A novel locus for Meckel-Gruber syndrome,MKS3, maps to chromosome 8q24

Meckel-Gruber syndrome (MKS), the most common monogenic cause of neural tube defects, is an autosomal recessive disorder characterised by a combination of renal cysts and variably associated features, including developmental anomalies of the central nervous system (typically encephalcoele), hepatic ductal dysplasia and cysts, and polydactyly. Locus heterogeneity has been demonstrated by the mapping of the MKS1locus to 17q21-24 in Finnish kindreds, and of MKS2 to 11q13 in North African-Middle Eastern cohorts. In the present study, we have investigated the genetic basis of MKS in eight consanguineous kindreds, originating from the Indian sub-continent, that do not show linkage to either MKS1 or MKS2. We report the localisation of a third MKS locus ( MKS3) to chromosome 8q24 in this cohort by a genome-wide linkage search using autozygosity mapping. We identified a 26-cM region of autozygosity between D8S586 and D8S1108 with a maximum cumulative two-point LOD score at D8S1179 ( Z(max)=3.04 at theta=0.06). A heterogeneity test provided evidence of one unlinked family. Exclusion of this family from multipoint analysis maximised the cumulative multipoint LOD score at locus D8S1128 ( Z(max)=5.65). Furthermore, a heterozygous SNP in DDEF1, a putative candidate gene, suggested that MKS3 mapped within a 15-cM interval. Comparison of the clinical features of MKS3-linked cases with reports of MKS1- and MKS2-linked kindreds suggests that polydactyly (and possibly encephalocele) appear less common in MKS3-linked families.     

Governance of indigenous policy in the neo-liberal age: indigenous disadvantage and the intersecting of paternalism and neo-liberalism as a racial project

Thinking about the governance of Indigenous poverty as an economic, social and racial project, the paper offers a way of understanding the dynamics of Indigenous policy formation in Australia in the neo-liberal age as what Howard Winant first coined a racial formation. In providing this analysis, this paper sits alongside a small, but growing body of work that reveals the racialized effects of governing through poverty in the neo-liberal age.     

Runs of homozygosity and population history in cattle

ABSTRACT: BACKGROUND: Runs of homozygosity (ROH) are contiguous lengths of homozygous genotypes that are present in an individual due to parents transmitting identical haplotypes to their offspring. The extent and frequency of ROHs may inform on the ancestry of an individual and its population. Here we use high density (n = 777,962) bi-allelic SNPs in a range of cattle breed samples to correlate ROH with the pedigree-based inbreeding coefficients and to validate subsequent analyses using 54,001 SNP genotypes. This study provides a first testing of the inference drawn from ROH through comparison with estimates of inbreeding from calculations based on the detailed pedigree data available for several breeds. RESULTS: All animals genotyped on the HD panel displayed at least one ROH that was between 1--5 Mb in length with certain regions of the genome more likely to be involved in a ROH than others. Strong correlations (r = 0.75, p < 0.0001) existed between the pedigree-based inbreeding coefficient and a statistic based on sum of ROH of length > 0.5 KB and suggests that in the absence of an animal's pedigree data, the extent of a genome under ROH may be used to infer aspects of recent population history even from relatively few samples. CONCLUSIONS: Our findings suggest that ROH are frequent across all breeds but differing patterns of ROH length and burden illustrate variations in breed origins and recent management.     

Soybean Aphid Response to their Alarm Pheromone E-ß-Farnesene (EBF)

When attacked by natural enemies some insect pests, including many aphid species, alert neighboring conspecifics with alarm pheromones. Cornicle secretions with pheromones benefit the attacked aphid but are costly to produce, while alarm pheromone benefits probably fall largely on alerted conspecifics. Given these variable benefits, the likelihood of a secretion may change depending on aphid density. Thus, we first hypothesized that the common alarm pheromone in aphids, E-ß-farnesene (EBF), was present in soybean aphid (Aphis glycines Matsumura) cornicle secretions and would elicit an alarm response in aphids exposed to it. Second, since aphids other than the secretor also benefit from cornicle secretions, we hypothesized that the likelihood of secretion would increase concurrently with the density of neighboring clonal conspecifics. Third, because alarm reaction behavior (e.g. feeding cessation) is probably costly, we hypothesized that alarm reaction behavior would decrease as conspecific density (i.e. alternative prey for an attacking natural enemy) increased. We found that soybean aphids 1) produce cornicle secretions using EBF as an alarm pheromone, 2) are less likely to release cornicle secretions when alone than in a small group (~10 individuals), but that the rate of secretion does not increase further with additional conspecific density, and 3) also exhibit alarm reaction behavior in response to cornicle secretions independent of aphid density. We show that soybean aphids can use their cornicle secretions to warn their neighbors of probable attack by natural enemies, but that both secretion and alarm reaction behavior does not change as density of nearby conspecifics rises above a few individuals.     

