Appearance Of Phenotype Research Articles

Cytoplasmic male sterility and prospects for its utilization in potato breeding, genetic studies and hybrid seed production

Increasing interest in cytoplasmic male sterility (CMS) and the search for pollen fertility restorer (Rf) genes in potato have arisen due to a new strategy in breeding of this important crop which is based on the development of heterotic hybrids produced by crossing of inbred diploid lines. The paper reviews the main results of the studies on the CMS-Rf genetic systems in different crop species, the modern methods and approaches of investigating the molecular mechanisms of CMS and pollen fertility restoration, and also the available published data on the status of these studies on potato. The nature of the chimeric mitochondrial genes associated with CMS is considered; the peculiarities of the structure and functions of pollen fertility restorer genes are discussed.Examples of CMS-Rf genetic systems in crop species including representatives of the Solanaceae family are presented. The main results of the research on the molecular mechanisms of CMS and fertility restoration obtained in the postgenomic era for various crop species using methods of transcriptomic and proteomic analyses are provided. As in many plant species, CMS in potato is of a hybrid origin. The results are presented of investigating the genetic control of male sterility in potato that have been carried out using conventional approaches (hybridological analysis) and that led to the formation of the concept of ‘genetic-cytoplasmic male sterility’ in some species of the Petota section of the Solanum genus. The characteristics of potato cytoplasmic types carrying male sterility factors are discussed. According to the modern classification of Hosaka and Sanetomo (2012) these types include T/beta, W/gamma, and D, each distinguished by the specific phenotypic appearance of male sterility traits and also by the frequency of their occurrence in the breeding gene pool and in various potato species. The results of the studies on developing DNA markers for identifying different cytoplasmic types in potato are presented.

Reverse geroscience: how does exposure to early diseases accelerate the age-related decline in health?

Aging is the major risk factor for both the development of chronic diseases and loss of functional capacity. Geroscience provides links among the biology of aging, the biology of disease, and the physiology of frailty, three fields where enormous progress has been made in the last few decades. While, previously, the focus was on the role of aging in susceptibility to disease and disability, the other side of this relationship, which is the contribution of disease to aging, has been less explored at the molecular/cellular level. Indeed, the role of childhood or early adulthood exposure to chronic disease and/or treatment on accelerating aging phenotypes is well known in epidemiology, but the biological basis is poorly understood. A recent summit co-organized by the National Institutes of Health GeroScience Interest Group and the New York Academy of Sciences explored these relationships, using three chronic diseases as examples: cancer, HIV/AIDS, and diabetes. The epidemiological literature clearly indicates that early exposure to any of these diseases and/or their treatments results in an acceleration of the appearance of aging phenotypes, including loss of functional capacity and accelerated appearance of clinical symptoms of aging-related diseases not obviously related to the earlier event. The discussions at the summit focused on the molecular and cellular relationships between each of these diseases and the recently defined molecular and cellular pillars of aging. Two major conclusions from the meeting include the desire to refine an operational definition of aging and to concomitantly develop biomarkers of aging, in order to move from chronological to physiological age. The discussion also opened a dialogue on the possibility of improving late-life outcomes in patients affected by chronic disease by including age-delaying modalities along with the standard care for the disease in question.

Is CYP2D6 phenotype predictable from CYP2D6 genotype?

