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Haemoglobin is a key molecule for oxygen transport in vertebrates. It exhibits remarkable gene diversity in teleost fishes, reflecting adaptation to various aquatic environments. In this study, we present the dynamic evolution of haemoglobin subunit genes based on a comparison of high-quality genome assemblies of 24 vertebrate species, including 17 teleosts (of which six are cichlids). Our findings indicate that teleost genomes contain a range of haemoglobin genes, from as few as five in fugu to as many as 43 in salmon, with the latter being the largest repertoire found in vertebrates. We find evidence that the teleost ancestor had at least four Hbα and three or four Hbβ subunit genes, and that the current gene diversity emerged during teleost radiation, driven primarily by (tandem) gene duplications, genome compaction, and rearrangement dynamics. We provide insights into the genomic organisation of haemoglobin clusters in different teleost species. We further show that the evolution of paralogous rhbdf1 genes flanking both teleost clusters (LA and MN) supports the hypothesis for the origin of the LA cluster by rearrangement within teleosts, rather than by the teleost specific whole-genome duplication. We specifically focus on cichlid fishes, where adaptation to low oxygen environment plays role in species diversification. Our analysis of six cichlid genomes, including Pungu maclareni from the Barombi Mbo crater lake, for which we sequenced a representative genome, reveals 18-32 copies of the Hb genes, and elevated rates of non-synonymous substitutions compared to other teleosts. Overall, this work facilitates a deeper understanding of how haemoglobin genes contribute to the adaptive potential of teleosts., (© 2024 The Author(s). Molecular Ecology published by John Wiley & Sons Ltd.)

Although implicated as deleterious in many organisms, aneuploidy can underlie rapid phenotypic evolution. However, aneuploidy will be maintained only if the benefit outweighs the cost, which remains incompletely understood. To quantify this cost and the molecular determinants behind it, we generated a panel of chromosome duplications in Saccharomyces cerevisiae and applied comparative modeling and molecular validation to understand aneuploidy toxicity. We show that 74%-94% of the variance in aneuploid strains' growth rates is explained by the cumulative cost of genes on each chromosome, measured for single-gene duplications using a genomic library, along with the deleterious contribution of small nucleolar RNAs (snoRNAs) and beneficial effects of tRNAs. Machine learning to identify properties of detrimental gene duplicates provided no support for the balance hypothesis of aneuploidy toxicity and instead identified gene length as the best predictor of toxicity. Our results present a generalized framework for the cost of aneuploidy with implications for disease biology and evolution., Competing Interests: Declaration of interests The authors have no competing interests to declare., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The adoption of agriculture triggered a rapid shift towards starch-rich diets in human populations 1 . Amylase genes facilitate starch digestion, and increased amylase copy number has been observed in some modern human populations with high-starch intake 2 , although evidence of recent selection is lacking 3,4 . Here, using 94 long-read haplotype-resolved assemblies and short-read data from approximately 5,600 contemporary and ancient humans, we resolve the diversity and evolutionary history of structural variation at the amylase locus. We find that amylase genes have higher copy numbers in agricultural populations than in fishing, hunting and pastoral populations. We identify 28 distinct amylase structural architectures and demonstrate that nearly identical structures have arisen recurrently on different haplotype backgrounds throughout recent human history. AMY1 and AMY2A genes each underwent multiple duplication/deletion events with mutation rates up to more than 10,000-fold the single-nucleotide polymorphism mutation rate, whereas AMY2B gene duplications share a single origin. Using a pangenome-based approach, we infer structural haplotypes across thousands of humans identifying extensively duplicated haplotypes at higher frequency in modern agricultural populations. Leveraging 533 ancient human genomes, we find that duplication-containing haplotypes (with more gene copies than the ancestral haplotype) have rapidly increased in frequency over the past 12,000 years in West Eurasians, suggestive of positive selection. Together, our study highlights the potential effects of the agricultural revolution on human genomes and the importance of structural variation in human adaptation., (© 2024. The Author(s).)

Background: Deletion or duplication in the DMD gene is one of the most common causes of Duchenne and Becker muscular dystrophy (DMD/BMD). However, the pathogenicity of complex rearrangements involving DMD, especially segmental duplications with unknown breakpoints, is not well understood. This study aimed to evaluate the structure, pattern, and potential impact of rearrangements involving DMD duplication., Methods: Two families with DMD segmental duplications exhibiting phenotypical differences were recruited. Optical genome mapping (OGM) was used to explore the cryptic pattern of the rearrangements. Breakpoints were validated using long-range polymerase chain reaction combined with next-generation sequencing and Sanger sequencing., Results: A multi-copy duplication involving exons 64-79 of DMD was identified in Family A without obvious clinical symptoms. Family B exhibited typical DMD neuromuscular manifestations and presented a duplication involving exons 10-13 of DMD. The rearrangement in Family A involved complex in-cis tandem repeats shown by OGM but retained a complete copy (reading frame) of DMD inferred from breakpoint validation. A reversed insertion with a segmental repeat was identified in Family B by OGM, which was predicted to disrupt the normal structure and reading frame of DMD after confirming the breakpoints., Conclusions: Validating breakpoint and rearrangement pattern is crucial for the functional annotation and pathogenic classification of genomic structural variations. OGM provides valuable insights into etiological analysis of DMD/BMD and enhances our understanding for cryptic effects of complex rearrangements., (© 2024. The Author(s).)

Structural variants (SVs) of unknown significance are great challenges for prenatal risk assessment, especially when involving dose-sensitive genes such as DMD The pathogenicities of 5'-terminal DMD duplications in the database remain controversial. Four prenatal cases with Xp21.1 duplications were identified by routine prenatal genomic testing, encompassing the 5'-UTR to exons 1-2 in family 1 and family 2, and to exons 1-9 in family 3. The duplication in family 4 was non-contiguous covering the 5'-UTR to exon 1 and exons 3-7. All were traced to unaffected males in the family pedigrees. A new genome-wide approach of optical genome mapping was performed in families 1, 2, and 3 to delineate the breakpoints and orientation of the duplicated fragments. The extra copies were tandemly inserted into the upstream of DMD , preserving the integrity of ORF from the second copy. The pathogenicities were thus reclassified as likely benign. Our data highlight the importance of structural delineation by optical genome mapping in prenatal risk assessment of incidentally identified SVs involving DMD and other similar large dose-sensitive genes., (© 2024 Zhang et al.)

Adaptive nanopore sequencing as a diagnostic method for imprinting disorders and episignature analysis revealed an intragenic duplication of Exon 6 and 7 in UBE3A (NM_000462.5) in a patient with relatively mild Angelman-like syndrome. In an all-in-one nanopore sequencing analysis DNA hypomethylation of the SNURF:TSS-DMR, known contributing deletions on the maternal allele and point mutations in UBE3A could be ruled out as disease drivers. In contrast, breakpoints and orientation of the tandem duplication could clearly be defined. Segregation analysis in the family showed that the duplication derived de novo in the maternal grandfather. Our study shows the benefits of an all-in-one nanopore sequencing approach for the diagnostics of Angelman syndrome and other imprinting disorders., (© 2024. The Author(s).)

