Association study of MTHFD1 coding polymorphisms R134K and R653Q with migraine susceptibility

Objective There is evidence that folate metabolism has a role in migraine pathophysiology, particularly in the migraine with aura subtype. In this study we investigate whether two non-synonymous single nucleotide polymorphisms (SNPs), rs1950902 (C401T; R134K) and rs2236225 (G1958A; R653Q), in MTHDF1 are associated with migraine in an Australian case-control population. Background Increased plasma levels of homocysteine (HCy), one of the metabolites produced in the folate pathway, has been found to be a risk factor for migraine. There is also a genetic link, as a common polymorphism (C667T) that reduces the catalytic activity of MTHFR, the enzyme that catalyses the formation of HCy, is associated with an increase in risk of the migraine with aura (MA) subtype. MTHFD1 is a crucial multifunctional enzyme that catalyses three separate reactions of the folate pathway and therefore variants in MTHFD1 may also influence migraine susceptibility. Methods The R134K and R653Q variants in MTHFD1 were genotyped in an Australian cohort of 520 unrelated migraineurs (162 were diagnosed with migraine without aura [MO] and 358 with MA) and 520 matched controls. Data were analysed for association with migraine and for interaction with the MTHFR C667T polymorphism. Results We find no significant differences in genotype or allele frequencies for either SNP between migraineurs and controls, or when either MO or MA cases were compared to controls. In addition these MTHFD1 polymorphisms did not appear to influence the risk of MA conferred by the MTHFR 667T allele. Conclusions We find no evidence for association of the MTHFD1 R134K and R653Q polymorphisms with migraine in our Australian case-control population. However, as folate metabolism appears to be important in migraine, particularly with respect to the aura component, future studies using high throughput methods to expand the number of SNPs in folate-related genes genotyped and investigation of interactions between SNPs may be justified.

Environmental, personal, and genetic determinants of response to vitamin D supplementation in older adults

CONTEXT AND OBJECTIVE: Suboptimal vitamin D status can be corrected by vitamin D supplementation, but individual responses to supplementation vary. We aimed to examine genetic and nongenetic determinants of change in serum 25-hydroxyvitamin D (25(OH)D) after supplementation. DESIGN AND PARTICIPANTS: We used data from a pilot randomized controlled trial in which 644 adults aged 60 to 84 years were randomly assigned to monthly doses of placebo, 30 000 IU, or 60 000 IU vitamin D3 for 12 months. Baseline characteristics were obtained from a self-administered questionnaire. Eighty-eight single-nucleotide polymorphisms (SNPs) in 41 candidate genes were genotyped using Sequenom MassArray technology. Serum 25(OH)D levels before and after the intervention were measured using the Diasorin Liaison platform immunoassay. We used linear regression models to examine associations between genetic and nongenetic factors and change in serum 25(OH)D levels. RESULTS: Supplement dose and baseline 25(OH)D level explained 24% of the variability in response to supplementation. Body mass index, self-reported health status, and ambient UV radiation made a small additional contribution. SNPs in CYP2R1, IRF4, MC1R, CYP27B1, VDR, TYRP1, MCM6, and HERC2 were associated with change in 25(OH)D level, although only CYP2R1 was significant after adjustment for multiple testing. Models including SNPs explained a similar proportion of variability in response to supplementation as models that included personal and environmental factors. CONCLUSION: Stepwise regression analyses suggest that genetic variability may be associated with response to supplementation, perhaps suggesting that some people might need higher doses to reach optimal 25(OH)D levels or that there is variability in the physiologically normal level of 25(OH)D.

A transcriptome resource for the koala (Phascolarctos cinereus) : insights into koala retrovirus transcription and sequence diversity

