Phenotype Ontologies and Cross-Species Analysis for Translational Research

Abstract

The use of model organisms as tools for the investigation of human genetic variation has significantly and rapidly advanced our understanding of the aetiologies underlying hereditary traits. However, while equivalences in the DNA sequence of two species may be readily inferred through evolutionary models, the identification of equivalence in the phenotypic consequences resulting from comparable genetic variation is far from straightforward, limiting the value of the modelling paradigm. In this review, we provide an overview of the emerging statistical and computational approaches to objectively identify phenotypic equivalence between human and model organisms with examples from the vertebrate models, mouse and zebrafish. Firstly, we discuss enrichment approaches, which deem the most frequent phenotype among the orthologues of a set of genes associated with a common human phenotype as the orthologous phenotype, or phenolog, in the model species. Secondly, we introduce and discuss computational reasoning approaches to identify phenotypic equivalences made possible through the development of intra- and interspecies ontologies. Finally, we consider the particular challenges involved in modelling neuropsychiatric disorders, which illustrate many of the remaining difficulties in developing comprehensive and unequivocal interspecies phenotype mappings.

Effective diagnosis of genetic disease by computational phenotype analysis of the disease-associated genome

“…Increasing the depth of annotation to these diseases would improve the performance (43). A number of challenges remain in the ontological modeling of certain classes of diseases and phenotypes in areas such as neurobehavioral abnormalities (44). The DAG panel, as presented here, currently contains baits only for protein coding genes.…”

Mechanisms of Origin, Phenotypic Effects and Diagnostic Implications of Complex Chromosome Rearrangements

“…This approach has allowed us to relate phenotypes such as intellectual delay, autism, or attention deficit/hyperactivity disorder to certain biological pathways [Marshall et al, 2008;Webber et al, 2009;Hehir-Kwa et al, 2010;Pinto et al, 2010;Poot et al, 2010b;Webber, 2011;Noh et al, 2013;Andrews et al, 2015;Hawi et al, 2015]. To associate CCRs, CNVs, genes, and biological pathways with phenotypes, these have to be categorized systematically in so-called phenotype-ontologies [Robinson and Webber, 2014;Deans et al, 2015]. Next, the phenotypes of model organisms with disruptions of the orthologous genes, and features of breakpoint regions of the human CCRs, such as LINE elements, segmental duplications, 'side effects' on transcription levels of genes in the vicinity of the breakpoints, markers of active promoters (e.g.…”

The failure of anxiolytic therapies in early clinical trials: what needs to be done

“…Finally, we encourage a crossdisciplinary dialogue and multi-level conceptualization of anxiety disorders, their clinical symptoms, neural circuits, molecular networks and the existing animal models. Several important, thoughtful papers published recently can be particularly recommended for further discussion on experimental anxiety models, their validity, applications for anxiolytic drug discovery [91][92][93][94][95] and cross-species phenomics [96], as well as the role of behavioral and cognifive factors in complex drug-environment interplay [97].…”