Disentangling prenatal and postnatal maternal genetic effects reveals persistent prenatal effects on offspring growth in mice

Mothers are often the most important determinant of traits expressed by their offspring. These "maternal effects" (MEs) are especially crucial in early development, but can also persist into adulthood. They have been shown to play a role in a diversity of evolutionary and ecological processes, especially when genetically based. Although the importance of MEs is becoming widely appreciated, we know little about their underlying genetic basis. We address the dearth of genetic data by providing a simple approach, using combined genotype information from parents and offspring, to identify "maternal genetic effects" (MGEs) contributing to natural variation in complex traits. Combined with experimental cross-fostering, our approach also allows for the separation of pre- and postnatal MGEs, providing rare insights into prenatal effects. Applying this approach to an experimental mouse population, we identified 13 ME loci affecting body weight, most of which (12/13) exhibited prenatal effects, and nearly half (6/13) exhibiting postnatal effects. MGEs contributed more to variation in body weight than the direct effects of the offsprings' own genotypes until mice reached adulthood, but continued to represent a major component of variation through adulthood. Prenatal effects always contributed more variation than postnatal effects, especially for those effects that persisted into adulthood. These results suggest that MGEs may be an important component of genetic architecture that is generally overlooked in studies focused on direct mapping from genotype to phenotype. Our approach can be used in both experimental and natural populations, providing a widely practicable means of expanding our understanding of MGEs.     

Parent-of-origin effects cause genetic variation in pig performance traits

In order to assess the relative importance of genomic imprinting for the genetic variation of traits economically relevant for pork production, a data set containing 21 209 records from Large White pigs was analysed. A total of 33 traits for growth, carcass composition and meat quality were investigated. All traits were recorded between 1997 and 2006 at a test station in Switzerland and the pedigree included 15 747 ancestors. A model with two genetic effects for each animal was applied: the first corresponds to a paternal and the second to a maternal expression pattern of imprinted genes. The imprinting variance was estimated as the sum of both corresponding genetic variances per animal minus twice the covariance. The null hypothesis of no imprinting was tested by a restricted maximum likelihood ratio test with two degrees of freedom. Genomic imprinting significantly contributed to the genetic variance of 19 traits. The proportion of the total additive genetic variance that could be attributed to genomic imprinting was of the order between 5% and 19%.     

Effects and consequences of prenatal irradiation

After a brief introduction about the historic development of risk estimates and maximum permissible doses of ionizing radiation, the risks of prenatal irradiation are discussed. Experimental data mainly obtained with mice indicate that the most important risk exists during the period of organogenesis and concerns the induction of malformations. Although in man this period lies between about 10 and 80 days after fertilization for most organs, the main development of the brain occurs later, namely between the 8th and 15th week after conception. Data from Japanese victims of the atomic bomb explosions above Hiroshima and Nagasaki indicate that during development the brain is the most sensitive organ to irradiation and maximal sensitivity is found between the 8th and 15th week after fertilization. A dose of one Gray received during this period induces a severe mental retardation in about 45% of the newborns. The dose response relationship is not significantly different from a linear one without a threshold dose. Studies of intelligence and school performance have shown that 1 Gray received during the 8th-15th week causes a shift of the average intelligence of about 30 points. Irradiation before the 8th week and after the 25th week had no effect on intelligence or mental retardation. During the 16th and 25th week sensitivity was about one fourth of that during the 8th-15th week. Although the irradiation of the embryo and fetus should be avoided as much as possible, the new data have led to an abandonment of the so-called 10-day rule. Generally an accidental irradiation of the embryo or fetus of less than 5 cGy is not considered as a medical indication for abortion. Retrospective studies showed that mothers from children who died from leukemia or other childhood tumors, had been subjected to a diagnostic irradiation of the pelvis or lower abdomen more frequently than mothers from children that did not develop a tumor. It has been estimated that prenatal sensitivity for induction of leukemia and tumors is higher than sensitivity after birth. However, it is still in discussion, whether the relationship between prenatal irradiation and a higher incidence of tumors is of a causal nature.     

