Mutations causing familial biparental hydatidiform mole implicate c6orf221 as a possible regulator of genomic imprinting in the human oocyte

Familial biparental hydatidiform mole (FBHM) is the only known pure maternal-effect recessive inherited disorder in humans. Affected women, although developmentally normal themselves, suffer repeated pregnancy loss because of the development of the conceptus into a complete hydatidiform mole in which extraembryonic trophoblastic tissue develops but the embryo itself suffers early demise. This developmental phenotype results from a genome-wide failure to correctly specify or maintain a maternal epigenotype at imprinted loci. Most cases of FBHM result from mutations of NLRP7, but genetic heterogeneity has been demonstrated. Here, we report biallelic mutations of C6orf221 in three families with FBHM. The previously described biological properties of their respective gene families suggest that NLRP7 and C6orf221 may interact as components of an oocyte complex that is directly or indirectly required for determination of epigenetic status on the oocyte genome.     

HLA and molar pregnancies (triploidies, hydatidiform moles and choriocarcinoma). Etiological and epidemiological study

Etiological and epidemiological studies of triploid and hydatidiform molar conceptuses were done using HLA polymorphism. The segregation of HLA markers allowed to know the etiology of 25 triploidies and 19 hydatidiform moles. Five other moles and a post molar choriocarcinoma were also studied by molecular hybridization. This confirms that triploidies in about 3/4 of the cases involved two sets of paternal chromosomes mainly by di-sperm. Hydatidiform moles from Algeria, France and Senegal were all of androgenic origin excepted for one case. DNA analysis of the choriocarcinoma demonstrated the presence of a paternal marker suggesting for this case a direct cellular lineage from the mole. Positive associations with HLA A 28 and B 7 were found which could be related to gametogenesis-fecundation dysfunction. A slight excess of antigens shared by parents of triploidies was shown. This was not observed for parents of hydatidiform moles but when they shared HLA antigens a preferential inheritance in the mole of the shared specificities was observed. This relative compatibility of the molar conceptus with the mother may be an element of the process that prevent its early rejection.     

Evolution of genomic imprinting with biparental care: implications for Prader-Willi and Angelman syndromes

The term “imprinted gene” refers to genes whose expression is conditioned by their parental origin. Among theories to unravel the evolution of genomic imprinting, the kinship theory prevails as the most widely accepted, because it sheds light on many aspects of the biology of imprinted genes. While most assumptions underlying this theory have not escaped scrutiny, one remains overlooked: mothers are the only source of parental investment in mammals. But, is it reasonable to assume that fathers'' contribution of resources is negligible? It is not in some key mammalian orders including humans. In this research, I generalize the kinship theory of genomic imprinting beyond maternal contribution only. In addition to deriving new conditions for the evolution of imprinting, I have found that the same gene may show the opposite pattern of expression when the investment of one parent relative to the investment of the other changes; the reversion, interestingly, does not require that fathers contribute more resources than mothers. This exciting outcome underscores the intimate connection between the kinship theory and the social structure of the organism considered. Finally, the insight gained from my model enabled me to explain the clinical phenotype of Prader-Willi syndrome. This syndrome is caused by the paternal inheritance of a deletion of the PWS/AS cluster of imprinted genes in human Chromosome 15. As such, children suffering from this syndrome exhibit a striking biphasic phenotype characterized by poor sucking and reduced weight before weaning but by voracious appetite and obesity after weaning. Interest in providing an evolutionary explanation to such phenotype is 2-fold. On the one hand, the kinship theory has been doubted as being able to explain the symptoms of patients with Prader-Willi. On the other hand, the post-weaning symptoms remain as one of the primary concern of pediatricians treating children with Prader-Willi. In this research, I reconcile the clinical phenotype of Prader-Willi syndrome with the kinship theory, contending that paternal investment relative to maternal investment increases after weaning. I also propose a genetic composition of the PWS/AS cluster, discuss the effects of new types of mutations, and contemplate the potential side effects of reactivating silent genes for medical purposes.     

