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Proceedings of the National Academy of... Jun 2024In many mammals, recombination events are concentrated in hotspots directed by a sequence-specific DNA-binding protein named PRDM9. Intriguingly, PRDM9 has been lost...
In many mammals, recombination events are concentrated in hotspots directed by a sequence-specific DNA-binding protein named PRDM9. Intriguingly, PRDM9 has been lost several times in vertebrates, and notably among mammals, it has been pseudogenized in the ancestor of canids. In the absence of PRDM9, recombination hotspots tend to occur in promoter-like features such as CpG islands. It has thus been proposed that one role of PRDM9 could be to direct recombination away from PRDM9-independent hotspots. However, the ability of PRDM9 to direct recombination hotspots has been assessed in only a handful of species, and a clear picture of how much recombination occurs outside of PRDM9-directed hotspots in mammals is still lacking. In this study, we derived an estimator of past recombination activity based on signatures of GC-biased gene conversion in substitution patterns. We quantified recombination activity in PRDM9-independent hotspots in 52 species of boreoeutherian mammals. We observe a wide range of recombination rates at these loci: several species (such as mice, humans, some felids, or cetaceans) show a deficit of recombination, while a majority of mammals display a clear peak of recombination. Our results demonstrate that PRDM9-directed and PRDM9-independent hotspots can coexist in mammals and that their coexistence appears to be the rule rather than the exception. Additionally, we show that the location of PRDM9-independent hotspots is relatively more stable than that of PRDM9-directed hotspots, but that PRDM9-independent hotspots nevertheless evolve slowly in concert with DNA hypomethylation.
Topics: Animals; Histone-Lysine N-Methyltransferase; Recombination, Genetic; Humans; Mammals; CpG Islands; Eutheria; Mice; Female; Gene Conversion; Evolution, Molecular
PubMed: 38809707
DOI: 10.1073/pnas.2401973121 -
Brazilian Journal of Medical and... 2024Colorectal cancer is one of the most common malignant cancers. Pseudogenes have been identified as oncogenes or tumor suppressor genes in the development of various...
Colorectal cancer is one of the most common malignant cancers. Pseudogenes have been identified as oncogenes or tumor suppressor genes in the development of various cancers. However, the function of pseudogene CSPG4P12 in colorectal cancer remains unclear. Therefore, the aim of this study was to investigate the potential role of CSPG4P12 in colorectal cancer and explore the possible underlying mechanism. The difference of CSPG4P12 expression between colorectal cancer tissues and adjacent normal tissues was analyzed using the online Gene Expression Profiling Interactive Analysis 2 (GEPIA2) database. Cell viability and colony formation assays were conducted to evaluate cell viability. Transwell and wound healing assays were performed to assess cell migration and invasion capacities. Western blot was used to measure the expression levels of epithelial-mesenchymal transition-related proteins. Colorectal cancer tissues had lower CSPG4P12 expression than adjacent normal tissues. The overexpression of CSPG4P12 inhibited cell proliferation, invasion, and migration in colorectal cancer cells. Overexpressed CSPG4P12 promoted the expression of E-cadherin, whereas it inhibited the expression of vimentin, N-cadherin, and MMP9. These findings suggested that CSPG4P12 inhibits colorectal cancer development and may serve as a new potential target for colorectal cancer.
Topics: Humans; Epithelial-Mesenchymal Transition; Colorectal Neoplasms; Pseudogenes; Cell Movement; Cell Proliferation; Disease Progression; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Blotting, Western; Cadherins; Cell Survival; Neoplasm Invasiveness
PubMed: 38808892
DOI: 10.1590/1414-431X2024e13645 -
Nucleic Acids Research May 2024Evidence for gene non-functionalization due to mutational processes is found in genomes in the form of pseudogenes. Pseudogenes are known to be rare in prokaryote...
