload by chronic workload. A value of greater than 1 represented an acute workload greater than chronic workload. All workload data were classified into discrete ranges by z-scores.
Compared with all other ratios, a very-high acute:chronic workload ratio (≥2.11) demonstrated the greatest risk of injury in the current week (16.7% injury risk) and subsequent week (11.8% injury risk). High chronic workload (>16 095 m) combined with a very-high 2-week average acute:chronic workload ratio (≥1.54) was associated with the greatest risk of injury (28.6% injury risk). High chronic workload combined with a moderate workload ratio (1.02-1.18) had a smaller risk of injury than low chronic workload combined with several workload ratios (relative risk range from 0.3 to 0.7×/÷1.4 to 4.4; likelihood range=88-94%, likely). Considering acute and chronic workloads in isolation (ie, not as ratios) did not consistently predict injury risk.
Higher workloads can have either positive or negative influences on injury risk in elite rugby league players. Specifically, compared with players who have a low chronic workload, players with a high chronic workload are more resistant to injury with moderate-low through moderate-high (0.85-1.35) acute:chronic workload ratios and less resistant to injury when subjected to 'spikes' in acute workload, that is, very-high acute:chronic workload ratios ∼1.5.
Kinetics of dCas9 target search in Escherichia coli Jones, Daniel Lawson; Leroy, Prune; Unoson, Cecilia ...
Science (American Association for the Advancement of Science),
09/2017, Letnik:
357, Številka:
6358
Journal Article
Recenzirano
Odprti dostop
How fast can a cell locate a specific chromosomal DNA sequence specified by a single-stranded oligonucleotide? To address this question, we investigate the intracellular search processes of the Cas9 ...protein, which can be programmed by a guide RNA to bind essentially any DNA sequence. This targeting flexibility requires Cas9 to unwind the DNA double helix to test for correct base pairing to the guide RNA. Here we study the search mechanisms of the catalytically inactive Cas9 (dCas9) in living Escherichia coli by combining single-molecule fluorescence microscopy and bulk restriction-protection assays. We find that it takes a single fluorescently labeled dCas9 6 hours to find the correct target sequence, which implies that each potential target is bound for less than 30 milliseconds. Once bound, dCas9 remains associated until replication. To achieve fast targeting, both Cas9 and its guide RNA have to be present at high concentrations.
Genetic architecture describes the characteristics of genetic variation that are responsible for heritable phenotypic variability. It depends on the number of genetic variants affecting a trait, ...their frequencies in the population, the magnitude of their effects and their interactions with each other and the environment. Defining the genetic architecture of a complex trait or disease is central to the scientific and clinical goals of human genetics, which are to understand disease aetiology and aid in disease screening, diagnosis, prognosis and therapy. Recent technological advances have enabled genome-wide association studies and emerging next-generation sequencing studies to begin to decipher the nature of the heritable contribution to traits and disease. Here, we describe the types of genetic architecture that have been observed, how architecture can be measured and why an improved understanding of genetic architecture is central to future advances in the field.
For the last 500 years, the Americas have been a melting pot both for genetically diverse humans and for the pathogenic and commensal organisms associated with them. One such organism is the ...stomach-dwelling bacterium Helicobacter pylori, which is highly prevalent in Latin America where it is a major current public health challenge because of its strong association with gastric cancer. By analyzing the genome sequence of H. pylori isolated in North, Central and South America, we found evidence for admixture between H. pylori of European and African origin throughout the Americas, without substantial input from pre-Columbian (hspAmerind) bacteria. In the US, strains of African and European origin have remained genetically distinct, while in Colombia and Nicaragua, bottlenecks and rampant genetic exchange amongst isolates have led to the formation of national gene pools. We found three outer membrane proteins with atypical levels of Asian ancestry in American strains, as well as alleles that were nearly fixed specifically in South American isolates, suggesting a role for the ethnic makeup of hosts in the colonization of incoming strains. Our results show that new H. pylori subpopulations can rapidly arise, spread and adapt during times of demographic flux, and suggest that differences in transmission ecology between high and low prevalence areas may substantially affect the composition of bacterial populations.
Genome sequences are known for two archaic hominins—Neanderthals and Denisovans—which interbred with anatomically modern humans as they dispersed out of Africa. We identified high-confidence archaic ...haplotypes in 161 new genomes spanning 14 island groups in Island Southeast Asia and New Guinea and found large stretches of DNA that are inconsistent with a single introgressing Denisovan origin. Instead, modern Papuans carry hundreds of gene variants from two deeply divergent Denisovan lineages that separated over 350 thousand years ago. Spatial and temporal structure among these lineages suggest that introgression from one of these Denisovan groups predominantly took place east of the Wallace line and continued until near the end of the Pleistocene. A third Denisovan lineage occurs in modern East Asians. This regional mosaic suggests considerable complexity in archaic contact, with modern humans interbreeding with multiple Denisovan groups that were geographically isolated from each other over deep evolutionary time.
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•A new dataset of 161 genomes covering the understudied Indonesia-New Guinea region•Introgressing Denisovans comprise at least three genetically divergent groups•Papuans carry haplotypes from two Denisovan groups, with one unique to Oceania•Some Denisovan introgression was recent and likely occurred in New Guinea or Wallacea
Genome sequences from Island Southeast Asia suggest two independent Denisovan lineages, distinct from the Altai Denisovan, that have contributed to modern Papuan genomes, with one group potentially present east of the Wallace Line and thus capable of crossing geographical barriers.
The nature of the CO
2
–
n
H
2
O interaction where
n
= 1, 2 and 3 is explored to evaluate the energetics of the CO
2
molecule and small water clusters using ab initio MP2 and CCSD(T). We are ...interested in the absorbance of CO
2
onto the water cluster and not those interactions that significantly alter the original water cluster. Thus, we characterize the interaction energy in terms of CO
2
binding to an intact water cluster. We provide 3 lowest energy isomers of the CO
2
–water trimer not previously reported. We include a description of the bond lengths between the CO
2
and the water and include AIM critical points to identify the hydrogen bond interactions.
Following the dispersal out of Africa, where hominins evolved in warm environments for millions of years, our species has colonised different climate zones of the world, including high latitudes and ...cold environments. The extent to which human habitation in (sub-)Arctic regions has been enabled by cultural buffering, short-term acclimatization and genetic adaptations is not clearly understood. Present day indigenous populations of Siberia show a number of phenotypic features, such as increased basal metabolic rate, low serum lipid levels and increased blood pressure that have been attributed to adaptation to the extreme cold climate. In this study we introduce a dataset of 200 individuals from ten indigenous Siberian populations that were genotyped for 730,525 SNPs across the genome to identify genes and non-coding regions that have undergone unusually rapid allele frequency and long-range haplotype homozygosity change in the recent past. At least three distinct population clusters could be identified among the Siberians, each of which showed a number of unique signals of selection. A region on chromosome 11 (chr11:66-69 Mb) contained the largest amount of clustering of significant signals and also the strongest signals in all the different selection tests performed. We present a list of candidate cold adaption genes that showed significant signals of positive selection with our strongest signals associated with genes involved in energy regulation and metabolism (CPT1A, LRP5, THADA) and vascular smooth muscle contraction (PRKG1). By employing a new method that paints phased chromosome chunks by their ancestry we distinguish local Siberian-specific long-range haplotype signals from those introduced by admixture.
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