Identification, replication, and fine-mapping of Loci associated with adult height in individuals of african ancestry

Adult height is a classic polygenic trait of high heritability (h ² ∼0.8). More than 180 single nucleotide polymorphisms (SNPs), identified mostly in populations of European descent, are associated with height. These variants convey modest effects and explain ∼10% of the variance in height. Discovery efforts in other populations, while limited, have revealed loci for height not previously implicated in individuals of European ancestry. Here, we performed a meta-analysis of genome-wide association (GWA) results for adult height in 20,427 individuals of African ancestry with replication in up to 16,436 African Americans. We found two novel height loci (Xp22-rs12393627, P = 3.4×10⁻¹² and 2p14-rs4315565, P = 1.2×10⁻⁸). As a group, height associations discovered in European-ancestry samples replicate in individuals of African ancestry (P = 1.7×10⁻⁴ for overall replication). Fine-mapping of the European height loci in African-ancestry individuals showed an enrichment of SNPs that are associated with expression of nearby genes when compared to the index European height SNPs (P<0.01). Our results highlight the utility of genetic studies in non-European populations to understand the etiology of complex human diseases and traits.     

Receptor activator of NF-kB (RANK) expression in primary tumors associates with bone metastasis occurrence in breast cancer patients

Background

Receptor activator of NFkB (RANK), its ligand (RANKL) and the decoy receptor of RANKL (osteoprotegerin, OPG) play a pivotal role in bone remodeling by regulating osteoclasts formation and activity. RANKL stimulates migration of RANK-expressing tumor cells in vitro, conversely inhibited by OPG.

Materials and Methods

We examined mRNA expression levels of RANKL/RANK/OPG in a publicly available microarray dataset of 295 primary breast cancer patients. We next analyzed RANK expression by immunohistochemistry in an independent series of 93 primary breast cancer specimens and investigated a possible association with clinicopathological parameters, bone recurrence and survival.

Results

Microarray analysis showed that lower RANK and high OPG mRNA levels correlate with longer overall survival (P = 0.0078 and 0.0335, respectively) and disease-free survival (P = 0.059 and 0.0402, respectively). Immunohistochemical analysis of RANK showed a positive correlation with the development of bone metastases (P = 0.023) and a shorter skeletal disease-free survival (SDFS, P = 0.037). Specifically, univariate analysis of survival showed that “RANK-negative” and “RANK-positive” patients had a SDFS of 105.7 months (95% CI: 73.9–124.4) and 58.9 months (95% CI: 34.7–68.5), respectively. RANK protein expression was also associated with accelerated bone metastasis formation in a multivariate analysis (P = 0.029).

Conclusions

This is the first demonstration of the role of RANK expression in primary tumors as a predictive marker of bone metastasis occurrence and SDFS in a large population of breast cancer patients.     

Functional polymorphisms in the TERT promoter are associated with risk of serous epithelial ovarian and breast cancers

Genetic variation at the TERT-CLPTM1L locus at 5p15.33 is associated with susceptibility to several cancers, including epithelial ovarian cancer (EOC). We have carried out fine-mapping of this region in EOC which implicates an association with a single nucleotide polymorphism (SNP) within the TERT promoter. We demonstrate that the minor alleles at rs2736109, and at an additional TERT promoter SNP, rs2736108, are associated with decreased breast cancer risk, and that the combination of both SNPs substantially reduces TERT promoter activity.     

Monitoring the process of HypF fibrillization and liposome permeabilization by protofibrils

Much information has appeared in the last few years on the low resolution structure of amyloid fibrils and on their non-fibrillar precursors formed by a number of proteins and peptides associated with amyloid diseases. The fine structure and the dynamics of the process leading misfolded molecules to aggregate into amyloid assemblies are far from being fully understood. Evidence has been provided in the last five years that protein aggregation and aggregate toxicity are rather generic processes, possibly affecting all polypeptide chains under suitable experimental conditions. This evidence extends the number of model proteins one can investigate to assess the molecular bases and general features of protein aggregation and aggregate toxicity. We have used tapping mode atomic force microscopy to investigate the morphological features of the pre-fibrillar aggregates and of the mature fibrils produced by the aggregation of the hydrogenase maturation factor HypF N-terminal domain (HypF-N), a protein not associated to any amyloid disease. We have also studied the aggregate-induced permeabilization of liposomes by fluorescence techniques. Our results show that HypF-N aggregation follows a hierarchical path whereby initial globules assemble into crescents; these generate large rings, which evolve into ribbons, further organizing into differently supercoiled fibrils. The early pre-fibrillar aggregates were shown to be able to permeabilize synthetic phospholipid membranes, thus showing that this disease-unrelated protein displays the same amyloidogenic behaviour found for the aggregates of most pathological proteins and peptides. These data complement previously reported findings, and support the idea that protein aggregation, aggregate structure and toxicity are generic properties of polypeptide chains.     

Sodium butyrate activates genes of early pancreatic development in embryonic stem cells

Embryonic stem (ES) cells can differentiate into any tissue, including pancreatic islet cell types. Protocols for the efficient generation of these cells in vitro could have therapeutic applications for type I diabetes. Here we describe a simple method for the differentiation of mouse ES cells into epithelial cells with a gene expression profile consistent with that expected of early pancreatic progenitors (PP). It is based on the addition of sodium butyrate, an agent known to induce chromatin rearrangements. Variations on the length of exposure to butyrate result in the generation of hepatocytes or PP-like cells. qRT-PCR indicates that butyrate induces mesendoderm/definitive endoderm, but not neuroectoderm differentiation. PPlike cells show a strong upregulation of Ipf1/Pdx1, p48, Isl-1 and Nkx6.1, but not Ngn3, NeuroD/ Beta2 or Pax4. PP-like cells also express the epithelial marker E-cadherin. Taken together, our observations suggest that butyrate stimulates early events of pancreatic specification, prior to the onset of endocrine differentiation. These findings are discussed in the context of the development of protocols for the in vitro differentiation of islets.     

Antagonistic Coevolution Accelerates the Evolution of Reproductive Isolation in Tribolium castaneum

Abstract The evolution of reproductive isolation among populations is often the result of selective forces. Among those, parasites exert strong selection on host populations and can thus also potentially drive reproductive isolation. This hypothesis has yet to be explicitly tested, and here we set up a multigenerational coevolution experiment to explore this possibility. Five lines of Tribolium castaneum were allowed to coevolve with their natural parasite, Nosema whitei; five paired lines of identical origin were maintained in the absence of parasites. After 17 generations, we measured resistance within and reproductive isolation between all lines. Host lines from the coevolution treatment had considerably higher levels of resistance against N. whitei than their paired host lines, which were maintained in the absence of parasites. Reproductive isolation was greater in the coevolved selection regime and correlated with phenotypic differentiation in parasite resistance between coevolved host lines. This suggests the presence of a selection-driven genetic correlation between offspring number and resistance. Our results show that parasites can be a driving force in the evolution of reproductive isolation and thus potentially speciation.