A haplotype map of allohexaploid wheat reveals distinct patterns of selection on homoeologous genomes

BackgroundBread wheat is an allopolyploid species with a large, highly repetitive genome. To investigate the impact of selection on variants distributed among homoeologous wheat genomes and to build a foundation for understanding genotype-phenotype relationships, we performed population-scale re-sequencing of a diverse panel of wheat lines.ResultsA sample of 62 diverse lines was re-sequenced using the whole exome capture and genotyping-by-sequencing approaches. We describe the allele frequency, functional significance, and chromosomal distribution of 1.57 million single nucleotide polymorphisms and 161,719 small indels. Our results suggest that duplicated homoeologous genes are under purifying selection. We find contrasting patterns of variation and inter-variant associations among wheat genomes; this, in addition to demographic factors, could be explained by differences in the effect of directional selection on duplicated homoeologs. Only a small fraction of the homoeologous regions harboring selected variants overlapped among the wheat genomes in any given wheat line. These selected regions are enriched for loci associated with agronomic traits detected in genome-wide association studies.ConclusionsEvidence suggests that directional selection in allopolyploids rarely acted on multiple parallel advantageous mutations across homoeologous regions, likely indicating that a fitness benefit could be obtained by a mutation at any one of the homoeologs. Additional advantageous variants in other homoelogs probably either contributed little benefit, or were unavailable in populations subjected to directional selection. We hypothesize that allopolyploidy may have increased the likelihood of beneficial allele recovery by broadening the set of possible selection targets.

Electronic supplementary material

The online version of this article (doi:10.1186/s13059-015-0606-4) contains supplementary material, which is available to authorized users.     

DNA Vaccination against Theiler’s Murine Encephalomyelitis Virus Leads to Alterations in Demyelinating Disease

Although the etiology of multiple sclerosis (MS) is not known, several factors play a role in this disease: genetic contributions, immunologic elements, and environmental factors. Viruses and virus infections have been associated with the initiation and/or enhancement of exacerbations in MS. Theiler’s murine encephalomyelitis virus (TMEV) infection of mice is one of the animal models used to mimic MS. In other animal model systems, DNA vaccination has been used to protect animals against a variety of virus infections. To explore the utility of DNA vaccination, we have constructed eukaryotic expression vectors encoding the TMEV capsid proteins VP1, VP2, and VP3. SJL/J mice were vaccinated intramuscularly once, twice, or three times with the different capsid protein cDNAs. This was followed by intracerebral TMEV infection to determine the effects of DNA vaccination on the course of TMEV-induced central nervous system (CNS) demyelinating disease. We found that vaccination of mice three times with cDNA encoding VP2 led to partial protection of mice from CNS demyelinating disease as determined by a decrease in clinical symptoms and histopathology. Vaccination of mice with cDNA encoding VP3 also led to a decrease in clinical symptoms. In contrast, mice vaccinated with cDNA encoding VP1 experienced a more severe disease with an earlier onset of clinical signs and enhanced histopathology compared with control mice. There was no correlation between anti-TMEV antibody titers and disease course. These results indicate that DNA immunization can modify chronic virus-induced demyelinating disease and may eventually lead to potential treatments for illnesses such as MS.     

Induced pluripotent stem cells from patients with Huntington's disease show CAG-repeat-expansion-associated phenotypes

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expanded stretch of CAG trinucleotide repeats that results in neuronal dysfunction and death. Here, The HD Consortium reports the generation and characterization of 14 induced pluripotent stem cell (iPSC) lines from HD patients and controls. Microarray profiling revealed CAG-repeat-expansion-associated gene expression patterns that distinguish patient lines from controls, and early onset versus late onset HD. Differentiated HD neural cells showed disease-associated changes in electrophysiology, metabolism, cell adhesion, and ultimately cell death for lines with both medium and longer CAG repeat expansions. The longer repeat lines were however the most vulnerable to cellular stressors and BDNF withdrawal, as assessed using a range of assays across consortium laboratories. The HD iPSC collection represents a unique and well-characterized resource to elucidate disease mechanisms in HD and provides a human stem cell platform for screening new candidate therapeutics.     