Accuracy of StepWatch? and ActiGraph Accelerometers for Measuring Steps Taken among Persons with Multiple Sclerosis

Introduction

There has been increased interest in the objective monitoring of free-living walking behavior using accelerometers in clinical research involving persons with multiple sclerosis (MS). The current investigation examined and compared the accuracy of the StepWatch activity monitor and ActiGraph model GT3X+ accelerometer for capturing steps taken during various speeds of prolonged, over-ground ambulation in persons with MS who had mild, moderate, and severe disability.

Methods

Sixty-three persons with MS underwent a neurological examination for generation of an EDSS score and undertook two trials of walking on the GAITRite electronic walkway. Participants were fitted with accelerometers, and undertook three modified six-minute walk (6MW) tests that were interspersed with 10–15 minutes of rest. The first 6MW was undertaken at a comfortable walking speed (CWS), and the two remaining 6MW tests were undertaken above (faster walking speed; FWS) or below (slower walking speed; SWS) the participant''s CWS. The actual number of steps taken was counted through direct observation using hand-tally counters.

Results

The StepWatch activity monitor (99.8%–99.9%) and ActiGraph model GT3X+ accelerometer (95.6%–97.4%) both demonstrated highly accurate measurement of steps taken under CWS and FWS conditions. The StepWatch had better accuracy (99.0%) than the ActiGraph (95.5%) in the overall sample under the SWS condition, and this was particularly apparent in those with severe disability (StepWatch: 95.7%; ActiGraph: 87.3%). The inaccuracy in measurement for the ActiGraph was associated with alterations of gait (e.g., slower gait velocity, shorter step length, wider base of support).

Conclusions

This research will help inform the choice of accelerometer to be adopted in clinical trials of MS wherein the monitoring of free-living walking behavior is of particular value.     

Essential role of Ca2+/calmodulin in Early Endosome Antigen-1 localization

Ca2+ is an essential requirement in membrane fusion, acting through binding proteins such as calmodulin (CaM). Ca2+/CaM is required for early endosome fusion in vitro, however, the molecular basis for this requirement is unknown. An additional requirement for endosome fusion is the protein Early Endosome Antigen 1 (EEA1), and its recruitment to the endosome depends on phosphatidylinositol 3-phosphate [PI(3)P] and the Rab5 GTPase. Herein, we demonstrate that inhibition of Ca2+/CaM, by using either chemical inhibitors or specific antibodies directed to CaM, results in a profound inhibition of EEA1 binding to endosomal membranes both in live cells and in vitro. The concentration of Ca2+/CaM inhibitors required for a full dissociation of EEA1 from endosomal membranes had no effect on the activity of phosphatidylinositol 3-kinases or on endogenous levels of PI(3)P. However, the interaction of EEA1 with liposomes containing PI(3)P was decreased by Ca2+/CaM inhibitors. Thus, Ca2+/CaM seems to be required for the stable interaction of EEA1 with endosomal PI(3)P, perhaps by directly or indirectly stabilizing the quaternary organization of the C-terminal FYVE domain of EEA1. This requirement is likely to underlie at least in part the essential role of Ca2+/CaM in endosome fusion.     

Multiple transporters associated with malaria parasite responses to chloroquine and quinine

Mutations and/or overexpression of various transporters are known to confer drug resistance in a variety of organisms. In the malaria parasite Plasmodium falciparum, a homologue of P-glycoprotein, PfMDR1, has been implicated in responses to chloroquine (CQ), quinine (QN) and other drugs, and a putative transporter, PfCRT, was recently demonstrated to be the key molecule in CQ resistance. However, other unknown molecules are probably involved, as different parasite clones carrying the same pfcrt and pfmdr1 alleles show a wide range of quantitative responses to CQ and QN. Such molecules may contribute to increasing incidences of QN treatment failure, the molecular basis of which is not understood. To identify additional genes involved in parasite CQ and QN responses, we assayed the in vitro susceptibilities of 97 culture-adapted cloned isolates to CQ and QN and searched for single nucleotide polymorphisms (SNPs) in DNA encoding 49 putative transporters (total 113 kb) and in 39 housekeeping genes that acted as negative controls. SNPs in 11 of the putative transporter genes, including pfcrt and pfmdr1, showed significant associations with decreased sensitivity to CQ and/or QN in P. falciparum. Significant linkage disequilibria within and between these genes were also detected, suggesting interactions among the transporter genes. This study provides specific leads for better understanding of complex drug resistances in malaria parasites.     

