Transgenerational Genetic Effects of the Paternal Y Chromosome on Daughters‘ Phenotypes

Nelson, Vicki R.; Spiezio, Sabrina H.; Nadeau, Joseph H.

doi:10.2217/epi.10.26

Cited by 51 publications

(42 citation statements)

References 43 publications

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“…One obvious source of behavioral differences is that the two strains have Y-chromosomes from different origins (reviewed in (Cox et al, 2014)). This difference has been shown to affect offspring behavior (Maxson et al, 1979; Nelson et al, 2010). …”

Section: Discussionmentioning

confidence: 99%

Number of X-chromosome genes influences social behavior and vasopressin gene expression in mice

Cox

Quinnies

Eschendroeder

et al. 2015

Psychoneuroendocrinology

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Summary Sex differences in behavior are widespread and often caused by hormonal differences between the sexes. In addition to hormones, the composition and numbers of the sex chromosomes also affect a variety of sex differences. In humans, X-chromosome genes are implicated in neurobehavioral disorders (i.e. fragile-X, autism). To investigate the role of X-chromosome genes in social behavior, we used a mouse model that has atypical sex chromosome configurations resembling Turner (45, XO) and Klinefelter syndromes (47, XXY). We examined a number of behaviors in juvenile mice. Mice with only one copy of most X-chromosome genes, regardless of gonadal sex, were less social in dyadic interaction and social preference tasks. In the elevated plus maze, mice with one X-chromosome spent less time in the distal ends of the open arms as compared to mice with two copies of X-chromosome genes. Using qRTPCR, we noted that amygdala from female mice with one X-chromosome had higher expression levels of vasopressin (Avp) as compared to mice in the other groups. Finally, in plasma from girls with Turner syndrome we detected reduced vasopressin (AVP) concentrations as compared to control patients. These novel findings link sex chromosome genes with social behavior via concentrations of AVP in brain, adding to our understanding of sex differences in neurobehavioral disorders.

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Section: Discussionmentioning

confidence: 99%

Number of X-chromosome genes influences social behavior and vasopressin gene expression in mice

Cox

Quinnies

Eschendroeder

et al. 2015

Psychoneuroendocrinology

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“…Possibilities offered include: a sample size too small to detect variants of small effects, the disease marker is not in complete linkage disequilibrium with the causal variant and thus underestimates heritability [11], overestimation of heritability based on family-based populations, rare or even “private” mutations, inherited patterns of epigenetic marks [12], epistasis [13], gene-gene interactions [14] and gene-environment interactions [5,6]. It is indeed evident that the environment affects the human genome.…”

Section: Introductionmentioning

confidence: 99%

A Database of Gene-Environment Interactions Pertaining to Blood Lipid Traits, Cardiovascular Disease and Type 2 Diabetes

Lee¹,

Lai²,

Ordovás³

et al. 2011

J Data Mining in Genom Proteomics

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As the role of the environment – diet, exercise, alcohol and tobacco use and sleep among others – is accorded a more prominent role in modifying the relationship between genetic variants and clinical measures of disease, consideration of gene-environment (GxE) interactions is a must. To facilitate incorporation of GxE interactions into single-gene and genome-wide association studies, we have compiled from the literature a database of GxE interactions relevant to nutrition, blood lipids, cardiovascular disease and type 2 diabetes. Over 550 such interactions have been incorporated into a single database, along with over 1430 instances where a lack of statistical significance was found. This database will serve as an important resource to researchers in genetics and nutrition in order to gain an understanding of which points in the human genome are sensitive to variations in diet, physical activity and alcohol use, among other lifestyle choices. Furthermore, this GxE database has been designed with future integration into a larger database of nutritional phenotypes in mind.

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“…These epigenetic changes can affect a remarkable variety of traits including behaviors, blood chemistry, pigmentation, heart development, embryonic viability, feeding habits, and susceptibility to diet-induced obesity (30)(31)(32)(33)(34)(35). These epigenetic effects can be as strong and as common as those that are inherited in a conventional manner (30)(31)(32)(33)(34)(35) and can persist for generations after exposure to the original genetic variant (30,35). Evidence for transgenerational genetic effects on TGCTs involves wild-type sons of Kitl-deletion heterozygotes that are tumor-free instead of showing the 7% risk expected based on their genotype (31).…”

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confidence: 99%

Transgenerational epigenetic effects of theApobec1cytidine deaminase deficiency on testicular germ cell tumor susceptibility and embryonic viability

Nelson

Heaney

Tesar

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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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...

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Transgenerational Genetic Effects of the Paternal Y Chromosome on Daughters‘ Phenotypes

Cited by 51 publications

References 43 publications

Number of X-chromosome genes influences social behavior and vasopressin gene expression in mice

Number of X-chromosome genes influences social behavior and vasopressin gene expression in mice

A Database of Gene-Environment Interactions Pertaining to Blood Lipid Traits, Cardiovascular Disease and Type 2 Diabetes

Transgenerational epigenetic effects of theApobec1cytidine deaminase deficiency on testicular germ cell tumor susceptibility and embryonic viability

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