The Interaction of Genetic Background and Mutational Effects in Regulation of Mouse Craniofacial Shape.

Inbred genetic background significantly influences the expression of phenotypes associated with known genetic perturbations and can underlie variation in disease severity between individuals with the same mutation. However, the effect of epistatic interactions on the development of complex traits, such as craniofacial morphology, is poorly understood. Here, we investigated the effect of three inbred backgrounds (129X1/SvJ, C57BL/6J, and FVB/NJ) on the expression of craniofacial dysmorphology in mice (Mus musculus) with loss of function in three members of the Sprouty family of growth factor negative regulators (Spry1, Spry2, or Spry4) in order to explore the impact of epistatic interactions on skull morphology. We found that the interaction of inbred background and the Sprouty genotype explains as much craniofacial shape variation as the Sprouty genotype alone. The most severely affected genotypes display a relatively short and wide skull, a rounded cranial vault, and a more highly angled inferior profile. Our results suggest that the FVB background is more resilient to Sprouty loss of function than either C57 or 129, and that Spry4 loss is generally less severe than loss of Spry1 or Spry2 While the specific modifier genes responsible for these significant background effects remain unknown, our results highlight the value of intercrossing mice of multiple inbred backgrounds to identify the genes and developmental interactions that modulate the severity of craniofacial dysmorphology. Our quantitative results represent an important first step toward elucidating genetic interactions underlying variation in robustness to known genetic perturbations in mice

Continuously Growing Rodent Molars Result from a Predictable Quantitative Evolutionary Change over 50 Million Years

The fossil record is widely informative about evolution, but fossils are not systematically used to study the evolution of stem-cell-driven renewal. Here, we examined evolution of the continuous growth (hypselodonty) of rodent molar teeth, which is fuelled by the presence of dental stem cells. We studied occurrences of 3,500 North American rodent fossils, ranging from 50 million years ago (mya) to 2 mya. We examined changes in molar height to determine whether evolution of hypselodonty shows distinct patterns in the fossil record, and we found that hypselodont taxa emerged through intermediate forms of increasing crown height. Next, we designed a Markov simulation model, which replicated molar height increases throughout the Cenozoic and, moreover, evolution of hypselodonty. Thus, by extension, the retention of the adult stem cell niche appears to be a predictable quantitative rather than a stochastic qualitative process. Our analyses predict that hypselodonty will eventually become the dominant phenotype.Peer reviewe

Computationally predicted gene regulatory networks in molluscan biomineralization identify extracellular matrix production and ion transportation pathways

Acknowledgements We would like to thank Prof Peter Kille for constructive comments on this work. Funding This work was supported by the Natural Environment Research Council Core Funding to the British Antarctic Survey, a DTG Studentship (Project Reference: NE/J500173/1) to V.A.S. and a Junior Research Fellowship to V.A.S from Wolfson College, University of Cambridge. Conflict of Interest: none declared.Peer reviewedPublisher PD

Oldest skeleton of a fossil flying squirrel casts new light on the phylogeny of the group

Flying squirrels are the only group of gliding mammals with a remarkable diversity and wide geographical range. However, their evolutionary story is not well known. Thus far, identification of extinct flying squirrels has been exclusively based on dental features, which, contrary to certain postcranial characters, are not unique to them. Therefore, fossils attributed to this clade may indeed belong to other squirrel groups. Here we report the oldest fossil skeleton of a flying squirrel (11.6 Ma) that displays the gliding-related diagnostic features shared by extant forms and allows for a recalibration of the divergence time between tree and flying squirrels. Our phylogenetic analyses combining morphological and molecular data generally support older dates than previous molecular estimates (\~23 Ma), being congruent with the inclusion of some of the earliest fossils (\~36 Ma) into this clade. They also show that flying squirrels experienced little morphological change for almost 12 million years

Evolution and Development of Dental Stem Cell Niches

The fossil record is widely informative about evolution, but fossils have not been systematically used to study the evolution of stem cells. Moreover, while the mechanisms underlying tooth development have been widely studied in model organisms, the role of genetic regulatory elements in patterning the different elements of the occlusal surface and crown height across species is not well understood. Here, I examined evolution of the rodent adult dental stem cell niche, which enables continuous growth (hypselodonty) of molar teeth. Moreover, I compared the variation in dental morphology across nine taxa of rodents to the variation in sequences of non-coding evolutionary conserved regions (ECRs) of Fgf3, 4, 8, 9, and 10 and the function of Fgf10 signaling on retention of molar stem cell niches. I studied the occurrences of 3500 North American fossil rodent specimens, ranging from 50 million years ago (mya) to 2 mya. I examined evolutionary changes in molar height to determine if evolution of continuously growing molars shows distinct patterns in the fossil record, and we found that hypselodont taxa emerged through intermediate forms of increasing crown height. Next, we designed a two-parameter Markov simulation model, which correctly accounted for molar height increases throughout the Cenozoic, and, moreover, evolution of hypselodonty. Finally, I correlated the variation in molar tooth cusp shape and the evolution of high molar crowns (hypsodonty) to the patterns of sequence variation in two ECRs, Fgf10ECR3 and Fgf9ECR1, respectively. By conducting luciferase and electrophoretic mobility shift assays, we determined that these ECRs could function as enhancers. Thus, by extension, the retention of the adult stem-cell niche appears to be a predictable quantitative rather than a stochastic qualitative process. Our analyses predict that hypselodonty will eventually become the dominant rodent phenotype. Mammalian dental morphology is under strong evolutionary pressure because of its importance for mastication and diet. My data suggest that emergence of hypsodonty and occlusal cusp patterning may have happened through the evolutionary changes in enhancers, such as Fgf9ECR1 and Fgf10ECR3, which affected the expression of major signaling molecules involved in tooth development

