Environmental agents and genetic variants can induce heritable epigenetic changes that affect phenotypic variation and disease risk in many species. These transgenerational effects challenge conventional understanding about the modes and mechanisms of inheritance, but their molecular basis is poorly understood. The Deadend1 (Dnd1) gene enhances susceptibility to testicular germ cell tumors (TGCTs) in mice, in part by interacting epigenetically with other TGCT modifier genes in previous generations. Sequence homology to A1cf, the RNA-binding subunit of the ApoB editing complex, raises the possibility that the function of Dnd1 is related to Apobec1 activity as a cytidine deaminase. We conducted a series of experiments with a genetically engineered deficiency of Apobec1 on the TGCT-susceptible 129/Sv inbred background to determine whether dosage of Apobec1 modifies susceptibility, either alone or in combination with Dnd1, and either in a conventional or a transgenerational manner. In the paternal germ-lineage, Apobec1 deficiency significantly increased susceptibility among heterozygous but not wild-type male offspring, without subsequent transgenerational effects, showing that increased TGCT risk resulting from partial loss of Apobec1 function is inherited in a conventional manner. By contrast, partial deficiency in the maternal germ-lineage led to suppression of TGCTs in both partially and fully deficient males and significantly reduced TGCT risk in a transgenerational manner among wild-type offspring. These heritable epigenetic changes persisted for multiple generations and were fully reversed after consecutive crosses through the alternative germ-lineage. These results suggest that Apobec1 plays a central role in controlling TGCT susceptibility in both a conventional and a transgenerational manner.epigenetics | testicular cancer | gametogenesis | epistasis E stablishing the genetic basis and mode of inheritance for most traits and diseases has proven to be remarkably elusive (1). Susceptibility to testicular germ cell tumors (TGCTs) is illustrative (2). Testicular cancer is the most common malignancy affecting young men (3), more than 90% of testicular cancers result from TGCTs (4), TGCTs rank third in heritability among all cancers (5), and family history is the strongest known risk factor with a two-to sixfold increase among sons and a 5-to 19-fold increase among brothers of affected individuals (6-9). Despite the strong evidence for heritability, the only TGCT susceptibility factors identified in genome-wide association studies are the gr/gr deletion on the Y chromosome and autosomal variants in KITLG, SPRY4, BAK1, and DMRT1, which together account for less than 10% of risk (10-14). The substantial difference in prevalence between sons and brothers of cases and the epidemiological evidence for maternal estrogens, birth order, birth weight, and other factors (15-17) together raise the possibility that maternal conditions, epigenetic effects, and perhaps unconventional modes of inheritance also contribute to TG...

Since Mendel, studies of phenotypic variation and disease risk have emphasized associations between genotype and phenotype among affected individuals in families and populations. Although this paradigm has led to important insights into the molecular basis for many traits and diseases, most of the genetic variants that control the inheritance of these conditions continue to elude detection. Recent studies suggest an alternative mode of inheritance where genetic variants that are present in one generation affect phenotypes in subsequent generations, thereby decoupling the conventional relations between genotype and phenotype, and perhaps, contributing to ‘missing heritability’. Under some conditions, these transgenerational genetic effects can be as frequent and strong as conventional inheritance, and can persist for multiple generations. Growing evidence suggests that RNA mediates these heritable epigenetic changes. The primary challenge now is to identify the molecular basis for these effects, characterize mechanisms and determine whether transgenerational genetic effects occur in humans.

Aims Recent evidence suggests that transgenerational genetic effects contribute to phenotypic variation in complex traits. To test for the general occurrence of these effects and to estimate their strength, we took advantage of chromosome substitution strains (CSSs) of mice where the Y chromosome of the host strain has been replaced with the Y chromosome of the donor strain. Daughters of these CSS-Y males and host strain females are genetically identical and should be phenotypically indistinguishable in the absence of transgenerational genetic effects of the fathers’ Y chromosome on daughters’ phenotypes. Materials & methods Assay results for a broad panel of physiological traits and behaviors were compared for genetically identical daughters of CSS-Y males and host strain females from the B6-ChrA/J and B6-ChrPWD panels of CSSs. In addition, behavioral traits including specific tests for anxiety-related behaviors were tested in daughters of B6-Chr129 and 129-ChrB6 CSS-Y males. Results Across a panel of 41 multigenic traits assayed in the B6-ChrA/J panel of CSSs females and 21 multigenic traits in the B6-ChrPWD panel females, the frequency and strength for transgenerational genetic effects were remarkably similar to those for conventional inheritance of substituted chromosomes. In addition, we found strong evidence that the Y chromosome from the 129 inbred strain significantly reduced anxiety levels among daughters of B6-Chr129 CSS-Y males. Conclusion We found that transgenerational genetic effects rival conventional genetic effects in frequency and strength, we suggest that some phenotypic variation found in conventional studies of complex traits are attributable in part to the action of genetic variants in previous generations, and we propose that transgenerational genetic effects contribute to ‘missing heritability’.

