Differences in transmission and ploidy between sex chromosomes and autosomes drive divergent evolutionary trajectories, with sex chromosomes generally evolving faster. Because sex-linked genes are transmitted less frequently, they are under less efficient selection. Conversely, exposure of recessive mutations on haploid sex chromosomes creates more efficient selection. In most systems, these effects occur simultaneously and are confounded. The fly families Sciaridae (fungus gnats) and Cecidomyiidae (gall midges) have X0 sex determination, but males transmit only maternally inherited chromosomes. This phenomenon results in equal transmission of the X and autosomes, allowing the effect of haploid selection to be studied in isolation. We discover that, unlike well-studied systems, X chromosomes diverge more slowly than autosomes in these flies. Using population genomic and expression data, we show that despite the X evolving more adaptively, stronger purifying selection explains slower divergence. Our findings demonstrate the utility of non-Mendelian inheritance systems for understanding fundamental evolutionary processes.
- MeSH
- X Chromosome * genetics MeSH
- Diptera * genetics MeSH
- Adaptation, Physiological * genetics MeSH
- Genome, Insect MeSH
- Haploidy MeSH
- Evolution, Molecular MeSH
- Paternal Inheritance * genetics MeSH
- Sex Determination Processes genetics MeSH
- Selection, Genetic MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Interspecific hybridization leads to complex interactions between the parental genomes, often in the form of genome dominance, where one genome prevails over the other. This phenomenon has been attributed to differential chromosome behavior during meiotic division and may involve either female or male meiosis, or both. In hybrids of Allium cepa × A. roylei, only female meiosis is involved, favoring the transmission of A. roylei chromosomes; male meiosis leads to the development of gametes with equal proportion of parental genomes. Female meiotic drive shifts the genome composition from 8R (A. roylei) + 8C (A. cepa) chromosomes in F1 to 9.3R + 6.7C in F2. In this study of two successive backcross generations with A. cepa (BC1 [first backcross generation] and BC1F1 [progeny after intercross of the first backcross generation]), we observed a change in genome dominance: the A. roylei genome, initially dominant during the meiosis in the F1 hybrids, became submissive in BC1, resulting in a genome composition skewed toward A. cepa. Among 23 BC1 and 236 BC1F1 plants, we observed a significant deviating trend of gradual reduction in A. roylei chromosome representation. The reduction was higher in the lineages with more unequal starting proportion of the parental genomes. This study highlights the dynamic nature of genomic interactions in hybrids and raises questions about the underlying molecular mechanisms driving these changes in dominance, as well as the potential for manipulating these interactions for agricultural benefit. Further exploration of the chromosomal behavior during meiosis across various hybrids will deepen our understanding of non-Mendelian inheritance patterns and their implications in plant breeding.
The U4 small nuclear RNA (snRNA) forms a duplex with the U6 snRNA and, together with U5 and ~30 proteins, is part of the U4/U6.U5 tri-snRNP complex, located at the core of the major spliceosome. Recently, recurrent de novo variants in the U4 RNA, transcribed from the RNU4-2 gene, and in at least two other RNU genes were discovered to cause neurodevelopmental disorder. We detected inherited and de novo heterozygous variants in RNU4-2 (n.18_19insA and n.56T>C) and in four out of the five RNU6 paralogues (n.55_56insG and n.56_57insG) in 135 individuals from 62 families with non-syndromic retinitis pigmentosa (RP), a rare form of hereditary blindness. We show that these variants are recurrent among RP families and invariably cluster in close proximity within the three-way junction (between stem-I, the 5' stem-loop and stem-II) of the U4/U6 duplex, affecting its natural conformation. Interestingly, this region binds to numerous splicing factors of the tri-snRNP complex including PRPF3, PRPF8 and PRPF31, previously associated with RP as well. The U4 and U6 variants identified seem to affect snRNP biogenesis, namely the U4/U6 di-snRNP, which is an assembly intermediate of the tri-snRNP. Based on the number of positive cases observed, deleterious variants in RNU4-2 and in RNU6 paralogues could be a significant cause of isolated or dominant RP, accounting for up to 1.2% of all undiagnosed RP cases. This study highlights the role of non-coding genes in rare Mendelian disorders and uncovers pleiotropy in RNU4-2, where different variants underlie neurodevelopmental disorder and RP.
