Genes

ABO blood system is an inborn trait determined by the ABO gene. The genetic-phenotypic mechanism underneath the four mutually exclusive and collectively exhaustive types of O, A, B and AB could theoretically be elucidated. However, genetic polymorphisms in the human populations render the link elusive, and importantly, past studies using genetically determined rather than biochemically determined ABO types were not and could not be evaluated for the inference errors. Upon both blood-typing and genotyping a cohort of 1008 people of the Han Chinese population, we conducted a genome-wide association study in parallel with both binomial and multinomial log-linear models. Significant genetic variants are all mapped to the ABO gene, and are quantitatively evaluated for binary and multi-class classification performances. Three single nucleotide polymorphisms of rs8176719, rs635634 and rs7030248 would together be sufficient to establish a multinomial predictive model that achieves high accuracy (0.98) and F1 scores (micro 0.99 and macro 0.97). Using the set of identified ABO-associated genetic variants as instrumental variables, we demonstrate the application in causal analysis by Mendelian randomization (MR) studies on blood pressures (one-sample MR) and severe COVID-19 with respiratory failure (two-sample MR). Full article

Hereditary erythrocytes disorders include a large group of conditions with heterogeneous molecular bases and phenotypes. We analyzed here a case series of 155 consecutive patients with clinical suspicion of hereditary erythrocyte defects referred to the Medical Genetics Unit from 2018 to 2020. All of the cases followed a diagnostic workflow based on a targeted next-generation sequencing panel of 86 genes causative of hereditary red blood cell defects. We obtained an overall diagnostic yield of 84% of the tested patients. Monogenic inheritance was seen for 69% (107/155), and multi-locus inheritance for 15% (23/155). PIEZO1 and SPTA1 were the most mutated loci. Accordingly, 16/23 patients with multi-locus inheritance showed dual molecular diagnosis of dehydrated hereditary stomatocytosis/xerocytosis and hereditary spherocytosis. These dual inheritance cases were fully characterized and were clinically indistinguishable from patients with hereditary spherocytosis. Additionally, their ektacytometry curves highlighted alterations of dual inheritance patients compared to both dehydrated hereditary stomatocytosis and hereditary spherocytosis. Our findings expand the genotypic spectrum of red blood cell disorders and indicate that multi-locus inheritance should be considered for analysis and counseling of these patients. Of note, the genetic testing was crucial for diagnosis of patients with a complex mode of inheritance. Full article

Urochloa (including Brachiaria, Megathyrus and some Panicum) tropical grasses are native to Africa and are now, after selection and breeding, planted worldwide, particularly in South America, as important forages with huge potential for further sustainable improvement and conservation of grasslands. We aimed to develop an optimized approach to determine ploidy of germplasm collection of this tropical forage grass group using dried leaf material, including approaches to collect, dry and preserve plant samples for flow cytometry analysis. Our methods enable robust identification of ploidy levels (coefficient of variation of G0/G1 peaks, CV, typically <5%). Ploidy of some 348 forage grass accessions (ploidy range from 2x to 9x), from international genetic resource collections, showing variation in basic chromosome numbers and reproduction modes (apomixis and sexual), were determined using our defined standard protocol. Two major Urochloa agamic complexes are used in the current breeding programs at CIAT and EMBRAPA: the ’brizantha’ and ’humidicola’ agamic complexes are variable, with multiple ploidy levels. Some U. brizantha accessions have odd level of ploidy (5x), and the relative differences in fluorescence values of the peak positions between adjacent cytotypes is reduced, thus more precise examination of this species is required. Ploidy measurement of U. humidicola revealed aneuploidy. Full article

CLN8 is a ubiquitously expressed membrane-spanning protein that localizes primarily in the ER, with partial localization in the ER-Golgi intermediate compartment. Mutations in CLN8 cause late-infantile neuronal ceroid lipofuscinosis (LINCL). We describe a female pediatric patient with LINCL. She exhibited a typical phenotype associated with LINCL, except she did not present spontaneous myoclonus, her symptoms occurrence was slower and developed focal sensory visual seizures. In addition, whole-exome sequencing identified a novel homozygous variant in CLN8, c.531G>T, resulting in p.Trp177Cys. Ultrastructural examination featured abundant lipofuscin deposits within mucosal cells, macrophages, and monocytes. We report a novel CLN8 mutation as a cause for NCL8 in a girl with developmental delay and epilepsy, cerebellar syndrome, visual loss, and progressive cognitive and motor regression. This case, together with an analysis of the available literature, emphasizes the existence of a continuous spectrum of CLN8-associated phenotypes rather than a sharp distinction between them. Full article