Despite strong heritability, little is known about the genetic control of susceptibility to testicular germ cell tumors (TGCT) in humans or mice. Although the mouse model of spontaneous TGCTs has been extensively studied, conventional linkage analysis has failed to locate the factors that control teratocarcinogenesis in the susceptible 129 family of inbred strains.

Context: Youth sport specialization may place young athletes at increased risk for negative impacts to their physical and/or psychological health. In response to these health concerns, several health organizations have created guidelines and position statements to guide parents and practitioners toward best practices for management of the young athlete. Objective: To systematically review and synthesize current organizations’ recommendations and guidelines regarding youth sport specialization. Data Sources: English-language articles from January 1, 2000, to December 31, 2018, in the NCBI Pubmed, Embase, Cochrane, CINAHL, and SPORTDiscus databases. Study Selection: Articles that reported on recommendations or interventions by health organizations or health representatives of sports organizations. A total of 56 articles were assessed, with 11 meeting inclusion eligibility criteria. Study Design: Systematic review. Level of Evidence: Level 4. Data Extraction: Two investigators independently identified all recommendations within the results that fit within a 15-item framework encompassing 4 domains: Psychological Development/Approach, Physical Development/Load, Facilities and Resources, and Timing and Monitoring of Specialization. Results: Recommendations across organizations were primarily clustered in the Physical Development/Load (43%), Facilities and Resources (48%), and Sport Specialization (55%) domains. In contrast, the Psychological Development/Approach domain had fewer recommendations (20%). The most common recommendations endorsed concepts: “Monitor athlete well-being,” “Youth athletes need access to well-trained, quality coaches,” “Multi-sport participation,” “Limit early organized participation and/or training,” and “Parents require awareness of training, coaching, and best practices.” The level of evidence provided to support a given recommendation varied significantly. The level of detail and the consistency of terms used throughout the results were typically low. Recommendations were frequently made without reference to potential outcome measures or specific strategies that could be used for practical implementation in the community. Conclusion: There was broad representation of different aspects of specialization but limited consistency between health organization guidelines. Adopting a framework for recommendations as used in this review could assist organizations in structuring future recommendations that are specific, measurable, and framed in a manner that will promote action in the youth sport community.

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This is the first investigation to examine the PAVS in a high-risk population. In these patients, reported levels of physical inactivity are 150% higher than other clinical settings, and the PAVS is only associated with improvements in 2 of 4 major cardiometabolic risk factors. For this group, self-reported levels of physical activity may need to be higher for cardiovascular benefits to be realized in all 4 cardiometabolic domains. The PAVS offers health professionals an opportunity to encourage lifestyle-based interventions to reduce cardiovascular risk, but refinements may be necessary to address this population.

Background: The physical activity vital sign (PAVS) is a simple, validated tool for assessing physical activity in adults that has not been previously studied in pediatrics. Hypothesis: Reported physical activity utilizing the PAVS in pediatric patients should vary according to known associations with physical activity, such as age, sex, blood pressure, and body mass index (BMI). Study Design: Cross-sectional study. Level of Evidence: Level 3. Methods: All patients within a family medicine residency clinic were assessed via the PAVS from October 1, 2015, to October 31, 2016, including 255 consecutive pediatric patients aged 5 to 18 years. Associations were examined between PAVS, age, sex, blood pressure, and BMI using 1-way analysis of variance. Results: The average PAVS reported for youth (5-11 years) was 384.9 ± 218.1 minutes per week, with 69.5% reporting sufficient physical activity (≥300 minutes per week). Adolescents (12-18 years) reported a mean PAVS of 278.3 ± 199.6 minutes per week, with 51.1% reporting sufficient physical activity. Physical activity was lower in older participants ( P < 0.0001) and was higher in male patients ( P < 0.03). Higher BMI was associated with lower PAVS ( P < 0.005), while lower systolic blood pressure was associated with a greater number of days per week of physical activity ( P < 0.005). Conclusion: The PAVS successfully identifies accepted associations between age, sex, and BMI in a pediatric population. Clinical Relevance: The correlation of the PAVS with age, sex, BMI, and blood pressure may inform future strategies to address and prevent cardiometabolic disease in pediatric patients.