Characterization of circRNA expression profiles associated with non-Mendelian inheritance in feather growth of chickens.

1. Non-coding RNAs, such as miRNAs, play a crucial role in chicken feather growth rate. However, circular RNA (circRNA) expression profiles in fast- and slow-feathering chickens that follow and do not follow Mendelian inheritance are unclear.2. The circRNA expression profiles was analysed by RNA sequencing of hair follicles of slow-feathering chickens that follow genetic rules and fast-feathering chickens that did not follow genetic rules. Differentially expressed circRNA-miRNA-mRNA competing endogenous RNA (ceRNA) network was then constructed and the key factors and regulation mechanisms controlling feather growth rate were identified.3. The results revealed that 67 circRNAs were significantly differentially expressed in hens, including 22 up-regulated and 45 down-regulated circRNAs in non-Mendelian inheritance-mediated fast-feathering hens compared with Mendelian inheritance-mediated slow-feathering hens. In addition, 16 significantly differentially expressed circRNAs were identified in cockerels, including nine up-regulated and seven down-regulated circRNAs in non-Mendelian inheritance-mediated fast- compared with Mendelian inheritance-mediated slow-feathering cocks. Moreover, circRNA-mediated ceRNA regulation of hair follicle formation was particularly abundant in the Jak-STAT, Wnt and Toll-like receptor signalling pathways. Furthermore, circABI3BP was seen to be a crucial circRNA in regulating feather growth rate, by binding with gga-miR-1649-5p to regulate SSTR2 expression.4. In conclusion, this study analysed circRNA expression profiles in fast- and slow-feathering chickens that follow and do not follow Mendelian inheritance, which laid the foundation for understanding the role of circRNA in chicken feather growth rate.

Clarifying Mendelian vs non-Mendelian inheritance.

Gregor Mendel developed the principles of segregation and independent assortment in the mid-1800s based on his detailed analysis of several traits in pea plants. Those principles, now called Mendel's laws, in fact, explain the behavior of genes and alleles during meiosis and are now understood to underlie "Mendelian inheritance" of a wide range of traits and diseases across organisms. When asked to give examples of inheritance that do NOT follow Mendel's laws, in other words, examples of non-Mendelian inheritance, students sometimes list incomplete dominance, codominance, multiple alleles, sex-linked traits, and multigene traits and cite as their sources the Khan Academy, Wikipedia, and other online sites. Against this background, the goals of this Perspective are to (1) explain to students, healthcare workers, and other stakeholders why the examples above, in fact, display Mendelian inheritance, as they obey Mendel's laws of segregation and independent assortment, even though they do not produce classic Mendelian phenotypic ratios and (2) urge individuals with an intimate knowledge of genetic principles to monitor the accuracy of learning resources and work with us and those resources to correct information that is misleading.

Transgenerational effects of the maternal gestational environment on the post-natal performance of beef cattle: A reaction norm approach.

In tropical beef cattle production systems, animals are commonly raised on pastures, exposing them to potential stressors. The end of gestation typically overlaps with a dry period characterized by limited food availability. Late gestation is pivotal for fetal development, making it an ideal scenario for inter- and transgenerational effects of the maternal gestational environment. Intergenerational effects occur due to exposure during gestation, impacting the development of the embryo and its future germline. Transgenerational effects, however, extend beyond direct exposure to the subsequent generations. The objective of the present study was to verify these effects on the post-natal performance of zebu beef cattle. We extended the use of a reaction norm model to identify genetic variation in the animals' responses to transgenerational effects. The inter- and transgenerational effects were predominantly positive (-0.09% to 19.74%) for growth and reproductive traits, indicating improved animal performance on the phenotypic scale in more favourable maternal gestational environments. Additionally, these effects were more pronounced in the reproductive performance of females. On average, the ratio of direct additive genetic variances of the slope and intercept of the reaction norm ranged from 1.23% to 3.60% for direct and from 10.17% to 11.42% for maternal effects. Despite its relatively modest magnitude, this variation proved sufficient to prompt modifications in parameter estimates. The average percentage variation of direct heritability estimates ranged from 19.3% for scrotal circumference to 33.2% for yearling weight across the environmental descriptors evaluated. Genetic correlations between distant environments for the studied traits were generally high for direct effects and far from unity for maternal effects. Changes in EBV rankings of sires across different gestational environments were also observed. Due to the multifaceted nature of inter- and transgenerational effects of the maternal gestational environment on various traits of beef cattle raised under tropical pasture conditions, they should not be overlooked by producers and breeders. There were differences in the specific response of beef cattle to variations in the quality of the maternal gestational environment, which can be partially explained by transgenerational epigenetic inheritance. Adopting a reaction norm model to capture a portion of the additive variance induced by inter- or transgenerational effects could be an alternative for future research and animal genetic evaluations.

