Aneuploidy as a mechanism for stress-induced liver adaptation

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

doi:10.1172/jci64026

Cited by 157 publications

(180 citation statements)

References 38 publications

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“…fumaryl-acetoacetate hydrolase (FahA), the enzyme that detoxifies the disease-causing IC, shows that selection favors liver cells that lack homogentisate dioxygenase (Hmg1), which is responsible for the production of the IC in the first place (41). Intriguingly, whereas the two genes form a divergently oriented DNGP in several fungi (Fig.…”

Section: Phytophthora Infestansmentioning

confidence: 99%

Physical linkage of metabolic genes in fungi is an adaptation against the accumulation of toxic intermediate compounds

McGary

Slot

Rokas

2013

Proc. Natl. Acad. Sci. U.S.A.

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Genomic analyses have proliferated without being tied to tangible phenotypes. For example, although coordination of both gene expression and genetic linkage have been offered as genetic mechanisms for the frequently observed clustering of genes participating in fungal metabolic pathways, elucidation of the phenotype(s) favored by selection, resulting in cluster formation and maintenance, has not been forthcoming. We noted that the cause of certain well-studied human metabolic disorders is the accumulation of toxic intermediate compounds (ICs), which occurs when the product of an enzyme is not used as a substrate by a downstream neighbor in the metabolic network. This raises the hypothesis that the phenotype favored by selection to drive gene clustering is the mitigation of IC toxicity. To test this, we examined 100 diverse fungal genomes for the simplest type of cluster, gene pairs that are both metabolic neighbors and chromosomal neighbors immediately adjacent to each other, which we refer to as "double neighbor gene pairs" (DNGPs). Examination of the toxicity of their corresponding ICs shows that, compared with chromosomally nonadjacent metabolic neighbors, DNGPs are enriched for ICs that have acutely toxic LD 50 doses or reactive functional groups. Furthermore, DNGPs are significantly more likely to be divergently oriented on the chromosome; remarkably, ∼40% of these DNGPs have ICs known to be toxic. We submit that the structure of synteny in metabolic pathways of fungi is a signature of selection for protection against the accumulation of toxic metabolic intermediates.gene cluster | gene orientation | inborn error of metabolism | secondary metabolism | specialized metabolism T here is a critical distinction between selection for a trait, which occurs at the phenotypic level, and selection of the underlying molecular genetic mechanisms that generate the trait (1). For example, some butterfly species avoid predation by mimicking the wing-pattern morphs of other butterflies that are toxic to birds (2, 3). In this case, predation avoidance selects for specific wing-pattern morphs, resulting in the selection of specific allelic combinations of genes in a supergene locus (4).The rise of molecular biology and subsequent abundance of genomic data have shifted the focus from phenotypes to genotypes, blurring the distinction between selection for and selection of. For example, many studies indicate that selection has sculpted the order and orientation of genes in eukaryotic genomes (5-13); although these analyses convincingly argue that specific genetic mechanisms are important in fine-tuning the structure of synteny on chromosomes, they implicitly assume that it is the genetic mechanisms themselves, rather than organismal phenotypes, that selection targets.One of the most conspicuous characteristics of fungal genomes is that the genes participating in a metabolic pathway are often physically linked, or clustered. Although both coordination of gene expression (5,6,(11)(12)(13)(14)(15)(16) and genetic linkage (7, 17) h...

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Section: Phytophthora Infestansmentioning

confidence: 99%

Physical linkage of metabolic genes in fungi is an adaptation against the accumulation of toxic intermediate compounds

McGary

Slot

Rokas

2013

Proc. Natl. Acad. Sci. U.S.A.

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“…During postnatal development, a scheduled division program characterized by incomplete cytokinesis results in the genesis of binuclear tetraploid hepatocytes (2x2n), which subsequently play a pivotal role in liver polyploidization (3,(9)(10)(11). Remarkably, during postnatal development and adult life, hepatocytes are able to increase their DNA content but also reduce it through a process call "ploidy reversal" (2,12). In fact, polyploid hepatocytes undergo multipolar mitosis, producing daughter cells with half the chromosome content but also with aneuploid content.…”

Section: Introductionmentioning

confidence: 99%

Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease

Gentric¹,

Maillet²,

Paradis³

et al. 2015

J. Clin. Invest.

209

196

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“…Duncan et al (13) suggested that polyploid hepatocytes underwent aberrant mitoses with high levels of chromosome mis-segregation, thereby generating aneuploidy among polyploid cells. The authors further speculated that aneuploidy endows hepatocytes with phenotypic variability and adaptability upon exposure to various noxious agents and metabolic stresses (15).…”

mentioning

confidence: 99%

Single cell sequencing reveals low levels of aneuploidy across mammalian tissues

Knouse

Whittaker

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

281

253

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Significance Aneuploidy refers to the gain or loss of individual chromosomes within a cell. Typically, aneuploidy is associated with detrimental consequences at both the cellular and organismal levels. However, reports of high levels of aneuploidy in the brain and liver suggested that aneuploidy might play a positive role in these organs. Here we use single cell sequencing to determine the prevalence of aneuploidy in somatic tissues. We find that aneuploidy is a rare occurrence in the liver and brain and is no more prevalent in these tissues than in skin. Our results demonstrate high karyotypic stability in somatic tissues, arguing against a role for aneuploidy in organ function and reinforcing its adverse effects at the cellular and organismal levels.

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Aneuploidy as a mechanism for stress-induced liver adaptation

Cited by 157 publications

References 38 publications

Physical linkage of metabolic genes in fungi is an adaptation against the accumulation of toxic intermediate compounds

Physical linkage of metabolic genes in fungi is an adaptation against the accumulation of toxic intermediate compounds

Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease

Single cell sequencing reveals low levels of aneuploidy across mammalian tissues

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