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Aneuploidy as a mechanism for stress-induced liver adaptation
Andrew W. Duncan, … , Arthur L. Beaudet, Markus Grompe
Andrew W. Duncan, … , Arthur L. Beaudet, Markus Grompe
Published August 6, 2012
Citation Information: J Clin Invest. 2012;122(9):3307-3315. https://doi.org/10.1172/JCI64026.
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Research Article Hepatology

Aneuploidy as a mechanism for stress-induced liver adaptation

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Abstract

Over half of the mature hepatocytes in mice and humans are aneuploid and yet retain full ability to undergo mitosis. This observation has raised the question of whether this unusual somatic genetic variation evolved as an adaptive mechanism in response to hepatic injury. According to this model, hepatotoxic insults select for hepatocytes with specific numerical chromosome abnormalities, rendering them differentially resistant to injury. To test this hypothesis, we utilized a strain of mice heterozygous for a mutation in the homogentisic acid dioxygenase (Hgd) gene located on chromosome 16. Loss of the remaining Hgd allele protects from fumarylacetoacetate hydrolase (Fah) deficiency, a genetic liver disease model. When adult mice heterozygous for Hgd and lacking Fah were exposed to chronic liver damage, injury-resistant nodules consisting of Hgd-null hepatocytes rapidly emerged. To determine whether aneuploidy played a role in this phenomenon, array comparative genomic hybridization (aCGH) and metaphase karyotyping were performed. Strikingly, loss of chromosome 16 was dramatically enriched in all mice that became completely resistant to tyrosinemia-induced hepatic injury. The frequency of chromosome 16–specific aneuploidy was approximately 50%. This result indicates that selection of a specific aneuploid karyotype can result in the adaptation of hepatocytes to chronic liver injury. The extent to which aneuploidy promotes hepatic adaptation in humans remains under investigation.

Authors

Andrew W. Duncan, Amy E. Hanlon Newell, Weimin Bi, Milton J. Finegold, Susan B. Olson, Arthur L. Beaudet, Markus Grompe

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Figure 4

Loss of chromosome 16 in injury-resistant livers from Hgd+/–Fah–/– mice.

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Loss of chromosome 16 in injury-resistant livers from Hgd+/–Fah–/– mice....
(A) Copy number variation from aCGH analysis is shown specifically for chromosome 16. Hybridization intensity for hepatic chromosomes is plotted as log2 ratio versus sex-mismatched diploid chromosomes derived from splenocytes. Green dots indicate log2 ratio of less than 0, and red dots indicate log2 ratio of more than 0. The extent of chromosome loss is indicated along each plot (shaded purple). (B) Illustration of mosaicism for copy number loss in a heterogeneous population of cells as detected by aCGH. Whole chromosome loss and terminal deletion events are indicated. (C) Summary showing the maximum extent of chromosome 16 loss, which includes the Hgd locus.

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