A major QTL controls susceptibility to spinal curvature in the curveback guppy

<p>Abstract</p> <p>Background</p> <p>Understanding the genetic basis of heritable spinal curvature would benefit medicine and aquaculture. Heritable spinal curvature among otherwise healthy children (<it>i.e. </it>Idiopathic Scoliosis and Scheuermann kyphosis) accounts for more than 80% of all spinal curvatures and imposes a substantial healthcare cost through bracing, hospitalizations, surgery, and chronic back pain. In aquaculture, the prevalence of heritable spinal curvature can reach as high as 80% of a stock, and thus imposes a substantial cost through production losses. The genetic basis of heritable spinal curvature is unknown and so the objective of this work is to identify quantitative trait loci (QTL) affecting heritable spinal curvature in the <it>curveback </it>guppy. Prior work with <it>curveback </it>has demonstrated phenotypic parallels to human idiopathic-type scoliosis, suggesting shared biological pathways for the deformity.</p> <p>Results</p> <p>A major effect QTL that acts in a recessive manner and accounts for curve susceptibility was detected in an initial mapping cross on LG 14. In a second cross, we confirmed this susceptibility locus and fine mapped it to a 5 cM region that explains 82.6% of the total phenotypic variance.</p> <p>Conclusions</p> <p>We identify a major QTL that controls susceptibility to curvature. This locus contains over 100 genes, including MTNR1B, a candidate gene for human idiopathic scoliosis. The identification of genes associated with heritable spinal curvature in the <it>curveback </it>guppy has the potential to elucidate the biological basis of spinal curvature among humans and economically important teleosts.</p

Structural and micro-anatomical changes in vertebrae associated with idiopathic-type spinal curvature in the curveback guppy model

Background: The curveback lineage of guppy is characterized by heritable idiopathic-type spinal curvature thatdevelops during growth. Prior work has revealed several important developmental similarities to the human idiopathicscoliosis (IS) syndrome. In this study we investigate structural and histological aspects of the vertebrae that areassociated with spinal curvature in the curveback guppy and test for sexual dimorphism that might explain a femalebias for severe curve magnitudes in the population.Methods: Vertebrae were studied from whole-mount skeletal specimens of curved and non-curved adult males andfemales. A series of ratios were used to characterize structural aspects of each vertebra. A three-way analysis of variancetested for effects of sex, curvature, vertebral position along the spine, and all 2-way interactions (i.e., sex and curvature,sex and vertebra position, and vertebra position and curvature). Histological analyses were used to characterize microarchitecturalchanges in affected vertebrae and the intervertebral region.Results: In curveback, vertebrae that are associated with curvature demonstrate asymmetric shape distortion,migration of the intervertebral ligament, and vertebral thickening on the concave side of curvature. There is sexualdimorphism among curved individuals such that for several vertebrae, females have more slender vertebrae than domales. Also, in the region of the spine where lordosis typically occurs, curved and non-curved females have a reducedwidth at the middle of their vertebrae, relative to males.Conclusions: Based on similarities to human spinal curvatures and to animals with induced curves, the concaveconvexbiases described in the guppy suggest that there is a mechanical component to curve pathogenesis incurveback. Because idiopathic-type curvature in curveback is primarily a sagittal deformity, it is structurally more similarto Scheuermann kyphosis than IS. Anatomical differences between teleosts and humans make direct biomechanicalcomparisons difficult. However, study of basic biological systems involved in idiopathic-type spinal curvature incurveback may provide insight into the relationship between a predisposing aetiology, growth, and biomechanics.Further work is needed to clarify whether observed sex differences in vertebral characteristics are related to the femalebias for severe curves that is observed in the population

Modularity and Intrinsic Evolvability of Hsp90-Buffered Change

Hsp90 controls dramatic phenotypic transitions in a wide array of morphological features of many organisms. The genetic-background dependence of specific abnormalities and their response to laboratory selection suggested Hsp90 could be an ‘evolutionary capacitor’, allowing developmental variation to accumulate as neutral alleles under normal conditions and manifest selectable morphological differences during environmental stress. The relevance of Hsp90-buffered variation for evolution has been most often challenged by the idea that large morphological changes controlled by Hsp90 are unconditionally deleterious. To address this issue, we tested an Hsp90-buffered abnormality in Drosophila for unselected pleiotropic effects and correlated fitness costs. Up to 120-fold differences in penetrance among six highly related selection lines, started from an initially small number of flies and rapidly selected for and against a deformed eye trait (dfe), did not translate into measurable differences in any of several tests of viability, lifespan or competitive fitness. Nor were 17 dfe Quantitative Trait Loci (QTL) associated with fitness effects in over 1,400 recombinant lines. Our ability to detect measurable effects of inbreeding, media environment and the white mutation in the selection line backgrounds independent of dfe penetrance suggests that, within the limitations of laboratory tests of fitness, this large morphological change controlled by Hsp90 was selectable independent of strong, correlated and unconditionally deleterious effects—abundant, polygenic variation hidden by Hsp90 allows potentially deleterious alleles to be readily replaced during selection by less deleterious alleles with similar phenotypic effects. Hsp90 links environmental stress with the expression of developmental variation controlling unprecedented morphological plasticity. As outlined here and in the companion paper of this issue, the complex genetic architecture of Hsp90-buffered variation supports a remarkable modularity of Hsp90 effects on quantitative and qualitative phenotypes, consistent with the ‘Hsp90 capacitor hypothesis’ and standard quantitative genetic models of threshold traits

Representative tests of penetrance, absolute and relative fitness.

<div><p>High (red) and low (blue) lines, genetically differentiated for <i>dfe</i> penetrance were not differentiated by tests of viability and fitness.</p> <p>Controls (grey) were either <i>Canton-S</i> (<i>CS</i>) flies tested at the same time or published values for wild-type flies (WT; <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0000076#pone.0000076-Ashburner1" target="_blank">[21]</a>).</p> <p>Experiments showing the most extreme between line differences are displayed.</p> <p>Error bars indicate the standard errors of the mean.</p> <p><b>A.</b> Penetrance of eye deformity in <i>dfe</i> lines and <i>CS</i> flies reared at 25°C.</p> <p><b>B.</b> Hatch rate of timed embryo collections measured at 36 hours post egg-laying.</p> <p><b>C.</b> Egg-to-adult survival measured as the number of adult flies emerging versus eggs laid.</p> <p><b>D.</b> Fractional survivial of <i>dfe</i> progeny in competition with <i>CS</i> flies co-cultured at high density.</p> <p><b>E.</b> Lifetime female production of eggs (wild-type values; <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0000076#pone.0000076-Ashburner1" target="_blank">[21]</a>) or viable adult offspring (high and low line <i>dfe</i> females).</p></div

Regression of early fecundity and viability onto penetrance in 1,432 recombinant isogenic lines.

<p>If genes for <i>dfe</i> had effects on viability and survival, a negative relationship would be expected, however penetrance was positively correlated with fitness in recombinant lines from <i>HE1</i> and <i>HE3</i>.</p