On how to reconcile flexibility with rigidity during evolution: the caudal system in seahorses

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Comparative anatomy and functional implications of variation in the buccal mass in coleoid cephalopods

In contrast to the well-studied articulated vertebrate jaws, the structure and function of cephalopod jaws remains poorly known. Cephalopod jaws are unique as the two jaw elements do not contact one another, are embedded in a muscular mass and connected through a muscle joint. Previous studies have described the anatomy of the buccal mass muscles in cephalopods and have proposed variation in muscle volume depending on beak shape. However, the general structure of the muscles has been suggested to be similar in octopuses, squids, and cuttlefish. Here we provide a quantitative analysis of the variation in the buccal mass of coleoids using traditional dissections, histological sections and contrast-enhanced computed tomography scans. Our results show that the buccal mass is composed of four main homologous muscles present in both decapodiforms and octopodiforms as suggested previously. However, we also report the presence of a muscle uniquely present in octopodiforms (the postero-lateral mandibular muscle). Our three dimensional reconstructions and quantitative analyses of the buccal mass muscles pave the way for future functional analyses allowing to better model jaw closing in coleoids. Finally, our results suggest differences in beak and muscle function that need to be validated using future in vivo functional analyses

Soft dentin results in unique flexible teeth in scraping catfishes

Teeth are generally used for actions in which they experience mainly compressive forces acting toward the base. The ordered tooth enamel(oid) and dentin structures contribute to the high compressive strength but also to the minor shear and tensile strengths. Some vertebrates, however, use their teeth for scraping, with teeth experiencing forces directed mostly normal to their long axis. Some scraping suckermouth catfishes (Loricariidae) even appear to have flexible teeth, which have not been found in any other vertebrate taxon. Considering the mineralized nature of tooth tissues, the notion of flexible teeth seems paradoxical. We studied teeth of five species, testing and measuring tooth flexibility, and investigating tooth (micro) structure using transmission electron microscopy, staining, computed tomography scanning, and scanning electron microscopy-energy-dispersive spectrometry. We quantified the extreme bending capacity of single teeth (up to 180 degrees) and show that reorganizations of the tooth (micro) structure and extreme hypomineralization of the dentin are adaptations preventing breaking by allowing flexibility. Tooth shape and internal structure appear to be optimized for bending in one direction, which is expected to occur frequently when feeding (scraping) under natural conditions. Not all loricariid catfishes possess flexible teeth, with the trait potentially having evolved more than once. Flexible teeth surely rank among the most extreme evolutionary novelties in known mineralized biological materials and might yield a better understanding of the processes of dentin formation and (hypo) mineralization in vertebrates, including humans

Dealing with Food and Eggs in Mouthbrooding Cichlids: Structural and Functional Trade-Offs in Fitness Related Traits

As in any vertebrate, heads of fishes are densely packed with functions. These functions often impose conflicting mechanical demands resulting in trade-offs in the species-specific phenotype. When phenotypical traits are linked to gender-specific parental behavior, we expect sexual differences in these trade-offs. This study aims to use mouthbrooding cichlids as an example to test hypotheses on evolutionary trade-offs between intricately linked traits that affect different aspects of fitness. We focused on the oral apparatus, which is not only equipped with features used to feed and breathe, but is also used for the incubation of eggs. We used this approach to study mouthbrooding as part of an integrated functional system with diverging performance requirements and to explore gender-specific selective environments within a species.Because cichlids are morphologically very diverse, we hypothesize that the implications of the added constraint of mouthbrooding will primarily depend on the dominant mode of feeding of the studied species. To test this, we compared the trade-off for two maternal mouthbrooding cichlid species: a "suction feeder" (Haplochromis piceatus) and a "biter" (H. fischeri). The comparison of morphology and performance of both species revealed clear interspecific and intersex differences. Our observation that females have larger heads was interpreted as a possible consequence of the fact that in both the studied species mouthbrooding is done by females only. As hypothesized, the observed sexual dimorphism in head shape is inferred as being suboptimal for some aspects of the feeding performance in each of the studied species. Our comparison also demonstrated that the suction feeding species had smaller egg clutches and more elongated eggs.Our findings support the hypothesis that there is a trade-off between mouthbrooding and feeding performance in the two studied haplochromine cichlids, stressing the importance of including species-specific information at the gender level when addressing interspecific functional/morphological differences

