Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

Circadian oscillations of cytosolic free calcium regulate the Arabidopsis circadian clock

In the last decade, the view of circadian oscillators has expanded from transcriptional feedback to incorporate post-transcriptional, post-translational, metabolic processes and ionic signalling. In plants and animals, there are circadian oscillations in the concentration of cytosolic-free Ca2+ ([Ca2+]cyt), though their purpose has not been fully characterised. We investigated whether circadian oscillations of [Ca2+] cyt regulate the circadian oscillator of Arabidopsis thaliana. We report that in Arabidopsis, [Ca2+]cyt circadian oscillations can regulate circadian clock function through the Ca2+-dependent action of CALMODULIN-LIKE24 (CML24). Genetic analyses demonstrate a linkage between CML24 and the circadian oscillator, through pathways involving the circadian oscillator gene TIMING OF CAB2 EXPRESSION1 (TOC1).Supported by BBSRC UK research grants BBSRC BB/D010381/1 (A.N.D.), BB/D017904/1 (F.R.) BB/M00113X/1 (H.J.H.) awarded to (A.A.R.W.), Research Studentship (K.H.) and BBSRC Industrial Case (T.H.). A Swiss Science Foundation Award (PBZHP3-123289) and the Isaac Newton Trust Cambridge (M.C.M.R. and S.A.), 678 the National Science Foundation under Grant No. MCB 0817976 (Y-C.T. and J.B.), a Royal Society Grant RG081257 and Corpus Christi College, Cambridge Junior Research Fellowship (M.J.G.), a Cordenadoria de Apoio ao Ensino Superior Brazil 25681 studentship (C.T.H.), IEF Marrie Curie (Project No. 272186) (M.C.M.R.), a Broodbank Fellowship (M.C.M.R.), a Malaysian Government Studentship (N.I.M-H.)

Standards for plant synthetic biology: A common syntax for exchange of DNA parts

© 2015 New Phytologist Trust. Inventors in the field of mechanical and electronic engineering can access multitudes of components and, thanks to standardization, parts from different manufacturers can be used in combination with each other. The introduction of BioBrick standards for the assembly of characterized DNA sequences was a landmark in microbial engineering, shaping the field of synthetic biology. Here, we describe a standard for Type IIS restriction endonuclease-mediated assembly, defining a common syntax of 12 fusion sites to enable the facile assembly of eukaryotic transcriptional units. This standard has been developed and agreed by representatives and leaders of the international plant science and synthetic biology communities, including inventors, developers and adopters of Type IIS cloning methods. Our vision is of an extensive catalogue of standardized, characterized DNA parts that will accelerate plant bioengineering

Age at first birth in women is genetically associated with increased risk of schizophrenia

Prof. Paunio on PGC:n jäsenPrevious studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is -0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health.Peer reviewe

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

Ticking over: Circadian systems across the kingdoms of life

The ability to anticipate the day–night cycle and direct physiology accordingly has proven to be a general phenomenon across all kingdoms of life. Considerable fitness benefits are conferred by an internal 24hour clock, which is known as a circadian clock. Extensive multidisciplinary studies in a range of model organisms have elucidated many of the components involved in generating and sustaining daily rhythms. When comparing the circadian systems across the kingdoms, it is fascinating to observe the commonalities and differences in their molecular architecture, and the many adaptations which have evolved to deal with organismspecific requirements of biological timing.</jats:p

In a plant's own sweet time: Sugar and circadian rhythms

Rotation of the Earth on its axis causes 24-h cycles in many features of the environment. Circadian rhythms generate a cellular measure of the time of day, providing a biological adaptation to daily changes in the environment. Plants need light to power photosynthesis in order to grow and reproduce, yet sunlight is only available for part of the 24-h day. It may therefore come as no surprise that circadian rhythms are extraordinarily important for plants. Experiments with the model plant Arabidopsis thaliana demonstrated that circadian rhythms increase plant productivity and photosynthesis1. Extension to other plant species is revealing how circadian rhythms are crucial for, and can be used to manipulate, agronomic traits of crops. Understanding and controlling the molecular bases for circadian regulation is therefore a crucial part of developing more productive crops for the next century.</jats:p

Circadian Rhythms: FLOWERING LOCUS T Extends Opening Hours

SummaryPlants are more sensitive to light in the day than at night due to the circadian clock. The protein that acts downstream from the clock to modulate blue light signalling in stomata comes as a surprise; it is FT, which is thought to be the long-distance regulator of flowering

Recent advances in understanding regulation of the Arabidopsis circadian clock by local cellular environment

Circadian clocks have evolved to synchronise an organism’s physiology with the environmental rhythms driven by the Earth’s rotation on its axis. Over the past two decades, many of the genetic components of the Arabidopsis thaliana circadian oscillator have been identified. The interactions between these components have been formulized into mathematical models that describe the transcriptional translational feedback loops of the oscillator. More recently, focus has turned to the regulation and functions of the circadian clock. These studies have shown that the system dynamically responds to environmental signals and small molecules. We describe advances that have been made in discovering the cellular mechanisms by which signals regulate the circadian oscillator of Arabidopsis in the context of tissue-specific regulation.</ns4:p