- Keywords
- hereditary disease, non-coding, retinitis pigmentosa, snRNA, spliceosome, splicing,
- Publication type
- Journal Article MeSH
- Preprint MeSH
The B chromosomes exhibit diverse behaviour compared with conventional genetic models. The capacity of the B chromosome either to accumulate or to be eliminated in a tissue-specific manner is dependent on biological processes related to aberrant cell division(s), but here yet remains compatible with normal development. We studied B chromosome elimination in Sorghum purpureosericeum embryos through cryo-sections and demonstrated the B chromosome instability during plant growth using flow cytometry, molecular markers and fluorescent in situ hybridization techniques. Consequently, using B chromosome-specific probes we revealed the non-Mendelian inheritance of B chromosomes in developing pollen. We disclosed that the occurrence of the B chromosome is specific to certain tissues or organs. The distribution pattern is mainly caused by an extensive elimination that functions primarily during embryo development and persists throughout plant development. Furthermore, we described that B chromosome accumulation can occur either by nondisjunction at first pollen mitosis (PMI) or the initiation of extra nuclear division(s) during pollen development. Our study demonstrates the existence of a not-yet-fully described B chromosome drive process, which is likely under the control of the B chromosome.
- Keywords
- B chromosome, accumulation mechanism, chromosome drive, chromosome elimination, extra pollen mitosis, nondisjunction, pollen mitosis, polymitosis,
- MeSH
- Chromosomes, Plant * genetics MeSH
- Mitosis * MeSH
- Nondisjunction, Genetic * MeSH
- Pollen * genetics cytology MeSH
- Seeds genetics growth & development MeSH
- Sorghum * genetics MeSH
- Publication type
- Journal Article MeSH
The recurrence of low-stage lung cancer poses a challenge due to its unpredictable nature and diverse patient responses to treatments. Personalized care and patient outcomes heavily rely on early relapse identification, yet current predictive models, despite their potential, lack comprehensive genetic data. This inadequacy fuels our research focus-integrating specific genetic information, such as pathway scores, into clinical data. Our aim is to refine machine learning models for more precise relapse prediction in early-stage non-small cell lung cancer. To address the scarcity of genetic data, we employ imputation techniques, leveraging publicly available datasets such as The Cancer Genome Atlas (TCGA), integrating pathway scores into our patient cohort from the Cancer Long Survivor Artificial Intelligence Follow-up (CLARIFY) project. Through the integration of imputed pathway scores from the TCGA dataset with clinical data, our approach achieves notable strides in predicting relapse among a held-out test set of 200 patients. By training machine learning models on enriched knowledge graph data, inclusive of triples derived from pathway score imputation, we achieve a promising precision of 82% and specificity of 91%. These outcomes highlight the potential of our models as supplementary tools within tumour, node, and metastasis (TNM) classification systems, offering improved prognostic capabilities for lung cancer patients. In summary, our research underscores the significance of refining machine learning models for relapse prediction in early-stage non-small cell lung cancer. Our approach, centered on imputing pathway scores and integrating them with clinical data, not only enhances predictive performance but also demonstrates the promising role of machine learning in anticipating relapse and ultimately elevating patient outcomes.