SNPs as Stochastic Oscillators in Inheritance of Human Diseases.

BACKGROUND/AIM: Genetic variants contribute to differences in disease susceptibility. The aim of the study was to elucidate if variants can affect human disease inheritance. MATERIALS AND METHODS: Recently, a list of germline hotspot genetic variants across human autosomal chromosomes was published. Recording the genetic variant hotspots across autosomal chromosomes, their frequency was calculated for each distinct type of genetic variant hotspot and for each autosomal chromosome. Then, OMIM autosomal dominant (AD) and recessive diseases (AR) were counted across each chromosome having maximum and minimum coverage of each type of genetic variant hotspot and the data were compared. Subsequently, the study focused on chromosome 16 with the maximum and chromosome 13 with the minimum number of SNP hotspots. AD and AR diseases were recorded, inside or near the reported SNP variant hotspots of chromosome 16 and 13, and the data were compared. The SPSS software was used for statistical analyses. RESULTS: Autosomal dominant diseases were mainly found in low SNP hotspot chromosomal regions compared to recessive ones, underlying SNPs' possible regulatory role in allelic imbalance. The haplotypic background may be the key factor for variant classification, which could explain the current inconsistencies among scientists with the same genetic variant to be classified as pathogenic, likely pathogenic, or of unknown significance. CONCLUSION: Which came first: the SNPs or the type of inheritance? Third next-generation sequencing with long reads could answer by phasing SNP alleles' haplotypes and tracing their in-cis and in-trans modulator function in human Mendelian and Complex inheritance.

Small vessel disease in primary familial brain calcification with novel truncating PDGFB variants.

INTRODUCTION: Primary familial brain calcification (PFBC) is a neurodegenerative disease characterised by bilateral calcification in the brain, especially in the basal ganglia, leading to neurological and neuropsychiatric manifestations. White matter hyperintensities (WMH) have been described in patients with PFBC and pathogenic variants in the gene for platelet-derived growth factor beta polypeptide (PDGFB), suggesting a manifest cerebrovascular process. We present below the cases of two PFBC families with PDGFB variants and stroke or transient ischaemic attack (TIA) episodes. We examine the possible correlation between PFBC and vascular events as stroke/TIA, and evaluate whether signs for vascular disease in this condition are systemic or limited to the cerebral vessels. MATERIAL AND METHODS: Two Swedish families with novel truncating PDGFB variants, p.Gln140* and p.Arg191*, are described clinically and radiologically. Subcutaneous capillary vessels in affected and unaffected family members were examined by light and electron microscopy. RESULTS: All mutation carriers showed WMH and bilateral brain calcifications. The clinical presentations differed, with movement disorder symptoms dominating in family A, and psychiatric symptoms in family B. However, affected members of both families had stroke, TIA, and/or asymptomatic intracerebral ischaemic lesions. Only one of the patients had classical vascular risk factors. Skin microvasculature was normal. CONCLUSIONS: Patients with these PDGFB variants develop microvascular changes in the brain, but not the skin. PDGFB-related small vessel disease can manifest radiologically as cerebral haemorrhage or ischaemia, and may explain TIA or stroke in patients without other vascular risk factors.

Dominant gingers - Discovery and inheritance of a new shell polymorphism in the great pond snail Lymnaea stagnalis.

Color polymorphism is a classic study system for evolutionary genetics. One of the most color-polymorphic animal taxa is mollusks, but the investigation of the genetic basis of color determination is often hindered by their life history and the limited availability of genetic resources. Here, we report on the discovery of shell color polymorphism in a much-used model species, the great pond snail Lymnaea stagnalis. While their shell is usually beige, some individuals from a Greek population show a distinct red shell color, which we nicknamed Ginger. Moreover, we found that the inheritance fits simple, single-locus Mendelian inheritance with dominance of the Ginger allele. We also compared crucial life-history traits between Ginger and wild-type individuals, and found no differences between morphs. We conclude that the relative simplicity of this polymorphism will provide new opportunities for a deeper understanding of the genetic basis of shell color polymorphism and its evolutionary origin.

