Evolvability of Chaperonin Substrate Proteins

Molecular chaperones ensure that their substrate proteins reach the functional native state, and prevent their aggregation. Recently, an additional function was proposed for molecular chaperones: they serve as buffers (_capacitors_) for evolution by permitting their substrate proteins to mutate and at the same time still allowing them to fold productively.

Using pairwise alignments of _E. coli_ genes with genes from other gamma-proteobacteria, we showed that the described buffering effect cannot be observed among substrate proteins of GroEL, an essential chaperone in _E. coli_. Instead, we find that GroEL substrate proteins evolve less than other soluble _E. coli_ proteins. We analyzed several specific structural and biophysical properties of proteins to assess their influence on protein evolution and to find out why specifically GroEL substrates do not show the expected higher divergence from their orthologs.

Our results culminate in four main findings: *1.* We find little evidence that GroEL in _E. coli_ acts as a capacitor for evolution _in vivo_. *2.* GroEL substrates evolved less than other _E. coli_ proteins. *3.* Predominantly structural features appear to be a strong determinant of evolutionary rate. *4.* Besides size, hydrophobicity is a criterion for exclusion for a protein as a chaperonin substrate

The expected neutral frequency spectrum of linked sites

We present an exact, closed expression for the expected neutral Site Frequency Spectrum for two neutral sites, 2-SFS, without recombination. This spectrum is the immediate extension of the well known single site $\theta/f$ neutral SFS. Similar formulae are also provided for the case of the expected SFS of sites that are linked to a focal neutral mutation of known frequency. Formulae for finite samples are obtained by coalescent methods and remarkably simple expressions are derived for the SFS of a large population, which are also solutions of the multi-allelic Kolmogorov equations. Besides the general interest of these new spectra, they relate to interesting biological cases such as structural variants and introgressions. As an example, we present the expected neutral frequency spectrum of regions with a chromosomal inversion.Comment: 26 pages, 5 figure

BlastR—fast and accurate database searches for non-coding RNAs

We present and validate BlastR, a method for efficiently and accurately searching non-coding RNAs. Our approach relies on the comparison of di-nucleotides using BlosumR, a new log-odd substitution matrix. In order to use BlosumR for comparison, we recoded RNA sequences into protein-like sequences. We then showed that BlosumR can be used along with the BlastP algorithm in order to search non-coding RNA sequences. Using Rfam as a gold standard, we benchmarked this approach and show BlastR to be more sensitive than BlastN. We also show that BlastR is both faster and more sensitive than BlastP used with a single nucleotide log-odd substitution matrix. BlastR, when used in combination with WU-BlastP, is about 5% more accurate than WU-BlastN and about 50 times slower. The approach shown here is equally effective when combined with the NCBI-Blast package. The software is an open source freeware available from www.tcoffee.org/blastr.htm

THE COMPLEX INTERPLAY BETWEEN VITAMIN D DEFICIENCY AND DIABETES

It has been recently highlighted the link between vitamin D and metabolic and immunological pro- cesses, which established its role as an essential component of human health preservation. Vitamin D has been defined as natural immune modulators, and through the activation of its receptors (VDRs), it regulates calcium metabolism, cellular growth, proliferation and apoptosis, and other immunological functions. In this setting, vita- min D has also been reported to influence glucose regulation via effects on insulin secretion and action. Vitamin D deficiency is strongly associated with obesity mostly due to the storage of vitamin D in adipose tissue because of its lipophilic properties. The decrease in vitamin D levels may occur through several mechanisms such as a decrease in the calcium concentration, an increase in PTH, or a direct effect of vitamin D on worsening insulin resistance and secretion, augmenting the risk of developing type 2 diabetes. On the other hand, retrospective analysis and observational studies demonstrated high prevalence of vitamin D deficiency in patients with type 1 diabetes and suggested a contributory role in the pathogenesis of type 1 diabetes, specially with certain allelic variations of the VDR. Vitamin D supplementation during pregnancy and early childhood decreased the risk of autoimmune dia- betes and perhaps, even after the onset of diabetes, it may improve glycemic control. In addition, in subjects that are affected by a high risk of developing diabetes (impaired fasting glucose and/or glucose tolerance, possibly without obesity) vitamin D supplementation could be helpful on the prevention of type 2 diabete

Dissecting structural and nucleotide genome-wide variation in inbred Iberian pigs