The duplication-triplication/inverted-duplication (DUP-TRP/INV-DUP) structure is a complex genomic rearrangement (CGR). Although it has been identified as an important pathogenic DNA mutation signature in genomic disorders and cancer genomes, its architecture remains unresolved. Here, we studied the genomic architecture of DUP-TRP/INV-DUP by investigating the DNA of 24 patients identified by array comparative genomic hybridization (aCGH) on whom we found evidence for the existence of 4 out of 4 predicted structural variant (SV) haplotypes. Using a combination of short-read genome sequencing (GS), long-read GS, optical genome mapping, and single-cell DNA template strand sequencing (strand-seq), the haplotype structure was resolved in 18 samples. The point of template switching in 4 samples was shown to be a segment of ∼2.2-5.5 kb of 100% nucleotide similarity within inverted repeat pairs. These data provide experimental evidence that inverted low-copy repeats act as recombinant substrates. This type of CGR can result in multiple conformers generating diverse SV haplotypes in susceptible dosage-sensitive loci., Competing Interests: Declaration of interests Baylor College of Medicine and Miraca Holdings have formed a joint venture with shared ownership and governance of BG, which performs clinical microarray analysis, clinical ES, and clinical biochemical studies. J.R.L. serves on the scientific advisory board of the BG. J.R.L. has stock ownership in 23andMe, is a paid consultant for Genomics International, and is a co-inventor on multiple US and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, genomic disorders, and bacterial genomic fingerprinting. E.H. and S.J. are employees of ONT and shareholders and/or share option holders of ONT. D.P. provides consulting services for Ionis Pharmaceuticals. F.J.S. receives research support from Genetech, Illumina, Pacbio, and ONT., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Whole-genome duplications (WGDs) are widespread genomic events in eukaryotes that are hypothesized to contribute to the evolutionary success of many lineages, including flowering plants, Saccharomyces yeast, and vertebrates. WGDs generally can be classified into autopolyploids (ploidy increase descended from one species) or allopolyploids (ploidy increase descended from multiple species). Assignment of allopolyploid progenitor species (called subgenomes in the polyploid) is important to understanding the biology and evolution of polyploids, including the asymmetric subgenome evolution following hybridization (biased fractionation). Here, I review the different methodologies used to identify the ancestors of allopolyploid subgenomes, discuss the advantages and disadvantages of these methods, and outline the implications of how these methods affect the subsequent evolutionary analysis of these genomes., Competing Interests: Declaration of interests The author declares no conflicts of interest., (Copyright © 2024 The Author. Published by Elsevier Ltd.. All rights reserved.)

Glutathione peroxidase-like enzyme is an important enzymatic antioxidant in plants. It is involved in scavenging reactive oxygen species, which can effectively prevent oxidative damage and improve resistance. GPXL has been studied in many plants but has not been reported in potatoes, the world's fourth-largest food crop. This study identified eight StGPXL genes in potatoes for the first time through genome-wide bioinformatics analysis and further studied the expression patterns of these genes using qRT-PCR. The results showed that the expression of StGPXL1 was significantly upregulated under high-temperature stress, indicating its involvement in potato defense against high-temperature stress, while the expression levels of StGPXL4 and StGPXL5 were significantly downregulated. The expression of StGPXL1, StGPXL2, StGPXL3, and StGPXL6 was significantly upregulated under drought stress, indicating their involvement in potato defense against drought stress. After MeJA hormone treatment, the expression level of StGPXL6 was significantly upregulated, indicating its involvement in the chemical defense mechanism of potatoes. The expression of all StGPXL genes is inhibited under biotic stress, which indicates that GPXL is a multifunctional gene family, which may endow plants with resistance to various stresses. This study will help deepen the understanding of the function of the potato GPXL gene family, provide comprehensive information for the further analysis of the molecular function of the potato GPXL gene family as well as a theoretical basis for potato molecular breeding.

KMT2A partial tandem duplication (KMT2A-PTD) is an adverse risk factor in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), a potential therapeutic target, and an attractive marker of measurable residual disease. High initial KMT2A-PTD RNA levels have been linked to poor prognosis, but mechanisms regulating KMT2A-PTD expression are not well understood. Although KMT2A-PTD has been reported to affect only a single allele, it has been theorized but not proven that genomic gains of a monoallelic KMT2A-PTD may occur, thereby potentially driving high expression and disease progression. In this study, we identified 94 patients with KMT2A-PTDs using targeted DNA next-generation sequencing (NGS) and found that 16% (15/94) had complex secondary events, including copy-neutral loss of heterozygosity and selective gain involving the KMT2A-PTD allele. High copy numbers indicating complexity were significantly enriched in AML vs MDS and correlated with higher RNA expression. Moreover, in serial samples, complexity was associated with relapse and secondary transformation. Taken together, we provide approaches to integrate quantitative and allelic assessment of KMT2A-PTDs into targeted DNA NGS and demonstrate that secondary genetic events occur in KMT2A-PTD by multiple mechanisms that may be linked to myeloid disease progression by driving increased expression from the affected allele., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Li-Fraumeni syndrome (LFS) is one of the most common cancer predisposition syndromes that affects both children and adults. Individuals with LFS are at an increased risk of developing various types of cancer over their lifetime including soft tissue sarcomas, osteosarcomas, breast cancer, leukemia, brain tumors, and adrenocortical carcinoma. Heterozygous germline pathogenic variants in the tumor suppressor gene TP53 are the known causal genetic defect for LFS. Single-nucleotide variants (SNVs) including missense substitutions that occur in the highly conserved DNA binding domain of the protein are the most common alterations, followed by nonsense and splice site variants. Gross copy-number changes in TP53 are rare and account for <1% of all variants. Using next-generation sequencing (NGS) panels, we identified a paternally inherited germline intragenic duplication of TP53 in a child with metastatic osteosarcoma who later developed acute myeloid leukemia (AML). Transcriptome sequencing (RNA-seq) demonstrated the duplication was tandem, encompassing exons 2-6 and 28 nt of the untranslated region (UTR) upstream of the start codon in exon 2. The inclusion of the 28 nt is expected to result in a frameshift with a stop codon 18 codons downstream from the exon 6, leading to a loss-of-function allele. This case highlights the significance of simultaneous identification of both significant copy-number variants as well as SNVs/indels using NGS panels., (© 2022 Xu et al.; Published by Cold Spring Harbor Laboratory Press.)

Brassica napus and its diploid progenitors ( B. rapa and B. oleracea ) are suitable for studying the problems associated with polyploidization. As an important anti-stress protein, RCI2 proteins widely exist in various tissues of plants, and are crucial to plant growth, development, and stress response. In this study, the RCI2 gene family was comprehensively identified and analyzed, and 9, 9, and 24 RCI2 genes were identified in B. rapa , B. oleracea , and B. napus , respectively. Phylogenetic analysis showed that all of the identified RCI2 genes were divided into two groups, and further divided into three subgroups. Ka/Ks analysis showed that most of the identified RCI2 genes underwent a purifying selection after the duplication events. Moreover, gene structure analysis showed that the structure of RCI2 genes is largely conserved during polyploidization. The promoters of the RCI2 genes in B. napus contained more cis -acting elements, which were mainly involved in plant development and growth, plant hormone response, and stress responses. Thus, B. napus might have potential advantages in some biological aspects. In addition, the changes of RCI2 genes during polyploidization were also discussed from the aspects of gene number, gene structure, gene relative location, and gene expression, which can provide reference for future polyploidization analysis.

