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Collateral blood flow varies greatly among humans for reasons that remain unclear, resulting in significant differences in ischemic tissue damage. A similarly large variation has also been found in mice that is caused by genetic background-dependent differences in the extent of collateral formation, termed collaterogenesis—a unique angiogenic process that occurs during development and determines collateral number and diameter in the adult. Previous studies have identified several quantitative trait loci (QTL) linked to this variation. However, understanding has been hampered by the use of closely related inbred strains that do not model the wide genetic variation present in the “outbred” human population. The Collaborative Cross (CC) multiparent mouse genetic reference panel was developed to address this limitation. Herein we measured the number and average diameter of cerebral collaterals in 60 CC strains, their 8 founder strains, 8 F1 crosses of CC strains selected for abundant versus sparse collaterals, and 2 intercross populations created from the latter. Collateral number evidenced 47-fold variation among the 60 CC strains, with 14% having poor, 25% poor-to-intermediate, 47% intermediate-to-good, and 13% good collateral abundance, that was associated with large differences in post-stroke infarct volume. Genome-wide mapping demonstrated that collateral abundance is a highly polymorphic trait. Subsequent analysis identified: 6 novel QTL circumscribing 28 high-priority candidate genes harboring putative loss-of-function polymorphisms (SNPs) associated with low collateral number; 335 predicted-deleterious SNPs present in their human orthologs; and 32 genes associated with vascular development but lacking protein coding variants. This study provides a comprehensive set of candidate genes for future investigations aimed at identifying signaling proteins within the collaterogenesis pathway whose variants potentially underlie genetic-dependent collateral insufficiency in brain and other tissues.

Additional file 7. Review history.

Additional file 1: Figure S1. Overview of protein and phosphopeptide quantification. Figure S2. Sex effects and heritability on the abundance of proteins and phosphopepitdes across tissues. Figure S3. pQTL and phQTL mapping from CC strains in heart, kidney and liver tissues. Figure S4. Mediation of phQTL through the abundance of their parent proteins (substrates). Figure S5. NZO allele drives the low abundances of MCAT pS41 in CC strains. Figure S6. pQTL and phQTL were identified to regulate phosphopeptide abundance together. Figure S7. Phosphorylation sites on one protein can be regulated coordinated and not coordinated.

Oscillations, a highly conserved brain function across mammalian species, are pivotal in brain physiology and pathology. Traumatic brain injury (TBI) often leads to subacute and chronic brain oscillatory alterations associated with complications like post-traumatic epilepsy (PTE) in patients and animal models. Our recent work longitudinally recorded local field potential from the contralateral hippocampus of 12 strains of recombinant inbred Collaborative Cross (CC) mice alongside classical laboratory inbred C57BL/6J mice after lateral fluid percussion injury. In this study, we profiled the acute (<12 hr post-injury) and subacute (12-48 hr post-injury) hippocampal oscillatory responses to TBI and evaluated their predictive value for PTE. We found dynamic high-amplitude rhythmic spikes with elevated power density and reduced entropy that prevailed during the acute phase in CC031 mice who later developed PTE. This characteristic early brain oscillatory alteration is absent in CC031 sham controls or other CC and reference C57BL/6J strains that did not develop PTE after TBI. Our work provides quantitative measures linking early brain oscillation to PTE at a population level in mice under controlled experimental conditions. These findings will offer insights into circuit mechanisms and potential targets for neuromodulatory intervention., Competing Interests: Authors’ disclosure statement: Neither of the authors has any conflict of interest to disclose.

Background: The development of peanut allergy is due to a combination of genetic and environmental factors, although specific genes have proven difficult to identify. Previously, we reported that peanut-sensitized CC027/GeniUnc (CC027) mice develop anaphylaxis upon oral challenge to peanut, unlike C3H/HeJ (C3H) mice., Objective: To determine the genetic basis of orally-induced anaphylaxis to peanut in CC027 mice., Methods: A genetic mapping population between CC027 and C3H mice was designed to identify the genetic factors that drive oral anaphylaxis. A total of 356 CC027xC3H backcrossed mice were generated, sensitized to peanut, then challenged to peanut by oral gavage. Anaphylaxis and peanut-specific IgE were quantified for all mice. T-cell phenotyping was conducted on CC027 and five additional CC strains., Results: Anaphylaxis to peanut was absent in 77% of backcrossed mice, with 19% showing moderate anaphylaxis, and 4% having severe anaphylaxis. A total of eight genetic loci were associated with variation in response to peanut challenge, six associated with anaphylaxis (temperature decrease) and two associated with peanut-specific IgE levels. There were two major loci that impacted multiple aspects of the severity of acute anaphylaxis, at which the CC027 allele was associated with worse outcome. At one of these loci, CC027 has a private genetic variant in the Themis (thymocyte-expressed molecule involved in selection) gene. Consistent with Themis' described functions, we found that CC027 have more immature T cells with fewer CD8+, CD4+, and CD4+CD25+CD127- regulatory T cells., Conclusion: Our results demonstrate a key role for Themis in the orally-reactive CC027 mouse model of peanut allergy.

Collateral blood flow varies greatly among humans for reasons that remain unclear, resulting in significant differences in ischemic tissue damage. A similarly large variation has also been found in mice that is caused by genetic background-dependent differences in the extent of collateral formation, termed collaterogenesis-a unique angiogenic process that occurs during development and determines collateral number and diameter in the adult. Previous studies have identified several quantitative trait loci (QTL) linked to this variation. However, understanding has been hampered by the use of closely related inbred strains that do not model the wide genetic variation present in the "outbred" human population. The Collaborative Cross (CC) multiparent mouse genetic reference panel was developed to address this limitation. Herein we measured the number and average diameter of cerebral collaterals in 60 CC strains, their 8 founder strains, 8 F1 crosses of CC strains selected for abundant versus sparse collaterals, and 2 intercross populations created from the latter. Collateral number evidenced 47-fold variation among the 60 CC strains, with 14% having poor, 25% poor-to-intermediate, 47% intermediate-to-good, and 13% good collateral abundance, that was associated with large differences in post-stroke infarct volume. Genome-wide mapping demonstrated that collateral abundance is a highly polymorphic trait. Subsequent analysis identified: 6 novel QTL circumscribing 28 high-priority candidate genes harboring putative loss-of-function polymorphisms (SNPs) associated with low collateral number; 335 predicted-deleterious SNPs present in their human orthologs; and 32 genes associated with vascular development but lacking protein coding variants. This study provides a comprehensive set of candidate genes for future investigations aimed at identifying signaling proteins within the collaterogenesis pathway whose variants potentially underlie genetic-dependent collateral insufficiency in brain and other tissues.