Selfing for the design of genomic selection experiments in biparental plant populations

Self-fertilization (selfing) is commonly used for population development in plant breeding, and it is well established that selfing increases genetic variance between lines, thus increasing response to phenotypic selection. Furthermore, numerous studies have explored how selfing can be deployed to maximal benefit in the context of traditional plant breeding programs (Cornish in Heredity 65:201–211,1990a, Heredity 65:213–220,1990b; Liu et al. in Theor Appl Genet 109:370–376, 2004; Pooni and Jinks in Heredity 54:255–260, 1985). However, the impact of selfing on response to genomic selection has not been explored. In the current study we examined how selfing impacts the two key aspects of genomic selection—GEBV prediction (training) and selection response. We reach the following conclusions: (1) On average, selfing increases genomic selection gains by more than 70 %. (2) The gains in genomic selection response attributable to selfing hold over a wide range population sizes (100–500), heritabilities (0.2–0.8), and selection intensities (0.01–0.1). However, the benefits of selfing are dramatically reduced as the number of QTLs drops below 20. (3) The major cause of the improved response to genomic selection with selfing is through an increase in the occurrence of superior genotypes and not through improved GEBV predictions. While performance of the training population improves with selfing (especially with low heritability and small population sizes), the magnitude of these improvements is relatively small compared with improvements observed in the selection population. To illustrate the value of these insights, we propose a practical genomic selection scheme that substantially shortens the number of generations required to fully capture the benefits of selfing. Specifically, we provide simulation evidence that indicates the proposed scheme matches or exceeds the selection gains observed in advanced populations (i.e. F ₈ and doubled haploid) across a broad range of heritability and QTL models. Without sacrificing selection gains, we also predict that fully inbred candidates for potential commercialization can be identified as early as the F ₄ generation.     

A new case of familial hyperproinsulinemia

We reported a case with increased serum immunoreactive insulin (IRI) and C-peptide immunoreactivity (CPR). The molar ratio of IRI to CPR was also increased. The propositus was diabetic with background retinopathy and neuropathy. No antibody to insulin or insulin receptor was detected in his serum and his insulin resistance was not so remarkable. When the serum was fractionated by gel filtration, about 90% of total IRI was recovered in the fraction where biosynthetic human proinsulin was eluted. The major part of the CPR was also recovered in the same fraction as proinsulin-like material. His daughter, 28 years old, a non-obese female, also had high IRI, CPR and a high molar ratio of IRI to CPR. A gel filtration study demonstrated the same elution profile as the propositus. Tryptic digestion failed to convert the proinsulin-like material from the propositus to insulin in a sufficient quantity to convert human proinsulin to insulin. These data strongly suggest that this family is a new case of familial hyperproinsulinemia, and the defect resides in the proinsulin molecule, not in the converting enzymes.     

Variance of the parental genome contribution to inbred lines derived from biparental crosses

The expectation of the parental genome contribution to inbred lines derived from biparental crosses or backcrosses is well known, but no theoretical results exist for its variance. Our objective was to derive the variance of the parental genome contribution to inbred lines developed by the single-seed descent or double haploid method from biparental crosses or backcrosses. We derived formulas and tabulated results for the variance of the parental genome contribution depending on the chromosome lengths and the mating scheme used for inbred line development. A normal approximation of the probability distribution function of the parental genome contribution fitted well the exact distribution obtained from computer simulations. We determined upper and lower quantiles of the parental genome contribution for model genomes of sugar beet, maize, and wheat using normal approximations. These can be employed to detect essentially derived varieties in the context of plant variety protection. Furthermore, we outlined the application of our results to predict the response to selection. Our results on the variance of the parental genome contribution can assist breeders and geneticists in the design of experiments or breeding programs by assessing the variation around the mean parental genome contribution for alternative crossing schemes.     

Discovery and validation of genomic regions associated with resistance to maize lethal necrosis in four biparental populations

In sub-Saharan Africa, maize is the key determinant of food security for smallholder farmers. The sudden outbreak of maize lethal necrosis (MLN) disease is seriously threatening the maize production in the region. Understanding the genetic basis of MLN resistance is crucial. In this study, we used four biparental populations applied linkage mapping and joint linkage mapping approaches to identify and validate the MLN resistance-associated genomic regions. All populations were genotyped with low to high density markers and phenotyped in multiple environments against MLN under artificial inoculation. Phenotypic variation for MLN resistance was significant and heritability was moderate to high in all four populations for both early and late stages of disease infection. Linkage mapping revealed three major quantitative trait loci (QTL) on chromosomes 3, 6, and 9 that were consistently detected in at least two of the four populations. Phenotypic variance explained by a single QTL in each population ranged from 3.9% in population 1 to 43.8% in population 2. Joint linkage association mapping across three populations with three biometric models together revealed 16 and 10 main effect QTL for MLN-early and MLN-late, respectively. The QTL identified on chromosomes 3, 5, 6, and 9 were consistent with the QTL identified by linkage mapping. Ridge regression best linear unbiased prediction with five-fold cross-validation revealed high accuracy for prediction across populations for both MLN-early and MLN-late. Overall, the study discovered and validated the presence of major effect QTL on chromosomes 3, 6, and 9 which can be potential candidates for marker-assisted breeding to improve the MLN resistance.     

