Opposing phenotypes in mice with Smith–Magenis deletion and Potocki–Lupski duplication syndromes suggest gene dosage effects on fluid consumption behavior

Abstract

A quantitative long-term fluid consumption and fluid licking assay was performed in two mouse models with either an ~ 2Mb genomic deletion, Df(11)17, or the reciprocal duplication CNV, Dp(11)17, analogous to the human genomic rearrangements causing either Smith-Magenis syndrome [SMS; OMIM #182290] or Potocki-Lupski syndrome [PTLS; OMIM #610883], respectively. Both mouse strains display distinct quantitative alteration in fluid consumption compared to their wild-type littermates; several of these changes are diametrically opposing between the two chromosome engineered mouse models. Mice with duplication vs. deletion showed longer vs. shorter intervals between visits to the waterspout, generated more vs. less licks per visit and had higher vs. lower variability in the number of licks per lick-burst as compared to their respective wild-type littermates. These findings suggest that copy number variation can affect long-term fluid consumption behavior in mice. Other behavior differences were unique for either the duplication or deletion mutants; the deletion CNV resulted in increased variability of the licking rhythm, and the duplication CNV resulted in a significant slowing of the licking rhythm. Our findings document a readily quantitated complex behavioral response that can be directly and reciprocally influenced by a gene dosage effect.

Genomic disorders 20 years on—mechanisms for clinical manifestations

“…Animal models with reciprocal deletions and duplications can inform dosage‐dependent phenotypes associated with a particular CNV . The 16p11.2 CNV mouse models demonstrate dosage‐dependent changes in gene expression, viability, brain architecture, and behavior, with the deletion being more severe than the duplication .…”

“…68,69 Recurrent deletion and duplication syndromes, as defined above, can either manifest with similar characteristics or with mirror image traits, that is, phenotypic extremes such as macrocephaly vs microcephaly at the 16p11.2 and 1q21.1 loci, or high vs low body mass index at the 17p11.2 locus. 22,[70][71][72][73] The dosage-sensitive gene has been identified in several genomic disorders and recurrent microdeletion/microduplication syndromes (see eg, Table 2). In other cases, a dosage-sensitive gene has been associated with a specific aspect of a mirror trait-for example, KCTD13 and head circumference size at the 16p11.2 locus (Table 3).…”

“…71 Animal models with reciprocal deletions and duplications can inform dosage-dependent phenotypes associated with a particular CNV. [73][74][75] The 16p11.2 CNV mouse models demonstrate dosagedependent changes in gene expression, viability, brain architecture, and behavior, with the deletion being more severe than the duplication. 74 However, caution must be exercised in cases where the data does not accurately reflect the phenotypes seen in humans; modifiers outside the CNV may exist and affect penetrance, expressivity and direction of effects in humans vs mice.…”

Structural variation mutagenesis of the human genome: Impact on disease and evolution

“…b). Even complex behaviors, as exemplified by “licking behavior” in mice “could be shown to objectively and quantitatively manifest as mirror traits in these del/dup CNV animal models [Heck et al, ]. This was of interest given that the PTLS duplication was initially reported in association with autism in some patients [Potocki et al, ] and objectively found in 11 of 15 subjects tested [Treadwell‐Deering et al, ].…”

Advances in Autism Research – The Genomic Basis of ASD

“…Many of these behavioral phenotypes are reciprocal or opposing to those seen in Df(11)17/+ mice, underscoring the dosage-sensitive nature of these disorders [109]. For example, a recent study investigating cerebellum-driven licking behavior in Dp(11)17/+ and Df (11)17/+ mice found that many of the quantitative licking behavior parameters analyzed were altered in a directly-opposing manner [110]. Specifically, the interval between visits to the waterspout, number of licks per visit, and variability in the number of licks per lick-burst were all altered in duplication and deletion animals in opposite directions compared to wild-type mice (ex: longer versus shorter intervals, etc).…”