This work studies the effects of the two rounds of Whole Genome Duplication (WGD) at the origin of the vertebrate lineage on the architecture of the human gene regulatory networks. We integrate information on transcriptional regulation, miRNA regulation, and protein-protein interactions to comparatively analyse the role of WGD and Small Scale Duplications (SSD) in the structural properties of the resulting multilayer network. We show that complex network motifs, such as combinations of feed-forward loops and bifan arrays, deriving from WGD events are specifically enriched in the network. Pairs of WGD-derived proteins display a strong tendency to interact both with each other and with common partners and WGD-derived transcription factors play a prominent role in the retention of a strong regulatory redundancy. Combinatorial regulation and synergy between different regulatory layers are in general enhanced by duplication events, but the two types of duplications contribute in different ways. Overall, our findings suggest that the two WGD events played a substantial role in increasing the multi-layer complexity of the vertebrate regulatory network by enhancing its combinatorial organization, with potential consequences on its overall robustness and ability to perform high-level functions like signal integration and noise control. Lastly, we discuss in detail the RAR/RXR pathway as an illustrative example of the evolutionary impact of WGD duplications in human., Competing Interests: The authors have declared that no competing interests exist.

Autosomal recessive cerebellar ataxias (ARCA) are characterized by the abnormal structure of the cerebellum and spinal cord. Spinocerebellar ataxia type 18 (MIM 616204), one of the ARCA, is caused by the loss-of-function mutations of the GRID2 gene due to deletions. Missense mutations in the GRID2 cause ataxia with the gain-of-function mechanism. We report a homozygous GRID2  duplication in childhood-onset ataxia in two siblings. The clinical exome sequencing was performed on one of the siblings. No disease-causing mutations were reported as a result of the clinical exome test. Chromosomal microarray analysis was performed on the entire family using Affymetrix Optima ® chips. Chromosomal microarray analysis showed a ~ 121-kb homozygous duplication of GRID2 (arr[GRCh37]4q22.2(94426536&#95;94613158) × 4), including exon 14, in both siblings. Previously, GRID2 has been associated with an autosomal recessive (loss-of-function) and autosomal semi-dominant (gain-of-function) forms of ataxia. To the best of our knowledge, this is the first study to identify a homozygous duplication of GRID2 causing loss of function of the GluRD2 protein. These findings provide us with the conclusion that copy number variation analyses should be in the diagnostic process of autosomal recessive ataxia types., (© 2020. Belgian Neurological Society.)

MECP2 duplication syndrome (MDS) is caused by copy number variation (CNV) spanning the MECP2 gene at Xq28 and is a major cause of intellectual disability (ID) in males. Herein, we describe two unrelated males harboring non-recurrent complex Xq28 rearrangements associated with MDS. Copy number gains were initially detected by quantitative real-time polymerase chain reaction and further delineated by high-resolution array comparative genomic hybridization, familial segregation, expression analysis and X-chromosome inactivation (XCI) evaluation in a carrier mother. SNVs within the rearrangements and/or fluorescent in situ hybridization (FISH) were used to assess the parental origin of the rearrangements. Patient 1 exhibited an intrachromosomal rearrangement, whose structure is consistent with a triplicated segment presumably embedded in an inverted orientation between two duplicated sequences (DUP-TRP/INV-DUP). The rearrangement was inherited from the carrier mother, who exhibits extreme XCI skewing and subtle psychiatric symptoms. Patient 2 presented a de novo (X;Y) unbalanced translocation resulting in duplication of Xq28 and deletion of Yp, originated in the paternal gametogenesis. Neurodevelopmental trajectory and non-neurological symptoms were consistent with previous reports, with the exception of cerebellar vermis hypoplasia in patient 2. Although both patients share the core MDS phenotype, patient 1 showed MECP2 transcript levels in blood similar to controls. Understanding the molecular mechanisms related to MDS is essential for designing targeted therapeutic strategies., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Backgrounds: Populus and Salix belong to Salicaceae and are used as models to investigate woody plant physiology. The variation of karyotype and nuclear DNA content can partly reflect the evolutionary history of the whole genome, and can provide critical information for understanding, predicting, and potentially ameliorating the woody plant traits. Therefore, it is essential to study the chromosome number (CN) and genome size in detail to provide information for revealing the evolutionary process of Salicaceae., Results: In this study, we report the somatic CNs of seventeen species from eight genera in Salicaceae. Of these, CNs for twelve species and for five genera are reported for the first time. Among the three subfamilies of Salicaceae, the available data indicate CN in Samydoideae is n = 21, 22, 42. The only two genera, Dianyuea and Scyphostegia, in Scyphostegioideae respectively have n = 9 and 18. In Salicoideae, Populus, Salix and five genera closely related to them (Bennettiodendron, Idesia, Carrierea, Poliothyrsis, Itoa) are based on relatively high CNs from n = 19, 20, 21, 22 to n = 95 in Salix. However, the other genera of Salicoideae are mainly based on relatively low CNs of n = 9, 10, 11. The genome sizes of 35 taxa belonging to 14 genera of Salicaceae were estimated. Of these, the genome sizes of 12 genera and all taxa except Populus euphratica are first reported. Except for Dianyuea, Idesia and Bennettiodendron, all examined species have relatively small genome sizes of less than 1 pg, although polyploidization exists., Conclusions: The variation of CN and genome size across Salicaceae indicates frequent ploidy changes and a widespread sharing of the salicoid whole genome duplication (WGD) by the relatives of Populus and Salix. The shrinkage of genome size after WGD indicates massive loss of genomic components. The phylogenetic asymmetry in clade of Populus, Salix, and their close relatives suggests that there is a lag-time for the subsequent radiations after the salicoid WGD event. Our results provide useful data for studying the evolutionary events of Salicaceae., (© 2021. The Author(s).)

Mitogen activated protein kinase kinase kinase (MAPKKK) form the upstream component of MAPK cascade. It is well characterized in several plants such as Arabidopsis and rice however the knowledge about MAPKKKs in tea plant is largely unknown. In the present study, MAPKKK genes of tea were obtained through a genome wide search using Arabidopsis thaliana as the reference genome. Among 59 candidate MAPKKK genes in tea, 17 genes were MEKK-like, 31 genes were Raf-like and 11 genes were ZIK- like. Additionally, phylogenetic relationships were established along with structural analysis, which includes gene structure, its location as well as conserved motifs, cis-acting regulatory elements and functional domain signatures that were systematically examined. Also, on the basis of one orthologous gene found between tea and Arabidopsis, functional interaction was carried out in C. sinensis based on an Arabidopsis association model. The expressional profiles indicated major involvement of MAPKKK genes from tea in response to various abiotic stress factors. Taken together, this study provides the targets for additional inclusive identification, functional study, and provides comprehensive knowledge for a better understanding of the MAPKKK cascade regulatory network in C. sinensis., Competing Interests: The authors have declared that no competing interests exist.

