"Passenger gene" problem in transgenic C57BL/6 mice used in hearing research. (September 2020)

• Record Type: Journal Article
• Authors: Suzuki, Jun; Inada, Hitoshi; Han, Chul; Kim, Mi-Jung; Kimura, Ryuichi; Takata, Yusuke; Honkura, Yohei; Owada, Yuji; Kawase, Tetsuaki; Katori, Yukio; Someya, Shinichi; Osumi, Noriko
• Is Part Of: Neuroscience research. Volume 158(2020)
• Page Start: 6
• Page End: 15
• Publication Date: 2020-09
• Subjects: AHL age-related hearing loss -- Cdh23 cadherin 23 -- Fabp7 fatty acid-binding protein 7 -- ES cells embryonic stem cells -- SNP single nucleotide polymorphism -- ABR auditory brainstem response -- KO knockout -- WT wild-type -- SPL sound pressure level -- PBS phosphate-buffered saline -- EDTA ethylenediaminetetraacetic acid disodium salt dehydrate -- H&E hematoxylin and eosin -- SG spiral ganglion -- OC organs of Corti -- OHC outer hair cell -- IHC inner hair cells -- TBS tris-buffered saline -- Tuj1 neuron-specific class III beta-tubulin -- 8-oxoG 8-Oxoguanine -- DAPI 4', 6-diamidino-2-phenylindole -- NHS normal horse serum -- ANOVA analysis of variance -- Slig spiral ligament -- Slim spiral limbus; Passenger gene -- Transgenic mouse -- Cadherin 23 -- C57BL/6 -- Hearing loss; Neurosciences -- Research -- Periodicals; Neurosciences -- Research -- Japan -- Periodicals; Neurology -- Periodicals; Neurosciences -- Periodicals; Neurosciences -- Recherche -- Périodiques; Neurosciences -- Recherche -- Japon -- Périodiques; Neurosciences -- Research; Japan; Periodicals; 612.8
• DOI: 10.1016/j.neures.2019.10.007
• Languages: English
• ISSNs: 0168-0102

Abstract

Highlights: Fabp7 knockout (KO) mice on a C57BL/6 background had remaining 129/Sv genes. The 129/Sv-derived Cdh23 753GG gene traveled with the target gene. The "passenger gene problem" should be considered in use of transgenic mice. Abstract: Despite recent advances in genome engineering technologies, traditional transgenic mice generated on a mixed genetic background of C57BL/6 and 129/Sv mice remain widely used in age-related hearing loss (AHL) research, since C57BL/6 mice exhibit early onset and progression of AHL due to a mutation in cadherin 23-encoding gene ( Cdh23 753G>A ). In these transgenic mice, backcrossing for more than 10 generations results in replacement of the donor background (129/Sv) with that of the recipient (C57BL/6), so that approximately 99.9% of genes are C57BL/6-derived and are considered congenic. However, the regions flanking the target gene may still be of 129/Sv origin, creating a so-called "passenger gene problem" where the normal 129/Sv-derived Cdh23 753G allele can travel with the target gene. In this study, we investigated the role of fatty acid-binding protein 7 (Fabp7), which is important for cellular uptake and intracellular trafficking of fatty acids in the cochlea, using traditional Fabp7 knockout (KO) mice on the C57BL/6 background. We found that Fabp7 KO mice showed delayed AHL progression and milder cochlear degeneration. However, the genotype of the Cdh23 region flanking Fabp7 was still that of 129/Sv origin ( Cdh23 753GG ). Our findings reveal the potential risk of contamination for traditional transgenic mice generated on the C57BL/6 background.