To identify Candidatus Neoehrlichia mikurensis infection in northeastern China, we tested blood samples from 622 febrile patients. We identified in 7 infected patients and natural foci for this bacterium. Field surveys showed that 1.6% of ticks and 3.8% of rodents collected from residences of patients were also infected.

General parameters of selection, such as the frequency and strength of positive selection in natural populations or the role of introgression, are still insufficiently understood. The house mouse (Mus musculus) is a particularly well-suited model system to approach such questions, since it has a defined history of splits into subspecies and populations and since extensive genome information is available. We have used high-density single-nucleotide polymorphism (SNP) typing arrays to assess genomic patterns of positive selection and introgression of alleles in two natural populations of each of the subspecies M. m. domesticus and M. m. musculus. Applying different statistical procedures, we find a large number of regions subject to apparent selective sweeps, indicating frequent positive selection on rare alleles or novel mutations. Genes in the regions include well-studied imprinted loci (e.g. Plagl1/Zac1), homologues of human genes involved in adaptations (e.g. alpha-amylase genes) or in genetic diseases (e.g. Huntingtin and Parkin). Haplotype matching between the two subspecies reveals a large number of haplotypes that show patterns of introgression from specific populations of the respective other subspecies, with at least 10% of the genome being affected by partial or full introgression. Using neutral simulations for comparison, we find that the size and the fraction of introgressed haplotypes are not compatible with a pure migration or incomplete lineage sorting model. Hence, it appears that introgressed haplotypes can rise in frequency due to positive selection and thus can contribute to the adaptive genomic landscape of natural populations. Our data support the notion that natural genomes are subject to complex adaptive processes, including the introgression of haplotypes from other differentiated populations or species at a larger scale than previously assumed for animals. This implies that some of the admixture found in inbred strains of mice may also have a natural origin.

Author Summary

Although there is abundant evidence for phenotypic adaptation in natural populations, it is still a challenge to understand the underlying genetic processes. House mice have colonized the world in several successive waves, the most recent ones in the wake of the spread of human agriculture and trans-oceanic shipping. They have adapted to many habitats and climates, and their populations provide a rich source of opportunities for studying the impact of adaptation and positive selection on the genome. By scanning the whole genome of four natural populations of mice, we detect abundant evidence for recent positive selection, including loci that are known to be involved in genetic diseases in humans. Unexpectedly, we also find a high proportion of gene exchange between populations that have long been separated. This finding supports the notion that hybridization and transfer of alleles can significantly contribute to new genetic material subject to positive selection.

Purpose. To investigate the effect of low tube voltage (80 kV) on image quality, radiation dose, and low-contrast detectability (LCD) at abdominal computed tomography (CT). Materials and Methods. A phantom containing low-contrast objects was scanned with a CT scanner at 80 and 120 kV, with tube current-time product settings at 150–650 mAs. The differences between image noise, contrast-to-noise ratio (CNR), and scores of LCD obtained with 80 kV at 150–650 mAs and those obtained with 120 kV at 300 mAs were compared respectively. Results. The image noise substantially increased with low tube voltage. However, with identical dose, use of 80 kV resulted in higher CNR compared with CNR at 120 kV. There were no statistically significant difference in CNR and scores of LCD between 120 kV at 300 mAs and 80 kV at 550–650 mAs (P > 0.05). The relative dose delivered at 80 kV ranged from 58% at 550 mAs to 68% at 650 mAs. Conclusion. With a reduction of the tube voltage from 120 kV to 80 kV at abdominal CT, the radiation dose can be reduced by 32% to 42% without degradation of CNR and LCD.

We evaluated the immunogenicity, safety, and antibody persistence of a Vero cell rabies vaccine manufactured in China, compared with those of Verorab. Adequate titers of antibody were observed for the two vaccines. ChengDa rabies vaccine could be a promising alternative vaccine for many developing countries which cannot afford expensive rabies vaccines.

In the title coordination polymer, [CdZn(CN)4(C5H5N)2]n, the ZnII atom (site symmetry 222) adopts a distorted ZnC4 tetra­hedral geometry, being coordinated by four crystallographically equivalent cyanide ions. The cyanide ion bridges to a CdII centre via its N atom. The Cd atom (site symmetry 2/m) coordination is a distorted CdN6 octa­hedron, arising from four cyanide N atoms and two pyridine N atoms. The complete pyridine mol­ecule is generated by m symmetry, with the N atom and one C atom lying on the reflecting plane. In the crystal, the bridging cyanide ions result in a three-dimensional network.

Background

Genome-wide scans of hundreds of thousands of single-nucleotide polymorphisms (SNPs) have resulted in the identification of new susceptibility variants to common diseases and are providing new insights into the genetic structure and relationships of human populations. Moreover, genome-wide data can be used to search for signals of recent positive selection, thereby providing new insights into the genetic adaptations that occurred as modern humans spread out of Africa and around the world.

