A comprehensive and comparative phenotypic analysis of the collaborative founder strains identifies new and known phenotypes

Abstract

The collaborative cross (CC) is a large panel of mouse-inbred lines derived from eight founder strains (NOD/ShiLtJ, NZO/ HILtJ, A/J, C57BL/6J, 129S1/SvImJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ). Here, we performed a comprehensive and comparative phenotyping screening to identify phenotypic differences and similarities between the eight founder strains. In total, more than 300 parameters including allergy, behavior, cardiovascular, clinical blood chemistry, dysmorphology, bone and cartilage, energy metabolism, eye and vision, immunology, lung function, neurology, nociception, and pathology were analyzed; in most traits from sixteen females and sixteen males. We identified over 270 parameters that were significantly different between strains. This study highlights the value of the founder and CC strains for phenotype-genotype associations of many genetic traits that are highly relevant to human diseases. All data described here are publicly available from the mouse phenome database for analyses and downloads.Jochen Graw: Retired. Electronic supplementary materialThe online version of this article (https ://doi.

Heritability of fat distributions in male mice from the founder strains of the Diversity Outbred mouse population

“…Relatedly, estimates of heritability derived in founder mice attribute differences between strains solely to genetics; it is possible that unknown nongenetic effects could influence differences and bias h 2 estimates, although this is unlikely given our careful control of environment. Within a given strain, we generally observed expected variability in body weight that is consistent with data from other studies ( Evsikova and Svenson 2009 ; Bogue et al 2015 , 2020 ; Kollmus et al 2020 ). A number of nongenetic factors may have contributed to this variability, including social hierarchy among mice in the same cage or development of underlying conditions affecting weight, such as diabetes in a subset of the NZO/HILtJ ( Kleinert et al 2018 ) or NOD/LtJ ( Bao et al 2002 ) mice.…”

Quantitative trait locus mapping identifies a locus linked to striatal dopamine and points to collagen IV alpha‐6 chain as a novel regulator of striatal axonal branching in mice

“…Two CC founder strain mice, A/J and PWK/PhJ, had significantly lower striatal DA than C57BL/6J mice (Figure 1, supplemental Table 3), and a different genotype at rs29282811 (https://www.sanger.ac.uk/sanger/Mouse_SnpViewer). Interestingly, these mice have also been reported to perform less well in motor tests than C57BL/6J mice 50 . However, compared to C57BL/6J mice, A/J mice performed worse than PWK/PhJ mice in tests commonly used to test voluntary motor performance: open field (distance traveled and rearing events) and rotarod (Figure 3 in Reference 50).…”

“…Interestingly, these mice have also been reported to perform less well in motor tests than C57BL/6J mice 50 . However, compared to C57BL/6J mice, A/J mice performed worse than PWK/PhJ mice in tests commonly used to test voluntary motor performance: open field (distance traveled and rearing events) and rotarod (Figure 3 in Reference 50). The lesser motor performance of A/J compared to C57BL/6J mice was already reported in an earlier study, 18 indicating that the difference between these two common laboratory strains is stable over generations and across labs.…”

“…Studies in zebra fish have shown that orthologs of type IV collagens, coded by gene products of Col4a5 and Col4a6 , control axonal guidance during development 24 . Based on the observed differences of A/J versus C57BL/6J mice in striatal DA concentration, motor performance, 50 the localization of Col4a6 gene in the associated QTL, the distinct neurodevelopmental expression profile of COL4A6 , and the role of collagen IV in neurite outgrowth and guidance (see references above), we hypothesized that DA neuron axonal fiber density would be different in the dorsal striatum of these two mouse strains. To test this, we performed TH immunostaining on brain sections from C57BL/6J and A/J mice (see Section 2).…”

Heritable variation in locomotion, reward sensitivity and impulsive behaviors in a genetically diverse inbred mouse panel

“…Finally, we correlated locomotor and impulsivity measures to acoustic startle response (ASR) and pre-pulse inhibition (PPI) data reported in a separate study (Kollmus et al, 2020) in the founder strains. Impulsive phenotypes and ASR/PPI are dependent on ventrostriatal dopamine transmission, and a correlation between impulsivity and impaired PPI has been identified within human literature (Gee et al, 2015;Swann et al, 2013).…”