title: Aneuploidy as a mechanism for stress-induced liver adaptation.
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.affiliation: Oregon Stem Cell Center, Papé Family Pediatric Research Institute, Portland, OR, USA. duncana@pitt.edu
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Duncan
authors.forename: Amy E
authors.initials: AE
authors.lastname: Hanlon Newell
authors.forename: Weimin
authors.initials: W
authors.lastname: Bi
authors.forename: Milton J
authors.initials: MJ
authors.lastname: Finegold
authors.forename: Susan B
authors.initials: SB
authors.lastname: Olson
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Beaudet
authors.forename: Markus
authors.initials: M
authors.lastname: Grompe
mesh_terms: D000222:Adaptation, Physiological; D000782:Aneuploidy; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D033481:Chromosomes, Mammalian / Q000235:genetics; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D005260:Female; D022781:Hepatocytes / Q000502:physiology; D050560:Homogentisate 1,2-Dioxygenase / Q000235:genetics; D059785:Karyotype; D008099:Liver / Q000166:cytology / Q000502:physiology*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013312:Stress, Physiological
chemical_list: D050560:Homogentisate 1,2-Dioxygenase