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High-throughput mouse phenomics for characterizing mammalian gene function

Abstract

We are entering a new era of mouse phenomics, driven by large-scale and economical generation of mouse mutants coupled with increasingly sophisticated and comprehensive phenotyping. These studies are generating large, multidimensional gene–phenotype data sets, which are shedding new light on the mammalian genome landscape and revealing many hitherto unknown features of mammalian gene function. Moreover, these phenome resources provide a wealth of disease models and can be integrated with human genomics data as a powerful approach for the interpretation of human genetic variation and its relationship to disease. In the future, the development of novel phenotyping platforms allied to improved computational approaches, including machine learning, for the analysis of phenotype data will continue to enhance our ability to develop a comprehensive and powerful model of mammalian gene–phenotype space.

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Fig. 1: Pleiotropy is central to our understanding of mammalian gene function.
Fig. 2: The IMPC phenotyping pipeline.
Fig. 3: Home-cage monitoring and machine learning.
Fig. 4: Ageing as a new dimension of high-throughput mouse phenotyping.
Fig. 5: Overview of data flow for large-scale, broad-based mouse phenotyping programmes.
Fig. 6: Integration of human and mouse data for rare-disease genetics.

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Acknowledgements

The authors are grateful to J. McMurry for help with Fig. 6, which is a composition of several images previously licensed under CC0 in Pixabay and some under CC-BY 4.0 in https://github.com/jmcmurry/open-illustrations. The authors also thank their colleagues in the International Mouse Phenotyping Consortium, who have contributed in no small measure to the consideration and future of mouse phenomics. The authors thank many colleagues who have participated with them in other consortia involving mouse phenomics, including European Union Mouse Genetics Research for Public Health and Industrial Applications (EUMORPHIA), European Mouse Disease Clinic (EUMODIC) and European Conditional Mouse Mutagenesis Program (EUCOMM). The views expressed in this article are based on the many discussions and insights that have emerged within these consortia over many years. Lastly, the authors are grateful to the Medical Research Council, UK (S.D.M.B., C.C.H., A-M.M. and S.W.), the National Institutes of Health Grant UM1-HG006370 (A-M.M., T.F.M. and D.S.), and the Engineering and Physical Sciences Research Council, UK (C.C.H.) for funding support.

Reviewer information

Nature Reviews thanks Jonathan Flint, K. C. Kent Lloyd and the other anonymous reviewer(s), for their contribution to the peer review of this work.

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All authors contributed to all aspects of this manuscript, including researching data, discussing content, writing, and reviewing and editing the manuscript before submission.

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Correspondence to Steve D. M. Brown or Chris C. Holmes or Ann-Marie Mallon or Terrence F. Meehan or Damian Smedley or Sara Wells.

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Related links

International Mouse Phenotyping Consortium (IMPC): http://www.mousephenotype.org

International Mouse Phenotyping Resource of Standardised Screens (IMPReSS): http://www.mousephenotype.org

Online Mendelian Inheritance in Man (OMIM): http://www.omim.org

Orphanet: http://www.orpha.net

Hybrid Mouse Diversity Panel (HMDP): https://systems.genetics.ucla.edu/

Edinburgh Mouse Atlas Project (EMAP): http://www.emouseatlas.org/

Phenotype And Trait Ontology (PATO): https://bioportal.bioontology.org/ontologies/PATO

Genotype–Tissue Expression (GTEx) Project: https://www.gtexportal.org/home/

Search Tool for the Retrieval of Interacting Genes/Proteins (STRING): https://string-db.org/

Monarch Initiative: https://monarchinitiative.org/

100,000 Genomes Project: https://www.genomicsengland.co.uk/

NIH Undiagnosed Diseases Network (UDN): https://undiagnosed.hms.harvard.edu/

Mouse Genome Informatics: http://www.informatics.jax.org

Glossary

Variable expressivity

Differing phenotypic features among individuals with the same genotype.