Nitrous Oxide Emission from Grazed Grassland Under Different Management Systems

Nitrous oxide (N₂O) emissions from grazed grasslands are estimated to be approximately 28% of global anthropogenic N₂O emissions. Estimating the N₂O flux from grassland soils is difficult because of its episodic nature. This study aimed to quantify the N₂O emissions, the annual N₂O flux and the emission factor (EF), and also to investigate the influence of environmental and soil variables controlling N₂O emissions from grazed grassland. Nitrous oxide emissions were measured using static chambers at eight different grasslands in the South of Ireland from September 2007 to August 2009. The instantaneous N₂O flux values ranged from -186 to 885.6 μg N₂O-N m⁻² h⁻¹ and the annual sum ranged from 2 ± 3.51 to 12.55 ± 2.83 kg N₂O-N ha⁻¹ y⁻¹ for managed sites. The emission factor ranged from 1.3 to 3.4%. The overall EF of 1.81% is about 69% higher than the Intergovernmental Panel on Climate Change (IPCC) default EF value of 1.25% which is currently used by the Irish Environmental Protection Agency (EPA) to estimate N₂O emission in Ireland. At an N applied of approximately 300 kg ha⁻¹ y⁻¹, the N₂O emissions are approximately 5.0 kg N₂O-N ha⁻¹ y⁻¹, whereas the N₂O emissions double to approximately 10 kg N ha⁻¹ for an N applied of 400 kg N ha⁻¹ y⁻¹. The sites with higher fluxes were associated with intensive N-input and frequent cattle grazing. The N₂O flux at 17°C was five times greater than that at 5°C. Similarly, the N₂O emissions increased with increasing water filled pore space (WFPS) with maximum N₂O emissions occurring at 60–80% WFPS. We conclude that N application below 300 kg ha⁻¹ y⁻¹ and restricted grazing on seasonally wet soils will reduce N₂O emissions.     

Genome-wide association study for calving performance using high-density genotypes in dairy and beef cattle

Background

Calving difficulty and perinatal mortality are prevalent in modern-day cattle production systems. It is well-established that there is a genetic component to both traits, yet little is known about their underlying genomic architecture, particularly in beef breeds. Therefore, we performed a genome-wide association study using high-density genotypes to elucidate the genomic architecture of these traits and to identify regions of the bovine genome associated with them.

Results

Genomic regions associated with calving difficulty (direct and maternal) and perinatal mortality were detected using two statistical approaches: (1) single-SNP (single nucleotide polymorphism) regression and (2) a Bayesian approach. Data included high-density genotypes on 770 Holstein-Friesian, 927 Charolais and 963 Limousin bulls. Several novel or previously identified genomic regions were detected but associations differed by breed. For example, two genomic associations, one each on chromosomes 18 and 2 explained 2.49 % and 3.13 % of the genetic variance in direct calving difficulty in the Holstein-Friesian and Charolais populations, respectively. Imputed Holstein-Friesian sequence data was used to refine the genomic regions responsible for significant associations. Several candidate genes on chromosome 18 were identified and four highly significant missense variants were detected within three of these genes (SIGLEC12, CTU1, and ZNF615). Nevertheless, only CTU1 contained a missense variant with a putative impact on direct calving difficulty based on SIFT (0.06) and Polyphen (0.95) scores. Using imputed sequence data, we refined a genomic region on chromosome 4 associated with maternal calving difficulty in the Holstein-Friesian population and found the strongest association with an intronic variant in the PCLO gene. A meta-analysis was performed across the three breeds for each calving performance trait to identify common variants associated with these traits in the three breeds. Our results suggest that a portion of the genetic variation in calving performance is common to all three breeds.

Conclusion

The genomic architecture of calving performance is complex and mainly influenced by many polymorphisms of small effect. We identified several associations of moderate effect size but the majority were breed-specific, indicating that breed-specific alleles exist for calving performance or that the linkage phase between genotyped allele and causal mutation varies between breeds.

Electronic supplementary material

The online version of this article (doi:10.1186/s12711-015-0126-4) contains supplementary material, which is available to authorized users.