Bubbling beyond the barrier: exosomal RNA as a vehicle for soma-germline communication.

'Weismann's barrier' has restricted theories of heredity to the transmission of genomic variation for the better part of a century. However, the discovery and elucidation of epigenetic mechanisms of gene regulation such as DNA methylation and histone modifications has renewed interest in studies on the inheritance of acquired traits and given them mechanistic plausibility. Although it is now clear that these mechanisms allow many environmentally acquired traits to be transmitted to the offspring, how phenotypic information is communicated from the body to its gametes has remained a mystery. Here, we discuss recent evidence that such communication is mediated by somatic RNAs that travel inside extracellular vesicles to the gametes where they reprogram the offspring epigenome and phenotype. How gametes learn about bodily changes has implications not only for the clinic, but also for evolutionary theory by bringing together intra- and intergenerational mechanisms of phenotypic plasticity and adaptation.

Transmission ratio distortion detection by neutral genetic markers in the Pura Raza Española horse breed.

Transmission Ratio Distortion (TRD) is a genetic phenomenon widely demonstrated in several livestock species, but barely in equine species. The TRD occurs when certain genotypes are over- or under-represented in the offspring of a particular mating and can be caused by a variety of factors during gamete formation or during embryonic development. For this study, 126 394 trios consisting of a stallion, mare, and offspring were genotyped using a panel of 17 neutral microsatellite markers recommended by the International Society for Animal Genetics for paternity tests and individual identification. The number of alleles available for each marker ranges from 13 to 18, been 268 the total number of alleles investigated. The TRDscan v.2.0 software was used with the biallelic procedure to identify regions with distorted segregation ratios. After completing the analysis, a total of 12 alleles (out of 11 microsatellites) were identified with decisive evidence for genotypic TRD; 3 and 9 with additive and heterosis patterns, respectively. In addition, 19 alleles (out of 10 microsatellites) were identified displaying allelic TRD. Among them, 14 and 5 were parent-unspecific and stallion-mare-specific TRD. Out of the TRD regions, 24 genes were identified and annotated, predominantly associated with cholesterol metabolism and homeostasis. These genes are often linked to non-specific symptoms like impaired fertility, stunted growth, and compromised overall health. The results suggest a significant impact on the inheritance of certain genetic traits in horses. Further analysis and validation are needed to better understand the TRD impact before the potential implementation in the horse breeding programme strategies.

Multicentric Osteolysis Nodulosis Arthropathy Syndrome Simulating Juvenile Idiopathic Arthritis in an Adult Female: A Case Report and a Literature Review.

Multicentric osteolysis, nodulosis, and arthropathy (MONA) syndrome is one of the rare genetic skeletal dysplasias, inherited as an autosomal recessive disorder, which predominantly involves carpal and tarsal bones with characteristic osteolytic lesions and can be misdiagnosed as juvenile idiopathic arthritis or rheumatoid arthritis. MONA syndrome includes diseases involving two genes: the matrix metalloproteinase 2 (MMP2) gene and matrix metalloproteinase 14 (MMP14). Both genes are assumed to cause phenotype variants of the same disease. Older patients may manifest some arthritic features, especially in the wrist, and minute pathological fractures can occur as well. These patients may be misdiagnosed as inflammatory arthritis and physicians might prescribe corticosteroid and disease-modifying immunosuppressive agents. Therefore, physicians should carefully evaluate genetic skeletal dysplasia to make a correct diagnosis and avoid unnecessary pharmacological intervention. We report a case of MONA syndrome in an adult female who came to our facility for an intensive rehabilitation program.

Incorporating ecology into gene drive modelling.

