Human and mouse essentiality screens as a resource for disease gene discovery

Cacheiro, Pilar; Muñoz-Fuentes, Violeta; Murray, Stephen A.; Dickinson, Mary E.; Bućan, Maja; Nutter, Lauryl M. J.; Peterson, Kevin A.; Haselimashhadi, Hamed; Flenniken, Ann M.; Morgan, Hugh W.; Westerberg, Henrik; Konopka, Tomasz; Hsu, Chih-Wei; Christiansen, Audrey E.; Lanza, Denise G.; Beaudet, Arthur L.; Heaney, Jason D.; Fuchs, Helmut; Gailus‐Durner, Valérie; Sorg, Tania; Procházka, Jan; Novosadová, Vendula; Lelliott, Christopher J.; Wardle‐Jones, Hannah; Wells, Sara; Teboul, Lydia; Cater, Heather; Stewart, Michelle; Hough, Tertius; Wurst, Wolfgang; Sedláček, Radislav; Adams, David J.; Seavitt, John R.; Tocchini‐Valentini, Glauco P.; Mammano, Fabio; Braun, Robert E.; McKerlie, Colin; Hérault, Yann; Angelis, Martin Hrabé de; Mallon, Ann‐Marie; Lloyd, Kent; Brown, Steve; Parkinson, Helen; Meehan, Terrence F.; Smedley, Damian

doi:10.1101/678250

Cited by 20 publications

(50 citation statements)

References 77 publications

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“…It is well established that there is an association between lethal genes in the mouse and human disease genes 15,29 . Our previous study showed that this enrichment was mainly driven by developmental lethal genes 16 so we hypothesised that the distribution of disease genes across WoL may not be uniform and that information about WoL could highlight additional correlations. When translating our WoL to relevant developmental stages in humans, the EL mouse category broadly correlates with the human pre-organogenesis stage occurring during the first two weeks of development.…”

Section: Resultsmentioning

confidence: 97%

“…We previously reported that EL genes show a considerable overlap with human cellular essential genes 16 . Plotting individual gene-based proliferations scores for different human cell lines across tissues obtained from CRISPR knockout screens through the Achilles pipeline 22 , we observed a clear distinction between the three WoL.…”

Section: Resultsmentioning

confidence: 99%

“…Additionally, mouse data on essentiality can be used as a discovery and prioritisation tool 14,15 . We previously developed a gene prioritisation strategy focused on neurodevelopmental disorders by integrating evidence of intolerance to loss-of-function (LoF) variation from multiple resources and bringing in data from large scale sequencing programs 16 . Through this approach combining viability data from mice and human cell line screens, we were able to identify a set of developmentally lethal genes, i.e.…”

Section: Introductionmentioning

confidence: 99%

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Mendelian gene identification through mouse embryo viability screening

Cacheiro

Westerberg

Mager

et al. 2022

Preprint

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The diagnostic rate of Mendelian disorders in sequencing studies continues to increase, along with the pace of novel disease gene discovery. However, variant interpretation in novel genes not currently associated with disease is particularly challenging and strategies combining gene functional evidence with approaches that evaluate the phenotypic similarities between patients and model organisms have proven successful. A full spectrum of intolerance to loss-of-function variation has been previously described, providing evidence that gene essentiality should not be considered as a simple and fixed binary property. Here we further dissected this spectrum by assessing the embryonic stage at which homozygous loss-of-function results in lethality in mice from the International Mouse Phenotyping Consortium, classifying the set of lethal genes into one of three windows of lethality: early, mid or late gestation lethal. We studied the correlation between these windows of lethality and various gene features including expression across development, paralogy and constraint metrics together with human disease phenotypes, and found that the members of the early gestation lethal category show distinctive characteristics and a strong enrichment for genes linked with recessive forms of inherited metabolic disease. Based on these findings, we explored a gene similarity approach for novel gene discovery focused on this subset of lethal genes. Finally, we investigated unsolved cases from the 100,000 Genomes Project recruited under this disease category to look for signs of enrichment of biallelic predicted pathogenic variants among early gestation lethal genes and highlight two novel candidates with phenotypic overlap between the patients and the mouse knockout.

