Edited by
David James et al.

Special Issue: Systems Genetics

In this Special Issue we present a range of studies that showcase novel approaches that researchers are exploring to better decipher the link between genotype and phenotype.
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Systems genetics works to understand how genetic diversity translates into phenotypic diversity by studying how information is transmitted from the genome through RNA, proteins and beyond.

It aims to explain how complex traits are influenced by many loci, at the organismal level and how this is influenced by environmental diversity as well as non-genetic and non-environmental factors.

Systems genetics also relies on the comprehensive multi-omics analysis of cells, tissues and organs, and attempts to integrate the information embedded in these networks so that we can better understand complex human diseases and other biological problems that remain somewhat intractable.

This Special Issue brings together research in this growing field.

To mark this publication the editors together with leaders in the field of systems genetics have written a Review Article which aims to describe some of the resources and tools of systems genetics, so that researchers in all areas of biology and medicine can make use of the data.

Note: Due to the timing of the call for papers, some articles included in this Special Issue were accepted for publication before the introduction of our new publishing model.


    1. Computational and Systems Biology
    2. Genetics and Genomics

    Systems genetics approaches for understanding complex traits with relevance for human disease

    Hooman Allayee, Charles R Farber ... Aldons J Lusis
    Systems genetics is a powerful approach that links DNA variation to complex clinical and physiological traits through the integration of intermediate phenotypes, such as RNA, protein, and metabolite levels.
    1. Cancer Biology
    2. Computational and Systems Biology

    Single-cell transcriptomics identifies Keap1-Nrf2 regulated collective invasion in a Drosophila tumor model

    Deeptiman Chatterjee, Caique Almeida Machado Costa ... Wu-Min Deng
    Comprehensive transcriptomic analyses describe the underlying tumorigenic gene expression state in the invasive Drosophila follicle cells following the loss of epithelial cell polarity and identify a non-canonical role of Keap1-Nrf2 signaling in regulating collective cell invasion.
    1. Computational and Systems Biology
    2. Genetics and Genomics

    Transcriptome-wide association study and eQTL colocalization identify potentially causal genes responsible for human bone mineral density GWAS associations

    Basel Maher Al-Barghouthi, Will T Rosenow ... Charles R Farber
    Systems genetics approaches identify potentially causal bone mineral density genes.
    1. Computational and Systems Biology

    Lack of evidence for increased transcriptional noise in aged tissues

    Olga Ibañez-Solé, Alex M Ascensión ... Ander Izeta
    An increase in transcriptional noise generally assumed to characterize aged cells and tissues is shown to derive instead from technical and biological issues that underlie single-cell RNA sequencing experiments.
    1. Computational and Systems Biology
    2. Genetics and Genomics

    Heritability enrichment in context-specific regulatory networks improves phenotype-relevant tissue identification

    Zhanying Feng, Zhana Duren ... Yong Wang
    Integrating chromatin accessibility and gene expression data into context-specific regulatory networks can provide better regulatory categories for heritability enrichment and relevant tissue identification.
    1. Genetics and Genomics

    Associations of genetic and infectious risk factors with coronary heart disease

    Flavia Hodel, Zhi Ming Xu ... Jacques Fellay
    In a prospective, population-based cohort, high polygenic risk and infection with Fusobacterium nucleatum have a small, yet independent impact on coronary heart disease risk.
    1. Genetics and Genomics

    Exploiting the mediating role of the metabolome to unravel transcript-to-phenotype associations

    Chiara Auwerx, Marie C Sadler ... Eleonora Porcu
    Integrating multi-omics quantitative trait loci and genome-wide association study data into a multivariable Mendelian randomization framework allows to identify metabolite-mediated transcript-to-phenotype causal relations missed by methods focusing on a single omics layer.
    1. Developmental Biology
    2. Genetics and Genomics

    A comprehensive survey of C. elegans argonaute proteins reveals organism-wide gene regulatory networks and functions

    Uri Seroussi, Andrew Lugowski ... Julie M Claycomb
    Systematically studying the expression, small RNA-binding partners, and loss-of-function phenotypes of all 19 Argonautes uncovers how small RNA regulatory pathways function and interact in Caenorhabditis elegans, a long-standing model for small RNA biology and RNAi.
    1. Computational and Systems Biology
    2. Genetics and Genomics

    The potential of integrating human and mouse discovery platforms to advance our understanding of cardiometabolic diseases

    Aaron W Jurrjens, Marcus M Seldin ... Anna C Calkin
    The benefits of integrating cross-species systems genetics platforms to advance knowledge in the underlying mechanisms that drive cardiometabolic diseases have been investigated.
    1. Developmental Biology
    2. Genetics and Genomics

    Quantitative trait and transcriptome analysis of genetic complexity underpinning cardiac interatrial septation in mice using an advanced intercross line