The term amyloidosis describes a group of rare diseases caused by protein conformation abnormalities resulting in extracellular deposition and accumulation of insoluble fibrillar aggregates. So far, 36 amyloid precursor proteins have been identified, and each one is responsible for a specific disease entity. Transthyretin amyloidosis (ATTRv) is one of the most common forms of systemic and ocular amyloidosis, due to the deposition of transthyretin (TTR), which is a transport protein mainly synthesized in the liver but also in the retinal pigment epithelial cells. ATTRv amyloidosis may be misdiagnosed with several other conditions, resulting in a significant diagnostic delay. Gelsolin and keratoepithelin are other proteins that, when mutated, are responsible for a systemic amyloid disease with significant ocular manifestations that not infrequently appear before systemic involvement. The main signs of ocular amyloid deposition are in the cornea, irido-corneal angle and vitreous, causing complications related to vasculopathy and neuropathy at the local level. This review aims at describing the main biochemical, histopathological and clinical features of systemic amyloidosis associated with eye involvement, with particular emphasis on the inherited forms. We discuss currently available treatments, focusing on ocular involvement and specific ophthalmologic management and highlighting the importance of a prompt treatment for the potential sight-threatening complications derived from amyloid deposition in ocular tissues. Full article

The functional FABP2 Ala54Thr polymorphism (rs1799883) is strongly associated with lipid and carbohydrate metabolism, although the function of its potential modifying effect on training-induced changes in obesity-related parameters is still unknown. The aim of the present study was to investigate the influence of the Ala54Thr polymorphism on post-training changes of selected body mass and body composition measurements, as well as with biochemical parameters of energy metabolism. Accordingly, alleles and genotypes distribution in a group of 168 young, nonobese Caucasian women measured for chosen body composition parameters, lipid profile, and glucose levels before and after the completion of a 12-week aerobic training program were studied. Although the obtained results showed changes in body mass, BMI, FM, %FM, FFM, TBW, HDL-C, and glucose levels during the training program, none of the examined parameters changed significantly across the FABP2 genotypes. Instead, we found a main effect of genotype on BMI (p = 0.033), with carriers of the Thr54 allele having a higher BMI during the whole study period compared with the Ala54 carriers. We confirm that the FABP2 Ala54Thr polymorphism may help identify women at risk for overweight and obesity. However, we did not notice evidence of an interaction between physical activity and the Ala54Thr polymorphism on the examined parameters. Full article

Transcriptomic reconstructions without reference (i.e., de novo) are common for data samples derived from non-model biological systems. These assemblies involve massive parallel short read sequence reconstructions from experiments, but they usually employ ad-hoc bioinformatic workflows that exhibit limited standardization and customization. The increasing number of transcriptome assembly software continues to provide little room for standardization which is exacerbated by the lack of studies on modularity that compare the effects of assembler synergy. We developed a customizable management workflow for de novo transcriptomics that includes modular units for short read cleaning, assembly, validation, annotation, and expression analysis by connecting twenty-five individual bioinformatic tools. With our software tool, we were able to compare the assessment scores based on 129 distinct single-, bi- and tri-assembler combinations with diverse k-mer size selections. Our results demonstrate a drastic increase in the quality of transcriptome assemblies with bi- and tri- assembler combinations. We aim for our software to improve de novo transcriptome reconstructions for the ever-growing landscape of RNA-seq data derived from non-model systems. We offer guidance to ensure the most complete transcriptomic reconstructions via the inclusion of modular multi-assembly software controlled from a single master console. Full article

Guar (Cyamopsis tetragonoloba (L.) Taub.) is an annual legume crop native to India and Pakistan. Seeds of the plant serve as a source of galactomannan polysaccharide (guar gum) used in the food industry as a stabilizer (E412) and as a gelling agent in oil and gas fracturing fluids. There were several attempts to introduce this crop to countries of more northern latitudes. However, guar is a plant of a short photoperiod, therefore, its introduction, for example, to Russia is complicated by a long day length during the growing season. Breeding of new guar varieties insensitive to photoperiod slowed down due to the lack of information on functional molecular markers, which, in turn, requires information on guar genome. Modern breeding strategies, e.g., genomic predictions, benefit from integration of multi-omics approaches such as transcriptome, proteome and metabolome assays. Here we present an attempt to use transcriptome-metabolome integration to understand the genetic determination of flowering time variation among guar plants that differ in their photoperiod sensitivity. This study was performed on nine early- and six delayed-flowering guar varieties with the goal to find a connection between 63 metabolites and 1,067 differentially expressed transcripts using Shiny GAM approach. For the key biomarker of flowering in guar myo-inositol we also evaluated the KEGG biochemical pathway maps available for Arabidopsis thaliana. We found that the phosphatidylinositol signaling pathway is initiated in guar plants that are ready for flowering through the activation of the phospholipase C (PLC) gene, resulting in an exponential increase in the amount of myo-inositol in its free form observed on GC-MS chromatograms. The signaling pathway is performed by suppression of myo-inositol phosphate kinases (phosphorylation) and alternative overexpression of phosphatases (dephosphorylation). Our study suggests that metabolome and transcriptome information taken together, provide valuable information about biomarkers that can be used as a tool for marker-assisted breeding, metabolomics and functional genomics of this important legume crop. Full article