Protein kinase C (PKC) was one of the first kinases identified in human cells. It is now known to constitute a family of kinases that respond to diacylglycerol, phosphatidylserine and for some family members, Ca 2+ . They have a plethora of different functions, such as cell cycle regulation, immune response and memory formation. In mammals, 12 PKC family members have been described, usually divided into 4 different subfamilies. We present here a comprehensive evolutionary analysis of the PKC genes in jawed vertebrates with special focus on the impact of the two tetraploidizations (1R and 2R) before the radiation of jawed vertebrates and the teleost tetraploidization (3R), as illuminated by synteny and paralogon analysis including many neighboring gene families. We conclude that the vertebrate predecessor had five PKC genes, as tunicates and lancelets still do, and that the PKC family should therefore ideally be organized into five subfamilies. The 1R and 2R events led to a total of 12 genes distributed among these five subfamilies. All 12 genes are still present in some of the major lineages of jawed vertebrates, including mammals, whereas birds and cartilaginous fishes have lost one member. The 3R event added another nine genes in teleosts, bringing the total to 21 genes. The zebrafish, a common experimental model animal, has retained 19. We have found no independent gene duplications. Thus, the genome doublings completely account for the complexity of this gene family in jawed vertebrates and have thereby had a huge impact on their evolution., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Vertebrate genome evolution remains a hotly debated topic, specifically as regards the number and the timing of putative rounds of whole genome duplication events. In this study, I sought to shed light to this conundrum through assessing the evolutionary history of the oxytocin/vasotocin receptor family. I performed ancestral analyses of the genomic segments containing oxytocin and vasotocin receptors (OTR-VTRs) by mapping them back to the reconstructed ancestral vertebrate/chordate karyotypes reported in five independent studies (Nakatani et al., 2007; Putnam et al., 2008; Smith and Keinath, 2015; Smith et al., 2018; Simakov et al., 2020) and found that two alternative scenarios can account for their evolution: one consistent with one round of whole genome duplication in the common ancestor of lampreys and gnathostomes, followed by segmental duplications in both lineages, and another consistent with two rounds of whole genome duplication, with the first occurring in the gnathostome-lamprey ancestor and the second in the jawed vertebrate ancestor. Combining the data reported here with synteny and phylogeny data reported in our previous study (Theofanopoulou et al., 2021), I put forward that a single round of whole genome duplication scenario is more consistent with the synteny and evolution of chromosomes where OTR-VTRs are encountered, without excluding the possibility of a scenario including two rounds of whole genome duplication. Although the analysis of one gene family is not able to capture the full complexity of vertebrate genome evolution, this study can provide solid insight, since the gene family used here has been meticulously analyzed for its genes' orthologous and paralogous relationships across species using high quality genomes., (Copyright © 2021 The Author. Published by Elsevier Inc. All rights reserved.)

Tree reconciliation costs are a popular choice to account for the discordance between the evolutionary history of a gene family (i.e., a gene tree), and the species tree through which this family has evolved. This discordance is accounted for by the minimum number of postulated evolutionary events necessary for reconciling the two trees. Such events include gene duplication, loss, and deep coalescence, and are used to define different types of tree reconciliation costs. For example, the duplication-loss cost for a gene tree and species tree accounts for the minimum number of gene duplications and losses necessary to reconcile these trees. Fundamental to the understanding of how gene trees and species trees relate to each other are the diameters of tree reconciliation costs. While such diameters have been well-researched, still absent from these studies are the unconstrained diameters for two of the classic tree reconciliation costs, namely the duplication-loss cost and the loss cost. Here, we show the essential mathematical properties of these diameters and provide efficient solutions for computing them. Finally, we analyze the distributions of these diameters using simulated datasets.

Gene order evolution of unichromosomal genomes, for example mitochondrial genomes, has been modelled mostly by four major types of genome rearrangements: inversions, transpositions, inverse transpositions, and tandem duplication random losses. Generalizing models that include all those rearrangements while admitting computational tractability are rare. In this paper, we study such a rearrangement model, namely the inverse tandem duplication random loss (iTDRL) model, where an iTDRL duplicates and inverts a continuous segment of a gene order followed by the random loss of one of the redundant copies of each gene. The iTDRL rearrangement has currently been proposed by several authors suggesting it to be a possible mechanisms of mitochondrial gene order evolution. We initiate the algorithmic study of this new model of genome rearrangement by proving that a shortest rearrangement scenario that transforms one given gene order into another given gene order can be obtained in quasilinear time. Furthermore, we show that the length of such a scenario, i.e., the minimum number of iTDRLs in the transformation, can be computed in linear time.

Nascent ribosomal 60S subunits undergo the last maturation steps in the cytoplasm. The last one involves removing the anti-association factor eIF6 from the 60S ribosomal surface by the joint action of the Elongation Factor-like 1 (EFL1) GTPase and the SBDS protein. Herein, we studied the evolutionary relationship of the EFL1 and EF-2 protein families and the functional conservation within EFL1 orthologues. Phylogenetic analysis demonstrated that the EFL1 proteins are exclusive of eukaryotes and share an evolutionary origin with the EF-2 and EF-G protein families. EFL1 proteins originated by gene duplication from the EF-2 proteins and specialized in ribosome maturation while the latter retained their function in translation. Some organisms have more than one EFL1 protein resulting from alternative splicing, while others are encoded in different genes originated by gene duplication. However, the function of these alternative EFL1 proteins is still unknown. We performed GTPase activity and complementation assays to study the functional conservation of EFL1 homologs alone and together with their SBDS counterparts. None of the orthologues or cross-species combinations could replace the function of the corresponding yeast EFL1•SBDS binomial. The complementation of SBDS interspecies chimeras indicates that domain 2 is vital for its function together with EFL1 and the 60S subunit. The results suggest a functional species-specificity and possible co-evolution between EFL1, SBDS, and the 60S ribosomal subunit. These findings set the basis for further studies directed to understand the molecular evolution of these proteins and their impact on ribosome biogenesis and disease., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Lineage-specific genes (LSGs) are the genes that have no recognizable homology to any sequences in other species, which are important drivers for the generation of new functions, phenotypic changes, and facilitating species adaptation to environment. Aegiceras corniculatum is one of major mangrove plant species adapted to waterlogging and saline conditions, and the exploration of aegiceras-specific genes (ASGs) is important to reveal its adaptation to the harsh environment. Here, we performed a systematic analysis on ASGs, focusing on their sequence characterization, origination and expression patterns. Our results reveal that there are 4823 ASGs in the genome, approximately 11.84% of all protein-coding genes. High proportion (45.78%) of ASGs originate from gene duplication, and the time of gene duplication of ASGs is consistent with the timing of two genome-wide replication (WGD) events that occurred in A. corniculatum, and also coincides with a short period of global warming during the Paleocene-Eocene Maximum (PETM, 55.5 million years ago). Gene structure analysis showed that ASGs have shorter protein lengths, fewer exons, and higher isoelectric point. Expression patterns analysis showed that ASGs had low levels of expression and more tissue-specific expression. Weighted gene co-expression network analysis (WGCNA) revealed that 86 ASGs co-expressed gene modules were primarily involved in pathways related to adversity stress, including plant hormone signal transduction, phenylpropanoid biosynthesis, photosynthesis, peroxisome and pentose phosphate pathway. This study provides a comprehensive analysis of the characteristics and potential functions of ASGs and identifies key candidate genes, which will contribute to the subsequent further investigation of the adaptation of A. corniculatum to intertidal coastal wetland habitats., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Nuclear factor Y (NF-Y) is a heterotrimeric transcription factor playing crucial roles in various biological process in plant. However, thorough research on NF-Y gene family of Tartary buckwheat (Fagopyrum tataricum) is little. In this study, 38 FtNF-Y genes (12 FtNF-YAs, 17 FtNF-YBs, and 9 FtNF-YCs) were identified and renamed on the basis of their subfamily and chromosomal location. Their gene structure, genomic mapping, motif composition, conserved domain, phylogenetic relationships, cis-acting elements and gene expression were investigated. Illustration of gene structures and conserved domains of FtNF-Ys revealed their functional conservation and specificity. Construction of phylogenetic trees of NF-Ys in Tartary buckwheat, Arabidopsis, tomato, rice and banana, allowed us to predict functional similarities among NF-Ys from different species. Gene expression analysis displayed that twenty-four FtNF-Ys were expressed in all the tissues and the transcript levels of them were different, suggesting their function varieties. Moreover, expression profiles of twenty FtNF-Ys along five different fruit development stages acquired by real-time quantitative PCR (RT-qPCR) demonstrated distinct abundance diversity at different stages, providing some clues of potential fruit development regulators. Our study could provide helpful reference information for further function characterization of FtNF-Ys and for the fruit quality enhancement of Tartary buckwheat., (Copyright © 2021. Published by Elsevier B.V.)

