The expanded BXD family of mice: A cohort for experimental systems genetics and precision medicine

Abstract

The challenge of precision medicine is to model complex interactions among DNA variants, sets of phenotypes, and complex environmental factors and confounders.We have expanded the BXD family, creating a powerful and extensible test bed for experimental precision medicine and an ideal cohort to study gene-by-environmental interactions.These BXD segregate for over 6 million variants, with a mean minor allele frequency close to 0.5. We have increased the family two-fold to 150 inbred strains, all derived from C57BL/6J and DBA/2J. We have also generated updated and comprehensive genotypes and an unrivaled deep phenome.Approximately 10,000 recombinations have been located, allowing precision of quantitative trait loci mapping of ±2.0 Mb over much of the genome and ±0.5 Mb for Mendelian loci. The BXD phenome includes more than 100 'omics data sets and >7000 quantitative and clinical phenotypes, all of which is publicly available.The BXD family is an enduring, collaborative, and replicable resource to test causal and mechanistic links between genomes and phenomes at many stages and under a wide variety of treatments and interventions. Background The origin of the BXD familyRecombinant inbred strains of mice, and the BXD family in particular, have been used for 45 years to map Mendelian and quantitative trait loci 1-5 . Production was started in 1971 by Benjamin A. Taylor by crossing a female C57BL/6J (B6 or B) and a male DBA/2J (D2 or D)-hence BXD. The first set of 26 (expanded in the 1990s to 35) recombinant inbred strains were intended mainly for mapping Mendelian loci 1,6 , but the family was soon used to map more complex quantitative traits-cancer susceptibility 7-9 , neuroanatomical traits 10-13 , and behavioral differences 14,15 , and pharmacological responses to toxicants and drugs [16][17][18][19] . All of these strains are still available from The Jackson Laboratory (JAX) and carry the strain suffix "/TyJ".Production of BXD43 through BXD102 started in the late 1990s at the University of Tennessee Health Science Center (UTHSC) 20,21 . These new strains were derived from advanced intercross (AI) progeny that had been bred for as many as 14 generations before inbreeding 22 (Figure 1; Supplementary figure 1; Supplementary table 1). AI-derived BXDs incorporate roughly twice as many fixed cross-over events (recombinations) between B and D parental genomes compared to F2-derived BXDs-80 versus 40 [22][23][24][25][26] (Figure 2). This improved both power and precision. statistic (LRS) scores at three cut-offs: 15 (suggestive), 20 (significant) and 25 (highly significant) ( Table 1). The new genotype files increase the number of QTLs detected at suggestive and significant LRS levels, increasing the percentage detected by 17-19% and 24-26% respectively. However, there is a much smaller increase (2% and 10% respectively) at the highly significant cutoff (LRS >25) because large effect QTLs and Mendelian loci are relatively insensitive to low marker density.

Genetic Dissection of Femoral and Tibial Microarchitecture

“…A straightforward alternative at this point would also be to extend the study using an independent panel of BXDs or their diallel progeny. There is an additional set of 80 BXD strains that have not been phenotyped at all . One could also broaden the analysis to include other intercrosses and Diversity Outbred stock …”

“…However, we were able to evaluate overall sex differences for all phenotypes and mapping results. Second, the sample size was still too small to detect epistatic interactions, but with the recent boost in the BXD family size to 150 strains, we can now detect stronger two‐locus interactions . Third, by incorporating a global analysis of gene ontologies we were able to efficiently filter gene candidates.…”

“…In comparison to intercrosses, these large families of isogenic, but diverse strains can be used to systematically test gene‐by‐environmental interactions, to establish replicability, and to test new therapies and treatments . Families of strains, such as the BXDs, are also advantageous because deep genomic, metabolic, metagenomic, and phenotypic data have already been generated . It therefore becomes practical to compare variation in bone and the skeletal system with those of many other traits in many other systems, and at multiple levels of organization …”

Genetic background modifies CNS‐mediated sensorimotor decline in the AD‐BXD mouse model of genetic diversity in Alzheimer's disease

“…Genetic reference panels such as the BXD family used here represent powerful tools for the analysis and genetic mapping of quantitative traits such as the sensorimotor traits investigated here. As such, they are ideal for discovering new genetic loci associated with complex traits . The high degree of heritability for the traits we examined here ( ≈ 0.6‐0.9) suggests they are amenable to QTL mapping to identify candidate genes and loci associated with sensorimotor performance.…”

“…As such, they are ideal for discovering new genetic loci associated with complex traits. 44 The high degree of heritability for the traits we examined here (h 2 RI x ≈ 0.6-0.9) suggests they are amenable to QTL mapping to identify candidate genes and loci associated with sensorimotor performance. However, the number of strains used in the present study is insufficient for this approach and additional strains will be needed to ensure we are adequately powered for such analysis.…”