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Current Issue of Trends in Genetics


Issue: Trends in Genetics

Feb 01, 2022

Volume 38Issue 2p109-210, e1-e2
The festival string lights shown on the cover image symbolize the intermittent activation of replication origins during genome duplication and the subsequent entanglements that might ensue if DNA synthesis is dysregulated. Cells avoid the deleterious effects of over-replication by constraining replication initiation from most potential replication origins, which are not routinely activated during normal cell growth but are ready to complete genome duplication if cells encounter replication stress. Because regulatory signals that orchestrate genome duplication to prevent excess replication are often missing in cancer, targeting the pathways that prevent over-replication or eliminate excess DNA is a promising avenue for therapeutic intervention. In this issue, Thakur et al. review diverse molecular pathways that orchestrate replication origin activation to prevent excess DNA synthesis and mitigate the ensuing genomic instability. Cover credit: Bhushan Thakur and Christophe Redon....
The festival string lights shown on the cover image symbolize the intermittent activation of replication origins during genome duplication and the subsequent entanglements that might ensue if DNA synthesis is dysregulated. Cells avoid the deleterious effects of over-replication by constraining replication initiation from most potential replication origins, which are not routinely activated during normal cell growth but are ready to complete genome duplication if cells encounter replication stress. Because regulatory signals that orchestrate genome duplication to prevent excess replication are often missing in cancer, targeting the pathways that prevent over-replication or eliminate excess DNA is a promising avenue for therapeutic intervention. In this issue, Thakur et al. review diverse molecular pathways that orchestrate replication origin activation to prevent excess DNA synthesis and mitigate the ensuing genomic instability. Cover credit: Bhushan Thakur and Christophe Redon.

Science & Society

  • In search of a cure: PACS1 Research Foundation as a model of rare disease therapy development

    • Lauren Rylaarsdam,
    • Taruna Reddy,
    • Alicia Guemez-Gamboa
    Rare diseases affect nearly 400 million people worldwide and have a devastating impact on patients and families. Although these diseases are collectively common, they are often overlooked by the research community. We present the ongoing work of the PACS1 Syndrome Research Foundation as a paradigm for approaching rare disease research.
  • Open practices in our science and our courtrooms

    • Michael D. Edge,
    • Jeanna Neefe Matthews
    Open Access
    Advocates of transparency in science often point to the benefits of open practices for the scientific process. Here, we focus on a possibly underappreciated effect of standards for transparency: their influence on non-scientific decisions. As a case study, we consider the current state of probabilistic genotyping software in forensics.

Forum

  • Heritable epigenetic changes at single genes: challenges and opportunities in Caenorhabditis elegans

    • Mary Chey,
    • Antony M. Jose
    Organisms rely on stereotyped patterns of gene expression for similar form and function in every generation. The analysis of epigenetic changes in the expression of different genes across generations can provide the rationale for measured actions in one generation that consider impact on future generations.
  • Epigenetic networks driving T cell identity and plasticity during immunosenescence

    • Ramon Maria Rodriguez,
    • María Laura Saiz,
    • Beatriz Suarez-Álvarez,
    • Carlos López-Larrea
    The aging process is associated with the accumulation of epigenetic alterations in immune cells, although the origin of these changes is not clear. Understanding this epigenetic drift in the immune system can provide essential information about the progression of the aging process and the immune history of each individual.
  • Histone lactylation: epigenetic mark of glycolytic switch

    • Xiaofeng Dai,
    • Xinyu Lv,
    • Erik W. Thompson,
    • Kostya (Ken) Ostrikov
    Histone lactylation and acetylation compete for epigenetic modification of lysines and mark the levels of lactates and acetyl-CoA. Whether pyruvate is committed to lactate or acetyl-CoA generation as the outlet of glycolysis determines cell fate towards malignancy or not. Taking control over the glycolytic switch as marked by lactylation suggests novel therapeutic opportunities against cancers.