Gene drive technology, in which fast-spreading engineered drive alleles are introduced into wild populations, represents a promising new tool in the fight against vector-borne diseases, agricultural pests and invasive species. Due to the risks involved, gene drives have so far only been tested in laboratory settings while their population-level behaviour is mainly studied using mathematical and computational models. The spread of a gene drive is a rapid evolutionary process that occurs over timescales similar to many ecological processes. This can potentially generate strong eco-evolutionary feedback that could profoundly affect the dynamics and outcome of a gene drive release. We, therefore, argue for the importance of incorporating ecological features into gene drive models. We describe the key ecological features that could affect gene drive behaviour, such as population structure, life-history, environmental variation and mode of selection. We review previous gene drive modelling efforts and identify areas where further research is needed. As gene drive technology approaches the level of field experimentation, it is crucial to evaluate gene drive dynamics, potential outcomes, and risks realistically by including ecological processes.

SGCD Missense Variant in a Lagotto Romagnolo Dog with Autosomal Recessively Inherited Limb-Girdle Muscular Dystrophy.

An 8-month-old female Lagotto Romagnolo dog was presented for a 1-month history of an initial severe reluctance to move, rapidly progressing to a marked stiff gait and progressive muscular weakness and evolving to tetraparesis, which persuaded the owner to request euthanasia. A primary muscle pathology was supported by necropsy and histopathological findings. Macroscopically, the muscles were moderately atrophic, except for the diaphragm and the neck muscles, which were markedly thickened. Histologically, all the skeletal muscles examined showed atrophy, hypertrophy, necrosis with calcification of the fibers, and mild fibrosis and inflammation. On immunohistochemistry, all three dystrophin domains and sarcoglycan proteins were absent. On Western blot analysis, no band was present for delta sarcoglycan. We sequenced the genome of the affected dog and compared the data to more than 900 control genomes of different dog breeds. Genetic analysis revealed a homozygous private protein-changing variant in the SGCD gene encoding delta- sarcoglycan in the affected dog. The variant was predicted to induce a SGCD:p.(Leu242Pro) change in the protein. In silico tools predicted the change to be deleterious. Other 770 Lagotto Romagnolo dogs were genotyped for the variant and all found to be homozygous wild type. Based on current knowledge of gene function in other mammalian species, including humans, hamsters, and dogs, we propose the SGCD missense variant as the causative variant of the observed form of muscular dystrophy in the index case. The absence of the variant allele in the Lagotto Romagnolo breeding population indicates a rare allele that has appeared recently.

Allelic expression of AhNSP2-B07 due to parent of origin affects peanut nodulation.

Legumes are well-known for establishing a symbiotic relationship with rhizobia in root nodules to fix nitrogen from the atmosphere. The nodulation signaling pathway 2 (NSP2) gene plays a critical role in the symbiotic signaling pathway. In cultivated peanut, an allotetraploid (2n = 4x = 40, AABB) legume crop, natural polymorphisms in a pair of NSP2 homoeologs (Na and Nb) located on chromosomes A08 and B07, respectively, can cause loss of nodulation. Interestingly, some heterozygous (NBnb) progeny produced nodules, while some others do not, suggesting non-Mendelian inheritance in the segregating population at the Nb locus. In this study, we investigated the non-Mendelian inheritance at the NB locus. Selfing populations were developed to validate the genotypical and phenotypical segregating ratios. Allelic expression was detected in roots, ovaries, and pollens of heterozygous plants. Bisulfite PCR and sequencing of the Nb gene in gametic tissue were performed to detect the DNA methylation variations of this gene in different gametic tissues. The results showed that only one allele at the Nb locus expressed in peanut roots during symbiosis. In the heterozygous (Nbnb) plants, if dominant allele expressed, the plants produced nodules, if recessive allele expressed, then no nodules were produced. qRT-PCR experiments revealed that the expression of Nb gene in the ovary was extremely low, about seven times lower than that in pollen, regardless of genotypes or phenotypes of the plants at this locus. The results indicated that Nb gene expression in peanut depends on the parent of origin and is imprinted in female gametes. However, no significant differences of DNA methylation level were detected between these two gametic tissues by bisulfite PCR and sequencing. The results suggested that the remarkable low expression of Nb in female gametes may not be caused by DNA methylation. This study provided a unique genetic basis of a key gene involved in peanut symbiosis, which could facilitate understanding the regulation of gene expression in symbiosis in polyploid legumes.

Unravelling transmission ratio distortion across the bovine genome: identification of candidate regions for reproduction defects.