Genetic polymorphism of cytochrome P450s results in clinically significant modifications in patients' drug metabolizing capacities. CYP2D6 has a crucial role in the elimination of several clinically important drugs (antiarrhythmics, beta-adrenergic blockers, psychopharmacons and analgesics); however, the prediction of the phenotypic appearance of CYP2D6 is a challenge. Since single nucleotide polymorphisms and gene copy number variations (gene deletion and multiplication) frequently occur in CYP2D6 gene, CYP2D6 activity particularly depends on the genetic factors.Microsomal CYP2D6 activities (dextromethorphan O-demethylation) and CYP2D6 genotypes for the most frequent allelic variants (CYP2D6*3, *4, *5, *6, *10, *41 and duplication) were determined in 128 human liver samples derived from Hungarian organ donors. Substantial inter-individual variations were observed in CYP2D6 metabolic activities that were successfully predicted from the CYP2D6 genotypes in 67% of the donors. The underestimation of CYP2D6 phenotypes in 12.5% of the donors was assumed to be originated from the overlapping ranges of CYP2D6 activity among similar diplotypes or from the presence of −1584C>G in the promoter region evoking increased transcription of the wild-type CYP2D6 allele. In an appreciable number of donors (20.3%), the genotype-based CYP2D6 phenotype prediction was overestimated because of the rare CYP2D6 allelic variants which were not included in our genotyping platform or some external factors that could alter CYP2D6 activity (medication with CYP2D6 substrate/inhibitor) and hepatic function (Augmentin therapy, chronic alcohol consumption).In conclusion, CYP2D6 genotyping for the most frequent allelic variants was able to reliably predict CYP2D6 phenotypes in most donors; however, the external factors modifying the phenotypic appearance of CYP2D6 had to be taken into account. Personalized medication strategy should include monitoring of CYP2D6 genotype in a more comprehensive manner and should take external factors into consideration for an appropriate prediction of CYP2D6 metabolizing capacity.

Sex-Biased Transcriptome of Schistosoma mansoni: Host-Parasite Interaction, Genetic Determinants and Epigenetic Regulators Are Associated with Sexual Differentiation.

BackgroundAmong more than 20,000 species of hermaphroditic trematodes, Schistosomatidae are unusual since they have evolved gonochorism. In schistosomes, sex is determined by a female heterogametic system, but phenotypic sexual dimorphism appears only after infection of the vertebrate definitive host. The completion of gonad maturation occurs even later, after pairing. To date, the molecular mechanisms that trigger the sexual differentiation in these species remain unknown, and in vivo studies on the developing schistosomulum stages are lacking. To study the molecular basis of sex determination and sexual differentiation in schistosomes, we investigated the whole transcriptome of the human parasite Schistosoma mansoni in a stage- and sex-comparative manner.Methodology/ Principal FindingsWe performed a RNA-seq on males and females for five developmental stages: cercariae larvae, three in vivo schistosomulum stages and adults. We detected 7,168 genes differentially expressed between sexes in at least one of the developmental stages, and 4,065 of them were functionally annotated. Transcriptome data were completed with H3K27me3 histone modification analysis using ChIP-Seq before (in cercariae) and after (in adults) the phenotypic sexual dimorphism appearance. In this paper we present (i) candidate determinants of the sexual differentiation, (ii) sex-biased players of the interaction with the vertebrate host, and (iii) different dynamic of the H3K27me3 histone mark between sexes as an illustration of sex-biased epigenetic landscapes.Conclusions/ SignificanceOur work presents evidence that sexual differentiation in S. mansoni is accompanied by distinct male and female transcriptional landscapes of known players of the host-parasite crosstalk, genetic determinants and epigenetic regulators. Our results suggest that such combination could lead to the optimized sexual dimorphism of this parasitic species. As S. mansoni is pathogenic for humans, this study represents a promising source of therapeutic targets, providing not only data on the parasite development in interaction with its vertebrate host, but also new insights on its reproductive function.

Developmental changes in electrophysiological characteristics of human-induced pluripotent stem cell–derived cardiomyocytes