The contribution of paralog buffering to tumor robustness

Tumor cells remain viable in the face of extensive gene loss, suggesting that they are highly robust to genetic perturbations. One potential mechanism of genetic robustness is buffering between paralog pairs – due to originating from an ancestral duplication event, some paralog pairs have redundant functionality that allows them to buffer each other’s loss. Paralog buffering can be observed as synthetic lethality, where individual loss of either gene is well tolerated but concurrent loss results in cell death. In model organisms, particularly Saccharomyces cerevisiae, paralog buffering has been shown to contribute substantially to genetic robustness. The overall aim of this thesis is to characterize the contribution of paralogs to maintaining the robustness of tumor cells. First, through analysis of genome-wide CRISPR screens and molecular profiles of hundreds of cancer cell lines, I show that paralogs are less frequently essential for cellular growth than singletons across a wide range of genetic backgrounds. Furthermore, I provide evidence that variation in gene essentiality can be attributed to paralog buffering relationships in ~13-17% of cases. Finding that certain paralog pairs, such as those that function in protein complexes, are more likely to exhibit buffering relationships, I then develop a classifier to make predictions, accompanied by feature-based explanations, of synthetic lethality between paralog pairs in cancer cell lines. I validate this classifier using results from existing combinatorial CRISPR screens in cancer cell lines, show that it can distinguish between robust and context-specific synthetic lethality, and make predictions for ~36K paralog pairs, which can be used to prioritize pairs for inclusion in future screens. Finally, I investigate the impact of paralog buffering on the evolution of tumor genomes – I show that, across two large patient cohorts, homozygous deletions are more likely to be observed for paralog than singleton non-driver genes and that this difference cannot be explained by other factors known to influence copy number variation. As paralogs essential for growth of cancer cells in vitro are less frequently deleted than non-essential paralogs, I propose that paralogs are more frequently deleted because they are generally more dispensable for tumor cells in vivo. Overall I show that paralog buffering contributes to tumor cell phenotype. Paralog buffering can provide tumor cells with phenotypic stability in the face of genotypic changes, but it can also be exploited, through synthetic lethality, for the development of targeted therapeutics

Interntional Conference on Interactive Digital Storytelling (ICIDS)

Narrative puzzles involve exploration, logical thinking and progressing a story. This paper presents a narrative design innovation in the form of a system for the procedural generation of such puzzles for use in story-rich games or games with large open worlds. The approach uses an extended type of context-free grammar as the basis for both the generation algorithm and the puzzle solving. Each designer-defined rule in the grammar defines a possible behavior of item types in the game world. Puzzles are generated at runtime on a per area basis, through recursive generation of inputs for outputs. Given a valid grammar, the system guarantees that its puzzles are solvable

Paralog dispensability shapes homozygous deletion patterns in tumor genomes

Abstract Genomic instability is a hallmark of cancer, resulting in tumor genomes having large numbers of genetic aberrations, including homozygous deletions of protein coding genes. That tumor cells remain viable in the presence of such gene loss suggests high robustness to genetic perturbation. In model organisms and cancer cell lines, paralogs have been shown to contribute substantially to genetic robustness—they are generally more dispensable for growth than singletons. Here, by analyzing copy number profiles of > 10,000 tumors, we test the hypothesis that the increased dispensability of paralogs shapes tumor genome evolution. We find that genes with paralogs are more likely to be homozygously deleted and that this cannot be explained by other factors known to influence copy number variation. Furthermore, features that influence paralog dispensability in cancer cell lines correlate with paralog deletion frequency in tumors. Finally, paralogs that are broadly essential in cancer cell lines are less frequently deleted in tumors than non‐essential paralogs. Overall, our results suggest that homozygous deletions of paralogs are more frequently observed in tumor genomes because paralogs are more dispensable

Paralog buffering contributes to the variable essentiality of genes in cancer cell lines.

What makes a gene essential for cellular survival? In model organisms, such as budding yeast, systematic gene deletion studies have revealed that paralog genes are less likely to be essential than singleton genes and that this can partially be attributed to the ability of paralogs to buffer each other's loss. However, the essentiality of a gene is not a fixed property and can vary significantly across different genetic backgrounds. It is unclear to what extent paralogs contribute to this variation, as most studies have analyzed genes identified as essential in a single genetic background. Here, using gene essentiality profiles of 558 genetically heterogeneous tumor cell lines, we analyze the contribution of paralogy to variable essentiality. We find that, compared to singleton genes, paralogs are less frequently essential and that this is more evident when considering genes with multiple paralogs or with highly sequence-similar paralogs. In addition, we find that paralogs derived from whole genome duplication exhibit more variable essentiality than those derived from small-scale duplications. We provide evidence that in 13-17% of cases the variable essentiality of paralogs can be attributed to buffering relationships between paralog pairs, as evidenced by synthetic lethality. Paralog pairs derived from whole genome duplication and pairs that function in protein complexes are significantly more likely to display such synthetic lethal relationships. Overall we find that many of the observations made using a single strain of budding yeast can be extended to understand patterns of essentiality in genetically heterogeneous cancer cell lines