Systems genetics identifies Hp1bp3 as a novel modulator of cognitive aging

Neuner, Sarah M.; Garfinkel, Benjamin P.; Wilmott, Lynda A.; Ignatowska‐Jankowska, Bogna M.; Citri, Ami; Orly, Joseph; Lu, Lu; Overall, Rupert W.; Mulligan, Megan K.; Kempermann, Gerd; Williams, Robert W.; O’Connell, Kathryn A; Kaczorowski, Catherine C.

doi:10.1016/j.neurobiolaging.2016.06.008

Cited by 38 publications

(37 citation statements)

References 79 publications

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“…Since HP1BP3 is widely expressed in the brain (Allen brain atlas and data not shown), it is difficult to predict which brain regions are directly affected by HP1BP3 deficiency, and future work will aim to map the location of HP1BP3 action. An interesting step in this direction is the recent description of a role for HP1BP3 in hippocampus‐dependent learning and memory (Neuner et al ).…”

Section: Discussionmentioning

confidence: 99%

HP1BP3 expression determines maternal behavior and offspring survival

Garfinkel

Arad

Neuner

et al. 2016

Genes Brain and Behavior

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Maternal care is an indispensable behavioral component necessary for survival and reproductive success in mammals, and postpartum maternal behavior is mediated by an incompletely understood complex interplay of signals including effects of epigenetic regulation. We approached this issue using our recently established mice with targeted deletion of heterochromatin protein 1 binding protein 3 (HP1BP3), which we found to be a novel epigenetic repressor with critical roles in postnatal growth. Here, we report a dramatic reduction in the survival of pups born to Hp1bp3(-/-) deficient mouse dams, which could be rescued by co-fostering with wild-type dams. Hp1bp3(-/-) females failed to retrieve both their own pups and foster pups in a pup retrieval test, and showed reduced anxiety-like behavior in the open-field and elevated-plus-maze tests. In contrast, Hp1bp3(-/-) females showed no deficits in behaviors often associated with impaired maternal care, including social behavior, depression, motor coordination and olfactory capability; and maintained unchanged anxiety-associated hallmarks such as cholinergic status and brain miRNA profiles. Collectively, our results suggest a novel role for HP1BP3 in regulating maternal and anxiety-related behavior in mice and call for exploring ways to manipulate this epigenetic process.

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Section: Discussionmentioning

confidence: 99%

HP1BP3 expression determines maternal behavior and offspring survival

Garfinkel

Arad

Neuner

et al. 2016

Genes Brain and Behavior

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“…A tractable and unbiased approach to studying phenotypic variation in the laboratory has been the application of invertebrate and vertebrate genetic reference panels (GRPs) in which genetic variation is fixed and well‐cataloged across large families of genetically related recombinant inbred (RI) strains. Thousands of quantitative traits have been studied in GRPs, including fine mapping of genetic loci that contribute to continuous variation in complex physiological and neurobiological traits across species . Mice are particularly advantageous for examining the genetic architecture of sociability because of their high levels and lifelong expression of affiliative behaviors .…”

Section: Introductionmentioning

confidence: 99%

“…Thousands of quantitative traits have been studied in GRPs, including fine mapping of genetic loci that contribute to continuous variation in complex physiological and neurobiological traits across species. [42][43][44][45][46][47][48][49] Mice are particularly advantageous for examining the genetic architecture of sociability because of their high levels and lifelong expression of affiliative behaviors. [50][51][52][53] Outbred and unrelated-inbred mouse strains show differences in affiliative and aggressive social behavior 9,54-56 and mutant mice have been the focus of numerous candidate gene studies.…”

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confidence: 99%

“…[61][62][63][64][65] The tasks differ in several important ways, including the characteristics of the social partner (age, familiarity), extent of physical contact with the social partner, ethological similarity, session duration and chamber size, providing an opportunity to examine the "behavioral architecture" of sociability by determining the degree to which social (and nonsocial) traits co-vary. Here, the BXD GRP is known to show continuous variation in a number of complex behaviors, 46,48,49,[66][67][68][69] including activity, anxiety and learning, providing an opportunity to examine whether there is heritable and correlated variation in nonsocial traits expressed during the social tasks. The studies show broad and heritable variation in social and nonsocial traits, which vary independently, providing an opportunity for whole-genome mapping that shows overlapping, yet distinct, loci for vocal communication, social approach, activity and anxiety-like behaviors.…”

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confidence: 99%

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Quantitative trait locus mapping and analysis of heritable variation in affiliative social behavior and co‐occurring traits

Knoll

Jiang

Levitt

2017

Genes Brain and Behavior

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Humans exhibit broad heterogeneity in affiliative social behavior. Twin and family studies show that individual differences in core dimensions of social behavior are heritable, yet there are knowledge gaps in understanding the underlying genetic and neurobiological mechanisms. Animal genetic reference panels (GRPs) provide a tractable strategy for examining the behavioral and genetic architecture of complex traits. Here, using males from 50 mouse strains from the BXD GRP, 4 domains of affiliative social behavior—social approach, social recognition, direct social interaction (DSI) (partner sniffing) and vocal communication—were examined in 2 widely used behavioral tasks—the 3‐chamber and DSI tasks. There was continuous and broad variation in social and nonsocial traits, with moderate to high heritability of social approach sniff preference (0.31), ultrasonic vocalization (USV) count (0.39), partner sniffing (0.51), locomotor activity (0.54‐0.66) and anxiety‐like behavior (0.36). Principal component analysis shows that variation in social and nonsocial traits are attributable to 5 independent factors. Genome‐wide mapping identified significant quantitative trait loci for USV count on chromosome (Chr) 18 and locomotor activity on Chr X, with suggestive loci and candidate quantitative trait genes identified for all traits with one notable exception—partner sniffing in the DSI task. The results show heritable variation in sociability, which is independent of variation in activity and anxiety‐like traits. In addition, a highly heritable and ethological domain of affiliative sociability—partner sniffing—appears highly polygenic. These findings establish a basis for identifying functional natural variants, leading to a new understanding typical and atypical sociability.

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“…Bckdhb for maple syrup urine disease, Dhtkd1 for diabetes 27 , Hp1bp3 for cognitive aging 94 , and Ahr for locomotor activity 95 .…”

Section: Improved Mapping Of Bxd Phenome and Omics Datamentioning

confidence: 99%

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

Ashbrook

Arends

Prins

et al. 2019

Preprint

Self Cite

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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.

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Systems genetics identifies Hp1bp3 as a novel modulator of cognitive aging

Cited by 38 publications

References 79 publications

HP1BP3 expression determines maternal behavior and offspring survival

HP1BP3 expression determines maternal behavior and offspring survival

Quantitative trait locus mapping and analysis of heritable variation in affiliative social behavior and co‐occurring traits

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

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