Bystander effects, adaptive response and genomic instability induced by prenatal irradiation

The developing human embryo and fetus undergo very radiosensitive stages during the prenatal development. It is likely that the induction of low dose related effects such as bystander effects, the adaptive response, and genomic instability would have profound effects on embryonic and fetal development. In this paper, I review what has been reported on the induction of these three phenomena in exposed embryos and fetuses. All three phenomena have been shown to occur in murine embryonic or fetal cells and structures, although the induction of an adaptive response (and also likely the induction of bystander effects) are limited in terms of when during development they can be induced and the dose or dose-rate used to treat animals in utero. In contrast, genomic instability can be induced throughout development, and the effects of radiation exposure on genome instability can be observed for long times after irradiation including through pre- and postnatal development and into the next generation of mice. There are clearly strain-specific differences in the induction of these phenomena and all three can lead to long-term detrimental effects. This is true for the adaptive response as well. While induction of an adaptive response can make fetuses more resistant to some gross developmental defects induced by a subsequent high dose challenge with ionizing radiation, the long-term effects of this low dose exposure are detrimental. The negative effects of all three phenomena reflect the complexity of fetal development, a process where even small changes in the timing of gene expression or suppression can have dramatic effects on the pattern of biological events and the subsequent development of the mammalian organism.     

Delayed effects of prenatal or postnatal exposure to diethylstilbestrol in the adult female guinea pig

Of 25 mature female guinea pigs exposed transplacentally to diethylstilbestrol (DES) for more than 20 days before term, 8 showed abnormal changes in the genital tract (stimulation of the epithelium and stroma, cystic glandular hyperplasia of the endometrial glands near the junction of the upper endocervix and endometrium) and 9 showed severe changes (cystic glandular hyperplasia of the endometrial glands throughout the corpus uteri and cornua, squamous metaplasia). Hyperkeratosis of the vulvar and nipple skin was also observed. No neoplastic changes were observed with one exception at 14 months in one ovary. Prenatal exposure to DES for less than 15 days before term or after birth for 3 days failed to result in abnormal changes in the adults. Prenatal exposure to estradiol for more than 20 days also was without effect in the adult, despite the higher tolerated doses given to the mothers. Cycling activity as judged by vaginal opening was abnormal in all experimental groups, suggesting a derangement of the pituitary-hypothalamic function not specifically related to DES exposure. It was concluded that there is a critical period of exposure of the Müllerian duct- and sinus-derived tissues with respect to the delayed effects of prenatal exposure to DES, which is estimated on the basis of embryological studies to range from the 28th to about the 45th day of gestation.     

Reproductive effects of prenatal exposure to nonylphenol on zebrafish (Danio rerio)

Mature female and male zebrafish were separated and exposed to nonylphenol (NP) at 0.1, 1, 10, 50, 100 and 500 microg/L, respectively, for 3 weeks. Gonadosomatic index (GSI) in both sexes and vitellogenin (VTG) induction in males was measured as the bioindicators for the impairment to the parents. The results indicated that 50 microg/L of NP was the non-observed effect concentration (NOEC) for GSI and VTG induction. Afterwards, the 50 microg/L NP exposed females and males, and the control females and males were cross-wise pair-bred in the control water for one week to examine the reproductive effects. The embryonic cathepsin D (CAT D) activity, eggshell thickness, fecundity, hatching rate and malformation (vertebral column flexure) rate of offspring were determined in the four pair-bred groups. While endpoints remained unchanged in the groups with exposed males, prenatal exposure of females to 50 microg/L of NP resulted in the impairment of reproduction in groups with exposed females including inhibition of CAT D activity (P < 0.05), decrease of eggshell thickness (by 23.6%) and elevation of malformation rate (P < 0.001). These results suggested NP could induce reproductive damage to zebrafish at NOEC for parents. The results also imply that alterations of CAT D activity and eggshell thickness may be more sensitive biomarkers to indicate the reproductive effects caused by endocrine disrupting chemicals.     