In contrast to international pig breeds, the Iberian breed has not been admixed with Asian germplasm. This makes it an important model to study both domestication and relevance of Asian genes in the pig. Besides, Iberian pigs exhibit high meat quality as well as appetite and propensity to obesity. Here we provide a genome wide analysis of nucleotide and structural diversity in a reduced representation library from a pool (n=9 sows) and shotgun genomic sequence from a single sow of the highly inbred Guadyerbas strain. In the pool, we applied newly developed tools to account for the peculiarities of these data. A total of 254,106 SNPs in the pool (79.6 Mb covered) and 643,783 in the Guadyerbas sow (1.47 Gb covered) were called. The nucleotide diversity (1.31x10 -3 per bp in autosomes) is very similar to that reported in wild boar. A much lower than expected diversity in the X chromosome was confirmed (1.79x10 -4 per bp in the individual and 5.83x10 -4 per bp in the pool). A strong (0.70) correlation between recombination and variability was observed, but not with gene density or GC content. Multicopy regions affected about 4% of annotated pig genes in their entirety, and 2% of the genes partially. Genes within the lowest variability windows comprised interferon genes and, in chromosome X, genes involved in behavior like HTR2C or MCEP2. A modified Hudson-Kreitman-Aguadé test for pools also indicated an accelerated evolution in genes involved in behavior, as well as in spermatogenesis and in lipid metabolism. This work illustrates the strength of current sequencing technologies to picture a comprehensive landscape of variability in livestock species, and to pinpoint regions containing genes potentially under selection. Among those genes, we report genes involved in behavior, including feeding behavior, and lipid metabolism. The pig X chromosome is an outlier in terms of nucleotide diversity, which suggests selective constraints. Our data further confirm the importance of structural variation in the species, including Iberian pigs, and allowed us to identify new paralogs for known gene families

BlastR—fast and accurate database searches for non-coding RNAs

We present and validate BlastR, a method for efficiently and accurately searching non-coding RNAs. Our approach relies on the comparison of di-nucleotides using BlosumR, a new log-odd substitution matrix. In order to use BlosumR for comparison, we recoded RNA sequences into protein-like sequences. We then showed that BlosumR can be used along with the BlastP algorithm in order to search non-coding RNA sequences. Using Rfam as a gold standard, we benchmarked this approach and show BlastR to be more sensitive than BlastN. We also show that BlastR is both faster and more sensitive than BlastP used with a single nucleotide log-odd substitution matrix. BlastR, when used in combination with WU-BlastP, is about 5% more accurate than WU-BlastN and about 50 times slower. The approach shown here is equally effective when combined with the NCBI-Blast package. The software is an open source freeware available from www.tcoffee.org/blastr.html

A comprehensive assessment of somatic mutation detection in cancer using whole-genome sequencing.

As whole-genome sequencing for cancer genome analysis becomes a clinical tool, a full understanding of the variables affecting sequencing analysis output is required. Here using tumour-normal sample pairs from two different types of cancer, chronic lymphocytic leukaemia and medulloblastoma, we conduct a benchmarking exercise within the context of the International Cancer Genome Consortium. We compare sequencing methods, analysis pipelines and validation methods. We show that using PCR-free methods and increasing sequencing depth to ∼ 100 × shows benefits, as long as the tumour:control coverage ratio remains balanced. We observe widely varying mutation call rates and low concordance among analysis pipelines, reflecting the artefact-prone nature of the raw data and lack of standards for dealing with the artefacts. However, we show that, using the benchmark mutation set we have created, many issues are in fact easy to remedy and have an immediate positive impact on mutation detection accuracy.We thank the DKFZ Genomics and Proteomics Core Facility and the OICR Genome Technologies Platform for provision of sequencing services. Financial support was provided by the consortium projects READNA under grant agreement FP7 Health-F4-2008-201418, ESGI under grant agreement 262055, GEUVADIS under grant agreement 261123 of the European Commission Framework Programme 7, ICGC-CLL through the Spanish Ministry of Science and Innovation (MICINN), the Instituto de Salud Carlos III (ISCIII) and the Generalitat de Catalunya. Additional financial support was provided by the PedBrain Tumor Project contributing to the International Cancer Genome Consortium, funded by German Cancer Aid (109252) and by the German Federal Ministry of Education and Research (BMBF, grants #01KU1201A, MedSys #0315416C and NGFNplus #01GS0883; the Ontario Institute for Cancer Research to PCB and JDM through funding provided by the Government of Ontario, Ministry of Research and Innovation; Genome Canada; the Canada Foundation for Innovation and Prostate Cancer Canada with funding from the Movember Foundation (PCB). PCB was also supported by a Terry Fox Research Institute New Investigator Award, a CIHR New Investigator Award and a Genome Canada Large-Scale Applied Project Contract. The Synergie Lyon Cancer platform has received support from the French National Institute of Cancer (INCa) and from the ABS4NGS ANR project (ANR-11-BINF-0001-06). The ICGC RIKEN study was supported partially by RIKEN President’s Fund 2011, and the supercomputing resource for the RIKEN study was provided by the Human Genome Center, University of Tokyo. MDE, LB, AGL and CLA were supported by Cancer Research UK, the University of Cambridge and Hutchison-Whampoa Limited. SD is supported by the Torres Quevedo subprogram (MI CINN) under grant agreement PTQ-12-05391. EH is supported by the Research Council of Norway under grant agreements 221580 and 218241 and by the Norwegian Cancer Society under grant agreement 71220-PR-2006-0433. Very special thanks go to Jennifer Jennings for administrating the activity of the ICGC Verification Working Group and Anna Borrell for administrative support.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms1000

Whole-epigenome analysis in multiple myeloma reveals DNA hypermethylation of B cell-specific enhancers

Contains fulltext : 140075.pdf (Publisher’s version ) (Open Access

Multi-Platform Next-Generation Sequencing of the Domestic Turkey (Meleagris gallopavo): Genome Assembly and Analysis

The combined application of next-generation sequencing platforms has provided an economical approach to unlocking the potential of the turkey genome