Dominance of one T-cell receptor in the H-2Kb/TNP response

T-cell receptors (TCRs) recognize foreign antigens in the context of major histocompatibility complex (MHC)-encoded cell surface proteins. These receptors are heterogeneous, dimeric glycoproteins composed of disulphide linked alpha- and beta-chains. We analysed the diversity of TCRs in a collection of H-2Kb-restricted, 2,4,6-trinitrophenyl (TNP)-specific (H-2Kb/TNP) cytotoxic T-cell (Tc) clones from C57BL/6 mice. Investigation of the beta-chain messenger RNAs revealed that nearly half of these independent clones expressed an identical beta-chain gene. We show here that almost all the Tc clones expressing the predominant beta-chain gene also express an identical alpha-chain gene. These results show that a strong selective pressure acted on the Tc population, resulting in a skewing of the TCR repertoire for H-2Kb/TNP and in the dominant expression of one TCR with this specificity. Possible explanations for this skewing include antigen-driven clonal expansion and network interactions.     

Drosophila Nesprin-1 controls glutamate receptor density at neuromuscular junctions

Nesprin-1 is a core component of a protein complex connecting nuclei to cytoskeleton termed LINC (linker of nucleoskeleton and cytoskeleton). Nesprin-1 is anchored to the nuclear envelope by its C-terminal KASH domain, the disruption of which has been associated with neuronal and neuromuscular pathologies, including autosomal recessive cerebellar ataxia and Emery–Dreifuss muscular dystrophy. Here, we describe a new and unexpected role of Drosophila Nesprin-1, Msp-300, in neuromuscular junction. We show that larvae carrying a deletion of Msp-300 KASH domain (Msp-300 ^?KASH ) present a locomotion defect suggestive of a myasthenia, and demonstrate the importance of muscle Msp-300 for this phenotype, using tissue-specific RNAi knock-down. We show that Msp-300 ^?KASH mutants display abnormal neurotransmission at the larval neuromuscular junction, as well as an imbalance in postsynaptic glutamate receptor composition with a decreased percentage of GluRIIA-containing receptors. We could rescue Msp-300 ^?KASH locomotion phenotypes by GluRIIA overexpression, suggesting that the locomotion impairment associated with the KASH domain deletion is due to a reduction in junctional GluRIIA. In summary, we found that Msp-300 controls GluRIIA density at the neuromuscular junction. Our results suggest that Drosophila is a valuable model for further deciphering how Nesprin-1 and LINC disruption may lead to neuronal and neuromuscular pathologies.     

Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes

We performed a genome-wide association scan to search for sequence variants conferring risk of prostate cancer using 1,501 Icelandic men with prostate cancer and 11,290 controls. Follow-up studies involving three additional case-control groups replicated an association of two variants on chromosome 17 with the disease. These two variants, 33 Mb apart, fall within a region previously implicated by family-based linkage studies on prostate cancer. The risks conferred by these variants are moderate individually (allele odds ratio of about 1.20), but because they are common, their joint population attributable risk is substantial. One of the variants is in TCF2 (HNF1beta), a gene known to be mutated in individuals with maturity-onset diabetes of the young type 5. Results from eight case-control groups, including one West African and one Chinese, demonstrate that this variant confers protection against type 2 diabetes.     

Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis

Multiple sclerosis is a demyelinating neurodegenerative disease with a strong genetic component. Previous genetic risk studies have failed to identify consistently linked regions or genes outside of the major histocompatibility complex on chromosome 6p. We describe allelic association of a polymorphism in the gene encoding the interleukin 7 receptor alpha chain (IL7R) as a significant risk factor for multiple sclerosis in four independent family-based or case-control data sets (overall P = 2.9 x 10(-7)). Further, the likely causal SNP, rs6897932, located within the alternatively spliced exon 6 of IL7R, has a functional effect on gene expression. The SNP influences the amount of soluble and membrane-bound isoforms of the protein by putatively disrupting an exonic splicing silencer.     

A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC

The proteins encoded by the classical HLA class I and class II genes in the major histocompatibility complex (MHC) are highly polymorphic and are essential in self versus non-self immune recognition. HLA variation is a crucial determinant of transplant rejection and susceptibility to a large number of infectious and autoimmune diseases. Yet identification of causal variants is problematic owing to linkage disequilibrium that extends across multiple HLA and non-HLA genes in the MHC. We therefore set out to characterize the linkage disequilibrium patterns between the highly polymorphic HLA genes and background variation by typing the classical HLA genes and >7,500 common SNPs and deletion-insertion polymorphisms across four population samples. The analysis provides informative tag SNPs that capture much of the common variation in the MHC region and that could be used in disease association studies, and it provides new insight into the evolutionary dynamics and ancestral origins of the HLA loci and their haplotypes.     

