Poor Homologous Synapsis 1 Interacts with Chromatin but Does Not Colocalise with ASYnapsis 1 during Early Meiosis in Bread Wheat

Chromosome pairing, synapsis, and DNA recombination are three key processes that occur during early meiosis. A previous study of Poor Homologous Synapsis 1 (PHS1) in maize suggested that PHS1 has a role in coordinating these three processes. Here we report the isolation of wheat (Triticum aestivum) PHS1 (TaPHS1), and its expression profile during and after meiosis. While the TaPHS1 protein has sequence similarity to other plant PHS1/PHS1-like proteins, it also possesses a unique region of oligopeptide repeat units. We show that TaPHS1 interacts with both single- and double-stranded DNA in vitro and provide evidence of the protein region that imparts the DNA-binding ability. Immunolocalisation data from assays conducted using antisera raised against TaPHS1 show that TaPHS1 associates with chromatin during early meiosis, with the signal persisting beyond chromosome synapsis. Furthermore, TaPHS1 does not appear to colocalise with the asynapsis protein (TaASY1) suggesting that these proteins are probably independently coordinated. Significantly, the data from the DNA-binding assays and 3-dimensional immunolocalisation of TaPHS1 during early meiosis indicates that TaPHS1 interacts with DNA, a function not previously observed in either the Arabidopsis or maize PHS1 homologues. As such, these results provide new insight into the function of PHS1 during early meiosis in bread wheat

Constitutively Nuclear FOXO3a Localization Predicts Poor Survival and Promotes Akt Phosphorylation in Breast Cancer

Background: The PI3K-Akt signal pathway plays a key role in tumorigenesis and the development of drug-resistance. Cytotoxic chemotherapy resistance is linked to limited therapeutic options and poor prognosis. Methodology/Principal Findings: Examination of FOXO3a and phosphorylated-Akt (P-Akt) expression in breast cancer tissue microarrays showed nuclear FOXO3a was associated with lymph node positivity (p = 0.052), poor prognosis (p = 0.014), and P-Akt expression in invasive ductal carcinoma. Using tamoxifen and doxorubicin-sensitive and -resistant breast cancer cell lines as models, we found that doxorubicin- but not tamoxifen-resistance is associated with nuclear accumulation of FOXO3a, consistent with the finding that sustained nuclear FOXO3a is associated with poor prognosis. We also established that doxorubicin treatment induces proliferation arrest and FOXO3a nuclear relocation in sensitive breast cancer cells. Induction of FOXO3a activity in doxorubicin-sensitive MCF-7 cells was sufficient to promote Akt phosphorylation and arrest cell proliferation. Conversely, knockdown of endogenous FOXO3a expression reduced PI3K/Akt activity. Using MDA-MB-231 cells, in which FOXO3a activity can be induced by 4-hydroxytamoxifen, we showed that FOXO3a induction up-regulates PI3K-Akt activity and enhanced doxorubicin resistance. However FOXO3a induction has little effect on cell proliferation, indicating that FOXO3a or its downstream activity is deregulated in the cytotoxic drug resistant breast cancer cells. Thus, our results suggest that sustained FOXO3a activation can enhance hyperactivation of the PI3K/Akt pathway. Conclusions/Significance: Together these data suggest that lymph node metastasis and poor survival in invasive ductal breast carcinoma are linked to an uncoupling of the Akt-FOXO3a signaling axis. In these breast cancers activated Akt fails to inactivate and re-localize FOXO3a to the cytoplasm, and nuclear-targeted FOXO3a does not induce cell death or cell cycle arrest. As such, sustained nuclear FOXO3a expression in breast cancer may culminate in cancer progression and the development of an aggressive phenotype similar to that observed in cytotoxic chemotherapy resistant breast cancer cell models. © 2010 Chen et al.published_or_final_versio

Identification of novel breast cancer susceptibility loci in meta-analyses conducted among Asian and European descendants

Abstract: Known risk variants explain only a small proportion of breast cancer heritability, particularly in Asian women. To search for additional genetic susceptibility loci for breast cancer, here we perform a meta-analysis of data from genome-wide association studies (GWAS) conducted in Asians (24,206 cases and 24,775 controls) and European descendants (122,977 cases and 105,974 controls). We identified 31 potential novel loci with the lead variant showing an association with breast cancer risk at P < 5 × 10−8. The associations for 10 of these loci were replicated in an independent sample of 16,787 cases and 16,680 controls of Asian women (P < 0.05). In addition, we replicated the associations for 78 of the 166 known risk variants at P < 0.05 in Asians. These findings improve our understanding of breast cancer genetics and etiology and extend previous findings from studies of European descendants to Asian women

Identification of novel breast cancer susceptibility loci in meta-analyses conducted among Asian and European descendants

Abstract: Known risk variants explain only a small proportion of breast cancer heritability, particularly in Asian women. To search for additional genetic susceptibility loci for breast cancer, here we perform a meta-analysis of data from genome-wide association studies (GWAS) conducted in Asians (24,206 cases and 24,775 controls) and European descendants (122,977 cases and 105,974 controls). We identified 31 potential novel loci with the lead variant showing an association with breast cancer risk at P < 5 × 10−8. The associations for 10 of these loci were replicated in an independent sample of 16,787 cases and 16,680 controls of Asian women (P < 0.05). In addition, we replicated the associations for 78 of the 166 known risk variants at P < 0.05 in Asians. These findings improve our understanding of breast cancer genetics and etiology and extend previous findings from studies of European descendants to Asian women

