Maternal Genes and Facial Clefts in Offspring: A Comprehensive Search for Genetic Associations in Two Population-Based Cleft Studies from Scandinavia

Background

Fetal conditions can in principle be affected by the mother''s genotype working through the prenatal environment.

Methodology/Principal Findings

Genotypes for 1536 SNPs in 357 cleft candidate genes were available from a previous analysis in which we focused on fetal gene effects [1]. After data-cleaning, genotypes for 1315 SNPs in 334 autosomal genes were available for the current analysis of maternal gene effects. Two complementary statistical methods, TRIMM and HAPLIN, were used to detect multi-marker effects in population-based samples from Norway (562 case-parent and 592 control-parent triads) and Denmark (235 case-parent triads). We analyzed isolated cleft lip with or without cleft palate (iCL/P) and isolated cleft palate only (iCP) separately and assessed replication by looking for genes detected in both populations by both methods. In iCL/P, neither TRIMM nor HAPLIN detected more genes than expected by chance alone; furthermore, the selected genes were not replicated across the two methods. In iCP, however, FLNB was identified by both methods in both populations. Although HIC1 and ZNF189 did not fully satisfy our stringency criterion for replication, they were strongly associated with iCP in TRIMM analyses of the Norwegian triads.

Conclusion/Significance

Except for FLNB, HIC1 and ZNF189, maternal genes did not appear to influence the risk of clefting in our data. This is consistent with recent epidemiological findings showing no apparent difference between mother-to-offspring and father-to-offspring recurrence of clefts in these two populations. It is likely that fetal genes make the major genetic contribution to clefting risk in these populations, but we cannot rule out the possibility that maternal genes can affect risk through interactions with specific teratogens or fetal genes.     

Light screening in lichen cortices can be quantified by chlorophyll fluorescence techniques for both reflecting and absorbing pigments

Lichens, representing mutualistic symbioses between photobionts and mycobionts, often accumulate high concentrations of secondary compounds synthesized by the fungal partner. Light screening is one function for cortical compounds being deposited as crystals outside fungal hyphae. These compounds can non-destructively be extracted by 100% acetone from air-dry living thalli. Extraction of atranorin from Physcia aipolia changed the lichen colour from pale grey to green in the hydrated state, whereas acetone-rinsed and control thalli were all pale grey when dry. Removal of parietin from Xanthoria parietina changed the colour of desiccated thalli from orange to grey. Colour changes were quantified by reflectance measurements. By a new chlorophyll fluorescence method, screening was assessed as the decrease in incident irradiance (PAR) necessary to reach identical effective quantum yields of PSII (Φ_PSII) in acetone-rinsed and control thalli. Thereby, we estimated a screening efficiency due to cortical atranorin crystals at 61, 38, and 40% of blue, green and red light, respectively, whereas parietin screened 81, 27 and 1% of these wavelength ranges. Removal of atranorin caused similar levels of increased photoinhibition for P. aipolia in blue, green and red light, whereas parietin-deficient thalli of X. parietina exhibited increased photoinhibition with decreasing wavelengths. Atranorin possibly prevents water from entering the spaces between the hyphae in the cortex. The air-filled cavities with white atranorin crystals reflect excess light, whereas the yellow compound parietin absorbs excess light. Thereby, both atranorin and parietin play significant photoprotective roles for symbiotic green algae, but with compound-specific screening mechanisms.     

Kinetics of n-3 fatty acids in Brachionus plicatilis and changes in the food supply

Moderately starved rotifers exhibited a two-phased increase in n-3 fatty acids when they were fed a diet rich in these fatty acids. The first 20–30 min of enrichment, the increase in n-3 fatty acids was primarily due to increased gut content. The subsequent slow increase was due to an incorporation of n-3 fatty acids into rotifers tissues. Saturation was achieved before 24 h of exposure and the saturation level was independent of the initial content of n-3 fatty acids in the rotifers.Starvation and limited feeding of the enriched rotifers for additional 4–8 h at 10–20 °C did not affect the accumulated fatty acids significantly. This was found for rotifers with high and low initial content of n-3 fatty acids. The n-3 fatty acids were assimilated with high efficiency from the feed and were not metabolized faster than other groups of fatty acids.Enriched rotifers retained their nutritional value for a sufficient period after enrichment to serve well as live feed for marine fish larvae.     

Effect of three-dimensional culture and incubator gas concentration on phenotype and differentiation capability of human mesenchymal stem cells

To obtain sufficient numbers of cells for tissue engineering applications, human bone marrow-derived mesenchymal stem cells (hBM-MSC) are commonly cultured as monolayers in incubators containing room air. In this study, we investigated whether three-dimensional (3D) culture conditions and incubator gas concentrations more similar to those observed in vivo impacted on cell expansion, differentiation capability, or phenotype of hBM-MSC. We found that 3D culture alone increased the expression of some molecules involved in osteogenic and adipogenic differentiation. In contrast, 3D culture did not induce chondrogenic differentiation, but enhanced the response to the chondrogenic differentiation medium. Changing the oxygen concentration to 6% and the carbon dioxide concentration to 7.5% did not impact on the results of any of our assays, showing that the hyperoxia of room air is not detrimental to hBM-MSC proliferation, differentiation, or phenotype.     