BACKGROUND: Biological mechanisms affecting gametogenesis, embryo development and postnatal viability have the potential to alter Mendelian inheritance expectations resulting in observable transmission ratio distortion (TRD). Although the discovery of TRD cases have been around for a long time, the current widespread and growing use of DNA technologies in the livestock industry provides a valuable resource of large genomic data with parent-offspring genotyped trios, enabling the implementation of TRD approach. In this research, the objective is to investigate TRD using SNP-by-SNP and sliding windows approaches on 441,802 genotyped Holstein cattle and 132,991 (or 47,910 phased) autosomal SNPs. RESULTS: The TRD was characterized using allelic and genotypic parameterizations. Across the whole genome a total of 604 chromosomal regions showed strong significant TRD. Most (85%) of the regions presented an allelic TRD pattern with an under-representation (reduced viability) of carrier (heterozygous) offspring or with the complete or quasi-complete absence (lethality) for homozygous individuals. On the other hand, the remaining regions with genotypic TRD patterns exhibited the classical recessive inheritance or either an excess or deficiency of heterozygote offspring. Among them, the number of most relevant novel regions with strong allelic and recessive TRD patterns were 10 and 5, respectively. In addition, functional analyses revealed candidate genes regulating key biological processes associated with embryonic development and survival, DNA repair and meiotic processes, among others, providing additional biological evidence of TRD findings. CONCLUSIONS: Our results revealed the importance of implementing different TRD parameterizations to capture all types of distortions and to determine the corresponding inheritance pattern. Novel candidate genomic regions containing lethal alleles and genes with functional and biological consequences on fertility and pre- and post-natal viability were also identified, providing opportunities for improving breeding success in cattle.

Complex traits and candidate genes: estimation of genetic variance components across multiple genetic architectures.

Large-effect loci-those statistically significant loci discovered by genome-wide association studies or linkage mapping-associated with key traits segregate amidst a background of minor, often undetectable, genetic effects in wild and domesticated plants and animals. Accurately attributing mean differences and variance explained to the correct components in the linear mixed model analysis is vital for selecting superior progeny and parents in plant and animal breeding, gene therapy, and medical genetics in humans. Marker-assisted prediction and its successor, genomic prediction, have many advantages for selecting superior individuals and understanding disease risk. However, these two approaches are less often integrated to study complex traits with different genetic architectures. This simulation study demonstrates that the average semivariance can be applied to models incorporating Mendelian, oligogenic, and polygenic terms simultaneously and yields accurate estimates of the variance explained for all relevant variables. Our previous research focused on large-effect loci and polygenic variance separately. This work aims to synthesize and expand the average semivariance framework to various genetic architectures and the corresponding mixed models. This framework independently accounts for the effects of large-effect loci and the polygenic genetic background and is universally applicable to genetics studies in humans, plants, animals, and microbes.

ChatGPT: a pioneering approach to complex prenatal differential diagnosis.

This commentary examines how ChatGPT can assist healthcare teams in the prenatal diagnosis of rare and complex cases by creating a differential diagnoses based on deidentified clinical findings, while also acknowledging its limitations.

Genetic evaluation of living kidney donor candidates: A review and recommendations for best practices.

The growing accessibility and falling costs of genetic sequencing techniques has expanded the utilization of genetic testing in clinical practice. For living kidney donation, genetic evaluation has been increasingly used to identify genetic kidney disease in potential candidates, especially in those of younger ages. However, genetic testing on asymptomatic living kidney donors remains fraught with many challenges and uncertainties. Not all transplant practitioners are aware of the limitations of genetic testing, are comfortable with selecting testing methods, comprehending test results, or providing counsel, and many do not have access to a renal genetic counselor or a clinical geneticist. Although genetic testing can be a valuable tool in living kidney donor evaluation, its overall benefit in donor evaluation has not been demonstrated and it can also lead to confusion, inappropriate donor exclusion, or misleading reassurance. Until more published data become available, this practice resource should provide guidance for centers and transplant practitioners on the responsible use of genetic testing in the evaluation of living kidney donor candidates.

How a paternal uniparental isodisomy of chromosome 17 leads to autosomal recessive limb-girdle muscular dystrophy R3.