Gene trees can differ from species trees due to a variety of biological phenomena, the most prevalent being gene duplication, horizontal gene transfer, gene loss, and coalescence. To explain topological incongruence between the two trees, researchers apply reconciliation methods, often relying on a maximum parsimony framework. However, while several studies have investigated the space of maximum parsimony reconciliations (MPRs) under the duplication-loss and duplication-transfer-loss models, the space of MPRs under the duplication-loss-coalescence (DLC) model remains poorly understood. To address this problem, we present new algorithms for computing the size of MPR space under the DLC model and sampling from this space uniformly at random. Our algorithms are efficient in practice, with runtime polynomial in the size of the species and gene tree when the number of genes that map to any given species is fixed, thus proving that the MPR problem is fixed-parameter tractable. We have applied our methods to a biological data set of 16 fungal species to provide the first key insights in the space of MPRs under the DLC model. Our results show that a plurality reconciliation, and underlying events, are likely to be representative of MPR space.

Maximum parsimony reconciliation is a fundamental technique for studying the evolutionary histories of pairs of entities such as genes and species, parasites and hosts, and species and their biogeographical habitats. In these contexts, reconciliation is generally performed using the duplication-transfer-loss (DTL) model in a maximum parsimony framework. While efficient maximum parsimony reconciliation algorithms are known for the DTL model, the number of such reconciliations can grow exponentially with the sizes of the two phylogenetic trees. Choosing a maximum parsimony reconciliation arbitrarily may lead to conclusions that are not supported, and may even be contradicted, by other equally optimal reconciliations. This paper addresses the fundamental problem of how well a single reconciliation can represent the entire space of optimal reconciliations.

Gene duplications generate new genes that can contribute to expression changes and the evolution of new functions. Genomes often consist of gene families that undergo expansions, some of which occur in specific lineages that reflect recent adaptive diversification. In this study, lineage-specific genes and gene family expansions were studied across five dictyostelid species to determine when and how they are expressed during multicellular development. Lineage-specific genes were found to be enriched among genes with biased expression (predominant expression in one developmental stage) in each species and at most developmental time points, suggesting independent functional innovations of new genes throughout the phylogeny. Biased duplicate genes had greater expression divergence than their orthologs and paralogs, consistent with subfunctionalization or neofunctionalization. Lineage-specific expansions in particular had biased genes with both molecular signals of positive selection and high expression, suggesting adaptive genetic and transcriptional diversification following duplication. Our results present insights into the potential contributions of lineage-specific genes and families in generating species-specific phenotypes during multicellular development in dictyostelids.

Cystatins, as reversible inhibitors of papain-like and legumain proteases, have been identified in several plant species. Although the cystatin family plays crucial roles in plant development and defense responses to various stresses, this family in wheat ( Triticum aestivum L.) is still poorly understood. In this study, 55 wheat cystatins ( TaCystatins ) were identified. All TaCystatins were divided into three groups and both the conserved gene structures and peptide motifs were relatively conserved within each group. Homoeolog analysis suggested that both homoeolog retention percentage and gene duplications contributed to the abundance of the TaCystatin family. Analysis of duplication events confirmed that segmental duplications played an important role in the duplication patterns. The results of codon usage pattern analysis showed that TaCystatins had evident codon usage bias, which was mainly affected by mutation pressure. TaCystatins may be regulated by cis-acting elements, especially abscisic acid and methyl jasmonate responsive elements. In addition, the expression of all selected TaCystatins was significantly changed following viral infection and cold stress, suggesting potential roles in response to biotic and abiotic challenges. Overall, our work provides new insights into TaCystatins during wheat evolution and will help further research to decipher the roles of TaCystatins under diverse stress conditions.

Genomic rearrangements cause congenital disorders, cancer, and complex diseases in human. Yet, they are still understudied in rare diseases because their detection is challenging, despite the advent of whole genome sequencing (WGS) technologies. Short-read (srWGS) and long-read WGS approaches are regularly compared, and the latter is commonly recommended in studies focusing on genomic rearrangements. However, srWGS is currently the most economical, accurate, and widely supported technology. In Caenorhabditis elegans (C. elegans), such variants, induced by various mutagenesis processes, have been used for decades to balance large genomic regions by preventing chromosomal crossover events and allowing the maintenance of lethal mutations. Interestingly, those chromosomal rearrangements have rarely been characterized on a molecular level. To evaluate the ability of srWGS to detect various types of complex genomic rearrangements, we sequenced three balancer strains using short-read Illumina technology. As we experimentally validated the breakpoints uncovered by srWGS, we showed that, by combining several types of analyses, srWGS enables the detection of a reciprocal translocation (eT1), a free duplication (sDp3), a large deletion (sC4), and chromoanagenesis events. Thus, applying srWGS to decipher real complex genomic rearrangements in model organisms may help designing efficient bioinformatics pipelines with systematic detection of complex rearrangements in human genomes., (© 2021. The Author(s).)

Fractionation is the genome-wide process of losing one gene per duplicate pair following whole genome doubling (WGD). An important type of evidence for duplicate gene loss is the frequency distribution of similarities between paralogous gene pairs in a genome or orthologous gene pairs in two species. We extend a previous branching process model for fractionation, originally accounting for paralog similarities, to encompass the distribution of ortholog similarities, after multiple rounds of whole genome doubling and fractionation, with the speciation event occurring at any point. We estimate the fractionation rates during all the inter-event periods in each lineage of the plant family Malvaceae. We suggest a major correction of the phylogenetic position of the durian sub-family, and discover a new triplication event in this lineage.

