From integrative genomics to systems genetics in the rat to link genotypes to phenotypes

Abstract

Complementary to traditional gene mapping approaches used to identify the hereditary components of complex diseases, integrative genomics and systems genetics have emerged as powerful strategies to decipher the key genetic drivers of molecular pathways that underlie disease. Broadly speaking, integrative genomics aims to link cellular-level traits (such as mRNA expression) to the genome to identify their genetic determinants. With the characterization of several cellular-level traits within the same system, the integrative genomics approach evolved into a more comprehensive study design, called systems genetics, which aims to unravel the complex biological networks and pathways involved in disease, and in turn map their genetic control points. The first fully integrated systems genetics study was carried out in rats, and the results, which revealed conserved trans-acting genetic regulation of a pro-inflammatory network relevant to type 1 diabetes, were translated to humans. Many studies using different organisms subsequently stemmed from this example. The aim of this Review is to describe the most recent advances in the fields of integrative genomics and systems genetics applied in the rat, with a focus on studies of complex diseases ranging from inflammatory to cardiometabolic disorders. We aim to provide the genetics community with a comprehensive insight into how the systems genetics approach came to life, starting from the first integrative genomics strategies [such as expression quantitative trait loci (eQTLs) mapping] and concluding with the most sophisticated gene network-based analyses in multiple systems and disease states. Although not limited to studies that have been directly translated to humans, we will focus particularly on the successful investigations in the rat that have led to primary discoveries of genes and pathways relevant to human disease.

Rheumatoid arthritis: identifying and characterising polymorphisms using rat models

“…Furthermore, although the targeted mutagenesis approach can be very useful for testing specific hypotheses, it does not explain variation in complex traits. Instead of being caused by a single sequence variant, phenotypic traits can be caused by QTLs that contribute effects from multiple causal variants within a single QTL (Baud et al, 2013, Moreno-Moral and Petretto, 2016), as could be the case in the MHC-III -region Ltab-Nc3 gene cluster, which is a conserved haplotype found in both inbred and wild rats (Yau et al, 2016). Although the positional cloning and functional assessment of genes in animal models is both time-consuming and expensive, it is by far more cost-effective than performing this research in humans, for example, in large-scale GWAS.…”

“…The use of these models in laboratory animals overcomes the challenges of genetic heterogeneity and environmental effects that feature in human studies. Animal models can also be used to identify disease loci, which can then be isolated on a fixed genetic background so that conclusive experiments can be performed to investigate specific disease pathways in vivo (Ahlqvist et al, 2011; Aitman et al, 2008; Baud et al, 2013; Vingsbo et al, 1996; Moreno-Moral and Petretto, 2016). …”

Identifying genes for neurobehavioural traits in rodents: progress and pitfalls

“…Gene identification typically starts with the mapping of QTLs and proceeds with integrative approaches, as reviewed recently by Moreno-Moral and Petretto (2016). A large number of QTLs for behaviour have been mapped in rodents [Mouse Genome Database, (Bult et al, 2016), ; Rat Genome Database (Hayman et al, 2016; Shimoyama et al, 2014), ], but the genetic variants and genes that mediate the effects of these QTLs remain unclear (Flint et al, 2005; Flint and Mackay, 2009; Parker and Palmer, 2011).…”

A RATional choice for translational research?

“…As highlighted by Aida Moreno-Moral and Enrico Petretto in the first of three new Reviews published in this issue, the first fully ‘integrative’ genomics study was performed in rats (Moreno-Moral and Petretto, 2016). The availability of specialised inbred strains and large panels for genetic mapping meant that several additional integrative-genomics (and, more recently, ‘systems-genetics’) studies exploiting the model to link genotype with phenotype then followed.…”