Analyzing complex traits with congenic strains

Abstract

Congenic strains continue to be a fundamental resource for dissecting the genetic basis of complex traits. Traditionally, genetic variants (QTLs) that account for phenotypic variation in a panel of congenic strains are sought first by comparing phenotypes for each strain to the host (reference) strain, and then by examining the results to identify a common chromosome segment that provides the best match between genotype and phenotype across the panel. However, this ‘‘common-segment’’ method has significant limitations, including the subjective nature of the genetic model and an inability to deal formally with strain phenotypes that do not fit the model. We propose an alternative that we call ‘‘sequential’’ analysis and that is based on a unique principle of QTL analysis where each strain, corresponding to a single genotype, is tested individually for QTL effects rather than testing the congenic panel collectively for common effects across heterogeneous backgrounds. A minimum spanning tree, based on principles of graph theory, is used to determine the optimal sequence of strain comparisons. For two traits in two panels of congenic strains in mice, we compared results for the sequential method with the common-segment method as well as with two standard methods of QTL analysis, namely, interval mapping and multiple linear regression. The general utility of the sequential method was demonstrated with analysis of five additional traits in congenic panels from mice and rats. Sequential analysis rigorously resolved phenotypic heterogeneity among strains in the congenic panels and found QTLs that other methods failed to detect.

High-Resolution Genetic Mapping of Complex Traits from a Combined Analysis of F2 and Advanced Intercross Mice

“…This time-and labor-intensive effort to identify specific genes is often derailed by the discovery that a single QTL of large effect is in fact caused by multiple loci of small effect located in the same chromosomal region (Legare et al 2000;Mott et al 2000;Cheng et al 2010;Shao et al 2010;Parker et al 2013). An AIL is an improvement over these traditional methods because it merges identification and fine-mapping into a single step, which can often discriminate between loci that are due to single vs. multiple alleles (Darvasi and Soller 1995).…”

Genetic mapping of variation in dauer larvae development in growing populations of Caenorhabditis elegans

“…Sequential IL analysis. This method was proposed by Shao et al (2010) and adjusted to the population used in this study. ILs that share one break-point were selected and used in sequential (two by two) analyses to identify QTLs.…”

“…The genome of an IL is composed of a recipient genome contributed by one of the parental strains (Bristol N2) and a short, homozygous segment of the donor genome contributed by CB4856. We first conducted a straightforward bin mapping approach, followed by comparisons to a common reference (N2), and then a sequential pairwise analysis (Shao et al, 2010). These analyses indicate that the genetic architecture of dauer traits is highly complex, with a large number of quantitative trait loci (QTLs) affecting dauer larvae development in growing populations.…”

From Peas to Disease: Modifier Genes, Network Resilience, and the Genetics of Health

“…52,55 In this model, naturally occurring protective A/J-derived alleles act in protective but context-dependent ways to modify the penetrance, expressivity, and pleiotropy of diet-induced MetS phenotypes on the genetically predisposed C57BL/6J background. Thus in this and other cases, 56 QTLs act as genetic modifiers, with highly non-additive effects and strong dependence on genetic background. Context dependence probably explains the contrast in the prevalence of evidence for modifier effects in genetically heterogeneous populations such as the Resil- 20 From Modified Phenotypes to Modifier Genes Strategies to Identify Genetic Modifiers in Humans Several approaches can be used to study modifier genes directly in human populations, including comparative expression profiling, genome-wide association studies (GWASs), and family-based association analyses.…”

“…Specialized inbred resources such as congenic strains, in which the causal target allele or candidate modifier locus has been transferred to an alternative strain background, 56 can be readily generated to identify genetic modifier effects and map the responsible loci. Genetic transfer can be achieved through selective breeding to isolate the variant on a distinct strain background or by direct genetic engineering of embryonic stem cells or oocytes and subsequent generation of founder mice.…”