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Should we build single-cell lineage trees from gene expression data?

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Τίτλος: Should we build single-cell lineage trees from gene expression data?
Συγγραφείς: Mulberry N; Department of Biosystems Science & Engineering, ETH Zürich, Basel 4058, Switzerland.; Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland., Stadler T; Department of Biosystems Science & Engineering, ETH Zürich, Basel 4058, Switzerland.; Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland.
Πηγή: Genetics [Genetics] 2026 Sep 02; Vol. 234 (1).
Τύπος έκδοσης: Journal Article; Research Support, Non-U.S. Gov't
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Oxford University Press Country of Publication: United States NLM ID: 0374636 Publication Model: Print Cited Medium: Internet ISSN: 1943-2631 (Electronic) Linking ISSN: 00166731 NLM ISO Abbreviation: Genetics Subsets: MEDLINE
Imprint Name(s): Publication: 2021- : [Oxford] : Oxford University Press
Original Publication: Austin, Tex. [etc.]
Ιατρικοί όροι (MeSH): Cell Lineage*/genetics , Single-Cell Analysis*/methods , Phylogeny* , Models, Genetic* , Transcriptome* , Gene Expression Profiling*, Single-Cell Gene Expression Analysis ; Animals
Περίληψη: Gene expression data have been proposed as a natural single-cell lineage marker. Here, we critically examine the feasibility of reconstructing lineage trees from single-cell transcriptomic data using both modeling and empirical data. We first introduce a notion of neutrality for transcriptomic data, and then, under a model for neutral gene expression, establish theoretical bounds for accurate lineage tree reconstruction. Our findings indicate that reconstruction guarantees for even small trees or sub-trees require thousands of independent, neutral traits-a condition that is likely rarely met in practice due to the dominance of non-neutral developmental signals. Furthermore, errors introduced by measurement sampling have the potential to destroy any existing lineage signal. We conclude that gene expression data have limited potential as a natural lineage recorder and should not be used for phylogenetic lineage tree inference without further, rigorous validation.
(© The Author(s) 2026. Published by Oxford University Press on behalf of The Genetics Society of America.)
Competing Interests: Conflicts of interest: We declare no conflicts of interest.
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Nat Commun. 2023 Dec 16;14(1):8388. (PMID: 38104156)
Theor Popul Biol. 2026 Apr;168:32-43. (PMID: 41554460)
Nat Rev Genet. 2025 Mar;26(3):203-222. (PMID: 39587306)
Nat Commun. 2024 Mar 29;15(1):2744. (PMID: 38553478)
Nat Rev Genet. 2021 Apr;22(4):235-250. (PMID: 33244170)
Bioinformatics. 2020 Dec 22;36(20):5007-5013. (PMID: 32619004)
Genome Biol. 2016 Apr 27;17:75. (PMID: 27122128)
Cell. 2023 Nov 9;186(23):5183-5199.e22. (PMID: 37852258)
Proc Natl Acad Sci U S A. 2023 Mar 21;120(12):e2203352120. (PMID: 36927151)
Cell Stem Cell. 2018 Aug 02;23(2):166-179. (PMID: 29754780)
Science. 2019 Sep 20;365(6459):. (PMID: 31488706)
Mol Biol Evol. 2026 Apr 01;43(4):. (PMID: 41883176)
Nat Rev Genet. 2022 Jun;23(6):325-341. (PMID: 34983971)
Evolution. 2003 Apr;57(4):717-45. (PMID: 12778543)
Science. 2010 Oct 29;330(6004):612-6. (PMID: 21030644)
Nature. 2022 Aug;608(7921):98-107. (PMID: 35794474)
Nat Commun. 2020 Jun 16;11(1):3055. (PMID: 32546686)
Nature. 2019 Feb;566(7745):490-495. (PMID: 30787436)
Bioinformatics. 2019 Feb 1;35(3):526-528. (PMID: 30016406)
Genome Biol. 2019 Dec 23;20(1):296. (PMID: 31870423)
Cell. 2020 Aug 20;182(4):947-959.e17. (PMID: 32735851)
Nat Commun. 2019 Mar 14;10(1):1208. (PMID: 30872573)
Nat Biotechnol. 2021 Aug;39(8):1008-1016. (PMID: 33927416)
Nat Methods. 2025 Mar;22(3):488-498. (PMID: 39820752)
PLoS Comput Biol. 2025 Feb 13;21(2):e1012789. (PMID: 39937844)
Science. 2011 Apr 22;332(6028):472-4. (PMID: 21415320)
Nat Commun. 2026 Jun 10;17(1):. (PMID: 42270637)
Nat Commun. 2021 Aug 16;12(1):4940. (PMID: 34400634)
Imeta. 2022 Sep 28;1(4):e56. (PMID: 38867905)
Science. 2021 Jan 15;371(6526):. (PMID: 33446527)
Mol Ther Methods Clin Dev. 2018 Aug 02;10:189-196. (PMID: 30094294)
Grant Information: 101001077 European Research Council (ERC)
Contributed Indexing: Keywords: gene expression; lineage trees; phylogeny; single-cell RNA sequencing
Molecular Sequence: GEO GSE315827
Entry Date(s): Date Created: 20260718 Date Completed: 20260902 Latest Revision: 20260918
Update Code: 20260919
PubMed Central ID: PMC13535251
DOI: 10.1093/genetics/iyag187
PMID: 42470686
Βάση Δεδομένων: MEDLINE
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  Data: Should we build single-cell lineage trees from gene expression data?