The effects of prenatal X irradiation on the appearance of reflexes and physiologic markers in the neonatal rat

Seventy pregnant adult Wistar strain rats were randomly assigned to 1 of 12 exposure groups; 9th or 17th day irradiation at the 0-, 0.1-, 0.2-, 0.4-, 0.6-, or 0.8-Gy dosage level. On the first day of postnatal life, litters were reduced to a maximum of eight pups per litter. A total of 508 pups were observed for the age of acquisition of five reflexes (air righting, surface righting, visual placing, negative geotaxis, auditory startle) and the appearance of four physiologic markers (pinna detachment, eye opening, vaginal opening, testes descent). A dose-response relationship for alterations in reflex acquisition and physiologic marker appearance was observed due to exposure above 0.2 Gy on the 17th day of gestation. Therefore, 0.2 to 0.4-Gy exposure may represent a threshold range for exposure on the 17th day using these postnatal parameters.     

猪PRDX6基因编码区的多态性及遗传效应分析

PRDX6基因属于抗氧化蛋白超家族,主要在应答氧化压力、脂分解代谢、磷脂分解代谢中发挥作用。根据PRDX6基因的生理生化功能,文章选择其为影响猪肉质性状的候选基因,探索PRDX6基因的多态性与猪肉质性状的关系。首先分离了猪PRDX6的部分编码区序列,并在不同猪种间进行序列比对,发现编码区第4外显子有2个潜在的SNPs分别位于第417 bp处(C/T突变)和第423 bp处(A/G突变),但均没有引起氨基酸的改变。采用Pyrosequencing焦磷酸测序方法对这两个位点在6个猪种和247头F2"大白×梅山"资源家系中进行了遗传变异分析和性状关联分析。结果表明:417C/T位点国外品种均以C等位基因为主,而国内品种均以T等位基因为主,该位点与肌内脂肪、肌肉水分存在显著关联(P<0.05);423A/G位点国外品种均以A等位基因为主,国内品种以G等位基因为主,该位点与失水率、系水力、肌内脂肪及肌肉水分存在显著关联(P<0.05)。由此推断:这两个位点很可能是影响猪肉质性状(尤其是肌肉嫩度)的分子标记。     

Reproductive compensation and human genetic disease

The effects of reproductive compensation on the population genetics of sex-linked recessive lethal mutations are investigated. Simple equations are presented which describe these effects, and so complement existing population genetic theory. More importantly, this type of mutation is responsible for several severe human genetic diseases such as Duchenne muscular dystrophy. It is argued that the applications of three modern reproductive technologies--effective family planning, in utero diagnosis with termination, and embryo sexing--will lead to reproductive compensation. The adoption of any of these technologies may rapidly elevate the frequencies of those mutations which are lethal in childhood. This increase is large, in the order of 33% upwards, and occurs rapidly over two to five generations. It also depends on the source of mutations, the effect being larger if most mutations are paternal. In utero diagnosis and/or embryo sexing increase the frequency of the mutation, but simultaneously decrease disease incidence by preventing the birth of affected offspring. In contrast, effective family planning may rapidly increase both mutation frequency and disease incidence.     

Oogenesis in pig ovaries during the prenatal period: ultrastructure and morphometry