Rumen-protected conjugated linoleic acid supplementation to dairy cows in late pregnancy and early lactation: effects on milk composition,milk yield,blood metabolites and gene expression in liver

After 27 years with no detected cases, an outbreak of anthrax occurred in a beef cattle herd in the south of Sweden. The outbreak was unusual as it occurred in winter, in animals not exposed to meat-and-bone meal, in a non-endemic country. The affected herd consisted of 90 animals, including calves and young stock. The animals were kept in a barn on deep straw bedding and fed only roughage. Seven animals died during 10 days, with no typical previous clinical signs except fever. The carcasses were reportedly normal in appearance, particularly as regards rigor mortis, bleeding and coagulation of the blood. Subsequently, three more animals died and anthrax was suspected at necropsy and confirmed by culture and PCR on blood samples. The isolated strain was susceptible to tetracycline, ciprofloxacin and ampicillin. Subtyping by MLVA showed the strain to cluster with isolates in the A lineage of Bacillus anthracis. Environmental samples from the holding were all negative except for two soil samples taken from a spot where infected carcasses had been kept until they were picked up for transport. The most likely source of the infection was concluded to be contaminated roughage, although this could not be substantiated by laboratory analysis. The suspected feed was mixed with soil and dust and originated from fields where flooding occurred the previous year, followed by a dry summer with a very low water level in the river allowing for the harvesting on soil usually not exposed. In the early 1900s, animal carcasses are said to have been dumped in this river during anthrax outbreaks and it is most likely that some anthrax spores could remain in the area. The case indicates that untypical cases in non-endemic areas may be missed to a larger extent than previously thought. Field tests allowing a preliminary risk assessment of animal carcasses would be helpful for increased sensitivity of detection and prevention of further exposure to the causative agent.     

Interactive response of the horn fly (Diptera: Muscidae) and selected breeds of beef cattle

Statistically significant differences were observed in the population density of the horn fly, Haematobia irritans irritans (L.), on different breeds of beef cattle. The European breed Chianina had a population density of horn flies generally less than or equal to 50% than that of the British cattle breeds (Angus, Hereford, Polled Hereford, and Red Poll) and another European breed (Charolais). Generally, no significant difference existed among numbers of horn flies on Hereford, Polled Hereford, and Red Poll cows in 1988 or among Angus, Hereford, Polled Hereford, and Red Poll cows in 1989. Factors other than color appeared to be involved in the selective process between the horn fly and its host. Population densities on two white European breeds (Charolais and Chianina) were significantly different on all weekly intervals except for 4 wk in both 1988 and 1989. No significant difference existed among Charolais and British breeds except during 4 wk in 1988 and 3 wk in 1989. When weaning weights of all calves were adjusted for the effects of age to 205 d, sex of calf, and age of dam, the indirect effect of the horn fly on weaning weight showed a significant linear regression. Each 100 flies per cow caused a reduction of 8.1 kg in calf weaning weight. Cows within each breed with low numbers of horn flies weaned significantly heavier calves than cows with higher numbers of horn flies.     

Tectonics,climate and the diversification of the tropical African terrestrial flora and fauna

Tropical Africa is home to an astonishing biodiversity occurring in a variety of ecosystems. Past climatic change and geological events have impacted the evolution and diversification of this biodiversity. During the last two decades, around 90 dated molecular phylogenies of different clades across animals and plants have been published leading to an increased understanding of the diversification and speciation processes generating tropical African biodiversity. In parallel, extended geological and palaeoclimatic records together with detailed numerical simulations have refined our understanding of past geological and climatic changes in Africa. To date, these important advances have not been reviewed within a common framework. Here, we critically review and synthesize African climate, tectonics and terrestrial biodiversity evolution throughout the Cenozoic to the mid-Pleistocene, drawing on recent advances in Earth and life sciences. We first review six major geo-climatic periods defining tropical African biodiversity diversification by synthesizing 89 dated molecular phylogeny studies. Two major geo-climatic factors impacting the diversification of the sub-Saharan biota are highlighted. First, Africa underwent numerous climatic fluctuations at ancient and more recent timescales, with tectonic, greenhouse gas, and orbital forcing stimulating diversification. Second, increased aridification since the Late Eocene led to important extinction events, but also provided unique diversification opportunities shaping the current tropical African biodiversity landscape. We then review diversification studies of tropical terrestrial animal and plant clades and discuss three major models of speciation: (i) geographic speciation via vicariance (allopatry); (ii) ecological speciation impacted by climate and geological changes, and (iii) genomic speciation via genome duplication. Geographic speciation has been the most widely documented to date and is a common speciation model across tropical Africa. We conclude with four important challenges faced by tropical African biodiversity research: (i) to increase knowledge by gathering basic and fundamental biodiversity information; (ii) to improve modelling of African geophysical evolution throughout the Cenozoic via better constraints and downscaling approaches; (iii) to increase the precision of phylogenetic reconstruction and molecular dating of tropical African clades by using next generation sequencing approaches together with better fossil calibrations; (iv) finally, as done here, to integrate data better from Earth and life sciences by focusing on the interdisciplinary study of the evolution of tropical African biodiversity in a wider geodiversity context.     

