Modifier Selection by Transgenes: The Case of Growth Hormone Transgenesis and Hyperactive Circling Mice

Abstract

Deleterious impacts of major mutations can be ameliorated by stabilising selection acting on modifier genes. We hypothesise that a new hyperactive circling mouse (counterspin: Cr) arises when modifier genes inadvertently selected to ameliorate the negative impacts of a growth hormone transgenic insertion segregate into the normal genetic background that lacks the transgene. We hypothesise that such modifiers generate a phenotype ''mirror image'' to the transgenics on the otherwise normal background. We highlight this by testing a priori hypotheses that counterspin and transgenic growth hormone mice deviate oppositely from normal mice across a broad spectrum of characteristics. Results spanning growth, sensorimotor performance, cognition and striatal neurotransmitters provide strong circumstantial evidence for the hypothesis. In a more direct test for selection in the transgenic mice, we found that those examined in 2008 slept *3 h/d less than they did 14 years ago (P \ 0.0005). This is a profound change strongly supporting the reality of modifier selection in these mice. Our results highlight that modifiers may act powerfully on genetically engineered constructs given a genetically variable background. Furthermore, we suggest that modifier selection might provide a novel method for deriving genetic models, and specifically, models phenotypically opposite to engineered constructs or natural mutations.

A multi‐ingredient dietary supplement abolishes large‐scale brain cell loss, improves sensory function, and prevents neuronal atrophy in aging mice

“…Essentially all variants of behavioral tests rely on movement of animals to infer emotionality levels [Trullas and Skolnick, , Carola et al, ; Chaudhry et al, ]. Intrinsic differences in activity levels between treatment groups (if present) may bias interpretation.…”

“…This test was developed in our lab and was used to assess emotionality in mice [Chaudhry et al, 2008]. Mice have an aversive response to bright, open areas, eliciting anxiety-like behavior; whereas dim illumination allows for observation of active or exploratory behavior [Trullas and Skolnick, 1993;Chaudhry et al, 2008]. A circular white arena 1 m in diameter was surrounded by a shaded overhang 5 cm high and 20 cm wide.…”

“…Variants of the open field test have been used to assess emotionality in rodents [Trullas and Skolnick, 1993, Belzung and Griebel, 2001, Voikar et al, 2001Carola et al, 2002;De Oliveira et al, 2007;Chaudhry et al, 2008]. However, depending on protocol variations and parameters scored, results may be more indicative of exploratory behavior than anxiety-driven responses [Trullas and Skolnick, 1993;Carola et al, 2002;Berry et al, 2007].…”

A complex dietary supplement augments spatial learning, brain mass, and mitochondrial electron transport chain activity in aging mice

“…In our previous studies with an eight-choice cued maze, 33% of normal mice (all untreated) also showed no evidence of learning particularly when older. Learning of both tasks tends to be an all-or-none phenomenon, mice either expressing steady incremental improvement or little progress (Lemon et al 2003;Chaudhry et al 2008;Rollo et al 1999). It is all the more remarkable then that older supplemented mice effectively learned the MWM, achieving a 46% reduction in latency to reach the hidden platform by day 5 (Fig.…”

“…Brain size is positively associated with intelligence in humans (Andreasen et al 1993), and growth hormone transgenic mice that have larger brains also had vastly superior learning on an eight-choice visually cued maze and novel object recognition and memory tests (Lemon et al 2003;Chaudhry et al 2008). Rodents selected for larger brains (and associated increases in body size) also display enhanced learning (Herman and Nagy 1977).…”