Forward Genetic Approaches to Understanding Complex Behaviors

Abstract

Assigning function to genes has long been a focus of biomedical research.Even with complete knowledge of the genomic sequences of humans, mice and other experimental organisms, there is still much to be learned about gene function and control. Ablation or overexpression of single genes using knockout or transgenic technologies has provided functional annotation for many genes, but these technologies do not capture the extensive genetic variation present in existing experimental mouse populations. Researchers have only recently begun to truly appreciate naturally occurring genetic variation resulting from single nucleotide substitutions,insertions, deletions, copy number variation, epigenetic changes (DNA methylation,histone modifications, etc.) and gene expression differences and how this variation contributes to complex phenotypes. In this chapter, we will discuss the benefits and limitations of different forward genetic approaches that capture the genetic variation present in inbred mouse strains and present the utility of these approaches for mapping QTL that influence complex behavioral phenotypes.

QTL mapping of flowering time and biomass yield in tetraploid alfalfa (Medicago sativa L.)

“…Similarly, involvement of some genes such as MsLFY [10], CONSTANS-LIKE [11], SPL13 [12], MsZFN [13], MsFRI-L [14], and MsFRI-L in alfalfa flowering time variation have been described using the reverse genetics approaches like molecular cloning and gene expression. However, single gene expression analysis with knockouts or transgenics seems insufficient to account for the extensive quantitative variation in the population [15], which can be explained using QTL mapping with a high-resolution genetic map.…”

Genetic Models of Sensorimotor Gating: Relevance to Neuropsychiatric Disorders

“…Phenotype-based or “forward genetics” approaches begin with the targeted behavioral phenotype (trait) and then involve subsequent genetic analysis of the trait. Most genetic studies of sensorimotor gating have focused on genebased approaches, and as such, these approaches are discussed in more detail than phenotype-based approaches, which are discussed more extensively in Tarantino and Eisener-Doman (2011). The goals for any genetic approach can be very different— some approaches seek to understand the more global role of a specific gene in a particular phenotype related to a disease, while others may be designed to elucidate the role of a particular gene in a cellular process, in neural circuit abnormalities, or in brain development.…”

“…ENU mutagenesis; (Tarantino and Bucan 2000) and quantitative trait loci (QTL) studies on crosses of inbred mouse strains with distinct phenotypes or on mice or rats selectively bred for PPI levels (Hitzemann et al 2008; Tarantino and Eisener-Doman 2011). Thus far, most of the PPI mutants identified through ENU mutagenesis screens have had some amount of hearing loss, and thus the specificity of the PPI “phenotype” was most likely confounded by deafness (Lisa Tarantino, personal communication).…”

Cellular, molecular, and genetic substrates underlying the impact of nicotine on learning

“…The studies discussed so far were conducted in C57BL/6 mice but genotype affects phenotype (Logue, Owen, Rasmussen, and Wehner, 1997; Owen, Logue, Rasmussen, and Wehner, 1997; Tarantino and Eisener-Dorman, 2012; Tarantino, Gould, Druhan, and Bucan, 2000). In an examination of the effects of acute, chronic, and withdrawal from chronic nicotine on hippocampus-dependent learning in 8 different inbred strains of mice, it was found that genetic background differentially affected the acute and withdrawal effects of nicotine on hippocampus dependent learning (Portugal et al, 2012a).…”