Common QTL and multi-purpose markers for the resistance of five synthetic hexaploids against two species of root lesion nematode

The root lesion nematodes Pratylenchus thornei and P. neglectus are major constraints to cereal production. Among cultivated wheats, there are few good sources of resistance. Among synthetic hexaploid wheats, several lines had been discovered with partial resistance against both nematode species. Using genome-wide marker arrays (SNP and DArTTM) we mapped quantitative trait loci (QTL) for resistance from five partially resistant synthetics of diverse origin (CPI133872, CPI133842, CPI133859, TAMD870167/AUS18913 and Yallaroi/AUS18913). The results were very similar among resistance sources and across nematode species, with QTL detected on chromosome 2B and in two regions of chromosome 6D. To provide tools that wheat breeders can use to select for the synthetic-derived resistance, we added more SNP markers to the QTL regions and assayed those markers on a validation panel of wheat cultivars. This allowed us to identify sets of two or three markers per QTL region. For each set, all five synthetics share a haplotype that is rare or absent among the cultivated wheats in the panel. These markers can be rapidly assayed using KASPTM end-point genotyping and could be adapted to other genotyping technologies for application in wheat breeding

A QTL on the Ca7 chromosome of chickpea affects resistance to the root‑lesion nematode Pratylenchus thornei

Abstract The root-lesion nematode Pratylenchus thornei Sher & Allen, 1953 is a damaging parasite of many crop plants, including the grain legume chickpea (Cicer arietinum L.). Within cultivated chickpea, there are no known sources of strong resistance to P. thornei, but some cultivars have partial resistance. In the research reported here, the genetic basis for differences in P. thornei resistance was analysed using a population derived by accelerated single seed descent from a cross between a partially resistant cultivar, PBA HatTrick, and a very susceptible cultivar, Kyabra. A genetic linkage map was constructed from genotyping-by-sequencing data. Two quantitative trait loci were mapped, one on the Ca4 chromosome and one on the Ca7 chromosome. The Ca7 locus had a greater and more consistent effect than the Ca4 locus. Marker assays designed for single nucleotide polymorphisms on Ca7 were applied to a panel of chickpea accessions. Some of these markers should be useful for marker-assisted selection in chickpea breeding. Haplotype analysis confirmed the Iranian landrace ICC14903 to be the source of the resistance allele in PBA HatTrick and indicated that other Australian cultivars inherited the same allele from other Iranian landraces. A candidate region was defined on the Ca7 pseudomolecule. Within that region, 69 genes have been predicted with high confidence. Among these, two have annotations related to biotic stress response. Three others have previously been reported to be expressed in roots of PBA HatTrick and Kyabra, including one that is more highly expressed in PBA HatTrick than in Kyabra

Preliminary characterisation of two early meiotic wheat proteins after identification through 2D gel electrophoresis proteomics

Various genetic-based approaches including mutant population screens, microarray analyses, cloning and transgenesis have broadened our knowledge of gene function during meiosis in plants. Nonetheless, these genetic tools are not without inherent limitations. One alternative approach to studying plant meiosis, especially in polyploids such as Triticum aestivum L. (bread wheat), is proteomics. However, protein-based approaches using proteomics have seldom been described, with only two attempts at studying early plant meiosis reported. Here, we report the investigation of early bread wheat meiosis using proteomics. Five differentially expressed protein spots were identified using 2D gel electrophoresis (2DGE) on protein extracts from four pooled stages of meiosis and three genotypes (Chinese Spring wild-type, ph1b and ph2a wheat mutant lines). Tandem mass spectrometry (MS/MS) identification of peptides from these protein spots led to the isolation and characterisation of the full-length clones of a wheat Speckle-typePOZprotein, an SF21-like protein and HSP70, and a partial coding sequence of a hexose transporter. Significantly, the putative functions of the Speckle-type POZ protein and HSP70 were confirmed using in vitro DNA binding assays. Through the use of a 2DGE proteomics approach, we show that proteomics is a viable alternative to genetic-based approaches when studying meiosis in wheat. More significantly, we report a potential role for a Speckle-type POZ protein and a HSP70 in chromosome pairing during the early stages of meiosis in bread wheat.Kelvin H.P. Khoo, Amanda J. Able, Timothy K. Chataway and Jason A. Abl

Identification of novel breast cancer susceptibility loci in meta-analyses conducted among Asian and European descendants.

Known risk variants explain only a small proportion of breast cancer heritability, particularly in Asian women. To search for additional genetic susceptibility loci for breast cancer, here we perform a meta-analysis of data from genome-wide association studies (GWAS) conducted in Asians (24,206 cases and 24,775 controls) and European descendants (122,977 cases and 105,974 controls). We identified 31 potential novel loci with the lead variant showing an association with breast cancer risk at P < 5 × 10-8. The associations for 10 of these loci were replicated in an independent sample of 16,787 cases and 16,680 controls of Asian women (P < 0.05). In addition, we replicated the associations for 78 of the 166 known risk variants at P < 0.05 in Asians. These findings improve our understanding of breast cancer genetics and etiology and extend previous findings from studies of European descendants to Asian women