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  Data: <searchLink fieldCode="AU" term="%22Mulberry+N%22">Mulberry N</searchLink>; Department of Biosystems Science & Engineering, ETH Zürich, Basel 4058, Switzerland.; Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland.<br /><searchLink fieldCode="AU" term="%22Stadler+T%22">Stadler T</searchLink>; Department of Biosystems Science & Engineering, ETH Zürich, Basel 4058, Switzerland.; Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland.
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  Data: <searchLink fieldCode="MM" term="%22Cell+Lineage%22">Cell Lineage*</searchLink>/<searchLink fieldCode="MM" term="%22Cell+Lineage+genetics%22">genetics</searchLink> <br /><searchLink fieldCode="MM" term="%22Single-Cell+Analysis%22">Single-Cell Analysis*</searchLink>/<searchLink fieldCode="MM" term="%22Single-Cell+Analysis+methods%22">methods</searchLink> <br /><searchLink fieldCode="MM" term="%22Phylogeny%22">Phylogeny*</searchLink> <br /><searchLink fieldCode="MM" term="%22Models%2C+Genetic%22">Models, Genetic*</searchLink> <br /><searchLink fieldCode="MM" term="%22Transcriptome%22">Transcriptome*</searchLink> <br /><searchLink fieldCode="MM" term="%22Gene+Expression+Profiling%22">Gene Expression Profiling*</searchLink><br /><searchLink fieldCode="MH" term="%22Single-Cell+Gene+Expression+Analysis%22">Single-Cell Gene Expression Analysis</searchLink> ; <searchLink fieldCode="MH" term="%22Animals%22">Animals</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Gene expression data have been proposed as a natural single-cell lineage marker. Here, we critically examine the feasibility of reconstructing lineage trees from single-cell transcriptomic data using both modeling and empirical data. We first introduce a notion of neutrality for transcriptomic data, and then, under a model for neutral gene expression, establish theoretical bounds for accurate lineage tree reconstruction. Our findings indicate that reconstruction guarantees for even small trees or sub-trees require thousands of independent, neutral traits-a condition that is likely rarely met in practice due to the dominance of non-neutral developmental signals. Furthermore, errors introduced by measurement sampling have the potential to destroy any existing lineage signal. We conclude that gene expression data have limited potential as a natural lineage recorder and should not be used for phylogenetic lineage tree inference without further, rigorous validation.<br /> (© The Author(s) 2026. Published by Oxford University Press on behalf of The Genetics Society of America.)
– Name: Abstract
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  Data: Conflicts of interest: We declare no conflicts of interest.
