Genome-wide association studies (GWAS) have revolutionized the field of complex disease genetics in the last six years. Many disease associations (i.e. genetic variants that increase risk for a specific disease) have been detected using this technique, but the reported variants tend to explain only small fractions of risk. Also, the causal variants that generate the associations unveiled by GWAS have not been identified. And their frequency and degree of sharing across different ethnical populations remains unknown.
Arcadi Navarro, from the Institute of Evolutionary Biology (UPF-CSIC), set out to study the degree of sharing of disease-associated variants across populations, in order to help solving these issues. Together with Urko Marigorta, they did a comprehensive survey of GWAS replicability across 28 diseases. As they report in their paper in PLOS Genetics, most loci and SNPs discovered in Europeans for these conditions had been extensively replicated using peoples of European and East Asian ancestry, while replication with individuals of African ancestry proved to be much less common.
The authors found a strong and significant correlation across Europeans and East Asians, indicating that underlying causal variants are common and shared between the two ancestries and that they tend to map close to the associated marker SNPs.
They also observed that GWAS with larger sample sizes have detected variants with weaker effects but not with lower frequencies. This indicates that most GWAS results are due to common variants.
Marigorta UM, Navarro A. High Trans-ethnic Replicability of GWAS Results Implies Common Causal Variants. PLoS Genet. 2013 Jun;9(6):e1003566
How is our health affected by pollution, green spaces, urban design and active transport? This is what Mark Nieuwenhuijsen is studying at the Centre for Research in Environmental Epidemiology (CREAL), located at the Barcelona Biomedical Research Park (PRBB). In this short video the Dutch researcher explains his studies on how outdoor contaminants affect health.
Females have an extra X chromosome as compared to males, and this can mean trouble – think of what happens when someone has an extra copy of any other chromosome, 21 being the most (in)famous! Dosage compensation is therefore essential, and there’s different ways of dealing with it. In humans, women inactivate one of their X chromosomes, while in the fruifly the opposite happens: males overactivate their only copy of X.
The complex in charge of doing so is called MSL and male-specific-lethal-2 (msl2) is one of its subunits. Female flies must inhibit this gene in order to survive, and Sex-lethal (SXL) is the protein which orchestrates this repression. So far, it was known that SXL binds to the 5′ and 3′ untranslated regions (UTRs) of the msl2 mRNA, inhibiting splicing in the nucleus and subsequent translation in the cytoplasm.
But Fatima Gebauer and colleagues at the CRG have now found a third way SXL can repress msl2: by inhibition of nucleocytoplasmic transport of msl2 mRNA.
To identify SXL cofactors in msl2 regulation, the researchers from the Regulation of Protein Synthesis in Eukaryotes group devised a two-step purification method termed GRAB (GST pull-down and RNA affinity binding) and identified Held-Out-Wings (HOW) as a component of the msl2 5′ UTR-associated complex.
Their experiments showed that HOW directly interacts with SXL and binds to two sequence elements in the msl2 5′ UTR. Depletion of HOW reduced the capacity of SXL to repress the expression of msl2 reporters without affecting SXL-mediated regulation of splicing or translation. Instead, HOW was required for SXL to retain msl2 transcripts in the nucleus.
These results, published in Genes & Development uncover a novel function of SXL in (msl2) nuclear mRNA retention – a third way for female control of sex-specific gene expression.
Graindorge A, Carré C, Gebauer F. Sex-lethal promotes nuclear retention of msl2 mRNA via interactions with the STAR protein HOW. Genes Dev. 2013 Jun 15;27(12):1421-33
This image, of an immunostaining of the nerve system of the scaleworm Harmothoeimbricata was taken by Masha Plyuscheva, from the Evolutionary Genomics laboratory (CRG). To study the bioluminescence of sea dwellers, Masha dived to collect this scaleworm. When scared, the worm detaches a glowing scale, allowing it to escape while the predator is distracted. Masha stained the scate using DAPI to mark the nuclei of the cells in blue, and labeling the nerve system in green. The blue and green cylindrical structures are tubercles, parts of the bioluminescence system where the oxidized products of the bioluminescence reaction accumulate.