Most coding genes in the human genome are annotated with multiple alternative transcripts. However, clear evidence for the functional relevance of the protein isoforms produced by these alternative transcripts is often hard to find. Alternative isoforms generated from tandem exon duplication-derived substitutions are an exception. These splice events are rare, but have important functional consequences. Here, we have catalogued the 236 tandem exon duplication-derived substitutions annotated in the GENCODE human reference set. We find that more than 90% of the events have a last common ancestor in teleost fish, so are at least 425 million years old, and twenty-one can be traced back to the Bilateria clade. Alternative isoforms generated from tandem exon duplication-derived substitutions also have significantly more clinical impact than other alternative isoforms. Tandem exon duplication-derived substitutions have >25 times as many pathogenic and likely pathogenic mutations as other alternative events. Tandem exon duplication-derived substitutions appear to have vital functional roles in the cell and may have played a prominent part in metazoan evolution., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Comparative transcriptomics, applied in an evolutionary context, has transformed the possibilities for studying phenotypic evolution in non-model taxa. We review recent discoveries about the development of novel, ecologically relevant phenotypes in hemipteran insects. These discoveries highlight the diverse genomic substrates of novelty: 'something old', when novelty results from changes in the regulation of existing genes or gene duplication; 'something new', wherein lineage-restricted genes contribute to the evolution of new phenotypes; and 'something borrowed', showcasing contributions of horizontal gene transfer to the evolution of novelty, including carotenoid synthesis (resulting in 'something red'). These findings show the power and flexibility of comparative transcriptomic approaches for expanding beyond the 'toolkit' model for the evolution of development. We conclude by raising questions about the relationship between new genes and new traits and outlining a research framework for answering them in Hemiptera., (Copyright © 2021. Published by Elsevier Ltd.)

The 14-3-3 family genes are highly conserved regulatory factors in eukaryotes with involvement in multiple important cellular processes. However, detailed investigations of this family in fishes are very limited. Here, a comparative genomic and transcriptomic survey were performed to investigate the 14-3-3 family in fishes. We confirmed that the numbers of 14-3-3 genes ranged from 5 to 7 in non-teleost fishes, as well as additional 14-3-3 genes (9 to 11) in teleost fishes. In addition, some special teleost fishes possess 17 to 25 14-3-3s, which undergone the fourth whole-genome duplication (WGD). We also found that six pairs of fish 14-3-3 genes were clustered with mammalian ε, γ, ς, η, τand β isotypes, respectively, while σ was absent with a potential specificity within mammals, on the basis of their phylogenetic and synteny analyses. According to our results, we inferred that the diversity of 14-3-3 genes in fishes seems to be generated from a combination of WGD and gene loss. Comparative transcriptomic analysis revealed that there are differences in tissue distribution, and we speculated that 14-3-3 genes may contribute to terrestrial adaptations in mudskippers. In addition, protein sequence alignments of 14-3-3s supported their differential roles in fishes. In summary, our present comparative genomic and transcriptomic survey will benefit for further functional investigations of these fish genes., (Copyright © 2021. Published by Elsevier B.V.)

It is a conventionally held dogma that the genetic basis underlying development is conserved in a long evolutionary time scale. Ample experiments based on mutational, biochemical, functional, and complementary knockdown/knockout approaches have revealed the unexpectedly important role of recently evolved new genes in the development of Drosophila. The recent progress in the genome-wide experimental testing of gene effects and improvements in the computational identification of new genes (< 40 million years ago, Mya) open the door to investigate the evolution of gene essentiality with a phylogenetically high resolution. These advancements also raised interesting issues in techniques and concepts related to phenotypic effect analyses of genes, particularly of those that recently originated. Here we reported our analyses of these issues, including reproducibility and efficiency of knockdown experiment and difference between RNAi libraries in the knockdown efficiency and testing of phenotypic effects. We further analyzed a large data from knockdowns of 11,354 genes (~75% of the Drosophila melanogaster total genes), including 702 new genes (~66% of the species total new genes that aged < 40 Mya), revealing a similarly high proportion (~32.2%) of essential genes that originated in various Sophophora subgenus lineages and distant ancestors beyond the Drosophila genus. The transcriptional compensation effect from CRISPR knockout were detected for highly similar duplicate copies. Knockout of a few young genes detected analogous essentiality in various functions in development. Taken together, our experimental and computational analyses provide valuable data for detection of phenotypic effects of genes in general and further strong evidence for the concept that new genes in Drosophila quickly evolved essential functions in viability during development., Competing Interests: The authors have declared that no competing interests exist.

Background: PTI1 (Pto-interacting 1) protein kinase belongs to the receptor-like cytoplasmic kinase (RLCK) group of receptor-like protein kinases (RLK), but lack extracellular and transmembrane domains. PTI1 was first identified in tomato (Solanum lycopersicum) and named SlPTI1, which has been reported to interact with bacterial effector Pto, a serine/threonine protein kinase involved in plant resistance to bacterial disease. Briefly, the host PTI1 specifically recognizes and interacts with the bacterial effector AvrPto, which triggers hypersensitive cell death to inhibit the pathogen growth in the local infection site. Previous studies have demonstrated that PTI1 is associated with oxidative stress and hypersensitivity., Results: We identified 12 putative PTI1 genes from the genome of foxtail millet (Setaria italica) in this study. Gene replication analysis indicated that both segmental replication events played an important role in the expansion of PTI1 gene family in foxtail millet. The PTI1 family members of model plants, i.e. S. italica, Arabidopsis (Arabidopsis thaliana), rice (Oryza sativa), maize (Zea mays), S. lycopersicum, and soybean (Glycine max), were classified into six major categories according to the phylogenetic analysis, among which the PTI1 family members in foxtail millet showed higher degree of homology with those of rice and maize. The analysis of a complete set of SiPTI1 genes/proteins including classification, chromosomal location, orthologous relationships and duplication. The tissue expression characteristics revealed that SiPTI1 genes are mainly expressed in stems and leaves. Experimental qRT-PCR results demonstrated that 12 SiPTI1 genes were induced by multiple stresses. Subcellular localization visualized that all of foxtail millet SiPTI1s were localized to the plasma membrane. Additionally, heterologous expression of SiPTI1-5 in yeast and E. coli enhanced their tolerance to salt stress., Conclusions: Our results contribute to a more comprehensive understanding of the roles of PTI1 protein kinases and will be useful in prioritizing particular PTI1 for future functional validation studies in foxtail millet.

Objective: To evaluate the performance of noninvasive prenatal testing (NIPT) and NIPT-PLUS for the detection of genome-wide microdeletion and microduplication syndromes (MMSs) at different sequencing depths. The NIPT sequencing depth was 0.15X, and the data volume was 3 million reads; the NIPT-PLUS sequencing depth was 0.4X, and the data volume was 8 million reads., Methods: A cohort of 50,679 pregnancies was recruited. A total of 42,969 patients opted for NIPT, and 7710 patients opted for NIPT-PLUS. All high-risk cases were advised to undergo invasive prenatal diagnosis and were followed up., Results: A total of 373 cases had a high risk of a copy number variation (CNV) as predicted by NIPT and NIPT-PLUS: NIPT predicted 250 high-risk CNVs and NIPT-PLUS predicted 123. NIPT-PLUS increased the detection rate by 1.02% (0.58% vs 1.60%, p < 0.001). A total of 291 cases accepted noninvasive prenatal diagnosis, with 197 cases of NIPT and 94 cases of NIPT-PLUS. The PPV of CNV > 10 Mb for NIPT-PLUS was significantly higher than that for NIPT (p = 0.02). The total PPV of NIPT-PLUS was 12.56% higher than that of NIPT (43.61% vs 30.96%, p = 0.03)., Conclusion: NIPT-PLUS had a better performance in detecting CNVs in terms of the total detection rate and total PPV. However, great care must be taken in presenting results and providing appropriate counseling to patients when deeper sequencing is performed in clinical practice.