Marker-based prediction of the parental genome contribution to inbred lines derived from biparental crosses

Molecular markers can be employed to predict the parental genome contribution to inbred lines. The proportion alpha of alleles originating from parent P1 at markers polymorphic between the parental lines P1 and P2 is commonly used as a predictor for the genome contribution of parent P1 to an offspring line. Our objectives were to develop a new marker-based predictor xi for the parental genome contribution, which takes into account not only the alleles at marker loci but also their map distance, and to compare the prediction precision of xi with that of alternative methods. We derived formulas for xi for inbreds derived from biparental crosses (F1 and backcrosses) with the single-seed descent or double-haploid method and presented an extension xi* possessing statistical optimum properties. In a simulation study, alpha showed a systematic overestimation of large parental genome contribution that was not observed for xi. The mean squared prediction error of xi was at least 50% smaller than that of alpha for linkage maps with unequal distances between adjacent markers. A data set from a study on plant variety protection in maize was used to illustrate the application of xi. We conclude that xi provides substantially greater prediction precision than the commonly used predictor alpha in a broad range of applications in genetics and breeding.     

The metaconule: A morphologic and familial analysis of a molar cusp in humans

Incidence and size variability of the metaconule, an accessory maxillary molar cusp, is analyzed in a series of 1,217 living Melanesians. The range of morphologic variation is quantified on a six-grade ordinal scale developed to standardize observations. Total incidence of the metaconule decreases along a mesial-to-distal gradient, while mean size and size variability increase from M1 to M3. So, while the trait is less common on distal molars, it is on average larger. Estimation of the additive genetic component is 65% for the first molar but only 15% for the second. Trait incidence and heritability estimates are generally higher for females indicating the need for separate analysis by sex.     

The acrosome: comparative morphology and development, contribution of a human familial globozoospermia case report

Sperm acrosome is known to play a role in the fertilization of the majority of animal species studied. As a general rule, the acrosome appeared as soon as the fertilization occurred out of aquaeous phase. The biochemical content of acrosome as well as its release mode could suggest it is a simple lysosome. But this would by pass its important morphogenic role in spermiogenesis. Its development is strongly linked to the development of the microtubules manchette system.Molecular data of animal mutagenesis contribute to the understanding of acrosome biogenesis mechanisms. Globozoospermia is a rare but severe human teratozoospermia, characterized by ejaculates entirely consisting of round-headed spermatozoa that lack an acrosome. It originates from a disturbed acrosome biogenesis. Recently, the genetic study of a familial globozoospermia led to highlight a homozygote mutation of the gene SPATA16, linked to the globozoospermic phenotype. This study contributes to the understanding of the mechanisms implied in human acrosome formation.     

Cytology of recurrent ameloblastoma with malignant change. A case report

BACKGROUND: Ameloblastoma is a rare tumor of the jaw that arises from the odontogenic epithelium. Ameloblastomas have a propensity for local recurrence and, rarely, for metastasis. The term malignant ameloblastoma is reserved for those metastasizing tumors that retain the typical morphology of ameloblastoma. Fine needle aspiration (FNA) reports on ameloblastomas are scant, and those on malignant ameloblastomas are still more so. CASE: In a case of malignant ameloblastoma diagnosed by FNA cytology, the clinical presentation was that of a malignant neoplasm. FNA smears were highly cellular and showed isolated, scattered cells and small groups of basaloid cells and polygonal squamous epithelial cells. Stellate and spindle-shaped cells were also seen in the background. The cytologic diagnosis was subsequently confirmed on histopathology. CONCLUSION: The characteristic combination of cells in FNA smears facilitated the diagnosis of ameloblastoma. Since the biologic behavior of the tumor was that of a malignant neoplasm, the slides were reviewed. The cytologic smears did not exhibit sufficient features of malignancy to label the lesion malignant.     

Cyclopia associated with triploidy and hydatidiform mole: a case report.

A live 22-week-old cyclops fetus with a 69 XYY chromosome pattern and partial hydatidiform mole of the placenta is reported. Although cyclopia and chromosomal triploidy have certain features in common they appear to be two quite distinct entities. As no other 69 XYY fetus has survived to 22 weeks gestation and no other case of cyclopia has been reported with a triploid set of chromosomes, the assumption that the two conditions occurred coincidently in this fetus will have to await the accumulation of additional case reports.