Oogenesis in fetal pig ovaries comprises the successive changes from the primordial germ cells to the dictyotene oocytes in primordial ovarian follicles. In this study the observations were carried out with an electron microscope and stereological analysis was performed. At the ultrastructural level there are no differences between the primordial germ cells and oogonia, but oogonia are connected with the intercellular bridges. The onset of the dictyotene phase was accompanied by the changes in the cytoplasm of oocytes. Near the nucleus, the yolk nucleus is formed containing numerous Golgi bodies, endoplasmic reticulum (ER), mitochondria and granules. ER proliferates in contact with the external leaflet of the nuclear envelope forming the narrow ER cisterns. Between the nuclear envelope and ER cisterns, the vesicles with grey content are visible. The proliferating ER forms numerous concentric cisterns around the nucleus. Next, the most external cisterns fragment, detach, and then form the cup-like structures. These structures separate the distinct areas of cytoplasm-compartments, which contain mitochondria, ribosomes and lipid droplets. The cells of cortical sex cords of the ovary, which encloses the oocyte, form the follicles. The volume of oocytes in forming follicle increases due to the increase in the number of the cell inclusions: lipid droplets, vacuoles and yolk globules. In the oocytes of primordial ovarian follicles, the compartments are transformed into the yolk globules, which are encountered by a sheath of ER cisterns and the grey vesicles; they contain the mitochondria, lipid droplets and light vacuoles. The role of the compartments and yolk globules as metabolic units is discussed in comparison with similar structures of the mature eggs of pigs and other mammal species.     

Reproductive biology and genetic structure in Lloydia serotina

Concern regarding the conservation status of small, isolated populations of the arctic-alpine plant species Lloydia serotina prompted research to establish the status and performance of this species in Wales, in comparison with large populations in its more typical alpine habitat. Relationships between reproductive strategies and genetic variation were investigated in a number of populations, representing a wide habitat, geographic and population size range. In all populations, vegetative reproduction predominates over sexual reproduction, but seed produced is viable and germinates readily under controlled conditions. Smaller, peripheral populations produced fewer flowers and seeds than the larger ones, but all populations studied supported significant percentages (>30%) of male plants, due to either the occurrence of androdioecy in this species or to a resource limited breeding system. Analysis of allozyme variation in sixteen populations from North America, the European Alps and Wales showed lower levels of genetic variation in smaller populations which averaged 1.1–1.2 alleles per locus and 10–20% of loci polymorphic, whereas larger populations averaged 1.4 alleles per locus and 30–40% polymorphic loci. This applied especially to the most northerly and southerly populations in North America, suggesting the occurrence of genetic drift in these small, peripheral populations. F-statistics suggest relatively high levels of differentiation among smaller populations, even among those closely related geographically, but genetic variation has been retained in all but one population, possibly due to infrequent sexual reproduction by long lived clones. RAPD analysis of four small populations in Wales provided further evidence of clonal growth and possible inbreeding dominating a mixed mating reproductive system with consequent genetic structuring in these populations.     

The genetic effects induced by an irradiation in low doses at Drosophila melanogaster

This article generalizes the results received by authors in researches of genetic effects of an irradiation for Drosophila. It is supposed, that the main effect of low intensity irradiation is connected with the induced genetic instability on which background the realization of effects of a different direction is possible.     

Adrenergic modulation of cardiac development in the rat: effects of prenatal exposure to propranolol via continuous maternal infusion

During early postnatal development, catecholamines are thought to modulate cardiac cell replication and differentiation, and to program future beta-adrenergic sensitivity. To determine if the sensitive period for these events extends to prenatal ages, pregnant rats were infused with propranolol continuously via osmotic minipumps from gestational day 7 through parturition and the offspring were examined for markers of cardiac cellular development (basal ornithine decarboxylase activity and levels of DNA and protein) and for reactivity to acute beta-adrenergic challenge (heart rate responses and stimulation of ornithine decarboxylase). During the propranolol infusion, fetal cardiac responses to terbutaline, a beta-adrenergic agonist, were completely blocked; after discontinuation of beta-blockade at birth, responses became normal and remained unaffected into young adulthood. Biochemical markers indicated a delay in cellular development caused by propranolol: basal ornithine decarboxylase activity was elevated in the fetus and DNA was subnormal for the first week after birth. Cardiac growth was maintained in the face of DNA deficits by cell enlargement (elevated protein/DNA) which persisted through weaning. By young adulthood, all markers were within normal limits. These data suggest that fetal catecholamines, acting on beta-receptors, do play an initial role in cardiac cellular development, but that the critical period for programming of beta-adrenergic responsiveness occurs later in maturation.