    Mahdi Moradi Marjaneh, Edwin P Kirk ... Richard P Harvey
    A high-resolution picture of genetic complexity and network perturbations underlying cardiac inter-atrial septal dysmorphology associated with patent foramen ovale, a common human congenital anomaly, using quantitative trait locus mapping, genome sequencing, and transcriptomics in a mouse model.
    1. Computational and Systems Biology

    Leveraging genetic diversity to identify small molecules that reverse mouse skeletal muscle insulin resistance

    Stewart WC Masson, Søren Madsen ... David E James
    A pharmacological approach for the validation of systems genetics data in the context of insulin resistance.
    1. Computational and Systems Biology

    Genetic and dietary modulators of the inflammatory response in the gastrointestinal tract of the BXD mouse genetic reference population

    Xiaoxu Li, Jean-David Morel ... Johan Auwerx
    A strategy combining large mouse and human genetic data sheds light on dietary and genetic drivers of gut inflammation.
    1. Cell Biology
    2. Genetics and Genomics

    Novel regulators of islet function identified from genetic variation in mouse islet Ca2+ oscillations

    Christopher H Emfinger, Lauren E Clark ... Alan D Attie
    Analysis of islet calcium oscillation responses will provide the field with a resource with which to determine the strain of interest for their specific islet biology questions.
    1. Computational and Systems Biology
    2. Genetics and Genomics

    Genetic architecture of heart mitochondrial proteome influencing cardiac hypertrophy

    Karthickeyan Chella Krishnan, Elie-Julien El Hachem ... Aldons J Lusis
    The discovery of three distinct and independent trans-regulating genomic loci influencing heart mass using a well-characterized mouse reference population provides evidence in support of the hypothesis that genetic diversity in the mitochondrial proteome plays a critical role in heart pathophysiology.
    1. Computational and Systems Biology
    2. Genetics and Genomics

    Systems level identification of a matrisome-associated macrophage polarisation state in multi-organ fibrosis

    John F Ouyang, Kunal Mishra ... Jacques Behmoaras
    A meta-analysis of single-cell data reveals an advanced and conserved polarisation state of SPP1+ macrophages in multiple human fibrotic tissues.
    1. Computational and Systems Biology
    2. Genetics and Genomics

    Broad functional profiling of fission yeast proteins using phenomics and machine learning

    María Rodríguez-López, Nicola Bordin ... Jürg Bähler
    Large-scale screens and computational approaches reveal phenotypes for 3492 genes and gene-ontology predictions for 783 genes, including hitherto unstudied genes, which provides a potent platform to further dissect protein function.
    1. Genetics and Genomics

    Leveraging inter-individual transcriptional correlation structure to infer discrete signaling mechanisms across metabolic tissues

    Mingqi Zhou, Ian Tamburini ... Marcus M Seldin
    A population resource to investigate mechanisms of organ communication.
    1. Computational and Systems Biology

    Predicting ventricular tachycardia circuits in patients with arrhythmogenic right ventricular cardiomyopathy using genotype-specific heart digital twins

    Yingnan Zhang, Kelly Zhang ... Natalia A Trayanova
    A novel computational approach integrates personal genetics into personalized whole heart digital twins to predict ventricular arrhythmia circuits for patients with arrhythmogenic right ventricular cardiomyopathy.
    1. Computational and Systems Biology

    Shared and distinct pathways and networks genetically linked to coronary artery disease between human and mouse

    Zeyneb Kurt, Jenny Cheng ... Xia Yang
    Cross-species multiomics network modeling revealed tissue-specific regulatory genes, pathways, and networks shared between mouse and human or unique to each species for atherosclerosis and coronary artery disease.
    1. Computational and Systems Biology

    Detection of new pioneer transcription factors as cell-type-specific nucleosome binders

    Yunhui Peng, Wei Song ... Anna R Panchenko
    A computational method has been developed for predicting the cell-type-specific binding of transcription factors to nucleosomes, and involves integration of ChIP-seq, MNase-seq, and DNase-seq data with details of nucleosome structure.
    1. Computational and Systems Biology

    The genetic and dietary landscape of the muscle insulin signalling network

    Julian van Gerwen, Stewart WC Masson ... David E James
    Genetic background and dietary environment interact to reshape metabolic signalling networks, and the resulting signalling diversity can illuminate regulatory mechanisms of complex traits.


  1. David James
    Senior Editor
  2. David Ashbrook
    Guest Editor
  3. Maroun Bou Sleiman
    Guest Editor
  4. Charles R. Farber
    Guest Editor
  5. Tune Pers
    Guest Editor
  6. Christine Queitsch
    Guest Editor
  7. Marcus M Seldin
    Reviewing Editor
  8. Leah Solberg Woods
    Guest Editor
  9. Evan Williams
    Guest Editor