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Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mendelian gene identification through mouse embryo viability screening

Cacheiro

Westerberg

Mager

et al. 2022

Preprint

Self Cite

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“…We then characterized the set of dynamic genes associated with the two neuron types using different metrics of functional constraints: the in vivo gene essentiality scores that measure tolerance to heterozygous inactivation in human population, and the in vitro score that is inferred from viability of human cell lines 38,39 . We found that dynamic genes are enriched for in vivo essential genes, but not for in vitro essential genes, likely because the latter include many genes involved in the cell cycle and cellular metabolism 40 (Fig. 3e, Extended Data Fig.…”

Section: Cell Type-defining Transcriptional Programsmentioning

confidence: 99%

Cellular development and evolution of the mammalian cerebellum

Sepp

Leiss

Sarropoulos

et al. 2021

Preprint

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The expansion of the neocortex, one of the hallmarks of mammalian evolution, was accompanied by an increase in the number of cerebellar neurons. However, little is known about the evolution of the cellular programs underlying cerebellum development in mammals. In this study, we generated single-nucleus RNA-sequencing data for ~400,000 cells to trace the development of the cerebellum from early neurogenesis to adulthood in human, mouse, and the marsupial opossum. Our cross-species analyses revealed that the cellular composition and differentiation dynamics throughout cerebellum development are largely conserved, except for human Purkinje cells. Global transcriptome profiles, conserved cell state markers, and gene expression trajectories across neuronal differentiation show that the cerebellar cell type-defining programs have been overall preserved for at least 160 million years. However, we also discovered differences. We identified 3,586 genes that either gained or lost expression in cerebellar cells in one of the species, and 541 genes that evolved new expression trajectories during neuronal differentiation. The potential functional relevance of these cross-species differences is highlighted by the diverged expression patterns of several human disease-associated genes. Altogether, our study reveals shared and lineage-specific programs governing the cellular development of the mammalian cerebellum, and expands our understanding of the evolution of mammalian organ development.

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“…Critically, already 360 IMPC lines (40%) have phenotypic similarity with 889 human disease genes, and the majority (78%) of these lines are the first reported mouse models for the associated human diseases (Meehan et al 2017 ). Beyond this, the IMPC resource has been used in more than 2000 published studies so far, and has led to the identification of essential genes for mouse viability (Cacheiro et al 2020 ), as well as candidate genes for metabolic homeostasis (Rozman et al 2018 ), eye development (Moore et al 2018 ), auditory dysfunction (Bowl et al 2017 ) and sexual dimorphism (Karp et al 2017 ).…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Genetic control of non-genetic inheritance in mammals: state-of-the-art and perspectives

Tomar

Teperino

2020

Mamm Genome

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Thought to be directly and uniquely dependent from genotypes, the ontogeny of individual phenotypes is much more complicated. Individual genetics, environmental exposures, and their interaction are the three main determinants of individual’s phenotype. This picture has been further complicated a decade ago when the Lamarckian theory of acquired inheritance has been rekindled with the discovery of epigenetic inheritance, according to which acquired phenotypes can be transmitted through fertilization and affect phenotypes across generations. The results of Genome-Wide Association Studies have also highlighted a big degree of missing heritability in genetics and have provided hints that not only acquired phenotypes, but also individual’s genotypes affect phenotypes intergenerationally through indirect genetic effects. Here, we review available examples of indirect genetic effects in mammals, what is known of the underlying molecular mechanisms and their potential impact for our understanding of missing heritability, phenotypic variation. and individual disease risk.

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Human and mouse essentiality screens as a resource for disease gene discovery

Cited by 20 publications

References 77 publications

Mendelian gene identification through mouse embryo viability screening

Mendelian gene identification through mouse embryo viability screening

Cellular development and evolution of the mammalian cerebellum

Genetic control of non-genetic inheritance in mammals: state-of-the-art and perspectives

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