Uniparental isodisomy is a condition where both chromosomes of a pair are inherited from one parental homologue. If a deleterious variant is present on the duplicated chromosome, its homozygosity can reveal an autosomal recessive disorder in the offspring of a heterozygous carrier. Limb-girdle muscular dystrophy (LGMD) R3 is an autosomal recessive inherited disease that is associated with alpha-sarcoglycan gene (SGCA) variants. We report the first published case of LGMDR3 due to a homozygous variant in SGCA unmasked by uniparental isodisomy. The patient is an 8-year-old who experienced delayed motor milestones but normal cognitive development. He presented with muscle pain and elevated plasma creatine kinase. Sequencing of the SGCA gene showed a homozygous pathogenic variant. Parents were not related and only the father was heterozygous for the pathogenic variant. A chromosomal microarray revealed a complete chromosome 17 copy number neutral loss of heterozygosity encompassing SGCA, indicating paternal uniparental isodisomy.

Exploring the mechanism of physcion-1-O-ß-D-monoglucoside against acute lymphoblastic leukaemia based on network pharmacology and experimental validation.

Objective: To explore the mechanism of PG against acute lymphoblastic leukaemia (ALL) by network pharmacology and experimental verification in vitro. Methods: First, the biological activity of PG against B-ALL was determined by CCK-8 and flow cytometry. Then, the potential targets of PG were obtained from the PharmMapper database. ALL-related genes were collected from the GeneCards, OMIM and PharmGkb databases. The two datasets were intersected to obtain the target genes of PG in ALL. Then, protein interaction networks were constructed using the STRING database. The key targets were obtained by topological analysis of the network with Cytoscape 3.8.0 software. In addition, the mechanism of PG in ALL was confirmed by protein‒protein interaction, gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. Furthermore, molecular docking was carried out by AutoDock Vina. Finally, Western blotting was performed to confirm the effect of PG on NALM6 cells. Results: PG inhibited the proliferation of NALM6 cells. A total of 174 antileukaemic targets of PG were obtained by network pharmacology. The key targets included AKT1, MAPK14, EGFR, ESR1, LCK, PTPN11, RHOA, IGF1, MDM2, HSP90AA1, HRAS, SRC and JAK2. Enrichment analysis found that PG had antileukaemic effects by regulating key targets such as MAPK signalling, and PG had good binding activity with MAPK14 protein (-8.9 kcal/mol). PG could upregulate the expression of the target protein p-P38, induce cell cycle arrest, and promote the apoptosis of leukaemia cells. Conclusion: MAPK14 was confirmed to be one of the key targets and pathways of PG by network pharmacology and molecular experiments.

Inherited retinal disorders: a genotype-phenotype correlation in an Indian cohort and the importance of genetic testing and genetic counselling.

PURPOSE: Recent advances in sequencing technologies have enabled radical and rapid progress in the genetic diagnosis of inherited retinal disorders (IRDs). Although the list of gene variations continues to grow, it lacks the genetic etiology of ethnic groups like South Asians. Differences in racial backgrounds and consanguinity add to genetic heterogeneity and phenotypic overlaps. METHODS: This retrospective study includes documented data from the Gen-Eye clinic from years 2014 to 2019. Medical records and pedigrees of 591 IRD patients of Indian origin and genetic reports of 117 probands were reviewed. Genotype-phenotype correlations were performed to classify as correlating, non-correlating and unsolved cases. RESULTS: Among the 591 patients, we observed a higher prevalence of clinically diagnosed retinitis pigmentosa (38.9%) followed by unspecified diagnoses (28.5%). Consanguinity was reported to be high (55.6%) in this cohort. Among the variants identified in 117 probands, 36.4% of variants were pathogenic, 19.2% were likely pathogenic, and 44.4% were of uncertain significance. Among the pathogenic and likely pathogenic variants, autosomal recessive inheritance showed higher prevalence. About 35% (41/117) of cases showed genotype-phenotype correlation. Within the correlating cases, retinitis pigmentosa and Stargardt disease were predominant. Novel variants identified in RP, Stargardt, and LCA are reported here. CONCLUSION: This first-of-a-kind report on an Indian cohort contributes to existing knowledge and expansion of variant databases, presenting relevant and plausible novel variants. Phenotypic overlap and variability lead to a differential diagnosis and hence a clear genotype-phenotype correlation helps in precise clinical confirmation. The study also emphasizes the importance of genetic counselling and testing for personalized vision care in a tertiary eye hospital.