Previous studies proposed that throughout differentiation of human induced Pluripotent Stem Cell-derived cardiomyocytes (iPSC-CMs), only 3 types of action potentials (APs) exist: nodal-, atrial-, and ventricular-like. To investigate whether there are precisely 3 phenotypes or a continuum exists among them, we tested 2 hypotheses: (1) During culture development a cardiac precursor cell is present that-depending on age-can evolve into the 3 phenotypes. (2) The predominant pattern is early prevalence of a nodal phenotype, transient appearance of an atrial phenotype, evolution to a ventricular phenotype, and persistence of transitional phenotypes. To test these hypotheses, we (1) performed fluorescence-activated cell sorting analysis of nodal, atrial, and ventricular markers; (2) recorded APs from 280 7- to 95-day-old iPSC-CMs; and (3) analyzed AP characteristics. The major findings were as follows: (1) fluorescence-activated cell sorting analysis of 30- and 60-day-old cultures showed that an iPSC-CMs population shifts from the nodal to the atrial/ventricular phenotype while including significant transitional populations; (2) the AP population did not consist of 3 phenotypes; (3) culture aging was associated with a shift from nodal to ventricular dominance, with a transient (57-70 days) appearance of the atrial phenotype; and (4) beat rate variability was more prominent in nodal than in ventricular cardiomyocytes, while pacemaker current density increased in older cultures. From the onset of development in culture, the iPSC-CMs population includes nodal, atrial, and ventricular APs and a broad spectrum of transitional phenotypes. The most readily distinguishable phenotype is atrial, which appears only transiently yet dominates at 57-70 days of evolution.

A missense mutation in solute carrier family 12, member 1 (SLC12A1) causes hydrallantois in Japanese Black cattle.

BackgroundHydrallantois is the excessive accumulation of fluid within the allantoic cavity in pregnant animals and is associated with fetal mortality. Although the incidence of hydrallantois is very low in artificial insemination breeding programs in cattle, recently 38 cows with the phenotypic appearance of hydrallantois were reported in a local subpopulation of Japanese Black cattle. Of these, 33 were traced back to the same sire; however, both their parents were reported healthy, suggesting that hydrallantois is a recessive inherited disorder. To identify autozygous chromosome segments shared by individuals with hydrallantois and the causative mutation in Japanese Black cattle, we performed autozygosity mapping using single-nucleotide polymorphism (SNP) array and exome sequencing.ResultsShared haplotypes of the affected fetuses spanned 3.52 Mb on bovine chromosome 10. Exome sequencing identified a SNP (g.62382825G > A, p.Pro372Leu) in exon 10 of solute carrier family 12, member 1 (SLC12A1), the genotype of which was compatible with recessive inheritance. SLC12A1 serves as a reabsorption molecule of Na+-K+-2Cl− in the apical membrane of the thick ascending limb of the loop of Henle in the kidney. We observed that the concentration of Na+-Cl− increased in allantoic fluid of homozygous SLC12A1 (g.62382825G > A) in a hydrallantois individual. In addition, SLC12A1-positive signals were localized at the apical membrane in the kidneys of unaffected fetuses, whereas they were absent from the apical membrane in the kidneys of affected fetuses. These results suggested that p.Pro372Leu affects the membrane localization of SLC12A1, and in turn, may impair its transporter activity. Surveillance of the risk-allele frequency revealed that the carriers were restricted to the local subpopulation of Japanese Black cattle. Moreover, we identified a founder individual that carried the mutation (g.62382825G > A).ConclusionsIn this study, we mapped the shared haplotypes of affected fetuses using autozygosity mapping and identified a de novo mutation in the SLC12A1 gene that was associated with hydrallantois in Japanese Black cattle. In kidneys of hydrallantois-affected fetuses, the mutation in SLC12A1 impaired the apical membrane localization of SLC12A1 and reabsorption of Na+-K+-2Cl− in the thick ascending limb of the loop of Henle, leading to a defect in the concentration of urine via the countercurrent mechanism. Consequently, the affected fetuses exhibited polyuria that accumulated in the allantoic cavity. Surveillance of the risk-allele frequency indicated that carriers were not widespread throughout the Japanese Black cattle population. Moreover, we identified the founder individual, and thus could effectively manage the disorder in the population.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3035-1) contains supplementary material, which is available to authorized users.

Whole exome sequencing of Rett syndrome-like patients reveals the mutational diversity of the clinical phenotype.

