Altered polyamine metabolism in the PRO/Re strain of inbred mice.
Ontology highlight
ABSTRACT:
SUBMITTER: Manen CA
PROVIDER: S-EPMC1164006 | biostudies-other | 1976 Sep
REPOSITORIES: biostudies-other
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Project description:Mutation provides the ultimate source of all new alleles in populations, including variants that cause disease and fuel adaptation. Recent whole genome sequencing studies have uncovered variation in the mutation rate among individuals and differences in the relative frequency of specific nucleotide changes (the mutation spectrum) between populations. Although parental age is a major driver of differences in overall mutation rate among individuals, the causes of variation in the mutation spectrum remain less well understood. Here, I use high-quality whole genome sequences from 29 inbred laboratory mouse strains to explore the root causes of strain variation in the mutation spectrum. My analysis leverages the unique, mosaic patterns of genetic relatedness among inbred mouse strains to identify strain private variants residing on haplotypes shared between multiple strains due to their recent descent from a common ancestor. I show that these strain-private alleles are strongly enriched for recent de novo mutations and lack signals of widespread purifying selection, suggesting their faithful recapitulation of the spontaneous mutation landscape in single strains. The spectrum of strain-private variants varies significantly among inbred mouse strains reared under standardized laboratory conditions. This variation is not solely explained by strain differences in age at reproduction, raising the possibility that segregating genetic differences affect the constellation of new mutations that arise in a given strain. Collectively, these findings imply the action of remarkably precise nucleotide-specific genetic mechanisms for tuning the de novo mutation landscape in mammals and underscore the genetic complexity of mutation rate control.
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Project description:BackgroundAlterations in the neural polyamine system are known to be associated with different brain pathological conditions. In addition, the regulation of enzymes involved in polyamine metabolism such as ornithine decarboxylase (ODC), antizymes (AZs), and antizyme inhibitors (AZINs) is critical during brain development. However, while most studies focus on ODC and AZs, less is known about AZIN expression and function in the brain. Thus, our aim was to analyze the expression pattern of AZIN2 during postnatal development, its brain distribution, and its possible implication in phenotypical alterations.MethodsThe expression pattern of Azin2 and other genes related to polyamine metabolism was analyzed by RT-qPCR. β-D-galactosidase staining was used to determine the anatomical distribution of AZIN2 in a Azin2 knockout model containing the βGeo marker. Brain polyamine content was determined by HPLC. The Rota-Rod and Pole functional tests were used to evaluate motor skills in Azin2-lacking mice.ResultsOur results showed that expression of genes codifying for AZs and AZINs showed a similar increasing pattern over time that coincided with a decrease in ODC activity and putrescine levels. The analysis of AZIN2 distribution demonstrated that it is strongly expressed in the cerebellum and distributed along the neuron body and dendrites. The ablation of Azin2 showed a decrease in putrescine levels and is related to reduced motor skills.ConclusionsOur study revealed that AZIN2 expression in the brain is particularly limited to the cerebellum. In addition, the ablation of Azin2 leads to a reduction in putrescine that relates to alterations in motor function, suggesting the role of AZIN2 in the functioning of dopaminergic neurons.
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