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  Data: PeerJ. 2024 Jan 5;12:e16505. (PMID: <searchLink fieldCode="PM" term="%2238192598%22">38192598)</searchLink><br />Nat Commun. 2023 Dec 16;14(1):8388. (PMID: <searchLink fieldCode="PM" term="%2238104156%22">38104156)</searchLink><br />Theor Popul Biol. 2026 Apr;168:32-43. (PMID: <searchLink fieldCode="PM" term="%2241554460%22">41554460)</searchLink><br />Nat Rev Genet. 2025 Mar;26(3):203-222. (PMID: <searchLink fieldCode="PM" term="%2239587306%22">39587306)</searchLink><br />Nat Commun. 2024 Mar 29;15(1):2744. (PMID: <searchLink fieldCode="PM" term="%2238553478%22">38553478)</searchLink><br />Nat Rev Genet. 2021 Apr;22(4):235-250. (PMID: <searchLink fieldCode="PM" term="%2233244170%22">33244170)</searchLink><br />Bioinformatics. 2020 Dec 22;36(20):5007-5013. (PMID: <searchLink fieldCode="PM" term="%2232619004%22">32619004)</searchLink><br />Genome Biol. 2016 Apr 27;17:75. (PMID: <searchLink fieldCode="PM" term="%2227122128%22">27122128)</searchLink><br />Cell. 2023 Nov 9;186(23):5183-5199.e22. (PMID: <searchLink fieldCode="PM" term="%2237852258%22">37852258)</searchLink><br />Proc Natl Acad Sci U S A. 2023 Mar 21;120(12):e2203352120. (PMID: <searchLink fieldCode="PM" term="%2236927151%22">36927151)</searchLink><br />Cell Stem Cell. 2018 Aug 02;23(2):166-179. (PMID: <searchLink fieldCode="PM" term="%2229754780%22">29754780)</searchLink><br />Science. 2019 Sep 20;365(6459):. (PMID: <searchLink fieldCode="PM" term="%2231488706%22">31488706)</searchLink><br />Mol Biol Evol. 2026 Apr 01;43(4):. (PMID: <searchLink fieldCode="PM" term="%2241883176%22">41883176)</searchLink><br />Nat Rev Genet. 2022 Jun;23(6):325-341. (PMID: <searchLink fieldCode="PM" term="%2234983971%22">34983971)</searchLink><br />Evolution. 2003 Apr;57(4):717-45. (PMID: <searchLink fieldCode="PM" term="%2212778543%22">12778543)</searchLink><br />Science. 2010 Oct 29;330(6004):612-6. (PMID: <searchLink fieldCode="PM" term="%2221030644%22">21030644)</searchLink><br />Nature. 2022 Aug;608(7921):98-107. (PMID: <searchLink fieldCode="PM" term="%2235794474%22">35794474)</searchLink><br />Nat Commun. 2020 Jun 16;11(1):3055. (PMID: <searchLink fieldCode="PM" term="%2232546686%22">32546686)</searchLink><br />Nature. 2019 Feb;566(7745):490-495. (PMID: <searchLink fieldCode="PM" term="%2230787436%22">30787436)</searchLink><br />Bioinformatics. 2019 Feb 1;35(3):526-528. (PMID: <searchLink fieldCode="PM" term="%2230016406%22">30016406)</searchLink><br />Genome Biol. 2019 Dec 23;20(1):296. (PMID: <searchLink fieldCode="PM" term="%2231870423%22">31870423)</searchLink><br />Cell. 2020 Aug 20;182(4):947-959.e17. (PMID: <searchLink fieldCode="PM" term="%2232735851%22">32735851)</searchLink><br />Nat Commun. 2019 Mar 14;10(1):1208. (PMID: <searchLink fieldCode="PM" term="%2230872573%22">30872573)</searchLink><br />Nat Biotechnol. 2021 Aug;39(8):1008-1016. (PMID: <searchLink fieldCode="PM" term="%2233927416%22">33927416)</searchLink><br />Nat Methods. 2025 Mar;22(3):488-498. (PMID: <searchLink fieldCode="PM" term="%2239820752%22">39820752)</searchLink><br />PLoS Comput Biol. 2025 Feb 13;21(2):e1012789. (PMID: <searchLink fieldCode="PM" term="%2239937844%22">39937844)</searchLink><br />Science. 2011 Apr 22;332(6028):472-4. (PMID: <searchLink fieldCode="PM" term="%2221415320%22">21415320)</searchLink><br />Nat Commun. 2026 Jun 10;17(1):. (PMID: <searchLink fieldCode="PM" term="%2242270637%22">42270637)</searchLink><br />Nat Commun. 2021 Aug 16;12(1):4940. (PMID: <searchLink fieldCode="PM" term="%2234400634%22">34400634)</searchLink><br />Imeta. 2022 Sep 28;1(4):e56. (PMID: <searchLink fieldCode="PM" term="%2238867905%22">38867905)</searchLink><br />Science. 2021 Jan 15;371(6526):. (PMID: <searchLink fieldCode="PM" term="%2233446527%22">33446527)</searchLink><br />Mol Ther Methods Clin Dev. 2018 Aug 02;10:189-196. (PMID: <searchLink fieldCode="PM" term="%2230094294%22">30094294)</searchLink>
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