Classical Rett syndrome (RTT) is a neurodevelopmental disorder where most of cases carry MECP2 mutations. Atypical RTT variants involve mutations in CDKL5 and FOXG1. However, a subset of RTT patients remains that do not carry any mutation in the described genes. Whole exome sequencing was carried out in a cohort of 21 female probands with clinical features overlapping with those of RTT, but without mutations in the customarily studied genes. Candidates were functionally validated by assessing the appearance of a neurological phenotype in Caenorhabditis elegans upon disruption of the corresponding ortholog gene. We detected pathogenic variants that accounted for the RTT-like phenotype in 14 (66.6 %) patients. Five patients were carriers of mutations in genes already known to be associated with other syndromic neurodevelopmental disorders. We determined that the other patients harbored mutations in genes that have not previously been linked to RTT or other neurodevelopmental syndromes, such as the ankyrin repeat containing protein ANKRD31 or the neuronal acetylcholine receptor subunit alpha-5 (CHRNA5). Furthermore, worm assays demonstrated that mutations in the studied candidate genes caused locomotion defects. Our findings indicate that mutations in a variety of genes contribute to the development of RTT-like phenotypes.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-016-1721-3) contains supplementary material, which is available to authorized users.

Domestication and tameness: brain gene expression in red junglefowl selected for less fear of humans suggests effects on reproduction and immunology.

The domestication of animals has generated a set of phenotypic modifications, affecting behaviour, appearance, physiology and reproduction, which are consistent across a range of species. We hypothesized that some of these phenotypes could have evolved because of genetic correlation to tameness, an essential trait for successful domestication. Starting from an outbred population of red junglefowl, ancestor of all domestic chickens, we selected birds for either high or low fear of humans for five generations. Birds from the fifth selected generation (S5) showed a divergent pattern of growth and reproduction, where low fear chickens grew larger and produced larger offspring. To examine underlying genetic mechanisms, we used microarrays to study gene expression in thalamus/hypothalamus, a brain region involved in fear and stress, in both the parental generation and the S5. While parents of the selection lines did not show any differentially expressed genes, there were a total of 33 genes with adjusted p-values below 0.1 in S5. These were mainly related to sperm-function, immunological functions, with only a few known to be relevant to behaviour. Hence, five generations of divergent selection for fear of humans produced changes in hypothalamic gene expression profiles related to pathways associated with male reproduction and to immunology. This may be linked to the effects seen on growth and size of offspring. These results support the hypothesis that domesticated phenotypes may evolve because of correlated effects related to reduced fear of humans.

Lamin Mutations Accelerate Aging via Defective Export of Mitochondrial mRNAs through Nuclear Envelope Budding

Defective RNA metabolism and transport are implicated in aging and degeneration [1, 2], but the underlying mechanisms remain poorly understood. A prevalent feature of aging is mitochondrial deterioration [3]. Here, we link a novel mechanism for RNA export through nuclear envelope (NE) budding [4, 5] that requires A-type lamin, an inner nuclear membrane-associated protein, to accelerated aging observed in Drosophila LaminC (LamC) mutations. These LamC mutations were modeled after A-lamin (LMNA) mutations causing progeroid syndromes (PSs) in humans. We identified mitochondrial assembly regulatory factor (Marf), a mitochondrial fusion factor (mitofusin), as well as other transcripts required for mitochondrial integrity and function, in a screen for RNAs that exit the nucleus through NE budding. PS-modeled LamC mutations induced premature aging in adult flight muscles, including decreased levels of specific mitochondrial protein transcripts (RNA) and progressive mitochondrial degradation. PS-modeled LamC mutations also induced the accelerated appearance of other phenotypes associated with aging, including a progressive accumulation of polyubiquitin aggregates [6, 7] and myofibril disorganization [8, 9]. Consistent with these observations, the mutants had progressive jumping and flight defects. Downregulating marf alone induced the above aging defects. Nevertheless, restoring marfwas insufficient for rescuing the aging phenotypes in PS-modeled LamC mutations, as other mitochondrial RNAs are affected by inhibition of NE budding. Analysis ofNE budding in dominant and recessive PS-modeled LamC mutations suggests a mechanism by which abnormal lamina organization prevents the egress of these RNAs via NE budding. These studies connect defects in RNA export through NE budding to progressive loss of mitochondrial integrity and premature aging.

A simple strategy guides the complex metabolic regulation in Escherichia coli.