Background The koala, Phascolarctos cinereus, is a biologically unique and evolutionarily distinct Australian arboreal marsupial. The goal of this study was to sequence the transcriptome from several tissues of two geographically separate koalas, and to create the first comprehensive catalog of annotated transcripts for this species, enabling detailed analysis of the unique attributes of this threatened native marsupial, including infection by the koala retrovirus. Results RNA-Seq data was generated from a range of tissues from one male and one female koala and assembled de novo into transcripts using Velvet-Oases. Transcript abundance in each tissue was estimated. Transcripts were searched for likely protein-coding regions and a non-redundant set of 117,563 putative protein sequences was produced. In similarity searches there were 84,907 (72%) sequences that aligned to at least one sequence in the NCBI nr protein database. The best alignments were to sequences from other marsupials. After applying a reciprocal best hit requirement of koala sequences to those from tammar wallaby, Tasmanian devil and the gray short-tailed opossum, we estimate that our transcriptome dataset represents approximately 15,000 koala genes. The marsupial alignment information was used to look for potential gene duplications and we report evidence for copy number expansion of the alpha amylase gene, and of an aldehyde reductase gene. Koala retrovirus (KoRV) transcripts were detected in the transcriptomes. These were analysed in detail and the structure of the spliced envelope gene transcript was determined. There was appreciable sequence diversity within KoRV, with 233 sites in the KoRV genome showing small insertions/deletions or single nucleotide polymorphisms. Both koalas had sequences from the KoRV-A subtype, but the male koala transcriptome has, in addition, sequences more closely related to the KoRV-B subtype. This is the first report of a KoRV-B-like sequence in a wild population. Conclusions This transcriptomic dataset is a useful resource for molecular genetic studies of the koala, for evolutionary genetic studies of marsupials, for validation and annotation of the koala genome sequence, and for investigation of koala retrovirus. Annotated transcripts can be browsed and queried at http://koalagenome.org

The implications of educational and methodological background for the career success of Nobel Laureates : an investigation of major awards

Nobel laureates have achieved the highest recognition in academia, reaching the boundaries of human knowledge and understanding. Owing to past research, we have a good understanding of the career patterns behind their performance. Yet, we have only limited understanding of the factors driving their recognition with respect to major institutionalized scientific honours. We therefore look at the award life cycle achievements of the 1901–2000 Nobel laureates in physics, chemistry, and physiology or medicine. The results show that Nobelists with a theoretical orientation achieved more awards than laureates with an empirical orientation. Moreover, it seems their educational background shapes their future recognition. Researchers educated in Great Britain and the US tend to attract more awards than other Nobelists, although there are career pattern differences. Among those, laureates educated at Cambridge or Harvard are more successful in Chemistry, those from Columbia and Cambridge excel in Physics, while Columbia educated laureates dominate in Physiology or Medicine.

Comparison of intraspecific genetic structure among related chironomids (Diptera) from New Zealand and Patagonia : disparity between potential and realized dispersal

Population genetic studies of freshwater invertebrate taxa in New Zealand and South America are currently few despite the geologically and climatically dynamic histories of these regions. The focus of our study was a comparison of the influence on realized dispersal of 2 closely related nonbiting midges (Chironomidae) of population fragmentation on these separated austral land masses. We used a 734-base pair (bp) fragment of cytochrome c oxidase subunit I (COI) to investigate intraspecific genetic structure in Naonella forsythi Boothroyd in New Zealand and Ferringtonia patagonica Edwards in Patagonia. We proposed hypotheses about their potential dispersal and, hence, expected patterns of genetic structure in these 2 species based on published patterns for the closely related Australian taxon Echinocladius martini Cranston. Genetic structure revealed for both N. forsythi and F. patagonica was characterized by several highly divergent (2.0–10.5%) lineages of late Miocene–Pliocene age within each taxon that were not geographically localized. Many were distributed widely. This pattern differed greatly from population structure in E. martini, which was typified by much greater endemicity of divergent genetic lineages. Nevertheless, diversification of lineages in all 3 taxa appeared to be temporally congruent with the onset of late Miocene glaciations in the southern hemisphere that may have driven fragmentation of suitable habitat, promoting isolation of populations and divergence in allopatry. We argue that differences in realized dispersal post-isolation may be the result of differing availability of suitable habitat in interglacial periods.

Use of genetic decompositions to scaffold the development of a structurally sequenced curriculum for mathematics acceleration

The authors have collaboratively used a graphical language to describe their shared knowledge of a small domain of mathematics, which has in turn scaffolded their re-development of a related curriculum for mathematics acceleration. This collaborative use of the graphical language is reported as a simple descriptive case study. This leads to an evaluation of the graphical language’s usefulness as a tool to support the articulation of the structure of mathematics knowledge. In turn, implications are drawn for how the graphical language may be utilised as the detail of the curriculum is further elaborated and communicated to teachers.

