Abstract
Genetic background of an individual can drastically influence an organism’s response upon environmental stress and pathological stimulus. Previous studies in inbred rats showed that compared to Brown Norway (BN), Dahl salt-sensitive (SS) rat exerts strong hypoxia susceptibility. However, despite extensive narrow-down approaches via the chromosome substitution methodology, this genome-based physiological predisposition could not be traced back to distinct quantitative trait loci. Upon the completion and public data availability of PhysGen SS-BN consomic (CS) rat platform, I employed systems biology approach attempting to further our understanding of the molecular basis of genetic background effect in light of hypoxia response. I analyzed the physiological screening data of 22 CS rat strains under normoxia and 2-weeks of hypoxia, and cross-compared them to the parental strains. The analyses showed that SS-9BN and SS-18BN represent the most hypoxia-resistant CS strains with phenotype similar to BN, whereas SS-6BN and SS-YBN segregated to the direction of SS. A meta-analysis on the transcriptomic profiles of these CS rat strains under hypoxia treatment showed that although polymorphisms on the substituted BN chromosomes could be directly involved in hypoxia resistance, this seems to be embedded in a more complex trans-chromosomal genetic regulatory network. Via information theory based modeling approach, this hypoxia relevant core genetic network was reverse engineered. Network analyses showed that the protective effects of BN chromosome 9 and 18 were reflected by a balanced activation of this core network centering on physiological homeostasis. Presumably, it is the system robustness constituted on such differential network activation that acts as hypoxia response modifier. Understanding of the intrinsic link between the individual genetic background and the network robustness will set a basis in the current scientific efforts toward personalized medicine.
Highlights
Hypoxia is a common environmental stressor, the effect of which depending on time and duration of hypoxia explosion
In this study, I first attempted to validate the differential hypoxia resistances of the SS and Brown Norway (BN) inbred rat strains using hypoxia sensitivity indexing. This was followed by a comprehensive phenotype investigation of the entire SS-BN CS rat platform under hypoxia and normoxia treatments, in order to identify indicative traits of hypoxic resistance
Hypoxia-resistant and hypoxia-susceptible CS rat strains were subsequently identified by a “phenotype rescue” assay
Summary
Hypoxia is a common environmental stressor, the effect of which depending on time and duration of hypoxia explosion. The fetal, and newborn brain is susceptible to hypoxia. In utero hypoxia can lead to inhibition of breathing movements, and increase the risk for neuronal developmental deficits (Cai et al, 1999). The period immediately after birth represents a critical time window in which hypoxia can cause long-term changes in the structural and functional properties of the respiratory systems (Teppema and Dahan, 2010). Developmental period, hypoxia can cause a suppressed pituitary growth hormone level through increased action of somatostatin (Xu et al, 2004). Exposure to chronic hypoxic paradigms induces a pathogenic increase in ventilation that may sustain (Teppema and Dahan, 2010)
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