Methodology

We genotyped approximately 500,000 SNPs in 255 individuals (5 individuals from each of 51 worldwide populations) from the Human Genome Diversity Panel (HGDP-CEPH). When merged with non-overlapping SNPs typed previously in 250 of these same individuals, the resulting data consist of over 950,000 SNPs. We then analyzed the genetic relationships and ancestry of individuals without assigning them to populations, and we also identified candidate regions of recent positive selection at both the population and regional (continental) level.

Conclusions

Our analyses both confirm and extend previous studies; in particular, we highlight the impact of various dispersals, and the role of substructure in Africa, on human genetic diversity. We also identified several novel candidate regions for recent positive selection, and a gene ontology (GO) analysis identified several GO groups that were significantly enriched for such candidate genes, including immunity and defense related genes, sensory perception genes, membrane proteins, signal receptors, lipid binding/metabolism genes, and genes involved in the nervous system. Among the novel candidate genes identified are two genes involved in the thyroid hormone pathway that show signals of selection in African Pygmies that may be related to their short stature.

Electrophoretic analysis of protein variation at the coagulation F13B locus has previously revealed three alleles, with alleles 1, 2, and 3 each being at high frequency in European, African, and Asian populations, respectively. To determine if this unusual pattern of interpopulation differentiation reflects local natural selection or neutral genetic drift, we re-sequenced 4.6 kb of the gene, encompassing all exons, splice junctions, and 1.4 kb of the promoter, in African, European, and Asian samples. These analyses revealed three major lineages, which correspond to the common protein alleles and differ from each other at a non-synonymous substitution in exon 3 and a novel splice acceptor in intron K. There is previous evidence that these lineages are not functionally equivalent; we therefore carried out case–control analyses and confirmed that variability at F13B modulates susceptibility and/or survivorship in coronary artery disease (P<0.05) and type II diabetes within the coronary artery disease cohort (P<0.01). Tajima's D and Fu and Li's tests did not indicate significant departures from neutral expectations. However, publicly available data from SeattleSNPs and HapMap do indicate highly unusual levels of population differentiation (P=0.003) and an excess of allele-specific, extended haplotype homozygosity within the African population (P=0.0125). Possible causes of this putative signal of selection include hematophagous organisms, infection by pathogens that cause disseminated intravascular coagulation, and metabolic or dietary factors.

In the centrosymmetric title compound, [Gd2(C7H3F2O2)6(C10H8N2)2], the asymmetric unit comprises one cation chelated by two 2,5-difluoro­benzoate and one 2,2′-bipyridine. Two cations are linked into dimers via three bridging carboxyl­ate groups from three 2,5-difluoro­benzoic acid units. The GdIII ion is nine-coord­inated by seven O atoms and two N atoms.

The title compound, [Co(C10H12NO)3], was synthesized from cobalt(III) fluoride and 2-(propyl­imino­meth­yl)phenol in refluxing methanol. The CoIII ion is hexa­coordinated by three N and three O atoms from three bidentate Schiff base ligands in an octa­hedral geometry.

The reported structure is a monoclinic polymorph of the title compound, [Mn2(C16H14N2O2)2(NCS)2], which has been characterized previously in an ortho­rhom­bic form. Each MnIII atom is chelated by a tetra­dentate 2,2′-[ethane-1,2-diylbis(nitrilo­methyl­idyne)]diphenolate ligand and by the N atom of a thio­cyanate anion, in a square-pyramidal arrangement. The complexes form centrosymmetric dimers, with an Mn—O contact of 2.557 (3) Å trans to each thio­cyanate anion, completing a distorted octa­hedral coordination geometry.

In the title compound, [Gd2(C7H3F2O2)6(C12H8N2)2], the asymmetric unit comprises one Gd3+ cation chelated by two 2,4-difluoro­benzoate and one 1,10-phenanthroline ligands. Two cations are linked into a centrosymmetric dimer via three bridging carboxyl­ate groups of 2,4-difluoro­benzoate ligands. Each Gd3+ ion is nine-coordinated by seven O atoms and two N atoms.

We identified and examined a candidate gene for local directional selection in Europeans, TRPV6, and conclude that selection has acted on standing genetic variation at this locus, creating parallel soft sweep events in humans. A novel modification of the extended haplotype homozygosity (EHH) test was utilized, which compares EHH for a single allele across populations, to investigate the signature of selection at TRPV6 and neighboring linked loci in published data sets for Europeans, Asians and African-Americans, as well as in newly-obtained sequence data for additional populations. We find that all non-African populations carry a signature of selection on the same haplotype at the TRPV6 locus. The selective footprints, however, are significantly differentiated between non-African populations and estimated to be younger than an ancestral population of non-Africans. The possibility of a single selection event occurring in an ancestral population of non-Africans was tested by simulations and rejected. The putatively-selected TRPV6 haplotype contains three candidate sites for functional differences, namely derived non-synonymous substitutions C157R, M378V and M681T. Potential functional differences between the ancestral and derived TRPV6 proteins were investigated by cloning the ancestral and derived forms, transfecting cell lines, and carrying out electrophysiology experiments via patch clamp analysis. No statistically-significant differences in biophysical channel function were found, although one property of the protein, namely Ca2+ dependent inactivation, may show functionally relevant differences between the ancestral and derived forms. Although the reason for selection on this locus remains elusive, this is the first demonstration of a widespread parallel selection event acting on standing genetic variation in humans, and highlights the utility of between population EHH statistics.

