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Category: genetics

A Developmentally Informed Study of Sleep and Circadian Polygenic Scores in Adolescence

Adult sleep GWAS-derived polygenic scores demonstrated comparable associations with corresponding sleep phenotypes in Adolescents, suggesting genetic influences on sleep persist across developmental stages.

Question Do genetic variants that are associated with adult sleep/circadian phenotypes influence sleep phenotypes in adolescents?

Findings In a population-based birth cohort study (N = 3903), genetic influences on all adult sleep phenotypes (sleep duration, insomnia, daytime sleepiness, napping, and chronotype as indexed by polygenic scores derived from adult genome-wide association studies) were associated with their corresponding sleep/circadian phenotypes in adolescents aged 15 years.

Meaning Genetic variants identified in adult genome-wide association studies may also be relevant to a variety of sleep phenotypes in adolescence, suggesting that these variants index sleep phenotypes during a key developmental stage in which sleep disturbances typically emerge.

Sustained proliferation in cancer: mechanisms and novel therapeutic targets

Cancer development results from the selection of cells with mutation(s) that provide survival and proliferative advantages. Normal barriers to proliferation are overcome as clones adapt to an ever changing hostile microenvironment, where low oxygen tension, low glucose levels, and an acidic extracellular pH (all of which increase genetic instability) are found. The hypoxia inducible factors, HIF-1 and HIF-2, are upregulated in response to these conditions. This could occur by constitutive activation of PI3K signaling or inactivating mutations in, for example, the von Hippel–Lindau tumor suppressor, VHL [35-37], which normally deacetylates HIF-1α, leading to HIF-1α polyubiquitination and proteasomal degradation [38]. HIFs trans activate genes mediating proliferation, angiogenesis, intermediate metabolism (glycolysis) and pH regulation, which promote tumor development [39].

HIF-1α stimulates production of growth factors, such as transforming growth factor β (TGF-β), insulin-like growth factor 2, interleukin-6 (IL-6), interleukin-8, macrophage migration inhibitory factor (MIF), and growth factor receptors, such as the epidermal growth factor receptor (EGFR), resulting in continuous proliferative signaling. In the hypoxic environment, constitutive activation of these signaling pathways (e.g., Ras [1] and PI3K [2]) stabilizes HIF-1 and may result in “oncogene addiction” that persists through the transition from adenoma to carcinoma. In the case of PI3K, constitutive activation may result from the appearance of mutations in tumor suppressor genes (e.g., the phosphatase and tensin homolog [PTEN]), from activating mutations in the PI3K complex itself, or from aberrant signaling in receptor tyrosine kinases [40].

Interplay between cancer cell lipotypes and disease states

Lipid metabolism in cancer.

Cancer cells exhibit distinct lipotypes to sustain functional states crucial for tumorigenesis.

Various lipid metabolism components like biosynthesis, uptake, storage, and degradation of lipids contribute to cancer cell fitness.

Cancer cells dynamically transition across lipotypes under microenvironmental stress.

Targeting essential nodes in lipid metabolism may offer novel cancer therapeutics. sciencenewshighlights ScienceMission https://sciencemission.com/cancer-cell-lipotypes

While the initial transformation of cancer cells is driven by genetic alterations, tumor cell behaviors and functional states are dynamically regulated by cell-intrinsic factors including proteins, metabolites and lipids, and extrinsic microenvironmental factors. Emerging multi-omics technologies highlighted that cancer cells exhibit distinct lipidome compositions and employ specific lipid metabolic circuits for chemical conversions – collectively defined as ‘lipotypes’. We review the interplay between cancer lipotypes and cellular states, focusing on interpreting how being at different positions along the spectra of representative lipid metabolic axes influences cancerous traits. We aim to instill a system biology perspective to integrate ‘lipotypes’ into the established ‘genotype–phenotype’ framework in cancer.

Continue reading “Interplay between cancer cell lipotypes and disease states” | >

Inositol Requiring Enzyme 1α Mediates Hypertension and Vascular Remodeling

A single genetic “switch” may be the secret to how the body’s cleanup crew grows up and keeps our organs running smoothly.

Scientists at the University of Liège have identified a crucial genetic regulator that allows macrophages to fully mature and help maintain healthy organs. This regulator, known as MafB, acts as a “molecular switch” that turns specific genes on or off at the right time and in the right cells.

By carefully controlling this genetic activity, MafB enables the development of macrophages that defend the body and support normal organ function. When MafB is missing, macrophages do not work as they should and lose their ability to carry out their protective duties.

Promoters and enhancers: Tool catches gene-controlling DNA sequences doing each other’s jobs

Researchers at the Weill Institute for Cell and Molecular Biology have uncovered new evidence that two major types of gene-controlling DNA sequences, promoters and enhancers, operate with a shared logic and often perform the same jobs. The finding, made possible through a high-throughput assay they developed called QUASARR-seq, could reshape how scientists design gene therapies, interpret disease-related mutations, and understand cancer genetics.

