Affected cell types for hundreds of Mendelian diseases revealed by analysis of human and mouse single-cell data

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Abstract

Mendelian diseases tend to manifest clinically in certain tissues, yet their affected cell types typically remain elusive. Single-cell expression studies showed that overexpression of disease-associated genes may point to the affected cell types. Here, we developed a method that infers disease-affected cell types from the preferential expression of disease-associated genes in cell types (PrEDiCT). We applied PrEDiCT to single-cell expression data of six human tissues, to infer the cell types affected in Mendelian diseases. Overall, we inferred the likely affected cell types for 328 diseases. We corroborated our findings by literature text-mining, expert validation, and recapitulation in mouse corresponding tissues. Based on these findings, we explored characteristics of disease-affected cell types, showed that diseases manifesting in multiple tissues tend to affect similar cell types, and highlighted cases where gene functions could be used to refine inference. Together, these findings expand the molecular understanding of disease mechanisms and cellular vulnerability.

Data availability

All data generated or analyzed during this study are included in the manuscript, in supporting files. All data generated or analyzed during this study are included in the manuscript, in supporting files. The Source Data file contains data used to generate all figures. Additional data and code to redo analysis are available at GitHub https://github.com/hekselman/PrEDiCT, and Dryad https://datadryad.org/stash/share/5j6T7Duzcbyx3jNVL_irARhUphpUeW0vuYGTQHofozM .

The following previously published data sets were used

(2022) he Tabula Sapiens: A multiple-organ, single-cell transcriptomic atlas of humans. Science 2022 May 13;376(6594):eabl4896. PMID: 35549404
NCBI Gene Expression Omnibus, GSE201333.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE201333
(2018) Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris. Nature 2018 Oct;562(7727):367-372. PMID: 30283141
NCBI Gene Expression Omnibus, GSE109774.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE109774
1. Hekselman I
2. Kerber L
3. Ziv M
4. Gruber G
5. Yeger-Lotem E
(2022) ODiseA
DOI: 10.1016/j.jmb.2022.167619.

https://netbio.bgu.ac.il/odisea/

Article and author information

Author details

Idan Hekselman

Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva, Israel

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-0529-7838
Assaf Vital

Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva, Israel

Competing interests
The authors declare that no competing interests exist.
Maya Ziv-Agam

Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva, Israel

Competing interests
The authors declare that no competing interests exist.
Lior Kerber

Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva, Israel

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0009-0005-0583-5618
Ido Yairi

Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva, Israel

Competing interests
The authors declare that no competing interests exist.
Esti Yeger-Lotem

Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva, Israel

For correspondence
estiyl@bgu.ac.il

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-8279-7898

Funding

Israel Science Foundation (317/19)

Esti Yeger-Lotem

Israel Science Foundation (401/22)

Esti Yeger-Lotem

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.