Dataset Information

Retrospective cell lineage reconstruction in humans by using short tandem repeats.

ABSTRACT: Cell lineage analysis aims to uncover the developmental history of an organism back to its cell of origin. Recently, novel in vivo methods utilizing genome editing enabled important insights into the cell lineages of animals. In contrast, human cell lineage remains restricted to retrospective approaches, which still lack resolution and cost-efficient solutions. Here, we demonstrate a scalable platform based on short tandem repeats targeted by duplex molecular inversion probes. With this human cell lineage tracing method, we accurately reproduced a known lineage of DU145 cells and reconstructed lineages of healthy and metastatic single cells from a melanoma patient who matched the anatomical reference while adding further refinements. This platform allowed us to faithfully recapitulate lineages of developmental tissue formation in healthy cells. In summary, our lineage discovery platform can profile informative somatic mutations efficiently and provides solid lineage reconstructions even in challenging low-mutation-rate healthy single cells.

SUBMITTER: Tao L

PROVIDER: S-EPMC8313865 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Publications

Retrospective cell lineage reconstruction in humans by using short tandem repeats.

Tao Liming L Raz Ofir O Marx Zipora Z Ghosh Manjusha S MS Huber Sandra S Greindl-Junghans Julia J Biezuner Tamir T Amir Shiran S Milo Lilach L Adar Rivka R Levy Ron R Onn Amos A Chapal-Ilani Noa N Berman Veronika V Ben Arie Asaf A Rom Guy G Oron Barak B Halaban Ruth R Czyz Zbigniew T ZT Werner-Klein Melanie M Klein Christoph A CA Shapiro Ehud E

Cell reports methods 20210726 3

Cell lineage analysis aims to uncover the developmental history of an organism back to its cell of origin. Recently, novel <i>in vivo</i> methods utilizing genome editing enabled important insights into the cell lineages of animals. In contrast, human cell lineage remains restricted to retrospective approaches, which still lack resolution and cost-efficient solutions. Here, we demonstrate a scalable platform based on short tandem repeats targeted by duplex molecular inversion probes. With this h ...[more]

PMID: 34341783

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Project description:Expansions of glutamine-coding CAG trinucleotide repeats cause a number of neurodegenerative diseases, including Huntington's disease and several of spinocerebellar ataxias. In general, age-at-onset of the polyglutamine diseases is inversely correlated with the size of the respective inherited expanded CAG repeat. Expanded CAG repeats are also somatically unstable in certain tissues, and age-at-onset of Huntington's disease corrected for individual HTT CAG repeat length (i.e. residual age-at-onset), is modified by repeat instability-related DNA maintenance/repair genes as demonstrated by recent genome-wide association studies. Modification of one polyglutamine disease (e.g. Huntington's disease) by the repeat length of another (e.g. ATXN3, CAG expansions in which cause spinocerebellar ataxia 3) has also been hypothesized. Consequently, we determined whether age-at-onset in Huntington's disease is modified by the CAG repeats of other polyglutamine disease genes. We found that the CAG measured repeat sizes of other polyglutamine disease genes that were polymorphic in Huntington's disease participants but did not influence Huntington's disease age-at-onset. Additional analysis focusing specifically on ATXN3 in a larger sample set (n = 1388) confirmed the lack of association between Huntington's disease residual age-at-onset and ATXN3 CAG repeat length. Additionally, neither our Huntington's disease onset modifier genome-wide association studies single nucleotide polymorphism data nor imputed short tandem repeat data supported the involvement of other polyglutamine disease genes in modifying Huntington's disease. By contrast, our genome-wide association studies based on imputed short tandem repeats revealed significant modification signals for other genomic regions. Together, our short tandem repeat genome-wide association studies show that modification of Huntington's disease is associated with short tandem repeats that do not involve other polyglutamine disease-causing genes, refining the landscape of Huntington's disease modification and highlighting the importance of rigorous data analysis, especially in genetic studies testing candidate modifiers.

Dataset Information

Retrospective cell lineage reconstruction in humans by using short tandem repeats.

Publications

Retrospective cell lineage reconstruction in humans by using short tandem repeats.

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