Pseudoxanthoma elasticum: reduced gamma-glutamyl carboxylation of matrix gla protein in a mouse model (Abcc6-/-)

Pseudoxanthoma elasticum (PXE), a heritable multi-system disorder manifesting with ectopic mineralization of soft connective tissues, is caused by mutations in the ABCC6/MRP6 gene/protein system, but the mechanisms how the ABCC6 mutations lead to aberrant mineralization are currently unknown. In this study, we utilized a transgenic mouse model, Abcc6^−/−, to examine the mineralization processes. We focused on matrix gla protein (MGP) which has been shown to be critical, when activated by γ-carboxylation of glutamyl residues, for prevention of unwanted mineralization. The concentration of MGP in the serum of Abcc6^−/− mice was significantly reduced when compared to wild-type controls (p < 0.004). More importantly, MGP isolated from the liver of Abcc6^−/− mice was largely under-carboxylated and therefore possesses no activity. Finally, examination of the Abcc6^−/− mice revealed association of total and under-carboxylated forms of MGP with ectopic mineralization while the γ-carboxylated form was essentially absent. These results suggest that MGP in Abcc6^−/− mice is largely in inactive form and is unable to prevent the unwanted mineralization of connective tissues in PXE.     

Molecular phylogenetic and molecular dating of the New Zealand Gleicheniaceae

The Gleicheniaceae are an ancient family of ferns, with three of the six extant genera occurring in New Zealand:Dicranopteris, Gleichenia, andSticherus. The biogeographic origins of this family in New Zeland are unknown, and the taxonomy ofGleichenia in particular is still unclear. To address aspects of these two issues, DNA sequences from thetrnL-trnF locus and therbcL gene were produced for all of the common Gleicheniaceae species in New Zealand, as well as forGleichenia alpina from Tasmania andSticherus cryptocarpus from Chile. SeveraltrnL-trnF haplotypes were found amongst New ZealandG. dicarpa. One of these haplotypes was also observed in TasmanianG. alpina, while the other New ZealandG. dicarpa trnL-trnF haplotypes were more similar to those ofG. microphylla. These results suggest the taxonomy of New ZealandGleichenia may be more complex than presently recognized. Molecular dating of therbcL sequences with the program r8s rejected vicariant explanations for the disjunct distributions between New Zealand and elsewhere for each ofDicranopteris, Gleichenia, andSticherus. However, the direction of the inferred long-distance dispersal was not resolved.     

In‐depth comparative analysis of Illumina® MiSeq run metrics: Development of a wet‐lab quality assessment tool

Whole genome sequencing of bacterial isolates has become a daily task in many laboratories, generating incredible amounts of data. However, data acquisition is not an end in itself; the goal is to acquire high‐quality data useful for understanding genetic relationships. Having a method that could rapidly determine which of the many available run metrics are the most important indicators of overall run quality and having a way to monitor these during a given sequencing run would be extremely helpful to this effect. Therefore, we compared various run metrics across 486 MiSeq runs, from five different machines. By performing a statistical analysis using principal components analysis and a K‐means clustering algorithm of the metrics, we were able to validate metric comparisons among instruments, allowing for the development of a predictive algorithm, which permits one to observe whether a given MiSeq run has performed adequately. This algorithm is available in an Excel spreadsheet: that is, MiSeq Instrument & Run (In‐Run) Forecast. Our tool can help verify that the quantity/quality of the generated sequencing data consistently meets or exceeds recommended manufacturer expectations. Patterns of deviation from those expectations can be used to assess potential run problems and plan preventative maintenance, which can save valuable time and funding resources.     

Genetic variation and possible origins of weedy rice found in California

Control of weeds in cultivated crops is a pivotal component in successful crop production allowing higher yield and higher quality. In rice‐growing regions worldwide, weedy rice (Oryza sativa f. spontanea Rosh.) is a weed related to cultivated rice which infests rice fields. With populations across the globe evolving a suite of phenotypic traits characteristic of weeds and of cultivated rice, varying hypotheses exist on the origin of weedy rice. Here, we investigated the genetic diversity and possible origin of weedy rice in California using 98 simple sequence repeat (SSR) markers and an Rc gene‐specific marker. By employing phylogenetic clustering analysis, we show that four to five genetically distinct biotypes of weedy rice exist in California. Analysis of population structure and genetic distance among individuals reveals diverse evolutionary origins of California weedy rice biotypes, with ancestry derived from indica, aus, and japonica cultivated rice as well as possible contributions from weedy rice from the southern United States and wild rice. Because this diverse parentage primarily consists of weedy, wild, and cultivated rice not found in California, most existing weedy rice biotypes likely originated outside California.     

Profound Perturbation of the Metabolome in Obesity Is Associated with Health Risk

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Mutations in NOTCH1 Cause Adams-Oliver Syndrome

Notch signaling determines and reinforces cell fate in bilaterally symmetric multicellular eukaryotes. Despite the involvement of Notch in many key developmental systems, human mutations in Notch signaling components have mainly been described in disorders with vascular and bone effects. Here, we report five heterozygous NOTCH1 variants in unrelated individuals with Adams-Oliver syndrome (AOS), a rare disease with major features of aplasia cutis of the scalp and terminal transverse limb defects. Using whole-genome sequencing in a cohort of 11 families lacking mutations in the four genes with known roles in AOS pathology (ARHGAP31, RBPJ, DOCK6, and EOGT), we found a heterozygous de novo 85 kb deletion spanning the NOTCH1 5′ region and three coding variants (c.1285T>C [p.Cys429Arg], c.4487G>A [p.Cys1496Tyr], and c.5965G>A [p.Asp1989Asn]), two of which are de novo, in four unrelated probands. In a fifth family, we identified a heterozygous canonical splice-site variant (c.743−1 G>T) in an affected father and daughter. These variants were not present in 5,077 in-house control genomes or in public databases. In keeping with the prominent developmental role described for Notch1 in mouse vasculature, we observed cardiac and multiple vascular defects in four of the five families. We propose that the limb and scalp defects might also be due to a vasculopathy in NOTCH1-related AOS. Our results suggest that mutations in NOTCH1 are the most common cause of AOS and add to a growing list of human diseases that have a vascular and/or bony component and are caused by alterations in the Notch signaling pathway.