Genetic divergence and echolocation call frequency in cryptic species of Hipposideros larvatus s.l. (Chiroptera : Hipposideridae) from the Indo-Malayan region

The intermediate leaf-nosed bat (Hipposideros larvatus) is a medium-sized bat distributed throughout the Indo-Malay region. In north-east India, bats identified as H. larvatus captured at a single cave emitted echolocation calls with a bimodal distribution of peak frequencies, around either 85 kHz or 98 kHz. Individuals echolocating at 85 kHz had larger ears and longer forearms than those echolocating at 98 kHz, although no differences were detected in either wing morphology or diet, suggesting limited resource partitioning. A comparison of mitochondrial control region haplotypes of the two phonic types with individuals sampled from across the Indo-Malay range supports the hypothesis that, in India, two cryptic species are present. The Indian 98-kHz phonic bats formed a monophyletic clade with bats from all other regional populations sampled, to the exclusion of the Indian 85-kHz bats. In India, the two forms showed 12–13% sequence divergence and we propose that the name Hipposideros khasiana for bats of the 85-kHz phonic type. Bats of the 98-kHz phonic type formed a monophyletic group with bats from Myanmar, and corresponded to Hipposideros grandis, which is suggested to be a species distinct from Hipposideros larvatus. Differences in echolocation call frequency among populations did not reflect phylogenetic relationships, indicating that call frequency is a poor indicator of evolutionary history. Instead, divergence in call frequency probably occurs in allopatry, possibly augmented by character displacement on secondary contact to facilitate intraspecific communication.

Comparative genomics of koala, cattle and sheep strains of Chlamydia pecorum

Background Chlamydia pecorum is an important pathogen of domesticated livestock including sheep, cattle and pigs. This pathogen is also a key factor in the decline of the koala in Australia. We sequenced the genomes of three koala C. pecorum strains, isolated from the urogenital tracts and conjunctiva of diseased koalas. The genome of the C. pecorum VR629 (IPA) strain, isolated from a sheep with polyarthritis, was also sequenced. Results Comparisons of the draft C. pecorum genomes against the complete genomes of livestock C. pecorum isolates revealed that these strains have a conserved gene content and order, sharing a nucleotide sequence similarity > 98%. Single nucleotide polymorphisms (SNPs) appear to be key factors in understanding the adaptive process. Two regions of the chromosome were found to be accumulating a large number of SNPs within the koala strains. These regions include the Chlamydia plasticity zone, which contains two cytotoxin genes (toxA and toxB), and a 77 kbp region that codes for putative type III effector proteins. In one koala strain (MC/MarsBar), the toxB gene was truncated by a premature stop codon but is full-length in IPTaLE and DBDeUG. Another five pseudogenes were also identified, two unique to the urogenital strains C. pecorum MC/MarsBar and C. pecorum DBDeUG, respectively, while three were unique to the koala C. pecorum conjunctival isolate IPTaLE. An examination of the distribution of these pseudogenes in C. pecorum strains from a variety of koala populations, alongside a number of sheep and cattle C. pecorum positive samples from Australian livestock, confirmed the presence of four predicted pseudogenes in koala C. pecorum clinical samples. Consistent with our genomics analyses, none of these pseudogenes were observed in the livestock C. pecorum samples examined. Interestingly, three SNPs resulting in pseudogenes identified in the IPTaLE isolate were not found in any other C. pecorum strain analysed, raising questions over the origin of these point mutations. Conclusions The genomic data revealed that variation between C. pecorum strains were mainly due to the accumulation of SNPs, some of which cause gene inactivation. The identification of these genetic differences will provide the basis for further studies to understand the biology and evolution of this important animal pathogen. Keywords: Chlamydia pecorum; Single nucleotide polymorphism; Pseudogene; Cytotoxin

Néstor-Guillermo Progeria Syndrome: a biochemical insight into Barrier-to-Autointegration Factor 1, alanine 12 threonine mutation

Background Premature aging syndromes recapitulate many aspects of natural aging and provide an insight into this phenomenon at a molecular and cellular level. The progeria syndromes appear to cause rapid aging through disruption of normal nuclear structure. Recently, a coding mutation (c.34G > A [p.A12T]) in the Barrier to Autointegration Factor 1 (BANF1) gene was identified as the genetic basis of Néstor-Guillermo Progeria syndrome (NGPS). This mutation was described to cause instability in the BANF1 protein, causing a disruption of the nuclear envelope structure. Results Here we demonstrate that the BANF1 A12T protein is indeed correctly folded, stable and that the observed phenotype, is likely due to the disruption of the DNA binding surface of the A12T mutant. We demonstrate, using biochemical assays, that the BANF1 A12T protein is impaired in its ability to bind DNA while its interaction with nuclear envelope proteins is unperturbed. Consistent with this, we demonstrate that ectopic expression of the mutant protein induces the NGPS cellular phenotype, while the protein localizes normally to the nuclear envelope. Conclusions Our study clarifies the role of the A12T mutation in NGPS patients, which will be of importance for understanding the development of the disease.