The study investigated carbapenemase-producing Klebsiella pneumoniae (CPKP) isolates of patients in an intensive care unit (ICU) in a public hospital in the KwaZulu-Natal province, South Africa using whole-genome sequencing (WGS). Ninety-seven rectal swabs, collected from all consenting adult patients (n = 31) on days 1, 3, and 7 and then weekly, were screened for carbapenemase-production using Chrome-ID selective media. Antibiotic susceptibility was determined for the fourteen positive CPKP isolates obtained using the VITEK 2 automated system. All isolates (100%) were resistant to ertapenem and meropenem, and 71.4% (n = 10) were resistant to imipenem. All CPKP isolates were subjected to ERIC/PCR, and a sub-sample of isolates was selected for WGS based on their antibiograms and clonality. All sequenced isolates harbored the bla_OXA-181 carbapenemase (100%) and co-carried other β-lactamase genes such as bla_OXA-1, bla_CTX-M-15, bla_TEM-1B, and bla_SHV-1. IncF, IncX3, and Col plasmid replicons groups and class I integrons (ln191 and ln27) were detected. All isolates belonged to the same sequence type ST307 and capsular serotypes (K102, O2v2). All the isolates carried the same virulence repertoire, reflecting the epidemiological relationship between isolates. bla_OXA-181 was located on a multi-replicon plasmid similar to that of E. coli p010_B-OXA181, and isolates were aligned with several South African and international clades, demonstrating horizontal and vertical transboundary distribution. The findings suggest that bla_OXA-181 producing K. pneumoniae is endemic in this ICU, colonizing the patients. CRE screening and enhanced infection prevention and control measures are urgently required. Full article

One of the recently described syndromes emerging from the massive study of cohorts of undiagnosed patients with autism spectrum disorders (ASD) and syndromic intellectual disability (ID) is White–Sutton syndrome (WHSUS) (MIM #616364), caused by variants in the POGZ gene (MIM *614787), located on the long arm of chromosome 1 (1q21.3). So far, more than 50 individuals have been reported worldwide, although phenotypic features and natural history have not been exhaustively characterized yet. The phenotypic spectrum of the WHSUS is broad and includes moderate to severe ID, microcephaly, variable cerebral malformations, short stature, brachydactyly, visual abnormalities, sensorineural hearing loss, hypotonia, sleep difficulties, autistic features, self-injurious behaviour, feeding difficulties, gastroesophageal reflux, and other less frequent features. Here, we report the case of a girl with microcephaly, brain malformations, developmental delay (DD), peripheral polyneuropathy, and adducted thumb—a remarkable clinical feature in the first years of life—and heterozygous for a previously unreported, de novo splicing variant in POGZ. This report contributes to strengthen and expand the knowledge of the clinical spectrum of WHSUS, pointing out the importance of less frequent clinical signs as diagnostic handles in suspecting this condition. Full article

MC4R, LEP, and LEPR genes are involved in the hypothalamic leptin-melanocortin regulation pathway, which is important for energy homeostasis. Our study aimed to evaluate the associations between the MC4R rs17782313, LEP rs7799039, and LEPR rs1137101 polymorphisms with obesity-related parameters in childhood and adulthood. The data were obtained from the Kaunas Cardiovascular Risk Cohort study, which started in 1977 with 1082 participants aged 12–13 years. In 2012–2014, the follow-up survey was carried out. Genotype analysis of all respondents (n = 509) aged 48–49 years was performed for the gene polymorphisms using Real-Time Polymerase Chain Reaction. Anthropometric measurements were performed in childhood and adulthood. In childhood, only skinfold thicknesses were associated with gene variants being the lowest in children with MC4R TT genotype and LEP AG genotype. In adulthood, odds of obesity and metabolic syndrome was higher in MC4R CT/CC genotype than TT genotype carriers (OR 1.8; 95% CI 1.2–2.8 and OR 1.6; 95% CI 1.1–2.4, respectively). In men, physical activity attenuated the effect of the MC4R rs17782313 on obesity. The LEP GG genotype was associated with higher BMI, waist circumference, and visceral fat level only in men. No associations of the LEPR rs1137101 polymorphisms with anthropometric measurements and leptin level were found. In conclusion, the associations of the MC4R and LEP gene polymorphisms with obesity-related parameters strengthened with age. Full article

