Unknown,Transcriptomics,Genomics,Proteomics

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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 whether this unusual somatic genetic variation evolved as an adaptive mechanism to hepatic injury. According to this model, hepatotoxic insults would select for hepatocytes with specific numerical chromosome abnormalities, rendering them differentially resistant to the injury. To test this hypothesis, we utilized a strain of mice heterozygous for a mutation in homogentisic acid dioxygenase (Hgd), located on chromosome 16. Loss of this allele can protect from fumarylacetoacetate hydrolase (Fah) deficiency. When adult Hgd+/- Fah-/- mice 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 ~50%. This result provides proof-of-principle that the 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 is under investigation. 8 mouse hepatocyte samples were analyzed. Genomic DNA samples were derived from wild type mice (2), Hgd-/- Fah-/- mice off NTBC (2) and Hgd+/- Fah-/- off NTBC (4). Samples were compared to sex-mismatched reference genomic DNA isolated from wild type mouse splenocytes.

ORGANISM(S): Mus musculus

SUBMITTER: Andrew Duncan

PROVIDER: E-GEOD-38963 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Aneuploidy, an imbalance in chromosome copy numbers, causes genetic disorders, and drives cancer progression, drug tolerance, and antimicrobial resistance. While aneuploidy can confer stress resistance, it is not well understood how cells overcome the fitness burden caused by aberrant chromosomal copy numbers. Studies using both systematically generated and natural aneuploid yeasts triggered an intense debate about the role of dosage compensation, concluding that aneuploidy is transmitted to the transcriptome and proteome without significant buffering at the chromosome-wide level, and is, at least in lab strains, associated with significant fitness costs. Conversely, systematic sequencing and phenotyping of large collections of natural isolates revealed that aneuploidy is frequent and has few, if any, fitness costs in nature. To address these discrepant findings, we developed a platform that yields highly precise proteomic measurements across large numbers of genetically diverse samples and applied it to natural isolates collected as part of the 1011 genomes project (Peter, J. et al, 2018). For 613 of the isolates, we were able to match the proteomes to their corresponding transcriptomes and genomes, subsequently quantifying the effect of aneuploidy on gene expression by comparing 95 aneuploid with 518 euploid strains. We find, as in previous studies, that aneuploid gene dosage is not buffered chromosome-wide at the transcriptome level. Importantly, in the proteome, we detect an attenuation of aneuploidy by about 25% below the aneuploid gene dosage in natural yeast isolates. Furthermore, this chromosome-wide dosage compensation is associated with the ubiquitin-proteasome system (UPS), which is expressed at higher levels and has increased activity across natural aneuploid strains. Thus, through systematic exploration of the species-wide diversity of the yeast proteome, we shed light on a long-standing debate about the biology of aneuploids, revealing that aneuploidy tolerance is mediated through chromosome-wide dosage compensation at the proteome level.

Project description:Preimplantation genetic diagnosis (PGD) of aneuploidy by fluorescence in situ hybridisation (FISH) has not delivered the expected clinical benefit. Many previous re-analysis studies of embryos deemed aneuploid by FISH on day 3 have found a high degree of chromosomal normalcy at the blastocyst stage. While most have interpreted this as âself correction,â there remains a lack of evidence for such a phenomenon. A more comprehensive technique for 24 chromosome aneuploidy screening was utilised here to re-evaluate blastocysts previously diagnosed as abnormal by FISH and investigate possible self correction mechanisms, including extrusion or duplication of aneuploid chromosomes resulting in uniparental isodisomy (UPID), and preferential segregation of aneuploidy to the trophectoderm (TE). Embryos that developed to a morphologically normal blastocyst after an aneuploidy diagnosis by cleavage stage FISH were biopsed into 4 sections, 3 TE and 1 inner cell mass (ICM), and randomised for evaluation by single nucleotide polymorphism (SNP) microarray based 24 chromosome aneuploidy screening (MA-PGD). Fifty-eight percent of blastocysts were euploid for all 24 chromosomes despite an aneuploid FISH result on day 3. Only 18% were consistent with the original FISH diagnosis, while the remaining 24% identified abnormalities that were different from the original FISH diagnosis. Abnormalities did not preferentially segregate to the TE and aneuploid chromosome extrusion or duplication resulting in UPID did not occur. Cleavage stage FISH is poorly predictive of aneuploidy in an embryo that develops into a morphologically normal blastocyst. Clinicians should consider re-evaluating embryos diagnosed as aneuploid by FISH that form morphologically normal blastocysts using a validated comprehensive 24 chromosome aneuploidy screening method. Affymetrix SNP arrays were processed according to the manufacturer's directions on DNA extracted from 50 cryopreserved blastocysts that were biopsied into 3 sections of trophectoderm and 1 inner cell mass section. Affymetrix SNP array analysis was successfully completed on 145 trophectoderm samples and 47 ICM samples from embryos, 8 lymphocyte samples from cell lines and 6 mixed male and female samples.

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Aneuploidy as a mechanism for stress-induced liver adaptation

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