A way to decipher the complexity of the cellular metabolism is to study the effect of different external perturbations. Through an analysis over a sufficiently large set of gene knockouts and growing conditions, one aims to find a unifying principle that governs the metabolic regulation. For instance, it is known that the cessation of the microorganism proliferation after a gene deletion is only transient. However, we do not know the guiding principle that determines the partial or complete recovery of the growth rate, the corresponding redistribution of the metabolic fluxes and the possible different phenotypes. In spite of this large variety in the observed metabolic adjustments, we show that responses of E. coli to several different perturbations can always be derived from a sequence of greedy and myopic resilencings. This simple mechanism provides a detailed explanation for the experimental dynamics both at cellular (proliferation rate) and molecular level (13C-determined fluxes), also in case of appearance of multiple phenotypes. As additional support, we identified an example of a simple network motif that is capable of implementing this myopic greediness in the regulation of the metabolism.

Growth hormone therapy for Prader-willi syndrome: challenges and solutions.

Prader–Willi syndrome (PWS) is characterized by a dysregulation of growth hormone (GH)/insulin-like growth factor I axis, as the consequence of a complex hypothalamic involvement. PWS’ clinical picture seems to resemble the classic non-PWS GH deficiency (GHD), including short stature, excessive body fat, decreased muscle mass, and impaired quality of life. GH therapy is able to ameliorate the phenotypic appearance of the syndrome, as well as to improve body composition, physical strength, and cognitive level. In this regard, however, some pathophysiologic and clinical questions still remain, representing a challenge to give the most appropriate care to PWS patients. Data about the prevalence of GHD in PWS children are not unequivocal, ranging from 40% to 100%. In this context, to establish whether the presence (or not) of GHD may have a different effect on clinical course during GH therapy may be helpful. In addition, the comparison of GH effects in PWS children diagnosed as small for gestational age with those obtained in subjects born appropriate for gestational age is of potential interest for future trials. Emerging information seems to demonstrate the maintenance of beneficial effects of GH therapy in PWS subjects after adolescent years. Thus, GH retesting after achievement of final height should be taken into consideration for all PWS patients. However, it is noteworthy that GH administration exerts positive effects both in PWS adults with and without GHD. Another critical issue is to clarify whether the genotype–phenotype correlations may be relevant to specific outcome measures related to GH therapy. Moreover, progress of our understanding of the role of GH replacement and concomitant therapies on bone characteristics of PWS is required. Finally, a long-term surveillance of benefits and risks of GH therapy is strongly recommended for PWS population, since most of the current studies are uncontrolled and of short duration.

A Markov random field image segmentation model for lizard spots

Animal identification as a method for fauna study and conservation can be implemented using phenotypic appearance features such as spots, stripes or morphology. This procedure has the advantage that it does not harm study subjects. The visual identification of the subjects must be performed by a trained professional, who may need to inspect hundreds or thousands of images, a time-consuming task. In this work, several classical segmentation and preprocessing techniques, such as threshold, adaptive threshold, histogram equalization, and saturation correction are analyzed. Instead of the classical segmentation approach, herein we propose a Markov random field segmentation model for spots, which we test under ideal, standard and challenging acquisition conditions. As study subject, the Diploglossus millepunctatus lizard is used. The proposed method achieved a maximum efficiency of 84.87%.

Laminin α5 in the keratinocyte basement membrane is required for epidermal–dermal intercommunication

Laminin α5 is broadly expressed in the epidermal basement membrane (BM) of mature mice and its elimination at this site (Lama5Ker5 mouse) results in hyperproliferation of basal keratinocytes and a delay in hair follicle development, which correlated with upregulation of the dermally-derived laminin α2 and laminin α4 chains in the epidermal BM and of tenascin-C subjacent to the BM. In vitro studies revealed laminin 511 to be strongly adhesive for primary keratinocytes and that loss of laminin α5 does not result in cell autonomous defects in proliferation. Flow cytometry reveals that the loss of laminin α5 resulted in increased numbers of CD45+, CD4+ and CD11b+ immune cells in the skin, which temporo-spatial analyses revealed were detectable only subsequent to the loss of laminin α5 and the appearance of the hyperproliferative keratinocyte phenotype. These findings indicate that immune cell changes are the consequence and not the cause of keratinocyte hyperproliferation. Loss of laminin α5 in the epidermal BM was also associated with changes in the expression of several dermally-derived growth factors involved in keratinocyte proliferation and hair follicle development in adult but not new born Lama5Ker5 skin, including KGF, EGF and KGF-2. In situ binding of FGF-receptor-2α (IIIb)-Fc chimera (FGFR2IIIb) to mouse skin sections revealed decoration of several BMs, including the epidermal BM, which was absent in Lama5Ker5 skin. This indicates reduced levels of FGFR2IIIb ligands, which include KGF and KGF-2, in the epidermal BM of adult Lama5Ker5 skin. Our data suggest an initial inhibitory effect of laminin α5 on basal keratinocyte proliferation and migration, which is exacerbated by subsequent changes in growth factor expression by epidermal and dermal cells, implicating laminin α5 in epidermal–dermal intercommunication.

Time Course of Molecular and Metabolic Events in the Development of Insulin Resistance in Fructose-Fed Rats.

We aimed to determine the time-course of metabolic changes related to the early onset of insulin resistance (IR), trying to evidence breaking points preceding the appearance of the clinical IR phenotype. The model chosen was the fructose (FRU)-fed rat compared to controls fed with starch. We focused on the hepatic metabolism after 0, 5, 12, 30, or 45 days of FRU intake. The hepatic molecular metabolic changes followed indeed a multistep trajectory rather than a continuous progression. After 5 d of FRU feeding, we observed deep modifications in the hepatic metabolism, driven by the induction of lipogenic genes and important glycogen depletion. Thereafter, a steady-state period between days 12 and 30 was observed, characterized by a switch from carbohydrate to lipid utilization at the hepatic level and increased insulin levels aiming at alleviating lipid accumulation and hyperglycemia, respectively. The FRU-fed animals were only clinically IR at day 45 (altered homeostasis model assessment-estimated insulin resistance and muscle glucose transport). Furthermore, the urine metabolome revealed even earlier metabolic trajectory changes that precede the hepatic alterations. We identified several candidate metabolites linked to the tryptophan-nicotinamide metabolism and the installation of fasting hyperglycemia that suggest a role of this metabolic pathway on the development of the IR phenotype in the FRU-fed rats.

Increased expression of the frontotemporal dementia risk factor TMEM106B causes C9orf72-dependent alterations in lysosomes.

Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is an important cause of dementia in individuals under age 65. Common variants in the TMEM106B gene were previously discovered by genome-wide association to confer genetic risk for FTLD-TDP (p = 1 × 10-11, OR = 1.6). Furthermore, TMEM106B may act as a genetic modifier affecting age at onset and age at death in the Mendelian subgoup of FTLD-TDP due to expansions of the C9orf72 gene. Evidence suggests that TMEM106B variants increase risk for developing FTLD-TDP by increasing expression of Transmembrane Protein 106B (TMEM106B), a lysosomal protein. To further understand the functional role of TMEM106B in disease pathogenesis, we investigated the cell biological effects of increased TMEM106B expression. Here, we report that increased TMEM106B expression results in the appearance of a vacuolar phenotype in multiple cell types, including neurons. Concomitant with the development of this vacuolar phenotype, cells over-expressing TMEM106B exhibit impaired lysosomal acidification and degradative function, as well as increased cytotoxicity. We further identify a potential lysosomal sorting motif for TMEM106B and demonstrate that abrogation of sorting to lysosomes rescues TMEM106B-induced defects. Finally, we show that TMEM106B-induced defects are dependent on the presence of C9orf72, as knockdown of C9orf72 also rescues these defects. In sum, our results suggest that TMEM106B exerts its effects on FTLD-TDP disease risk through alterations in lysosomal pathways. Furthermore, TMEM106B and C9orf72 may interact in FTLD-TDP pathophysiology.

Corticosterone may interact with peripubertal development to shape adult resistance to social defeat

Studies of social stress in adult mice have revealed two distinct defeat-responsive behavioral phenotypes; “susceptible” and “resistant,” characterized by social avoidance and social interaction, respectively. Typically, these phenotypes are observed at least 1day after the last defeat in adults, but may extend up to 30days later. The current study examined the impact of peripubertal social defeat on immediate (1day) and adult (30day) social stress phenotypes and neuroendocrine function in male C57BL/6 mice. Initially, peripubertal (P32) mice were resistant to social defeat. When the same mice were tested for social interaction again as adults (P62), two phenotypes emerged; a group of mice were characterized as susceptible evidenced by significantly lower social interaction, whereas the remaining mice exhibited normal social interaction, characteristic of resistance. A repeated analysis of corticosterone revealed that the adult (P62) resistant mice had elevated corticosterone following the social interaction test as juveniles. This was when all mice, regardless of adult phenotype, displayed equivalent levels of social interaction. Peripubertal corticosterone was positively correlated with adult social interaction levels in defeated mice, suggesting early life stress responsiveness impacts adult social behavior. In addition, adult corticotropin-releasing factor (CRF) mRNA in the paraventricular nucleus of the hypothalamus (PVN) was elevated in all defeated mice, but there were no differences in CRF mRNA expression between the phenotypes. Thus, there is a delayed appearance of social stress-responsive phenotypes suggesting that early life stress exposure, combined with the resultant physiological responses, may interact with pubertal development to influence adult social behavior.

Two novel mutations in RNU4ATAC in two siblings with an atypical mild phenotype of microcephalic osteodysplastic primordial dwarfism type 1

Taybi–Linder syndrome or microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1) (MIM # 210710) is a rare autosomal recessive developmental disorder, originally described in 1967 (Taybi and Linder, 1967). The patients present with severe intrauterine and postnatal growth retardation, microcephaly, facial dysmorphism, sparse thin hair and dry skin (Meinecke and Passarge, 1991). Radiological findings include dysplasia of the skeleton with cleft vertebral arches, horizontal acetabula and short and bowed long bones (Sigaudy et al., 1998). Neurological findings typically include profound developmental delay, blindness, hearing deficits, central nervous system malformations, early-onset epilepsy and neuroendocrine dysfunction (Pierce and Morse, 2012). MOPD1 has been shown to result from biallelic mutations in the RNU4ATAC gene encoding the small nuclear RNA (snRNA) U4atac, which is a component of the minor spliceosome. Although accounting for splicing of only about 800 introns, the minor spliceosome is involved in the correct splicing of many essential gene products. Thus, minor intron splicing has a critical role in human development (He et al., 2011). At present, only around 40 patients with MOPD1 and 10 different RNU4ATAC mutations have been reported according to the Human Gene Mutation Database. The condition is usually severe, and the patients do not generally live beyond the age of 3 years (Meinecke and Passarge, 1991). A few cases with a slightly milder phenotype have been reported (Abdel-Salam et al., 2012; Nagy et al., 2012), but no patients have yet been reported to survive into adulthood. We report on two adult siblings with MOPD1 presenting with an atypical mild phenotypic appearance compared with the previously reported cases.

Simultaneous age-dependent and age-independent sexual selection in the lekking black grouse (Lyrurus tetrix).