New research from the lab of Haiyuan Yu, Tisch University Professor of Computational Biology at Cornell University’s College of Agriculture and Life Sciences (CALS) and faculty at the Weill Institute, reveals that drawing a distinction between the two classes gene controllers may be too black and white—they seem to respond to the same biological rules and act in concert.

In a study published in Nature Communications on Jan. 30 and led by Mauricio Paramo, a graduate student at the Weill Institute, the team developed a technology capable of measuring an element’s promoter and enhancer activity simultaneously, in close collaboration with the lab of John Lis, Barbara McClintock Professor of Molecular Biology & Genetics. This is significant because, until now, most technologies could measure only one function at a time, leaving open the question of whether—and how—the two activities interact inside the same DNA sequence.

The Virtual Biotech: A Multi-Agent AI Framework for Therapeutic Discovery and Development

Drug discovery and development requires integrating diverse evidence across biological scales and data modalities. However, relevant data, tools, and expertise remain fragmented across teams and organizations, making integration difficult. To address these challenges, we introduce the Virtual Biotech, a coordinated team of AI agents that mirrors the structure of human therapeutic research organizations to support end-to-end computational discovery. The Virtual Biotech is led by a Chief Scientific Officer agent that receives scientific queries, delegates them to domain-specialized scientist agents, and integrates their outputs through data-driven reasoning. Scientist agents leverage complementary tools and knowledge sources spanning statistical genetics, functional genomics, pathways and interactions, chemoinformatics, disease biology, and clinical data. We showcase the Virtual Biotech across three translational applications. First, the agents autonomously annotated and analyzed outcomes from 55,984 clinical trials to identify genomic features of drug targets associated with trial success. More than 37,000 clinical-trialist agents curated structured trial outcomes and linked targets to multi-omic annotations, including cell-type-specific features derived by the agents from single-cell RNA-sequencing atlases. The agents discovered that drugs targeting cell-type-specific genes were 40% more likely to progress from Phase I to Phase II and 48% more likely to reach market (Phase IV), while exhibiting 32% lower adverse event rates. Second, the Virtual Biotech evaluated B7-H3 as a lung cancer target, integrating statistical genetics, single-cell, spatial, and clinicogenomic evidence to propose an antibody–drug conjugate strategy while identifying key liabilities and differentiation opportunities. Third, the platform analyzed a terminated ulcerative colitis trial targeting OSMR β to infer potential failure mechanisms and proposed biomarker-guided enrollment strategies to address precision-medicine gaps. Together, these results illustrate how the Virtual Biotech can enable more transparent, efficient, and comprehensive multi-scale therapeutic analyses, helping to accelerate early-stage drug discovery workflows while keeping human scientists in the loop.

The authors have declared no competing interest.

Balancing IL-17–mediated protection and IFN-γ–driven pathology at mucocutaneous barriers

Controlling mucocutaneous barriers by cytokines.

Impaired IL-17 leads to mucocutaneous bacterial and fungal infections, whereas enhanced IL-17 promotes psoriasis and periodontitis.

Interferon (IFN)-γ deficiency causes infections by intracellular pathogens, whereas exacerbated mucosal IFN-γ activity promotes oral candidiasis, even when IL-17 responses are intact.

JAK inhibition in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy remits oral candidiasis and multiorgan autoimmunity.

IFN-γ drives Candida auris skin infection by impairing the epithelial barrier. Excess IFN-γ, tumor necrosis factor, and types I/III IFN activities contribute to pathology during bacterial and protozoan skin infections and pulmonary viral, bacterial, mycobacterial, and fungal infections.

Although immune deficiency causes mucosal infection, epithelial disruption by immunopathology represents a novel and underappreciated mechanism of infection susceptibility at barrier sites. sciencenewshighlights ScienceMission https://sciencemission.com/Balancing-IL-17

Continue reading “Balancing IL-17–mediated protection and IFN-γ–driven pathology at mucocutaneous barriers” | >

Jumping DNA Sequences Drive Early Tumor Growth

New research reveals that LINE-1 retrotransposons don’t just nudge genes, they also trigger massive structural upheavals early in cancer development.

Read about the findings.

Where there’s a bountiful host, there are parasites ready to take advantage of the resources. This holds true even at microscopic levels. Lying within human DNA are repetitive elements called LINE-1 (L1) retrotransposons that promote their own propagation at the cost of the host organism’s health.1 These genetic parasites create copies of themselves that then get inserted at new locations within the genome. Until recently, scientists thought that the activity of L1s mostly resulted in local alterations to genes.

Now, in a new study published in Science, researchers have demonstrated that L1s can trigger dramatic structural changes in DNA, resulting in cancer-causing mutations.2 These findings, which shed light on the intricate relationship between cancer evolution and the genome, could lead to improved diagnostic and therapeutic strategies for different cancers.

“Cancer genomes are more influenced by these jumping fragments of DNA parasites than we previously thought,” said José Tubio, a molecular biologist at the University of Santiago de Compostela, in a statement.

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