Accumulation of α-Synuclein (αSyn) in nigral dopaminergic neurons is commonly seen in patients with Parkinson′s disease (PD). We recently reported that transduction of intracellular single-chain intrabody targeting the 53–87 amino acid residues of human αSyn by recombinant adeno associated viral vector (AAV-NAC32) downregulated αSyn protein in SH-SY5Y cells and rat brain. This study characterizes the behavioral phenotype and dopaminergic protection in animals receiving AAV-NAC32. Our results show that adult DAT-Cre rats selectively overexpress αSyn in nigra dopaminergic neurons after local administration of AAV-DIO-αSyn. These animals develop PD-like phenotype, including bradykinesia and loss of tyrosine hydroxylase (TH) immunoreactivity in substantia nigra pars compacta dorsal tier (SNcd). An injection of AAV-NAC32 to nigra produces a selective antibody against αSyn and normalizes the behavior. AAV-NAC32 significantly increases TH, while reduces αSyn immunoreactivity in SNcd. Altogether, our data suggest that an AAV-mediated gene transfer of NAC32 antibody effectively antagonizes αSyn-mediated dopaminergic degeneration in nigra, which may be a promising therapeutic candidate for synucleinopathy or PD. Full article

Lettuce plants tend to undergo floral initiation by elongation of flower stalks (bolting) under high-temperature and long-day conditions, which is a serious problem for summer lettuce production. Our objective was to generate a high-density genetic map using SNPs obtained from genotyping-by-sequencing (GBS) analysis of F5 recombinant inbred lines (RILs) and to map QTLs involved in stem growth and flowering time in lettuce. A set of 127 intra-specific RIL mapping populations derived from a cross between two varieties, green and red leaf lettuce, were used to identify QTLs related to the number of days from sowing to bolting (DTB), to flowering of the first flower (DTF), to seed-setting of the first flower (DTS), and the total number of leaves (LN), plant height (PH), and total number of branches of main inflorescence (BN) for two consecutive years. Of the 15 QTLs detected, one that controls DTB, DTF, DTS, LN, and PH detected on LG 7, and another QTL that controls DTF, DTS, and PH detected on LG 1. Analysis of the genomic sequence corresponding to the QTL detected on LG 7 led to the identification of 22 putative candidate genes. A consistent QTL related to bolting and flowering time, and corresponding candidate genes has been reported. This study will be valuable in revealing the genetic basis of stem growth and flowering time in lettuce. Full article

Obesity is a chronic disease, which needs to be early detected early and treated in order prevent its complications. Changes in telomere length (TL) have been associated with obesity and its complications, such as diabetes mellitus and metabolic syndrome. Therefore, we conducted a systematic review to summarize results of studies that have measured TL in children and adolescents with obesity. Fourteen studies aiming to assess TL in pediatric patients with either obesity or who were overweight were included in this review. In conclusion, obesity and adiposity parameters are negatively associated with TL. Shorter telomeres are observed in children with obesity compared with their lean counterparts. Factors involved in obesity etiology, such as diet and physical activity, may contribute to maintenance of TL integrity. In the long term, TL change could be used as a biomarker to predict response to obesity treatment. Full article

Joubert syndrome (OMIM #213300) is a rare neurodevelopmental disease characterized by abnormal breathing patterns, intellectual impairment, ocular findings, renal cysts, and hepatic fibrosis. It is classified as a ciliopathy disease, where cilia function or structure in various organs are affected. Here, we report a 17-year-old male whose main clinical findings are oculomotor apraxia and truncal ataxia. Magnetic resonance imaging revealed the characteristic molar tooth sign of Joubert syndrome. He also has obsessive–compulsive disorder concomitantly, which is not a known feature of Joubert syndrome. Molecular genetic analysis revealed a homozygous c.2106G>A (p.(Thr702=)) variation in the Abelson helper integration 1 (AHI1) gene and another homozygous c.1739C>T (p.Thr580Ile) variation in the coiled-coil and C2 domain-containing protein 1A (CC2D1A) gene. Even though certain AHI1 variations were previously associated with Joubert syndrome (JS), c.2106G>A (p.(Thr702=)) was only reported in one patient in trans with another known pathogenic JS variant. The CC2D1A c.1739C>T (p.Thr580Ile) variation, on the other hand, has been reported to cause autosomal recessive nonsyndromic mental retardation, but there are conflicting interpretations about its pathogenicity. Overall, to our knowledge, this is the first patient representing a severe ciliopathy phenotype caused by a homozygous synonymous AHI1 variation. Further investigations should be performed to determine any involvement of the CC2D1A gene in ciliopathy phenotypes such as Joubert syndrome. Full article

