Interpreting Gene Expression Effects of Disease-Associated Variants: A Lesson from SNCA rs356168

The SNCA intronic single nucleotide polymorphism (SNP), rs356168, has been associated with Parkinson’s disease (PD) in large genome wide association studies (GWAS). Recently, the PD-risk allele, rs356168-G was shown to increase SNCA-mRNA expression using genome edited human induced pluripotent stem cells (iPSC)-derived neurons. In this study, as means of validation, we tested the effect of rs356168 on total SNCA-mRNA levels using brain tissues, temporal and frontal cortex, from healthy control donors. Carriers of the rs356168-G allele demonstrated a borderline significant decrease of SNCA-mRNA levels in temporal brain tissues (p = 0.02) compared to individuals homozygous for the ‘A’ allele. Similar trend, but weak, was observed in the analysis of frontal cortex samples, however, this analysis did not reach statistical significance. These results conflict with the recently reported effect of SNCA SNP rs356168 described above. Our study conveys the need to carefully interpret the precise molecular mechanism by which rs356168, or another tightly linked variant, affects the regulation of SNCA expression. The regulatory mechanisms that contribute to the observed associations between PD and the SNCA-3′ linkage disequilibrium region warrant further investigations

Concurrent and future risk of endometrial cancer in women with endometrial hyperplasia: A systematic review and meta-analysis

BACKGROUND:To inform treatment decisions in women diagnosed with endometrial hyperplasia, quantification of the potential for concurrent endometrial cancer and the future risk of progression to cancer is required. METHODS:We identified studies up to September 2018 that reported on the prevalence of concurrent cancer (within three months of endometrial hyperplasia diagnosis), or the incidence of cancer, identified at least three months after hyperplasia diagnosis. Random-effects meta-analyses produced pooled estimates and 95% confidence intervals (CIs). RESULTS:A total of 36 articles were identified; 15 investigating concurrent and 21 progression to cancer. In pooled analysis of 11 studies of atypical hyperplasia, the pooled prevalence of concurrent endometrial cancer was 32.6% (95% CI: 24.1%, 42.4%) while no studies evaluated concurrent cancer in non-atypical hyperplasia. The risk of progression to cancer was high in atypical hyperplasia (n = 5 studies, annual incidence rate = 8.2%, 95% CI 3.9%, 17.3%) and only one study reported on non-atypical hyperplasia (annual incidence rate = 2.6%, 95% CI: 0.6%, 10.6%). CONCLUSIONS:Overall, a third of women with atypical hyperplasia had concurrent endometrial cancer, although the number of studies, especially population-based, is small. Progression to cancer in atypical hyperplasia was high, but few studies were identified. Population-based estimates are required, in both atypical and non-atypical hyperplasia patients to better inform treatment strategies

\u3ci\u3eDrosophila\u3c/i\u3e Muller F Elements Maintain a Distinct Set of Genomic Properties Over 40 Million Years of Evolution

The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25–50%) than euchromatic reference regions (3–11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11–27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4–3.6 vs. 8.4–8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu