genetic contribution
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AbstractPsychiatric disorders are highly prevalent and display considerable clinical and genetic overlap. Dopaminergic and serotonergic neurotransmission have been shown to play an important role in many psychiatric disorders. Here we aim to assess the genetic contribution of these systems to eight psychiatric disorders (attention-deficit hyperactivity disorder (ADHD), anorexia nervosa (ANO), autism spectrum disorder (ASD), bipolar disorder (BIP), major depression (MD), obsessive-compulsive disorder (OCD), schizophrenia (SCZ) and Tourette’s syndrome (TS)) using publicly available GWAS analyses performed by the Psychiatric Genomics Consortium that include more than 160,000 cases and 275,000 controls. To do so, we elaborated four different gene sets: two ‘wide’ selections for dopamine (DA) and for serotonin (SERT) using the Gene Ontology and KEGG pathways tools, and two’core’ selections for the same systems, manually curated. At the gene level, we found 67 genes from the DA and/or SERT gene sets significantly associated with one of the studied disorders, and 12 of them were associated with two different disorders. Gene-set analysis revealed significant associations for ADHD and ASD with the wide DA gene set, for BIP with the wide SERT gene set, and for MD with the core SERT set. Interestingly, interrogation of a cross-disorder GWAS meta-analysis of the eight psychiatric conditions displayed association with the wide DA gene set. To our knowledge, this is the first systematic examination of genes encoding proteins essential to the function of these two neurotransmitter systems in these disorders. Our results support a pleiotropic contribution of the dopaminergic and serotonergic systems in several psychiatric conditions.

Abstract Background: Various external and internal factors affect the gut microbiota of animals. The colonization and proliferation of gut microbes have been studied in a diverse array of animal taxa but remain poorly known in snakes. Here, we used the 16S rRNA gene sequencing technology on the Roach 454 platform to analyze the gut microbiota composition using fecal samples collected from three snake groups [gravid females, newly hatched (preprandial) hatchlings and postprandial hatchlings] of two congeneric colubrid snake species (Elaphe carinata and E. taeniura) that are sympatric across a wide range in mainland China. We tested two hypotheses. First, the gut microbiota should not differ between the two species at hatching if the maternal or genetic contribution has no role in affecting post-hatching gut microbial colonization. Second, differences in the gut microbiota between newly hatched (preprandial) and postprandial hatchlings should not exist in both species if the dietary contribution has no role in affecting post-hatching gut microbial colonization.Results: The top three dominant phyla were Firmicutes, Bacteroidetes, and Proteobacteria in both species. None of the measured alpha diversity indexes differed among the three snake groups or between the two species. The relative abundance of the gut microbiota differed among the three snake groups and between the two species, and so did the relative abundances of the functions associated with the metabolism, cellular processes and environmental information processing. Evidence from gravid females and hatchlings showed that the gut microbiota composition was similar between the two species. The metabolism held the overwhelming predominance of functional categories at the top level in both species.Conclusion: Only the relative abundance of the gut microbiota differed between the two species, and the gut microbiota composition changed rapidly in postprandial hatchlings and differed among the three snakes groups in both species. From these findings, we may conclude that the dietary rather than the maternal or genetic contribution affects gut microbial colonization in snakes.

This study aimed to evaluate population parameters, genetic diversity and identify the ancestors with the highest genetic contribution of an open population of Silla Argentino horses in Colombia using pedigree data. 508 horses born between 1998 and 2018 were evaluated, called reference population (RP). The ancestors of the RP were added, defining the total population (TP) whit 1,861 horses born since 1905. Population parameters were estimated, including inbreeding coefficient (F), effective population size (Ne), effective number of founders (fe), ancestors (fa), and founder genomes (fg) and generation interval (GIN). The GIN was 10.1 (TP) and 7.7 (RP) years. The estimate of F for the RP was 0.3%, indicating control in mattings. The Ne was 317 (RP) and 179 (TP). The probability of genes origin indicated values for fe, fa and fg of 386, 187 and 351 (TP), and 161, 64 and 56 (RP), respectively, evidencing a reduction of genetic variability in the RP. Half of the genetic variation in the equine population studied was explained by 40 ancestors. The results show loss of genetic diversity in the RP and the genetic contribution of the ancestors suggests the need to increase the number of stallions for breeding and guide mating to increase genetic diversity in the new generations of Silla Argentino horses of the Colombian National Police

AbstractCryptic local adaptation—where an environmental effect masks the magnitude of the genetic contribution to a phenotype—has long been a topic of interest in ecology and evolution. Here, we systematically document the magnitude and drivers of two common forms of cryptic local adaptation—counter- and cogradient variation. Using a hierarchical Bayesian meta-analysis, we calculated the overall effect size as 1.03 for countergradient variation and 0.90 for cogradient variation. This result indicates that the genetic effect of cryptic local adaptation is approximately equal to a one standard deviation change in trait value between the most disparate populations. We also found that the abiotic and biotic covariates with the largest mean effects were temperature (2.50) and gamete size (2.78), although there was substantial variance. Our results demonstrate the pervasiveness and large effect of cryptic local adaptation in wild populations and underscores the importance of accounting for these effects in future studies.

Abstract Background: Neurofibromatosis type 1 (NF1) is a common human genetic disease with age-dependent phenotype progression. The overview of clinical and radiological findings evaluated by whole-body magnetic resonance imaging (WBMRI) in NF1 patients <3 years old assessed with a genetic contribution to disease progression is presented herein.Methods: This study included 70 clinically or genetically diagnosed NF1 patients who received WBMRI before 3 years old. Clinical, genetic, and radiologic features were collected by retrospective chart review. In NF1+, widely spread diffuse cutaneous neurofibromas, developmental delay, autism, seizure, cardiac abnormalities, hearing defect, optic pathway glioma, severe plexiform neurofibromas (>3 cm in diameter, disfigurement, accompanying pain, bony destruction, or located para-aortic area), brain tumors, nerve root tumors, malignant peripheral nerve sheath tumors, moyamoya disease, and bony dysplasia were included.Results: The age at WBMRI was 1.6 ± 0.7 years old, and NF1 mutations were found in 66 patients (94.3%). Focal areas of signal intensity (FASI) were the most common WBMRI finding (66.1%), followed by optic pathway glioma (15.7%), spine dural ectasia (12.9%), and plexiform neurofibromas (10.0%). Plexiform neurofibromas and NF1+ were more prevalent in familial case (28.7% vs 5.7%, p = 0.030; 71.4% vs 30.2%, p = 0.011). Follow-up WBMRI was conducted in 42 patients (23 girls and 19 boys) after 1.21 ± 0.50 years. FASI and radiologic progression were more frequent in patients with mutations involving GTPase activating protein-related domain (77.8% vs 52.4%, p = 0.047; 46.2% vs 7.7%, p = 0.029).Conclusions: WBMRI provides important information for the clinical care for young pediatric NF1 patients. As NF1 progresses in even these young patients, and is related to family history and the affected NF1 domains, serial evaluation with WBMRI should be assessed based on the clinical and genetic features for the patients’ best care.

Abstract Among neonatal cardiomyopathies, primary endocardial fibroelastosis (pEFE) remains a mysterious disease of the endomyocardium that is poorly genetically characterized, affecting 1/5000 live births and accounting for 25% of the entire pediatric dilated cardiomyopathy (DCM) with a devastating course and grave prognosis. To investigate the potential genetic contribution to pEFE, we performed integrative genomic analysis, using whole exome sequencing (WES) and RNA-seq in a female infant with confirmed pathological diagnosis of pEFE. Within regions of homozygosity in the proband genome, WES analysis revealed novel parent-transmitted homozygous mutations affecting three genes with known roles in cilia assembly or function. Among them, a novel homozygous variant [c.1943delA] of uncertain significance in ALMS1 was prioritized for functional genomic and mechanistic analysis. Loss of function mutations of ALMS1 have been implicated in Alstrom syndrome (AS) [OMIM 203800], a rare recessive ciliopathy that has been associated with cardiomyopathy. The variant of interest results in a frameshift introducing a premature stop codon. RNA-seq of the proband’s dermal fibroblasts confirmed the impact of the novel ALMS1 variant on RNA-seq reads and revealed dysregulated cellular signaling and function, including the induction of epithelial mesenchymal transition (EMT) and activation of TGFβ signaling. ALMS1 loss enhanced cellular migration in patient fibroblasts as well as neonatal cardiac fibroblasts, while ALMS1-depleted cardiomyocytes exhibited enhanced proliferation activity. Herein, we present the unique pathological features of pEFE compared to DCM and utilize integrated genomic analysis to elucidate the molecular impact of a novel mutation in ALMS1 gene in an AS case. Our report provides insights into pEFE etiology and suggests, for the first time to our knowledge, ciliopathy as a potential underlying mechanism for this poorly understood and incurable form of neonatal cardiomyopathy. Key message Primary endocardial fibroelastosis (pEFE) is a rare form of neonatal cardiomyopathy that occurs in 1/5000 live births with significant consequences but unknown etiology. Integrated genomics analysis (whole exome sequencing and RNA sequencing) elucidates novel genetic contribution to pEFE etiology. In this case, the cardiac manifestation in Alstrom syndrome is pEFE. To our knowledge, this report provides the first evidence linking ciliopathy to pEFE etiology. Infants with pEFE should be examined for syndromic features of Alstrom syndrome. Our findings lead to a better understanding of the molecular mechanisms of pEFE, paving the way to potential diagnostic and therapeutic applications.