Changes in pools of depsidones and melanins, and their function, during growth and acclimation under contrasting natural light in the lichen Lobaria pulmonaria

This study analysed relationships between secondary chemistry, lichen growth rates and external habitat factors for two groups of UV-B-absorbing secondary compounds in the lichen Lobaria pulmonaria in order to test some hypotheses on their formation and function. Medullary depsidones and cortical melanins were quantified in thalli transplanted to three successional forest stands (shaded young forest, open old forest, sun-exposed clear-cut area) and subjected to different watering regimes (spraying with water, water + nitrogen, no spraying). Growth rates were already known. The total concentration of all seven depsidones was constant across the entire range of growth rates and sun exposures, showing that these depsidones serve functions other than photoprotection. Thalli from the well-lit transplantation sites had the highest synthesis of melanins. Within each forest type there was a trade-off between growth and melanin synthesis. Melanins and photosynthetic acclimation enhanced survival on a subsequent exposure to high light intensity, despite excessive temperatures resulting from higher absorption of solar energy in melanic thalli relative to pale thalli. In conclusion, the highly responsive melanic pigments play a photoprotective role in light acclimation, whereas the constant amount of depsidones across a wide spectrum of growth ranges and irradiances is consistent with herbivore defence functions.     

Homocarnosinosis: Influence of dietary restriction of histidine

Homocarnosinosis, an inherited disorder, is characterized by an elevated level of the dipeptide homocarnosine (Hca) in the CSF and the brain and, in addition, by carnosinuria and serum carnosinase deficiency. In three children with homocarnosinosis the biochemical abberation co-exists with paraplegia, retinitis pigmentosa, and a progressive mental deficiency. In the mother, however, only the biochemical abberation was present without clinical symptoms. In order to study whether this elevated level of Hca and increased excretion of carnosine (Car) could be reduced towards normal, a dietary regimen with restriction of histidine (His) was maintained for nearly 2 1/2 years for two of the patients, 33 and 39 years old, with homocarnosinosis associated with neurological symptoms. His was reduced by about 90% in the CSF, in the plasma and in the urine. Within 5–6 months CSF Hca was reduced by about 70%, and urinary Car by 22 and 42%. The clinical neurological symptoms, however, did not alter significantly together with these biochemical changes.     

The significance of thallus size for the water economy of the cyanobacterial old-forest lichen Degelia plumbea

Rosette-formed, circular thalli of Degelia plumbea were studied in the laboratory. Regardless of thallus size, the optimal quantum yield of photosystem II (F _V/F _M) remained at a high, constant level during a drying cycle starting with fully hydrated thalli until the thallus water content reached about 200%. Net photosynthesis reached a maximum level at this hydration level. Thereafter, both F _V/F _M and net photosynthesis fell rapidly to zero at a water content of somewhat less than 100%. There was a highly significant, positive relationship between thallus size and the water-holding capacity, as well as a strong, negative correlation between size and water loss per thallus area. Consequently, an increase in thallus size from 1 to 36 cm² lead to a tenfold prolongation of the photosynthetically active period during a drying cycle at a low radiation regime. The improved water-holding capacity in larger thalli is mainly a result of a thicker hypothallus. The fast desiccation of small thalli suggests that the regeneration of D. plumbea could be severely hampered by nearby logging that raises the evaporative demand by increasing radiation loads and wind exposure at remaining lichen sites. Received: 12 December 1997 / Accepted: 20 March 1998     

Biometrical modeling of twin and family data using standard mixed model software

Summary .   Biometrical genetic modeling of twin or other family data can be used to decompose the variance of an observed response or 'phenotype' into genetic and environmental components. Convenient parameterizations requiring few random effects are proposed, which allow such models to be estimated using widely available software for linear mixed models (continuous phenotypes) or generalized linear mixed models (categorical phenotypes). We illustrate the proposed approach by modeling family data on the continuous phenotype birth weight and twin data on the dichotomous phenotype depression. The example data sets and commands for Stata and R/S-PLUS are available at the Biometrics website.     

X-Chromosomal Maternal and Fetal SNPs and the Risk of Spontaneous Preterm Delivery in a Danish/Norwegian Genome-Wide Association Study

Background

Recent epidemiological studies suggest that the maternal genome is an important contributor to spontaneous preterm delivery (PTD). There is also a significant excess of males among preterm born infants, which may imply an X-linked mode of inheritance for a subset of cases. To explore this, we examined the effect of maternal and fetal X-chromosomal single nucleotide polymorphisms (SNPs) on the risk of PTD in two independent genome-wide association studies and one replication study.

Methods

Participants were recruited from the Danish National Birth Cohort and the Norwegian Mother and Child cohort studies. Data from these two populations were first analyzed independently, and then combined in a meta-analysis. Overall, we evaluated 12,211 SNPs in 1,535 case-mother dyads and 1,487 control-mother dyads. Analyses were done using a hybrid design that combines case-mother dyads and control-mother dyads, as implemented in the Haplin statistical software package. A sex-stratified analysis was performed for the fetal SNPs. In the replication study, 10 maternal and 16 fetal SNPs were analyzed using case-parent triads from independent studies of PTD in the United States, Argentina and Denmark.

Results

In the meta-analysis, the G allele at the maternal SNP rs2747022 in the FERM domain containing 7 gene (FRMD7) increased the risk of spontaneous PTD by 1.2 (95% confidence interval (CI): 1.1, 1.4). Although an association with this SNP was confirmed in the replication study, it was no longer statistically significant after a Bonferroni correction for multiple testing.

Conclusion

We did not find strong evidence in our data to implicate X-chromosomal SNPs in the etiology of spontaneous PTD. Although non-significant after correction for multiple testing, the mother’s G allele at rs2747022 in FRMD7 increased the risk of spontaneous PTD across all populations in this study, thus warranting further investigation in other populations.