Reverse breeding in Arabidopsis thaliana generates homozygous parental lines from a heterozygous plant

Traditionally, hybrid seeds are produced by crossing selected inbred lines. Here we provide a proof of concept for reverse breeding, a new approach that simplifies meiosis such that homozygous parental lines can be generated from a vigorous hybrid individual. We silenced DMC1, which encodes the meiotic recombination protein DISRUPTED MEIOTIC cDNA1, in hybrids of A. thaliana, so that non-recombined parental chromosomes segregate during meiosis. We then converted the resulting gametes into adult haploid plants, and subsequently into homozygous diploids, so that each contained half the genome of the original hybrid. From 36 homozygous lines, we selected 3 (out of 6) complementing parental pairs that allowed us to recreate the original hybrid by intercrossing. In addition, this approach resulted in a complete set of chromosome-substitution lines. Our method allows the selection of a single choice offspring from a segregating population and preservation of its heterozygous genotype by generating homozygous founder lines.     

Whole-genome analysis of diverse Chlamydia trachomatis strains identifies phylogenetic relationships masked by current clinical typing

Chlamydia trachomatis is responsible for both trachoma and sexually transmitted infections, causing substantial morbidity and economic cost globally. Despite this, our knowledge of its population and evolutionary genetics is limited. Here we present a detailed phylogeny based on whole-genome sequencing of representative strains of C. trachomatis from both trachoma and lymphogranuloma venereum (LGV) biovars from temporally and geographically diverse sources. Our analysis shows that predicting phylogenetic structure using ompA, which is traditionally used to classify Chlamydia, is misleading because extensive recombination in this region masks any true relationships present. We show that in many instances, ompA is a chimera that can be exchanged in part or as a whole both within and between biovars. We also provide evidence for exchange of, and recombination within, the cryptic plasmid, which is another key diagnostic target. We used our phylogenetic framework to show how genetic exchange has manifested itself in ocular, urogenital and LGV C. trachomatis strains, including the epidemic LGV serotype L2b.     

Ecological impacts of seed harvester ants on soil attributes in a Larrea -dominated shrubland

The influence of seed harvester ant ( Pogonomyrmex rugosus ) colonies on soil properties and soil surface and moisture characteristics was investigated through comparison of adjacent, nonnest (reference, 4 m beyond ant colony) areas in Las Vegas, Nevada. Effects of ant colonies on both terrace and slope sites were investigated. Soil moisture content and soil bulk density in a creosote bush ( Larrea tridentata )--dominated shrubland were significantly lower, while soil temperature, soil organic matter, and percent pore space were significantly higher in soils with ant nests relative to adjacent reference soils. Soil pH and texture did not differ significantly between nest and reference soils. Among soil surface characteristics, percent bare soil and rock (gravel, cobble, and boulder) cover were not significantly different between nest and reference soils. In evaluating soil moisture characteristics, soils with ant nests had a significantly higher water infiltrability and greater depth of water penetration, but a significantly lower area of water spread (surface-water runoff) at both terrace and slope sites. Between the 2 geomorphic surfaces, water infiltrability and depth of water penetration were significantly greater at the terrace than at the slope. Water-borne soil movement (fluvial erosion) was significantly greater at the slope than terrace but did not differ significantly between nest and reference soils. The presence of active P. rugosus colonies in the L. tridentata -dominated shrubland altered certain soil properties and appeared to have a protective influence on the soil by fostering more infiltration and less runoff of surface water in southern Nevada.     

Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss

DNA methyltransferase 1 (DNMT1) is crucial for maintenance of methylation, gene regulation and chromatin stability. DNA mismatch repair, cell cycle regulation in post-mitotic neurons and neurogenesis are influenced by DNA methylation. Here we show that mutations in DNMT1 cause both central and peripheral neurodegeneration in one form of hereditary sensory and autonomic neuropathy with dementia and hearing loss. Exome sequencing led to the identification of DNMT1 mutation c.1484A>G (p.Tyr495Cys) in two American kindreds and one Japanese kindred and a triple nucleotide change, c.1470-1472TCC>ATA (p.Asp490Glu-Pro491Tyr), in one European kindred. All mutations are within the targeting-sequence domain of DNMT1. These mutations cause premature degradation of mutant proteins, reduced methyltransferase activity and impaired heterochromatin binding during the G2 cell cycle phase leading to global hypomethylation and site-specific hypermethylation. Our study shows that DNMT1 mutations cause the aberrant methylation implicated in complex pathogenesis. The discovered DNMT1 mutations provide a new framework for the study of neurodegenerative diseases.