The phenomenon of whole-body regeneration means rebuilding of the whole body of an animal from a small fragment or even a group of cells. In this process, the old axial relationships are often lost, and new ones are established. An amazing model for studying this process is sponges, some of which are able to regenerate into a definitive organism after dissociation into cells. We hypothesized that during the development of cell aggregates, primmorphs, new axes are established due to the activation of the Wnt and TGF-beta signaling pathways. Using in silico analysis, RNA-seq, and whole-mount in situ hybridization, we identified the participants in these signaling pathways and determined the spatiotemporal changes in their expression in demosponge Halisarca dujardinii. It was shown that Wnt and TGF-beta ligands are differentially expressed during primmorph development, and transcripts of several genes are localized at the poles of primmorphs, in the form of a gradient. We suppose that the Wnt and TGF-beta signaling cascades are involved in the initial axial patterning of the sponge body, which develops from cells after dissociation. Full article

Distal arthrogryposis and lethal congenital contracture syndromes describe a broad group of disorders that share congenital limb contractures in common. While skeletal muscle sarcomeric genes comprise many of the first genes identified for Distal Arthrogyposis, other mechanisms of disease have been demonstrated, including key effects on peripheral nerve function. While Distal Arthrogryposis and Lethal Congenital Contracture Syndromes display superficial similarities in phenotype, the underlying mechanisms for these conditions are diverse but overlapping. In this review, we discuss the important insights gained into these human genetic diseases resulting from in vitro molecular studies and in vivo models in fruit fly, zebrafish, and mice. Full article

The existing research on dairy cow mammary gland genes is extensive, but there have been few reports about dynamic changes in dairy cow mammary gland genes as milk yield decrease. For the first time, transcriptome analysis based on short time-series expression miner (STEM) and histological observations were performed using the Holstein dairy cow mammary gland to explore gene expression patterns in this process of decrease (at peak, mid-, and late lactation). Histological observations suggested that the number of mammary acinous cells at peak/mid-lactation was significantly higher than that at mid-/late lactation, and the lipid droplets area secreted by dairy cows was almost unaltered across the three stages of lactation (p > 0.05). Totals of 882 and 1439 genes were differentially expressed at mid- and late lactation, respectively, compared to peak lactation. Function analysis showed that differentially expressed genes (DEGs) were mainly related to apoptosis and energy metabolism (fold change ≥ 2 or fold change ≤ 0.5, p-value ≤ 0.05). Transcriptome analysis based on STEM identified 16 profiles of differential gene expression patterns, including 5 significant profiles (false discovery rate, FDR ≤ 0.05). Function analysis revealed DEGs involved in milk fat synthesis were downregulated in Profile 0 and DEGs in Profile 12 associated with protein synthesis. These findings provide a foundation for future studies on the molecular mechanisms underlying mammary gland development in dairy cows. Full article

Genetic testing is increasingly part of routine clinical care. However, testing decisions may be characterized by regret as findings also implicate blood relatives. It is not known if genetic testing decisions are affected by the way information is presented (i.e., framing effects). We employed a randomized factorial design to examine framing effects on hypothetical genetic testing scenarios (common, life-threatening disease and rare, life-altering disease). Participants (n = 1012) received one of six decision frames: choice, default (n = 2; opt-in, opt-out), or enhanced choice (n = 3, based on the Theory of Planned Behavior). We compared testing decision, satisfaction, regret, and decision cognitions across decision frames and between scenarios. Participants randomized to ‘choice’ were least likely to opt for genetic testing compared with default and enhanced choice frames (78% vs. 83–91%, p < 0.05). Neither satisfaction nor regret differed across frames. Perceived autonomy (behavioral control) predicted satisfaction (B = 0.085, p < 0.001) while lack of control predicted regret (B = 0.346, p < 0.001). Opting for genetic testing did not differ between disease scenarios (p = 0.23). Results suggest framing can nudge individuals towards opting for genetic testing. These findings have important implications for individual self-determination in the genomic era. Similarities between scenarios with disparate disease trajectories point to possible modular approaches for web-based decisional support. Full article