The specification of imprints in mammals.

At the heart of genomic imprinting in mammals are imprinting control regions (ICRs), which are the discrete genetic elements that confer imprinted monoallelic expression to several genes in imprinted gene clusters. A characteristic of the known ICRs is that they acquire different epigenetic states, exemplified by differences in DNA methylation, in the sperm and egg, and these imprint marks remain on the sperm- and oocyte-derived alleles into the next generation as a lifelong memory of parental origin. Although there has been much focus on gametic marking of ICRs as the point of imprint specification, recent mechanistic studies and genome-wide DNA methylation profiling do not support the existence of a specific imprinting machinery in germ cells. Rather, ICRs are part of more widespread methylation events that occur during gametogenesis. Instead, a decisive component in the specification of imprints is the choice of which sites of gamete-derived methylation to maintain in the zygote and preimplantation embryo at a time when much of the remainder of the genome is being demethylated. Among the factors involved in this selection, the zinc-finger protein Zfp57 can be regarded as an imprint-specific, sequence-specific DNA binding factor responsible for maintaining methylation at most ICRs. The recent insights into the balance of gametic and zygotic contributions to imprint specification should help understand mechanistic opportunities and constraints on the evolution of imprinting in mammals.

Maternal NLRP7 and C6orf221 variants are not a common risk factor for androgenetic moles, triploidy and recurrent miscarriage.

Maternal effect genes control early events of embryogenesis. Maternal homozygous and compound mutations in two such genes, NLRP7 and c6orf221, have been detected in the majority of women experiencing recurrent biparental hydatidiform moles. It was suggested that other forms of reproductive wastage, including diploid androgenetic moles, partial moles, polyploidy, recurrent spontaneous abortions and stillbirths of uncertain etiology, may be caused by NLRP7 or c6orf221 mutations in the mother. To elucidate which subpopulations of women with adverse reproductive outcomes should be screened for NLRP7/C6orf221 variants, we sequenced coding sequence and exon/intron boundaries of NLRP7 and C6orf221 in a well-defined group of 17 women with recurrent miscarriage and additional triploidy or complete hydatidiform moles. The major findings for this group were non-synonymous variants of NLRP7, rather than clearly pathogenic mutations. To assess the role of these variants, we genotyped them in a larger group including women with primary recurrent miscarriage (n = 39), paternal triploid conceptions (n = 22) and women with proven fertility after age 37 and no prior history of miscarriage or pregnancy complications (n = 52). No associations between non-synonymous NLRP7 variants and primary recurrent miscarriage or partial hydatidiform molar pregnancies were detected. Our findings suggest that neither mutations nor variants in NLRP7 and C6orf221 are major factors contributing to the risk of these types of pregnancy complications. Further studies in larger groups of patients and controls are needed to specify the impact of NLRP7 rare non-synonymous variants on genetic susceptibility to recurrent reproductive wastage.

The -521 C/T variant in the dopamine-4-receptor gene (DRD4) is associated with skiing and snowboarding behavior.

Sensation seeking is the tendency to seek out new and thrilling experiences and to take risks for the sake of such experiences. A single-nucleotide polymorphism, -521 C/T (rs1800955) in the promoter region of the dopamine-4-receptor gene (DRD4), is associated with approach-related traits including novelty seeking and extraversion, in some, but not all studies. To our knowledge, no studies have been conducted on the genetics of risk-taking behavior in sports. Using a joint-analysis approach, we measured sensation seeking in two cohorts of experienced male and female skiers and snowboarders (n = 503) using a sports-specific tool developed for this study, the Contextual Sensation Seeking Questionnaire for Skiing and Snowboarding (CSSQ-S), and a more general trait measure, the Zuckerman-Kuhlman Personality Questionnaire impulsive sensation-seeking subscale. We detected, and then replicated a significant association between the DRD4 -521CC genotype and sports-specific sensation seeking as measured using the CSSQ-S (P < 0.001). These data suggest that the DRD4 -521 C/T polymorphism contributes to a "risk-taking phenotype" in skiers and snowboarders, but the variant was not associated with impulsive sensation seeking (P = 0.9).

Prenatal and perinatal environmental influences on the human fetal and placental epigenome.

Drug, hormonal, and nutritional exposures in pregnancy can cause birth defects, or have more subtle influences that may affect adult health through epigenetic developmental programming. Characterizing these epigenetic changes may provide valuable insight into the mechanism by which our health is influenced by the environment and provide biomarkers of exposure; however, currently there are few data from human studies directly addressing this. We review data on three types of exposures-nutritional, glucocorticoid, and endocrine-disrupting chemicals-and discuss how these may be associated with epigenetic changes in the fetus and the placenta, a key mediator of in utero environment. In addition, we outline some considerations for investigation of epigenetic effects in the fetus and placenta that are important to consider in the design of studies for the future.