The Interaction of Genetic Background and Mutational Effects in Regulation of Mouse Craniofacial Shape

Inbred genetic background significantly influences the expression of phenotypes associated with known genetic perturbations and can underlie variation in disease severity between individuals with the same mutation. However, the effect of epistatic interactions on the development of complex traits, such as craniofacial morphology, is poorly understood. Here, we investigated the effect of three inbred backgrounds (129X1/SvJ, C57BL/6J, and FVB/NJ) on the expression of craniofacial dysmorphology in mice (Mus musculus) with loss of function in three members of the Sprouty family of growth factor negative regulators (Spry1, Spry2, or Spry4) in order to explore the impact of epistatic interactions on skull morphology. We found that the interaction of inbred background and the Sprouty genotype explains as much craniofacial shape variation as the Sprouty genotype alone. The most severely affected genotypes display a relatively short and wide skull, a rounded cranial vault, and a more highly angled inferior profile. Our results suggest that the FVB background is more resilient to Sprouty loss of function than either C57 or 129, and that Spry4 loss is generally less severe than loss of Spry1 or Spry2. While the specific modifier genes responsible for these significant background effects remain unknown, our results highlight the value of intercrossing mice of multiple inbred backgrounds to identify the genes and developmental interactions that modulate the severity of craniofacial dysmorphology. Our quantitative results represent an important first step toward elucidating genetic interactions underlying variation in robustness to known genetic perturbations in mice

The Interaction of Genetic Background and Mutational Effects in Regulation of Mouse Craniofacial Shape.

Inbred genetic background significantly influences the expression of phenotypes associated with known genetic perturbations and can underlie variation in disease severity between individuals with the same mutation. However, the effect of epistatic interactions on the development of complex traits, such as craniofacial morphology, is poorly understood. Here, we investigated the effect of three inbred backgrounds (129X1/SvJ, C57BL/6J, and FVB/NJ) on the expression of craniofacial dysmorphology in mice (Mus musculus) with loss of function in three members of the Sprouty family of growth factor negative regulators (Spry1, Spry2, or Spry4) in order to explore the impact of epistatic interactions on skull morphology. We found that the interaction of inbred background and the Sprouty genotype explains as much craniofacial shape variation as the Sprouty genotype alone. The most severely affected genotypes display a relatively short and wide skull, a rounded cranial vault, and a more highly angled inferior profile. Our results suggest that the FVB background is more resilient to Sprouty loss of function than either C57 or 129, and that Spry4 loss is generally less severe than loss of Spry1 or Spry2 While the specific modifier genes responsible for these significant background effects remain unknown, our results highlight the value of intercrossing mice of multiple inbred backgrounds to identify the genes and developmental interactions that modulate the severity of craniofacial dysmorphology. Our quantitative results represent an important first step toward elucidating genetic interactions underlying variation in robustness to known genetic perturbations in mice

Continuously Growing Rodent Molars Result from a Predictable Quantitative Evolutionary Change over 50 Million Years

The fossil record is widely informative about evolution, but fossils are not systematically used to study the evolution of stem-cell-driven renewal. Here, we examined evolution of the continuous growth (hypselodonty) of rodent molar teeth, which is fuelled by the presence of dental stem cells. We studied occurrences of 3,500 North American rodent fossils, ranging from 50 million years ago (mya) to 2 mya. We examined changes in molar height to determine whether evolution of hypselodonty shows distinct patterns in the fossil record, and we found that hypselodont taxa emerged through intermediate forms of increasing crown height. Next, we designed a Markov simulation model, which replicated molar height increases throughout the Cenozoic and, moreover, evolution of hypselodonty. Thus, by extension, the retention of the adult stem cell niche appears to be a predictable quantitative rather than a stochastic qualitative process. Our analyses predict that hypselodonty will eventually become the dominant phenotype

Identification of novel Fgf enhancers and their role in dental evolution

Mammalian dental morphology is under strong evolutionary pressure because of its importance for mastication and diet. While the mechanisms underlying tooth development have been widely studied in model organisms, the role of genetic regulatory elements in patterning the different elements of the occlusal surface and crown height across species is not well understood. Previous studies showed that Fibroblast Growth Factor (FGF) genes are important regulators of tooth development that influence morphological variation. We hypothesized that inter-specific variation in rodent dental morphology could be governed by nucleotide variation in genetic regulatory elements that modulate the spatial and temporal expression of the genes encoding FGF signaling molecules. In this study, we compared the variation in dental morphology across nine taxa of rodents to the variation in sequences of non-coding evolutionary conserved regions (ECRs) of Fgf3, 4, 8, 9, and 10. We correlated the variation in molar tooth cusp shape and the evolution of high molar crowns (hypsodonty) to the patterns of sequence variation in two ECRs, Fgf10ECR3, and Fgf9ECR1, respectively. By conducting luciferase and electrophoretic mobility shift assays, we determined that these ECRs could function as enhancers. These data suggest that emergence of hypsodonty and occlusal cusp patterning may have happened through the evolutionary changes in enhancers, such as Fgf9ECR1 and Fgf10ECR3, which affected the expression of major signaling molecules involved in tooth development