Individuals' reproductive success is often strongly associated with their age, with typical patterns of early-life reproductive improvement and late-life senescence. These age-related patterns are due to the inherent trade-offs between life-history traits competing for a limited amount of resources available to the organisms. In males, such trade-offs are exacerbated by the resource requirements associated with the expression of costly sexual traits, leading to dynamic changes in trait expression throughout their life span. Due to the age dependency of male phenotypes, the relationship between the expression of male traits and mating success can also vary with male age. Hence, using longitudinal data in a lekking species with strong sexual selection - the black grouse Lyrurus tetrix - we quantified the effects of age, life span and age of first lek attendance (AFL) on male annual mating success (AMS) to separate the effects of within-individual improvement and senescence on AMS from selective (dis)appearance of certain phenotypes. Then, we used male AMS to quantify univariate and multivariate sexual selection gradients on male morphological and behavioural traits with and without accounting for age and age-related effects of other traits. Male AMS increased with age, and there was no significant reproductive senescence. Most males never copulated, and of the ones that did, the majority had only one successful year. Life span was unrelated to AMS, but early AFL tended to lead to higher AMS at ages 1-3. AMS was related to most morphological and behavioural traits when male age was ignored. Accounting for age and age-specific trait effects (i.e. the interaction between a trait and age) reduced the magnitude of the selection gradients and revealed that behavioural traits are under consistent sexual selection, while sexual selection on morphological traits is stronger in old males. Therefore, sexual selection in black grouse operates primarily on male behaviour and morphological traits may act as additional cues to supplement female choice. These results demonstrate the multifaceted influence of age on both fitness and sexual traits and highlight the importance of accounting for such effects when quantifying sexual selection.

Scaffold-free Tissue Formation Under Real and Simulated Microgravity Conditions.

Scaffold-free tissue formation in microgravity is a new method in regenerative medicine and an important topic in Space Medicine. In this MiniReview, we focus on recent findings in the field of tissue engineering that were observed by exposing cells to real microgravity in space or to devices simulating to at least some extent microgravity conditions on Earth (ground-based facilities). Under both conditions - real and simulated microgravity - a part of the cultured cells of various populations detaches from the bottom of a culture flask. The cells form three-dimensional (3D) aggregates resembling the organs from which the cells have been derived. As spaceflights are rare and extremely expensive, cell culture under simulated microgravity allows more comprehensive and frequent studies on the scaffold-free 3D tissue formation in some aspects, as a number of publications have proven during the last two decades. In this MiniReview, we summarize data from our own studies and work from various researchers about tissue engineering of multi-cellular spheroids formed by cancer cells, tube formation by endothelial cells and cartilage formation by exposing the cells to ground-based facilities such as the 3D Random Positioning Machine (RPM), the 2D Fast-Rotating Clinostat (FRC) or the Rotating Wall Vessel (RWV). Subsequently, we investigated self-organization of 3D aggregates without scaffolds pursuing to enhance the frequency of 3D formation and to enlarge the size of the organ-like aggregates. The density of the monolayer exposed to real or simulated microgravity as well as the composition of the culture media revealed an impact on the results. Genomic and proteomic alterations were induced by simulated microgravity. Under microgravity conditions, adherent cells expressed other genes than cells grown in spheroids. In this MiniReview, the recent improvements in scaffold-free tissue formation are summarized and relationships between phenotypic and molecular appearance are highlighted.

Stable partial migration under a genetic threshold model of migratory behaviour

Many species show migratory behaviour in response to seasonal changes in environmental conditions. A peculiar, yet widespread phenomenon is partial migration, when a single population consists of both migratory and non‐migratory individuals. There are still many open questions regarding the stability and evolutionary significance of such populations. For passerines the inheritance of migratory activity is best described by the threshold model of quantitative genetics. Such a model has not yet been employed in theoretical studies, in which stability of partially migratory populations is usually linked to group differences in survival or reproduction. Here we develop a parsimonious model featuring a conditional genetic threshold for passerine migratory behaviour under which stable partial migration can be observed, and we explore the resulting selection landscape. Our model results show a cline in migratory behaviour across the landscape, from fully migratory populations to fully residential populations, with a fairly wide zone of partially migratory populations, which is stable in both time and space under a wide range of parameter settings. Temporal stability of the zone is linked with the yearly variance in both migration survival and resident winter survival. In contrast to other theoretical studies, we show that density dependence in winter survival is not essential for observing partially migratory populations. In addition, we observe that selection on the genetic threshold value occurs mainly at the borders of the zone of partial migration. This result suggests that fully migratory and fully residential populations in areas far from the zone of partial migration can harbour genetic diversity that allows the appearance of the alternative phenotype under (a wide range of) different conditions.