Phenotypic expansion

The expanding array of phenotypes that may be associated with mutations in a specific gene.

Genome-wide association studies

(GWAS). Genome-wide analyses of single nucleotide polymorphisms (SNPs) in human cohorts to test for associations between SNPs and traits.

Phenome-wide association studies

(PheWAS). Testing genetic variants for an association with multiple phenotypes or traits (the phenome) in human cohorts.

Pre-pulse inhibition

(PPI). Used to assess sensorimotor gating. In the PPI test, sensorimotor gating is assessed by measuring the innate reduction of the startle reflex induced by a weak prestimulus (prepulse) before a subsequent strong startle stimulus (pulse). Deficits in PPI responses are noted in patients suffering from a range of illnesses, including schizophrenia.

Optokinetic drum

Assesses the threshold of visual acuity by placing a mouse in the centre of a rotating drum and measuring reflexive head turning in response to the rotation of stripes, which subsequently decrease in width and distance of separation.

Auditory brainstem response

Measures the electrical response in the auditory nerve and brainstem to either a defined frequency or a longer, complex auditory stimulus. This allows frequency-specific auditory thresholds to be determined.

Gene trapping

A random insertional mutation into an intron or exon of a gene that disrupts expression of the trapped gene.

Gene targeting

Targeting by homologous recombination into embryonic stem cells to introduce mutations ranging from single base pair substitutions to large deletions.

Endophenotypes

A heritable and measurable component of a phenotype, which is intermediate between gene and disease.

Coisogenic

Isogenic strains differing only at a single locus. Thus, all International Mouse Phenotyping Consortium (IMPC) lines are coisogenic on the C57BL/6 N background.

Optical projection tomography

(OPT). An optical computed tomography technique that is used to acquire 3D images of early embryo morphology in the mouse.

Micro-computed tomography

(µCT). High-resolution X-ray computed tomography to acquire 3D images of embryo morphology in the mouse, usually during later stages of development.

High-resolution episcopic microscopy

(HREM). A method for the determination of the 3D structure of embryos using recurrent block surface (episcopic) imaging of sections from histological samples.

Subviable lines

Mouse mutant lines for which some individual mice show embryonic lethality, whereas others of identical genotype survive.

Paralogue

Paralogues are pairs of genes that derive from a common ancestral gene and may undertake similar functions.

Recombinant inbred

(RI). Mouse lines that are derived by the intercrossing and subsequent inbreeding of two distinct inbred lines. Each line carries a differing patchwork of chromosome segments from the two parental lines, allowing researchers to relate phenotypic differences between the parental inbred strains to the underlying genetic loci involved.

Collaborative Cross

(CC). Mouse lines that are a multi-parental recombinant inbred panel derived from crosses between eight inbred lines (including three wild-derived inbred strains), capturing a greater genetic diversity more evenly spread across the genome.

Quantitative trait locus

(QTL). A locus that contributes some proportion of the total phenotypic variance of the quantitative trait. Many quantitative traits are determined by multiple genes (or QTLs), each of which may have small or large effects on the phenotype.

Heterogeneous Stock

(HS). A type of mouse population that enables fine-resolution mapping of traits and is created by the intercrossing of inbred or recombinant inbred lines followed by mating schemes that minimize inbreeding.

Diversity Outbred

(DO). A mouse population that is a Heterogeneous Stock that was derived by random mating of 144 partially inbred Collaborative Cross lines, providing single-gene mapping resolution.

Ontology

Phenotype ontologies encompass the naming, description and interrelationship of phenotypes.

Orphan drugs

Drugs that are developed to treat a rare medical condition, an orphan disease.

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Brown, S.D.M., Holmes, C.C., Mallon, AM. et al. High-throughput mouse phenomics for characterizing mammalian gene function. Nat Rev Genet 19, 357–370 (2018). https://doi.org/10.1038/s41576-018-0005-2

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