The amyloid precursor protein (APP) in brain is processed either by an amyloidogenic pathway by β-secretase and γ-secretase to yield Aβ (β-amyloid 4 kDa) peptide or by α-secretase within the β-amyloid domain to yield non-amyloidogenic products. We have studied blood platelet levels of a 22-kDa fragment containing the Aβ (β-amyloid 4 kDa) peptide, β-secretase (BACE1), α-secretase (ADAM10), and APP isoform ratios of the 120–130 kDa to 110 kDa peptides from 31 Alzheimer's disease (AD) patients and 10 age-matched healthy control subjects. We found increased levels of Aβ4, increased activation of β-secretase (BACE1), decreased activation of α-secretase (ADAM10) and decreased APP ratios in AD patients compared to normal control subjects. These observations indicate that the blood platelet APP is processed by the same amyloidogenic and non-amyloidogenic pathways as utilized in brain and that APP processing in AD patients is altered compared to control subjects and may be a useful bio-marker for the diagnosis of AD, the progression of disease and for monitoring drug responses in clinical trials.

The title compound, [Cr2Cl2O(C18H18N4)2](PF6)2, is isostructural with the VIII analogue. Each CrIII atom is chelated by the tetra­dentate tris­(2-pyridylmeth­yl)amine ligand via four N atoms, and further coordinated by one Cl atom and one bridging O atom, giving a slightly distorted octa­hedral coordination geometry. The dinuclear complex is centrosymmetric, with the bridging O atom lying on a centre of inversion.

In the title compound, [Co(N3)2(C6H6N4)2], the CoII atom lies on a centre of inversion and is bonded to two azide ions and two bidentate 2,2′-biimidizole ligands, giving a slightly distorted octa­hedral CoN6 coordination geometry. In the crystal structure, inter­molecular N—H⋯N hydrogen bonds exist between the 2,2′-biimidizole ligands and the azide ions, linking the complexes into sheets.

Genome-wide scanning for signals of recent positive selection is essential for a comprehensive and systematic understanding of human adaptation. Here, we present a genomic survey of recent local selective sweeps, especially aimed at those nearly or recently completed. A novel approach was developed for such signals, based on contrasting the extended haplotype homozygosity (EHH) profiles between populations. We applied this method to the genome single nucleotide polymorphism (SNP) data of both the International HapMap Project and Perlegen Sciences, and detected widespread signals of recent local selection across the genome, consisting of both complete and partial sweeps. A challenging problem of genomic scans of recent positive selection is to clearly distinguish selection from neutral effects, given the high sensitivity of the test statistics to departures from neutral demographic assumptions and the lack of a single, accurate neutral model of human history. We therefore developed a new procedure that is robust across a wide range of demographic and ascertainment models, one that indicates that certain portions of the genome clearly depart from neutrality. Simulations of positive selection showed that our tests have high power towards strong selection sweeps that have undergone fixation. Gene ontology analysis of the candidate regions revealed several new functional groups that might help explain some important interpopulation differences in phenotypic traits.

Author Summary

The evolution of new functions and adaptation to new environments occurs by positive selection, whereby beneficial mutations increase in frequency and eventually become fixed in a population. Detecting such selection in humans is crucial for understanding the importance of past genetic adaptations and their role in contemporary common diseases. Methods have already been developed for detecting the signature of positive selection in large, genome-scale datasets (such as the “HapMap”). Positive selection is expected to more rapidly increase the frequency of an allele, and hence, the length of the haplotype (extent of DNA segment) associated with the selected allele, relative to those that are not under selection. Such methods compare haplotype lengths within a single population. Here, we introduce a new method that compares the lengths of haplotypes associated with the same allele in different populations. We demonstrate that our method has greater power to detect selective sweeps that are fixed or nearly so, and we construct a statistical framework that shows that our method reliably detects positive selection. We applied our method to the HapMap data and identified approximately 500 candidate regions in the human genome that show a signature of recent positive selection. Further targeted studies of these regions should reveal important genetic adaptations in our past.

The authors present a novel genome-scan approach for detecting local positive selection. The approach is designed to detect selective events that have resulted in complete or near-complete fixation of a beneficial allele.