- Keywords
- Knowledge graph embedding, Link prediction, Machine learning, Non-small-cell lung cancer, Tumor recurrence prediction,
- MeSH
- Databases, Genetic MeSH
- Genomics * methods MeSH
- Humans MeSH
- Neoplasm Recurrence, Local genetics MeSH
- Lung Neoplasms * genetics MeSH
- Carcinoma, Non-Small-Cell Lung * genetics MeSH
- Machine Learning * MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Hybrid taxa from the genus Pelophylax can propagate themselves in a modified way of sexual reproduction called hybridogenesis ensuring the formation of clonal gametes containing the genome of only one parental (host) species. Pelophylax grafi from South-Western Europe is a hybrid composed of P. ridibundus and P. perezi genomes and it lives with a host species P. perezi (P-G system). Yet it is unknown, whether non-Mendelian inheritance is fully maintained in such populations. In this study, we characterize P. perezi and P. grafi somatic karyotypes by using comparative genomic hybridization, genomic in situ hybridization, fluorescent in situ hybridization, and actinomycin D-DAPI. Here, we show the homeology of P. perezi and P. grafi somatic karyotypes to other Pelophylax taxa with 2n = 26 and equal contribution of ridibundus and perezi chromosomes in P. grafi which supports F1 hybrid genome constitution as well as a hemiclonal genome inheritance. We show that ridibundus chromosomes have larger regions of interstitial (TTAGGG)n repeats flanking the nucleolus organizing region on chromosome no. 10 and a high quantity of AT pairs in the centromeric regions. In P. perezi, we found species-specific sequences in metaphase chromosomes and marker structures in lampbrush chromosomes. Pericentromeric RrS1 repeat sequence was present in perezi and ridibundus chromosomes, but the blocks were stronger in ridibundus. Various cytogenetic techniques applied to the P-G system provide genome discrimination between ridibundus and perezi chromosomal sets. They could be used in studies of germ-line cells to explain patterns of clonal gametogenesis in P. grafi and broaden the knowledge about reproductive strategies in hybrid animals.
- Keywords
- Pelophylax grafi, Pelophylax perezi, comparative genomic hybridization, fluorescent in situ hybridization, hybridogenesis, karyotype,
- MeSH
- Centromere * genetics MeSH
- In Situ Hybridization, Fluorescence MeSH
- Karyotyping MeSH
- Ranidae * genetics MeSH
- Comparative Genomic Hybridization MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Some interspecific plant hybrids show unequal transmission of chromosomes from parental genomes to the successive generations. It has been suggested that this is due to a differential behavior of parental chromosomes during meiosis. However, underlying mechanism is unknown. We analyzed chromosome composition of the F2 generation of Festuca × Lolium hybrids and reciprocal backcrosses to elucidate effects of male and female meiosis on the shift in parental genome composition. We studied male meiosis, including the attachment of chromosomes to the karyokinetic spindle and gene expression profiling of the kinetochore genes. We found that Lolium and Festuca homoeologues were transmitted differently to the F2 generation. Female meiosis led to the replacement of Festuca chromosomes by their Lolium counterparts. In male meiosis, Festuca univalents were attached less frequently to microtubules than Lolium univalents, lagged in divisions and formed micronuclei, which were subsequently eliminated. Genome sequence analysis revealed a number of non-synonymous mutations between copies of the kinetochore genes from Festuca and Lolium genomes. Furthermore, we found that outer kinetochore proteins NDC80 and NNF1 were exclusively expressed from the Lolium allele. We hypothesize that silencing of Festuca alleles results in improper attachment of Festuca chromosomes to karyokinetic spindle and subsequently their gradual elimination.
- Keywords
- NDC80, NNF1, centromere, chromosome elimination, genome dominance, interspecific hybrid, kinetochore, pollen meiosis,
- MeSH
- Chromosomes, Plant genetics MeSH
- Festuca * genetics MeSH
- Genome, Plant MeSH
- Hybridization, Genetic MeSH
- Lolium * genetics MeSH
- Meiosis genetics MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Germline-restricted chromosomes (GRCs) are accessory chromosomes that occur only in germ cells. They are eliminated from somatic cells through programmed DNA elimination during embryo development. GRCs have been observed in several unrelated animal taxa and show peculiar modes of non-Mendelian inheritance and within-individual elimination. Recent cytogenetic and phylogenomic evidence suggests that a GRC is present across the species-rich songbirds, but absent in non-passerine birds, implying that over half of all 10,500 bird species have extensive germline/soma genome differences. Here, we review recent insights gained from genomic, transcriptomic, and cytogenetic approaches with regard to the genetic content, phylogenetic distribution, and inheritance of the songbird GRC. While many questions remain unsolved in terms of GRC inheritance, elimination, and function, we discuss plausible scenarios and future directions for understanding this widespread form of programmed DNA elimination.
