Disentangling mechanisms behind the pleiotropic effects of proximal 16p11.2 BP4-5 CNVs.

Whereas 16p11.2 BP4-5 copy-number variants (CNVs) represent one of the most pleiotropic etiologies of genomic syndromes in both clinical and population cohorts, the mechanisms leading to such pleiotropy remain understudied. Identifying 73 deletion and 89 duplication carrier individuals among unrelated White British UK Biobank participants, we performed a phenome-wide association study (PheWAS) between the region's copy number and 117 complex traits and diseases, mimicking four dosage models. Forty-six phenotypes (39%) were affected by 16p11.2 BP4-5 CNVs, with the deletion-only, mirror, U-shape, and duplication-only models being the best fit for 30, 10, 4, and 2 phenotypes, respectively, aligning with the stronger deleteriousness of the deletion. Upon individually adjusting CNV effects for either body mass index (BMI), height, or educational attainment (EA), we found that sixteen testable deletion-driven associations-primarily with cardiovascular and metabolic traits-were BMI dependent, with EA playing a more subtle role and no association depending on height. Bidirectional Mendelian randomization supported that 13 out of these 16 associations were secondary consequences of the CNV's impact on BMI. For the 23 traits that remained significantly associated upon individual adjustment for mediators, matched-control analyses found that 10 phenotypes, including musculoskeletal traits, liver enzymes, fluid intelligence, platelet count, and pneumonia and acute kidney injury risk, remained associated under strict Bonferroni correction, with 10 additional nominally significant associations. These results paint a complex picture of 16p11.2 BP4-5's pleiotropic pattern that involves direct effects on multiple physiological systems and indirect co-morbidities consequential to the CNV's impact on BMI and EA, acting through trait-specific dosage mechanisms.

Breaking down causes, consequences, and mediating effects of telomere length variation on human health.

BACKGROUND: Telomeres form repeated DNA sequences at the ends of chromosomes, which shorten with each cell division. Yet, factors modulating telomere attrition and the health consequences thereof are not fully understood. To address this, we leveraged data from 326,363 unrelated UK Biobank participants of European ancestry. RESULTS: Using linear regression and bidirectional univariable and multivariable Mendelian randomization (MR), we elucidate the relationships between leukocyte telomere length (LTL) and 142 complex traits, including diseases, biomarkers, and lifestyle factors. We confirm that telomeres shorten with age and show a stronger decline in males than in females, with these factors contributing to the majority of the 5.4% of LTL variance explained by the phenome. MR reveals 23 traits modulating LTL. Smoking cessation and high educational attainment associate with longer LTL, while weekly alcohol intake, body mass index, urate levels, and female reproductive events, such as childbirth, associate with shorter LTL. We also identify 24 traits affected by LTL, with risk for cardiovascular, pulmonary, and some autoimmune diseases being increased by short LTL, while longer LTL increased risk for other autoimmune conditions and cancers. Through multivariable MR, we show that LTL may partially mediate the impact of educational attainment, body mass index, and female age at childbirth on proxied lifespan. CONCLUSIONS: Our study sheds light on the modulators, consequences, and the mediatory role of telomeres, portraying an intricate relationship between LTL, diseases, lifestyle, and socio-economic factors.

Bringing science to the public in the light of evolution.

Evolution stands as a foundational pillar within modern biology, shaping our understanding of life. Studies related to evolution, for example constructing phylogenetic trees, are often carried out using DNA or protein sequences. These data, readily accessible from public databases, represent a treasure trove of resources that can be harnessed to create engaging activities with the public. At the heart of our project lies a collection of "stories" about evolution, each rooted in genuine scientific publications that furnish both biological context and supporting evidence. These narratives serve as the focal point of our LightOfEvolution.org website. Each story is accompanied by a dedicated "Your Turn to Play" section. Within this section, we furnish user-friendly activities and step-by-step guidelines, equipping visitors with the means to replicate analyses showcased in the highlighted publications. For example, the website OhMyGenes.org, relying on authentic scientific data, provides the capability to compute the proportion of shared genes across different species. Here, visitors can address the captivating question: "How many genes do we share with a banana?" To extend the educational reach, we have developed a series of modular activities, also related to the stories. These activities have been thoughtfully designed to be adaptable for face-to-face workshops held in classrooms or presented during public events. We aim to create stories and activities that resonate with participants, offering a tangible and enjoyable experience. By providing opportunities that reflect real-world scientific practices, we seek to offer participants valuable insights into the current workings of scientists "in the light of evolution."