Efficiency of parallelisation of genetic algorithms in the data analysis context

Most real-life data analysis problems are difficult to solve using exact methods, due to the size of the datasets and the nature of the underlying mechanisms of the system under investigation. As datasets grow even larger, finding the balance between the quality of the approximation and the computing time of the heuristic becomes non-trivial. One solution is to consider parallel methods, and to use the increased computational power to perform a deeper exploration of the solution space in a similar time. It is, however, difficult to estimate a priori whether parallelisation will provide the expected improvement. In this paper we consider a well-known method, genetic algorithms, and evaluate on two distinct problem types the behaviour of the classic and parallel implementations.

Lecturing for non-law background students: Assessing the cognitive load of case and legislation-based lecturing approaches

Lecturing is a traditional method for teaching in discipline-based teaching environments and its success in legal discipline depends upon its alignment with learner backgrounds, learning objectives and the lecturing approaches utilised in the classes. In a situation where students do not have any prior knowledge of the given discipline that requires a particular lecturing approach, a mismatch in such an alignment would place learner knowledge acquisition into a challenging situation. From this perspective, this study tests the suitability of two dominant lecturing approaches—the case and the law-based lecturing approaches. It finds that a lecturer should put more emphasis on the case-based approach while lecturing to non-law background business students at the postgraduate level, provided that such an emphasis should be relative to the cognitive ability of the students and their motivation for learning law units.

Genetic characterisation and structural analysis of the O-specific polysaccharide of Yersinia pseudotuberculosis serotype O:1c

Many, but not all, of the current 21 serotypes of Yersinia pseudotuberculosis have been investigated with regard to the chemical structures of their O-specific polysaccharide (OPS) and the genetic basis of their biosynthesis. Completion of the genetics and structures of the remaining serotypes will enhance our understanding of the emerging relationship between genetics and structures within this species. Here, we present a structural and genetic analysis of the Y. pseudotuberculosis serotype O:1c OPS. Our results showed that this OPS has the same backbone as Y. pseudotuberculosis O:2b, but with a 3,6-dideoxy-D-ribo-hexofuranose (paratofuranose, Parf) side-branch instead of a 3,6-dideoxy-D-xylo-hexopyranose (abequopyranose, Abep). The 3'-end of the gene cluster is the same as for O:2b and has the genes for synthesis of the backbone and for processing the completed repeat unit. The 5'-end of the cluster consists of the same genes as O:1b for synthesis of Parf and a related gene for its transfer to the repeating unit backbone.

Variable phenotype in 16p duplication within a family

Background More individuals are now being identified with very rare genetic syndromes. We present a family with an inherited duplication of 16p11.2 to 16q12.1 in ring formation. Three of the four children, (aged 15 months to 10 years), mother, uncle, and grandmother are affected. Our aim was to provide preliminary evidence of possible phenotypic patterns of learning and behaviour associated with this chromosome anomaly. Method Psychometric assessments were undertaken with all four children. The mother and uncle also agreed to participate in the study. Measures of development (Bayley or Mullen), intellectual ability (WISC-IV or WAIS-III), academic achievement (WIAT-II), adaptive behaviour (Vinelands), and other relevant aspects of functioning (e.g., Children’s Memory Scale) were administered. Results. The first-born child is the only one who is unaffected. Her intellectual ability was assessed as being within the superior range. The second child experienced early difficulties with speech and motor skills. Although his intelligence is average, he has learning difficulties and significant auditory memory problems. The third child’s speech and motor milestones were markedly delayed. He has a complex medical history that includes a vitamin B12 deficiency. On the Mullen Scales at age 4 his scores ranged from average to very low. The development of the youngest child (aged 15 months), who also had a B12 deficiency but was treated early, was assessed as being within typical limits. Conclusions There is considerable developmental variability among the three children with this inherited 16p duplication. We discuss the intriguing similarities and differences, considering common features that may reflect phenotypic patterns and speculating about possible explanations for the variable presentations.