- Keywords
- B chromosome, Chromosome elimination, Germline-restricted chromosome, Germline/soma genome difference, Non-Mendelian inheritance,
- MeSH
- Chromosomes genetics MeSH
- DNA MeSH
- Phylogeny MeSH
- Dreams MeSH
- Germ Cells MeSH
- Songbirds * genetics MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
- Names of Substances
- DNA MeSH
Sex chromosomes are generally derived from a pair of classical type-A chromosomes, and relatively few alternative models have been proposed up to now.1,2 B chromosomes (Bs) are supernumerary and dispensable chromosomes with non-Mendelian inheritance found in many plant and animal species3,4 that have often been considered as selfish genetic elements that behave as genome parasites.5,6 The observation that in some species Bs can be either restricted or predominant in one sex7-14 raised the interesting hypothesis that Bs could play a role in sex determination.15 The characterization of putative B master sex-determining (MSD) genes, however, has not yet been provided to support this hypothesis. Here, in Astyanax mexicanus cavefish originating from Pachón cave, we show that Bs are strongly male predominant. Based on a high-quality genome assembly of a B-carrying male, we characterized the Pachón cavefish B sequence and found that it contains two duplicated loci of the putative MSD gene growth differentiation factor 6b (gdf6b). Supporting its role as an MSD gene, we found that the Pachón cavefish gdf6b gene is expressed specifically in differentiating male gonads, and that its knockout induces male-to-female sex reversal in B-carrying males. This demonstrates that gdf6b is necessary for triggering male sex determination in Pachón cavefish. Altogether these results bring multiple and independent lines of evidence supporting the conclusion that the Pachón cavefish B is a "B-sex" chromosome that contains duplicated copies of the gdf6b gene, which can promote male sex determination in this species.
- Keywords
- B chromosome, cavefish, gdf6, genome, sex chromosomes, sex determination, sex differentiation, gonads,
- MeSH
- Biological Evolution MeSH
- Characidae * genetics MeSH
- Caves MeSH
- Sex Chromosomes genetics MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
Hypertrophic cardiomyopathy (HCM) is a common inherited heart disease with an estimated prevalence of up to 1 in 200 individuals. In the majority of cases, HCM is considered a Mendelian disease, with mainly autosomal dominant inheritance. Most pathogenic variants are usually detected in genes for sarcomeric proteins. Nowadays, the genetic basis of HCM is believed to be rather complex. Thousands of mutations in more than 60 genes have been described in association with HCM. Nevertheless, screening large numbers of genes results in the identification of many genetic variants of uncertain significance and makes the interpretation of the results difficult. Patients lacking a pathogenic variant are now believed to have non-Mendelian HCM and probably have a better prognosis than patients with sarcomeric pathogenic mutations. Identifying the genetic basis of HCM creates remarkable opportunities to understand how the disease develops, and by extension, how to disrupt the disease progression in the future. The aim of this review is to discuss the brief history and recent advances in the genetics of HCM and the application of molecular genetic testing into common clinical practice.
- Keywords
- genetics, hypertrophic cardiomyopathy, molecular genetic testing, next-generation sequencing, pathogenic mutations, variants of uncertain significance,
- MeSH
- Genetic Testing * MeSH
- Cardiomyopathy, Hypertrophic diagnosis genetics MeSH
- Humans MeSH
- Mutation * MeSH
- Sarcomeres genetics MeSH
- Muscle Proteins genetics MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
- Names of Substances
- Muscle Proteins MeSH
