Genetic Analysis of Hematological Parameters in Incipient Lines of the Collaborative Cross

Abstract

Hematological parameters, including red and white blood cell counts and hemoglobin concentration, are widely used clinical indicators of health and disease. These traits are tightly regulated in healthy individuals and are under genetic control. Mutations in key genes that affect hematological parameters have important phenotypic consequences, including multiple variants that affect susceptibility to malarial disease. However, most variation in hematological traits is continuous and is presumably influenced by multiple loci and variants with small phenotypic effects. We used a newly developed mouse resource population, the Collaborative Cross (CC), to identify genetic determinants of hematological parameters. We surveyed the eight founder strains of the CC and performed a mapping study using 131 incipient lines of the CC. Genome scans identified quantitative trait loci for several hematological parameters, including mean red cell volume (Chr 7 and Chr 14), white blood cell count (Chr 18), percent neutrophils/lymphocytes (Chr 11), and monocyte number (Chr 1). We used evolutionary principles and unique bioinformatics resources to reduce the size of candidate intervals and to view functional variation in the context of phylogeny. Many quantitative trait loci regions could be narrowed sufficiently to identify a small number of promising candidate genes. This approach not only expands our knowledge about hematological traits but also demonstrates the unique ability of the CC to elucidate the genetic architecture of complex traits.

Genetic Regulation ofZfp30, CXCL1, and Neutrophilic Inflammation in Murine Lung

“…We obtained 151 male preCC mice (ages 10-14 weeks) from Oak Ridge National Laboratory (Chesler et al 2008;Kelada et al 2012;Kelada et al 2014). Each mouse was from an independent CC line that had undergone 5-14 generations of inbreeding.…”

“…Genotypes for 131of preCC mice used in these experiments have been previously reported (Kelada et al 2012). Twenty additional mice are included in this study.…”

“…The genomes of the CC founder strains Yalcin et al 2011) and the features of the CC population have been described recently (Collaborative Cross Consortium 2012). Results obtained using incipient CC lines that were partially inbred (referred to as "preCC" mice) have been notable in terms of phenotypic diversity and identification of new QTL (Aylor et al 2011;Bottomly et al 2012;Kelada et al 2012;Ferris et al 2013;Kelada et al 2014).…”

Varying Coefficient Models for Mapping Quantitative Trait Loci Using Recombinant Inbred Intercrosses

“…This study is largely motivated by the availability of the CC lines (Collaborative Cross Consortium 2012; Kelada et al 2012). The CC project aims to generate and maintain .300 multiparental CC RI lines, and our ability to map complex traits will be greatly increased by making use of these resources.…”

“…In our simulations, we applied single marker analysis because the high marker density of the parental RI (Aylor et al 2011;Durrant et al 2011;Collaborative Cross Consortium 2012;Kelada et al 2012), and thus RIX, makes results similar to those that would be obtained using more complicated mapping methods, such as traditional interval mapping (Lander and Botstein 1989) or regression interval mapping . We also assume no parentof-origin QTL and polygenic effects.…”