Biodiversity is not evenly distributed among related groups, raising questions about the factors contributing to such disparities. The sunflower family (Asteraceae, >26,000 species) is among the largest and most diverse plant families, but its species diversity is concentrated in a few subfamilies, providing an opportunity to study the factors affecting biodiversity. Phylotranscriptomic analyses here of 244 transcriptomes and genomes produced a phylogeny with strong support for the monophyly of Asteraceae and the monophyly of most subfamilies and tribes. This phylogeny provides a reference for detecting changes in diversification rates and possible factors affecting Asteraceae diversity, which include global climate shifts, whole-genome duplications (WGDs), and morphological evolution. The origin of Asteraceae was estimated at ~83 Mya, with most subfamilies having diverged before the Cretaceous-Paleocene boundary. Phylotranscriptomic analyses supported the existence of 41 WGDs in Asteraceae. Changes to herbaceousness and capitulescence with multiple flower-like capitula, often with distinct florets and scaly pappus/receptacular bracts, are associated with multiple upshifts in diversification rate. WGDs might have contributed to the survival of early Asteraceae by providing new genetic materials to support morphological transitions. The resulting competitive advantage for adapting to different niches would have increased biodiversity in Asteraceae., (© 2021 The Authors. Journal of Integrative Plant Biology Published by John Wiley & Sons Australia, Ltd on behalf of Institute of Botany, Chinese Academy of Sciences.)

Background: Hereditary motor and sensory neuropathy, also referred to as Charcot-Marie-Tooth disease (CMT), is most often caused by a duplication of the peripheral myelin protein 22 (PMP22) gene. This duplication causes CMT type 1A (CMT1A). CMT1A rarely occurs in combination with other hereditary neuromuscular disorders. However, such rare genetic coincidences produce a severe phenotype and have been reported in terms of "double trouble" overlapping syndrome. Waardenburg syndrome (WS) is the most common form of a hereditary syndromic deafness. It is primarily characterized by pigmentation anomalies and classified into four major phenotypes. A mutation in the SRY sex determining region Y-box 10 (SOX10) gene causes WS type 2 or 4 and peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, WS, and Hirschsprung disease. We describe a 11-year-old boy with extreme hypertrophic neuropathy because of a combination of CMT1A and WS type 2. This is the first published case on the co-occurrence of CMT1A and WS type 2., Case Presentation: The 11-year-old boy presented with motor developmental delay and a deterioration in unstable walking at 6 years of age. In addition, he had congenital hearing loss and heterochromia iridis. The neurological examination revealed weakness in the distal limbs with pes cavus. He was diagnosed with CMT1A by the fluorescence in situ hybridization method. His paternal pedigree had a history of CMT1A. However, no family member had congenital hearing loss. His clinical manifestation was apparently severe than those of his relatives with CMT1A. In addition, a whole-body magnetic resonance neurography revealed an extreme enlargement of his systemic cranial and spinal nerves. Subsequently, a genetic analysis revealed a heterozygous frameshift mutation c.876delT (p.F292Lfs*19) in the SOX10 gene. He was eventually diagnosed with WS type 2., Conclusions: We described a patient with a genetically confirmed overlapping diagnoses of CMT1A and WS type 2. The double trouble with the genes created a significant impact on the peripheral nerves system. Severe phenotype in the proband can be attributed to the cumulative effect of mutations in both PMP22 and SOX10 genes, responsible for demyelinating neuropathy.

It is not clear how Fms-like tyrosine kinase 3-internal tandem duplications (FLT3-ITD) regulates checkpoint kinase 1 (CHK1) in acute myeloid leukemia (AML). In this study, we investigated the regulatory effect of FLT3-ITD on CHK1. Our results showed that CHK1 was highly expressed in FLT3-ITD positive AML. The overall survival rate and disease-free survival rate of AML patients with high CHK1 level were lower than those of patients with low CHK1 level. Mechanistically, FLT3-ITD recruited p300 to the CHK1 promoter and subsequently acetylated H3K27, thereby enhancing the transcription of CHK1. Interfering with the expression of CHK1 significantly inhibited the cell proliferation and induced cell apoptosis in FLT3-ITD positive MV4-11 cells. In addition, CHK1 knockdown promoted the sensitivity of MV4-11 cells to the epigenetic inhibitors JQ1 and C646. This study discovers a new therapeutic target for FLT3-ITD + AML and provided evidence for the combination of epigenetic inhibitors for AML treatment.

Major protein components of the mammalian skin barrier are encoded by genes clustered in the Epidermal Differentiation Complex (EDC). The skin of cetaceans, i.e. whales, porpoises and dolphins, differs histologically from that of terrestrial mammals. However, the genetic regulation of their epidermal barrier is only incompletely known. Here, we investigated the EDC of cetaceans by comparative genomics. We found that important epidermal cornification proteins, such as loricrin and involucrin are conserved and subtypes of small proline-rich proteins (SPRRs) are even expanded in numbers in cetaceans. By contrast, keratinocyte proline rich protein (KPRP), skin-specific protein 32 (XP32) and late-cornified envelope (LCE) genes with the notable exception of LCE7A have been lost in cetaceans. Genes encoding proline rich 9 (PRR9) and late cornified envelope like proline rich 1 (LELP1) have degenerated in subgroups of cetaceans. These data suggest that the evolution of an aquatic lifestyle was accompanied by amplification of SPRR genes and loss of specific other epidermal differentiation genes in the phylogenetic lineage leading to cetaceans.

Heritable breast cancers account for 5% to 10% of all breast cancers, and monogenic, highly penetrant genes cause them. Around 90% of pathogenic variants in BRCA1 and BRCA2 are observed using gene sequencing, with another 10% identified through gene duplication/deletion analysis, which differs across various communities. In this study, we performed a next-generation sequencing panel and MLPA on 1484 patients to explain the importance of recurrent germline duplications/deletions of BRCA1-2 and their clinical results and determine how often BRCA gene LGRs were seen in people suspected of hereditary breast and ovarian cancer syndrome. The large genomic rearrangements (LGRs) frequency was approximately 1% (14/1484). All 14 mutations were heterozygous and detected in patients with breast cancer. BRCA1 mutations were more predominant (n = 8, 57.1%) than BRCA2 mutations (6, 42.9%). The most common recurrent mutations were BRCA2 exon three and BRCA1 exon 24 (23) deletions. To the best of our knowledge, BRCA1 5'UTR-exon11 duplication has never been reported before. Testing with MLPA is essential to identify patients at high risk. Our data demonstrate that BRCA1-2 LGRs should be considered when ordering genetic testing for individuals with a personal or family history of cancer, particularly breast cancer. Further research could shed light on BRCA1-2 LGRs' unique carcinogenesis roles., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

All-trans retinoic acid (ATRA) and pre-upfront arsenic trioxide (ATO) have revolutionized the therapy of acute promyelocytic leukemia (APL). However, internal tandem duplication of FMS-like tyrosine kinase 3 (FLT3-ITD) mutations is associated with increased risk of relapse. The aim of this study was to analyze the prognostic impact of FLT3-ITD on APL patients who received remission induction with ATRA, idarubicin (IDA) and/or ATO, followed by ATRA plus ATO along with anthracycline, as consolidation therapy. A total of 72 patients newly diagnosed with APL were included in this study. 83.3% of the patients achieved complete remission (CR) after induction therapy. FLT3-ITD mutations were detected in 16 (22.2%) patients and closely related to bcr-3 PML-RARa transcript (P<0.001). The 5-year overall survival (OS) rate was 100% in both FLT3-ITD positive and FLT3-ITD negative groups, and there was no significant difference in 5-year event-free survival (EFS) between the two groups (78.3% vs. 83.3%, P=0.85). ATRA plus ATO and anthracycline-based chemotherapy achieved great outcome in newly diagnosed APL regardless of the FLT3-ITD mutation status., (© 2021. Huazhong University of Science and Technology.)

