Characterizing genomic alterations in cancer by complementary functional associations.

Systematic efforts to sequence the cancer genome have identified large numbers of mutations and copy number alterations in human cancers. However, elucidating the functional consequences of these variants, and their interactions to drive or maintain oncogenic states, remains a challenge in cancer research. We developed REVEALER, a computational method that identifies combinations of mutually exclusive genomic alterations correlated with functional phenotypes, such as the activation or gene dependency of oncogenic pathways or sensitivity to a drug treatment. We used REVEALER to uncover complementary genomic alterations associated with the transcriptional activation of β-catenin and NRF2, MEK-inhibitor sensitivity, and KRAS dependency. REVEALER successfully identified both known and new associations, demonstrating the power of combining functional profiles with extensive characterization of genomic alterations in cancer genomes

Faced with inequality: chicken do not have a general dosage compensation of sex-linked genes

<p>Abstract</p> <p>Background</p> <p>The contrasting dose of sex chromosomes in males and females potentially introduces a large-scale imbalance in levels of gene expression between sexes, and between sex chromosomes and autosomes. In many organisms, dosage compensation has thus evolved to equalize sex-linked gene expression in males and females. In mammals this is achieved by X chromosome inactivation and in flies and worms by up- or down-regulation of X-linked expression, respectively. While otherwise widespread in systems with heteromorphic sex chromosomes, the case of dosage compensation in birds (males ZZ, females ZW) remains an unsolved enigma.</p> <p>Results</p> <p>Here, we use a microarray approach to show that male chicken embryos generally express higher levels of Z-linked genes than female birds, both in soma and in gonads. The distribution of male-to-female fold-change values for Z chromosome genes is wide and has a mean of 1.4–1.6, which is consistent with absence of dosage compensation and sex-specific feedback regulation of gene expression at individual loci. Intriguingly, without global dosage compensation, the female chicken has significantly lower expression levels of Z-linked compared to autosomal genes, which is not the case in male birds.</p> <p>Conclusion</p> <p>The pronounced sex difference in gene expression is likely to contribute to sexual dimorphism among birds, and potentially has implication to avian sex determination. Importantly, this report, together with a recent study of sex-biased expression in somatic tissue of chicken, demonstrates the first example of an organism with a lack of global dosage compensation, providing an unexpected case of a viable system with large-scale imbalance in gene expression between sexes.</p

Health status of adults with Short Stature: A comparison with the normal population and one well-known chronic disease (Rheumatoid Arthritis)

BACKGROUND: To examine the subjective health status of adults with short stature (ShSt) and compare with the general population (GP) and one well-known chronic disease, rheumatoid artritis (RA). In addition, to explore the association between age, gender, height, educational level and different aspects of health status of adults with short stature. METHODS: A questionnaire was mailed to 72 subjects with short stature registered in the database of a Norwegian resource centre for rare disorders, response rate 61% (n = 44, age 16–61). Health status was assessed with SF-36 version 2. Comparison was done with age and gender matched samples from the general population in Norway (n = 264) and from subjects with RA (n = 88). RESULTS: The ShSt sample reported statistically significant impaired health status in all SF-36 subscales compared with the GP sample, most in the physical functioning, Mean Difference (MD) 34 (95% Confidence Interval (CI) 25–44). The ShSt reported poorer health status in mental health, MD 11 (95% CI 4–18) and social functioning, MD 11 (95% CI 2–20) but better in role physical MD 13 (95% CI 1–25) than the RA sample. On the other subscales there were minor difference between the ShSt and the RA sample. Within the short stature group there was a significant association between age and all SF-36 physical subcales, height was significantly associated with physical functioning while level of education was significantly associated with mental health. CONCLUSION: People with short stature reported impaired health status in all SF-36 subscales indicating that they have health problems that influence their daily living. Health status seems to decline with increasing age, and earlier than in the general population

Monazite trumps zircon: applying SHRIMP U–Pb geochronology to systematically evaluate emplacement ages of leucocratic, low-temperature granites in a complex Precambrian orogen

Although zircon is the most widely used geochronometer to determine the crystallisation ages of granites, it can be unreliable for low-temperature melts because they may not crystallise new zircon. For leucocratic granites U–Pb zircon dates, therefore, may reflect the ages of the source rocks rather than the igneous crystallisation age. In the Proterozoic Capricorn Orogen of Western Australia, leucocratic granites are associated with several pulses of intracontinental magmatism spanning ~800 million years. In several instances, SHRIMP U–Pb zircon dating of these leucocratic granites either yielded ages that were inconclusive (e.g., multiple concordant ages) or incompatible with other geochronological data. To overcome this we used SHRIMP U–Th–Pb monazite geochronology to obtain igneous crystallisation ages that are consistent with the geological and geochronological framework of the orogen. The U–Th–Pb monazite geochronology has resolved the time interval over which two granitic supersuites were emplaced; a Paleoproterozoic supersuite thought to span ~80 million years was emplaced in less than half that time (1688–1659 Ma) and a small Meso- to Neoproterozoic supersuite considered to have been intruded over ~70 million years was instead assembled over ~130 million years and outlasted associated regional metamorphism by ~100 million years. Both findings have consequences for the duration of associated orogenic events and any estimates for magma generation rates. The monazite geochronology has contributed to a more reliable tectonic history for a complex, long-lived orogen. Our results emphasise the benefit of monazite as a geochronometer for leucocratic granites derived by low-temperature crustal melting and are relevant to other orogens worldwide

Migraine polygenic risk score associates with efficacy of migraine-specific drugs

Objective To assess whether the polygenic risk score (PRS) for migraine is associated with acute and/or prophylactic migraine treatment response. Methods We interviewed 2,219 unrelated patients at the Danish Headache Center using a semistructured interview to diagnose migraine and assess acute and prophylactic drug response. All patients were genotyped. A PRS was calculated with the linkage disequilibrium pred algorithm using summary statistics from the most recent migraine genome-wide association study comprising ∼375,000 cases and controls. The PRS was scaled to a unit corresponding to a twofold increase in migraine risk, using 929 unrelated Danish controls as reference. The association of the PRS with treatment response was assessed by logistic regression, and the predictive power of the model by area under the curve using a case-control design with treatment response as outcome. Results A twofold increase in migraine risk associates with positive response to migraine-specific acute treatment (odds ratio [OR] = 1.25 [95% confidence interval (CI) = 1.05–1.49]). The association between migraine risk and migraine-specific acute treatment was replicated in an independent cohort consisting of 5,616 triptan users with prescription history (OR = 3.20 [95% CI = 1.26–8.14]). No association was found for acute treatment with non–migraine-specific weak analgesics and prophylactic treatment response. Conclusions The migraine PRS can significantly identify subgroups of patients with a higher-than-average likelihood of a positive response to triptans, which provides a first step toward genetics-based precision medicine in migraine