Dataset Information

Dimensional reduction of phenotypes from 53 000 mouse models reveals a diverse landscape of gene function.

ABSTRACT: Animal models have long been used to study gene function and the impact of genetic mutations on phenotype. Through the research efforts of thousands of research groups, systematic curation of published literature and high-throughput phenotyping screens, the collective body of knowledge for the mouse now covers the majority of protein-coding genes. We here collected data for over 53 000 mouse models with mutations in over 15 000 genomic markers and characterized by more than 254 000 annotations using more than 9000 distinct ontology terms. We investigated dimensional reduction and embedding techniques as means to facilitate access to this diverse and high-dimensional information. Our analyses provide the first visual maps of the landscape of mouse phenotypic diversity. We also summarize some of the difficulties in producing and interpreting embeddings of sparse phenotypic data. In particular, we show that data preprocessing, filtering and encoding have as much impact on the final embeddings as the process of dimensional reduction. Nonetheless, techniques developed in the context of dimensional reduction create opportunities for explorative analysis of this large pool of public data, including for searching for mouse models suited to study human diseases.

Availability and implementation

Source code for analysis scripts is available on GitHub at https://github.com/tkonopka/mouse-embeddings. The data underlying this article are available in Zenodo at https://doi.org/10.5281/zenodo.4916171.

Contact

t.konopka@qmul.ac.uk.

Supplementary information

Supplementary data are available at Bioinformatics Advances online.

SUBMITTER: Konopka T

PROVIDER: S-EPMC8633315 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Dimensional reduction of phenotypes from 53 000 mouse models reveals a diverse landscape of gene function.

Konopka Tomasz T Vestito Letizia L Smedley Damian D

Bioinformatics advances 20211011 1

Animal models have long been used to study gene function and the impact of genetic mutations on phenotype. Through the research efforts of thousands of research groups, systematic curation of published literature and high-throughput phenotyping screens, the collective body of knowledge for the mouse now covers the majority of protein-coding genes. We here collected data for over 53 000 mouse models with mutations in over 15 000 genomic markers and characterized by more than 254 000 annotations u ...[more]

PMID: 34870209

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Project description:BackgroundRepetitive action, resistance to environmental change and fine motor disruptions are hallmarks of autism spectrum disorder (ASD) and other neurodevelopmental disorders, and vary considerably from individual to individual. In animal models, conventional behavioral phenotyping captures such fine-scale variations incompletely. Here we observed male and female C57BL/6J mice to methodically catalog adaptive movement over multiple days and examined two rodent models of developmental disorders against this dynamic baseline. We then investigated the behavioral consequences of a cerebellum-specific deletion in Tsc1 protein and a whole-brain knockout in Cntnap2 protein in mice. Both of these mutations are found in clinical conditions and have been associated with ASD.MethodsWe used advances in computer vision and deep learning, namely a generalized form of high-dimensional statistical analysis, to develop a framework for characterizing mouse movement on multiple timescales using a single popular behavioral assay, the open-field test. The pipeline takes virtual markers from pose estimation to find behavior clusters and generate wavelet signatures of behavior classes. We measured spatial and temporal habituation to a new environment across minutes and days, different types of self-grooming, locomotion and gait.ResultsBoth Cntnap2 knockouts and L7-Tsc1 mutants showed forelimb lag during gait. L7-Tsc1 mutants and Cntnap2 knockouts showed complex defects in multi-day adaptation, lacking the tendency of wild-type mice to spend progressively more time in corners of the arena. In L7-Tsc1 mutant mice, failure to adapt took the form of maintained ambling, turning and locomotion, and an overall decrease in grooming. However, adaptation in these traits was similar between wild-type mice and Cntnap2 knockouts. L7-Tsc1 mutant and Cntnap2 knockout mouse models showed different patterns of behavioral state occupancy.LimitationsGenetic risk factors for autism are numerous, and we tested only two. Our pipeline was only done under conditions of free behavior. Testing under task or social conditions would reveal more information about behavioral dynamics and variability.ConclusionsOur automated pipeline for deep phenotyping successfully captures model-specific deviations in adaptation and movement as well as differences in the detailed structure of behavioral dynamics. The reported deficits indicate that deep phenotyping constitutes a robust set of ASD symptoms that may be considered for implementation in clinical settings as quantitative diagnosis criteria.

Dataset Information

Dimensional reduction of phenotypes from 53 000 mouse models reveals a diverse landscape of gene function.

Availability and implementation

Contact

Supplementary information

Publications

Dimensional reduction of phenotypes from 53 000 mouse models reveals a diverse landscape of gene function.

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