Cholinergic α7 nicotinic receptors encoded by the CHRNA7 gene are ligand-gated ion channels directly related to memory and immunomodulation. Exons 5-7 in CHRNA7 can be duplicated and fused to exons A-E of FAR7a , resulting in a hybrid gene known as CHRFAM7A , unique to humans. Its product, denoted herein as Dupα7, is a truncated subunit where the N-terminal 146 residues of the ligand binding domain of the α7 receptor have been replaced by 27 residues from FAM7. Dupα7 negatively affects the functioning of α7 receptors associated with neurological disorders, including Alzheimer's diseases and schizophrenia. However, the stoichiometry for the α7 nicotinic receptor containing dupα7 monomers remains unknown. In this work, we developed computational models of all possible combinations of wild-type α7 and dupα7 pentamers and evaluated their stability via atomistic molecular dynamics and coarse-grain simulations. We assessed the effect of dupα7 subunits on the Ca 2+ conductance using free energy calculations. We showed that receptors comprising of four or more dupα7 subunits are not stable enough to constitute a functional ion channel. We also showed that models with dupα7/α7 interfaces are more stable and are less detrimental for the ion conductance in comparison to dupα7/dupα7 interfaces. Based on these models, we used protein-protein docking to evaluate how such interfaces would interact with an antagonist, α-bungarotoxin, and amyloid Aβ 42 . Our findings show that the optimal stoichiometry of dupα7/α7 functional pentamers should be no more than three dupα7 monomers, in favour of a dupα7/α7 interface in comparison to a homodimer dupα7/dupα7 interface. We also showed that receptors bearing dupα7 subunits are less sensitive to Aβ 42 effects, which may shed light on the translational gap reported for strategies focused on nicotinic receptors in 'Alzheimer's disease research.

In most eukaryotes, centromeric histone (CenH3) proteins mediate mitosis and meiosis and ensure epigenetic inheritance of centromere identity. We hypothesized that disparate chromatin environments in soma versus germline might impose divergent functional requirements on single CenH3 genes, which could be ameliorated by gene duplications and subsequent specialization. Here, we analyzed the cytological localization of two recently identified CenH3 paralogs, Cid1 and Cid5, in Drosophila virilis using specific antibodies and epitope-tagged transgenic strains. We find that only ancestral Cid1 is present in somatic cells, whereas both Cid1 and Cid5 are expressed in testes and ovaries. However, Cid1 is lost in male meiosis but retained throughout oogenesis, whereas Cid5 is lost during female meiosis but retained in mature sperm. Following fertilization, only Cid1 is detectable in the early embryo, suggesting that maternally deposited Cid1 is rapidly loaded onto paternal centromeres during the protamine-to-histone transition. Our studies reveal mutually exclusive gametic specialization of divergent CenH3 paralogs. Duplication and divergence might allow essential centromeric genes to resolve an intralocus conflict between maternal and paternal centromeric requirements in many animal species., (© 2021 Kursel et al.)

Miscanthus, a member of the Saccharinae subtribe that includes sorghum and sugarcane, has been widely studied as a feedstock for cellulosic biofuel production. Here, we report the sequencing and assembly of the Miscanthus floridulus genome by the integration of PacBio sequencing and Hi-C mapping, resulting in a chromosome-scale, high-quality reference genome of the genus Miscanthus. Comparisons among Saccharinae genomes suggest that Sorghum split first from the common ancestor of Saccharum and Miscanthus, which subsequently diverged from each other, with two successive whole-genome duplication events occurring independently in the Saccharum genus and one whole-genome duplication occurring in the Miscanthus genus. Fusion of two chromosomes occurred during rediploidization in M. floridulus and no significant subgenome dominance was observed. A survey of cellulose synthases (CesA) in M. floridulus revealed quite high expression of most CesA genes in growing stems, which is in agreement with the high cellulose content of this species. Resequencing and comparisons of 75 Miscanthus accessions suggest that M. lutarioriparius is genetically close to M. sacchariflorus and that M. floridulus is more distantly related to other species and is more genetically diverse. This study provides a valuable genomic resource for molecular breeding and improvement of Miscanthus and Saccharinae crops.

Graph models often give us a deeper understanding of real-world networks. In the case of biological networks they help in predicting the evolution and history of biomolecule interactions, provided we map properly real networks into the corresponding graph models. In this paper, we show that for biological graph models many of the existing parameter estimation techniques overlook the critical property of graph symmetry (also known formally as graph automorphisms), thus the estimated parameters give statistically insignificant results concerning the observed network. To demonstrate it and to develop accurate estimation procedures, we focus on the biologically inspired duplication-divergence model, and the up-to-date data of protein-protein interactions of seven species including human and yeast. Using exact recurrence relations of some prominent graph statistics, we devise a parameter estimation technique that provides the right order of symmetries and uses phylogenetically old proteins as the choice of seed graph nodes. We also find that our results are consistent with the ones obtained from maximum likelihood estimation (MLE). However, the MLE approach is significantly slower than our methods in practice.

During the past few years several high-quality genomes has been published from Charophyte algae, bryophytes, lycophytes and ferns. These genomes have not only elucidated the origin and evolution of early land plants, but have also provided important insights into the biology of the seed-free lineages. However, critical gaps across the phylogeny remain and many new questions have been raised through comparing seed-free and seed plant genomes. Here, we review the reference genomes available and identify those that are missing in the seed-free lineages. We compare patterns of various levels of genome and epigenomic organization found in seed-free plants to those of seed plants. Some genomic features appear to be fundamentally different. For instance, hornworts, Selaginella and most liverworts are devoid of whole-genome duplication, in stark contrast to other land plants. In addition, the distribution of genes and repeats appear to be less structured in seed-free genomes than in other plants, and the levels of gene body methylation appear to be much lower. Finally, we highlight the currently available (or needed) model systems, which are crucial to further our understanding about how changes in genes translate into evolutionary novelties.

Polyploidy has played a crucial role in plant evolution, development and function. Synthetic autopolyploid represents an ideal system to investigate the effects of polyploidization on transcriptional regulation. In this study, we deciphered the impact of genome duplication at phenotypic and molecular levels in watermelon. Overall, 88% of the genes in tetraploid watermelon followed a >1:1 dosage effect, and accordingly, differentially expressed genes were largely upregulated. In addition, a great number of hypomethylated regions (1688) were identified in an isogenic tetraploid watermelon. These differentially methylated regions were localized in promoters and intergenic regions and near transcriptional start sites of the identified upregulated genes, which enhances the importance of methylation in gene regulation. These changes were reflected in sophisticated higher-order chromatin structures. The genome doubling caused switching of 108 A and 626 B compartments that harbored genes associated with growth, development and stress responses., (© 2021 Society for Experimental Biology and John Wiley & Sons Ltd.)