Single-chain polymorphism analysis in long QT syndrome using planar waveguide fluorescent biosensors

Rapid detection of single nucleotide polymorphisms (SNPs) has potential applications in both genetic screening and pharmacogenomics. Planar waveguide fluorescent biosensor technology was employed to detect SNPs using a simple hybridization assay with the complementary strand ("capture oligo") immobilized on the waveguide. This technology allows real-time measurements of DNA hybridization kinetics. Under normal conditions, both the wild-type sequence and the SNP-containing sequence will hybridize with the capture oligo, but with different reaction kinetics and equilibrium duplex concentrations. A "design of experiments" approach was used to maximize the differences in the kinetics profiles of the two. Nearly perfect discrimination can be achieved at short times (2 min) with temperatures that destabilize or melt the heteroduplex while maintaining the stability of the homoduplex. The counter ion content of the solvent was shown to have significant effect not only on the melting point of the heteroduplex and the homoduplex but also on the hybridization rate. Changes in both the stability and the difference between the hybridization rates of the hetero- and homoduplex were observed with varying concentrations of three different cations (Na(+), K(+), Mg(2+)). With the difference in hybridization rates maximized, discrimination between the hetero- and the homoduplex can be obtained at lower, less rigorous temperatures at hybridization times of 7.5 min or longer.     

The acute hypoxic ventilatory response: testing the adaptive significance in human populations

The acute Hypoxic Ventilatory Response (HVR) is an important component of human hypoxia tolerance, hence presumably physiological adaptation to high altitude. We measured the isocapnic HVR (L min(-1) %(-1)) in two genetically divergent low altitude southern African populations. The HVR does not differ between African Xhosas (X) and Caucasians (C) (X:-0.34+/-0.36; C:-0.42+/-0.33; P > 0.34), but breathing patterns do. Among all Xhosa subjects, size-independent tidal volume was smaller (X: 0.75+/-0.20; C: 1.11+/-0.32 L; P < 0.01), breathing frequency higher (X: 22.2+/-5.7; C: 14.3+/-4.2 breaths min(-1); P < 0.01) and hypoxic oxygen saturation lower than among Caucasians (X: 78.4+/-4.7%; C: 81.7+/-4.7%; P < 0.05). The results remained significant if subjects from Xhosa and Caucasian groups were matched for gender, body mass index and menstrual cycle phase in the case of females. The latter also employed distinct breathing patterns between populations in normoxia. High repeatability (intra-class correlation coefficient) of the HVR in both populations (0.77-0.87) demonstrates that one of the prerequisites for natural selection, consistent between-individual variation, is met. Finally, we explore possible relationships between inter-population genetic distances and HVR differences among Xhosa, European, Aymara Amerindians, Tibetan and Chinese populations. Inter-population differences in the HVR are not attributable to genetic distance (Mantel Z-test, P = 0.59). The results of this study add novel support for the hypothesis that differences in the HVR, should they be found between other human populations, may reflect adaptation to hypoxia rather than genetic divergence through time.     

Cyclic variations in nitrogen uptake rate in soybean plants

Uptake of NO₃⁻ by nonnodulated soybean plants (Glycine max L. Merr. cv Ransom) growing in flowing hydroponic culture at 22 and 14°C root temperatures was measured daily during a 31-day growth period. Ion chromatography was used to determine removal of NO₃⁻ from solution during each 24-hour period. At both root-zone temperatures, rate of NO₃⁻ uptake per plant oscillated with a periodicity of 3 to 5 days. The rate of NO₃⁻ uptake per plant was consistently lower at 14°C than 22°C. The lower rate of NO₃⁻ uptake at 14°C during the initial 5 to 10 days was caused by reduced uptake rates per gram root dry weight, but with time uptake rates per gram root became equal at 14 and 22°C. Thereafter, the continued reduction in rate of NO₃⁻ uptake per plant at 14°C was attributable to slower root growth.     

Effect of intravesical mitomycin C on recurrence of newly diagnosed superficial bladder cancer: interim report from the Medical Research Council Subgroup on Superficial Bladder Cancer (Urological Cancer Working Party)

A randomised control trial of intravesical instillation of mitomycin C was conducted in 457 patients with cancer of the bladder that was confined to the submucosa on histological examination. The events studied were the recurrence free rate, the recurrence rate/year, and the number of new tumours developing/year. At the initial cystoscopy the tumours were completely resected and the patients randomised to have no instillation of mitomycin C, a single instillation of 40 mg in 40 ml of water at that cystoscopy, or a single instillation and then four further instillations. All patients had follow up cystoscopies every three months for the first year, twice in the second year, and yearly thereafter. After a median of 12 months, follow up information was available for 397 patients.Patients receiving both the single instillation of mitomycin C and the instillations at five cystoscopic examinations had significantly lower yearly recurrence rates and tumour rates than those in the control group, and the group receiving multiple instillations fared significantly better than those receiving a single instillation. The figures on progression to invasive cancer were too small to allow conclusions to be drawn.