Opinions

  • Intricacies of single-cell multi-omics data integration

    • Pia Rautenstrauch,
    • Anna Hendrika Cornelia Vlot,
    • Sepideh Saran,
    • Uwe Ohler
    A wealth of single-cell protocols makes it possible to characterize different molecular layers at unprecedented resolution. Integrating the resulting multimodal single-cell data to find cell-to-cell correspondences remains a challenge. We argue that data integration needs to happen at a meaningful biological level of abstraction and that it is necessary to consider the inherent discrepancies between modalities to strike a balance between biological discovery and noise removal. A survey of current methods reveals that a distinction between technical and biological origins of presumed unwanted variation between datasets is not yet commonly considered.
  • How does genetic variation modify ND-CNV phenotypes?

    • Thomas J. Dinneen,
    • Fiana Ní Ghrálaigh,
    • Ruth Walsh,
    • Lorna M. Lopez,
    • Louise Gallagher
    Rare copy-number variants (CNVs) associated with neurodevelopmental disorders (NDDs), i.e., ND-CNVs, provide an insight into the neurobiology of NDDs and, potentially, a link between biology and clinical outcomes. However, ND-CNVs are characterised by incomplete penetrance resulting in heterogeneous carrier phenotypes, ranging from non-affected to multimorbid psychiatric, neurological, and physical phenotypes. Recent evidence indicates that other variants in the genome, or ‘other hits’, may partially explain the variable expressivity of ND-CNVs.

Feature Review

  • Advances in integrative African genomics

    • Chao Zhang,
    • Matthew E.B. Hansen,
    • Sarah A. Tishkoff
    There has been a rapid increase in human genome sequencing in the past two decades, resulting in the identification of millions of previously unknown genetic variants. However, African populations are under-represented in sequencing efforts. Additional sequencing from diverse African populations and the construction of African-specific reference genomes is needed to better characterize the full spectrum of variation in humans. However, sequencing alone is insufficient to address the molecular and cellular mechanisms underlying variable phenotypes and disease risks.

Reviews

  • Preventing excess replication origin activation to ensure genome stability

    • Bhushan L. Thakur,
    • Anagh Ray,
    • Christophe E. Redon,
    • Mirit I. Aladjem
    Cells activate distinctive regulatory pathways that prevent excessive initiation of DNA replication to achieve timely and accurate genome duplication. Excess DNA synthesis is constrained by protein–DNA interactions that inhibit initiation at dormant origins. In parallel, specific modifications of pre-replication complexes prohibit post-replicative origin relicensing. Replication stress ensues when the controls that prevent excess replication are missing in cancer cells, which often harbor extrachromosomal DNA that can be further amplified by recombination-mediated processes to generate chromosomal translocations.
  • Crosstalk between epitranscriptomic and epigenetic mechanisms in gene regulation

    • Ryan L. Kan,
    • Jianjun Chen,
    • Tamer Sallam
    Open Access
    Epigenetic modifications occur on genomic DNA and histones to influence gene expression. More recently, the discovery that mRNA undergoes similar chemical modifications that powerfully impact transcript turnover and translation adds another layer of dynamic gene regulation. Central to precise and synchronized regulation of gene expression is intricate crosstalk between multiple checkpoints involved in transcript biosynthesis and processing. There are more than 100 internal modifications of RNA in mammalian cells.
  • Therapeutic and prognostic insights from the analysis of cancer mutational signatures

    • Samuel W. Brady,
    • Alexander M. Gout,
    • Jinghui Zhang
    Open Access
    The somatic mutations in each cancer genome are caused by multiple mutational processes, each of which leaves a characteristic imprint (or ‘signature’), potentially caused by specific etiologies or exposures. Deconvolution of these signatures offers a glimpse into the evolutionary history of individual tumors. Recent work has shown that mutational signatures may also yield therapeutic and prognostic insights, including the identification of cell-intrinsic signatures as biomarkers of drug response and prognosis.

Genome of the Month

  • Picochlorum sp. SENEW3

    • Patrick A. da Roza,
    • Hugh D. Goold,
    • Ian T. Paulsen
    Picochlorum sp. SENEW3 is a picoeukaryotic green alga that displays broad halotolerance and robust growth in the face of fluctuating environmental conditions [1]. This pico-sized alga possesses a small genome, similar to that of the pico-prasinophyte Ostreococcus tauri [2] (Figure 1), and provides an intriguing case of genome minimisation and streamlining in photosynthetic eukaryotes, which tend to have large and redundant genomes. It exhibits a surprising flexibility in growth conditions, that is less pronounced in O.
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