Evidence for gene non-functionalization due to mutational processes is found in genomes in the form of pseudogenes. Pseudogenes are known to be rare in prokaryote chromosomes, with the exception of lineages that underwent an extreme genome reduction (e.g. obligatory symbionts). Much less is known about the frequency of pseudogenes in prokaryotic plasmids; those are genetic elements that can transfer between cells and may encode beneficial traits for their host. Non-functionalization of plasmid-encoded genes may alter the plasmid characteristics, e.g. mobility, or their effect on the host. Analyzing 10 832 prokaryotic genomes, we find that plasmid genomes are characterized by threefold-higher pseudogene density compared to chromosomes. The majority of plasmid pseudogenes correspond to deteriorated transposable elements. A detailed analysis of enterobacterial plasmids furthermore reveals frequent gene non-functionalization events associated with the loss of plasmid self-transmissibility. Reconstructing the evolution of closely related plasmids reveals that non-functionalization of the conjugation machinery led to the emergence of non-mobilizable plasmid types. Examples are virulence plasmids in Escherichia and Salmonella. Our study highlights non-functionalization of core plasmid mobility functions as one route for the evolution of domesticated plasmids. Pseudogenes in plasmids supply insights into past transitions in plasmid mobility that are akin to transitions in bacterial lifestyle.
PubMed: 38808675
DOI: 10.1093/nar/gkae430 -
Biomedicines May 2024To elucidate the currently unknown molecular mechanisms responsible for the similarity and difference during the acquirement of resistance against gemcitabine (GEM) and...
To elucidate the currently unknown molecular mechanisms responsible for the similarity and difference during the acquirement of resistance against gemcitabine (GEM) and paclitaxel (PTX) in patients with pancreatic carcinoma, we examined two-dimensional (2D) and three-dimensional (3D) cultures of parent MIA PaCa-2 cells (MIA PaCa-2-PA) and their GEM resistance cell line (MIA PaCa-2-GR) and PTX resistance (MIA PaCa-2-PR). Using these cells, we examined 3D spheroid configurations and cellular metabolism, including mitochondrial and glycolytic functions, with a Seahorse bio-analyzer and RNA sequencing analysis. Compared to the MIA PaCa-2-PA, (1) the formation of the 3D spheroids of MIA PaCa-2-GR or -PR was much slower, and (2) their mitochondrial and glycolytic functions were greatly modulated in MIA PaCa-2-GR or -PR, and such metabolic changes were also different between their 2D and 3D culture conditions. RNA sequencing and bioinformatic analyses of the differentially expressed genes (DEGs) using an ingenuity pathway analysis (IPA) suggested that various modulatory factors related to epithelial -mesenchymal transition (EMT) including STAT3, GLI1, ZNF367, NKX3-2, ZIC2, IFIT2, HEY1 and FBLX, may be the possible upstream regulators and/or causal network master regulators responsible for the acquirement of drug resistance in MIA PaCa-2-GR and -PR. In addition, among the prominently altered DEGs (Log2 fold changes more than 6 or less than -6), FABP5, IQSEC3, and GASK1B were identified as unique genes associated with their antisense RNA or pseudogenes, and among these, FABP5 and GASK1B are known to function as modulators of cancerous EMT. Therefore, the observations reported herein suggest that modulations of cancerous EMT may be key molecular mechanisms that are responsible for inducing chemoresistance against GEM or PTX in MIA PaCa-2 cells.
PubMed: 38790973
DOI: 10.3390/biomedicines12051011 -
Genes Apr 2024is considered the closest relative to the invasive weed in China, making it an important native species for studying the invasive mechanisms and adaptations of .... (Comparative Study)
Comparative Study
is considered the closest relative to the invasive weed in China, making it an important native species for studying the invasive mechanisms and adaptations of . Chloroplasts play a crucial role in a plant's environmental adaptation, with their genomes being pivotal in the evolution and adaptation of both invasive and related species. However, the chloroplast genome of has remained unknown until now. In this study, we sequenced and assembled the complete chloroplast genome of using high-throughput sequencing. The chloroplast genome is 151,935 base pairs long, comprising two inverted repeat regions, a large single copy region, and a small single copy region. This chloroplast genome contains 128 genes, including 8 rRNA-coding genes, 37 tRNA-coding genes, 4 pseudogenes, and 83 protein-coding genes. When compared to the chloroplast genome of the invasive weed and other Amaranthaceae species, we observed significant variations in the , , and regions in the chloroplast genome. Moreover, two genes, and , were found to be undergoing rapid evolution due to positive selection pressure. The phylogenetic trees were constructed for the Amaranthaceae family, estimating the time of independent species formation between and to be approximately 3.5186-8.8242 million years ago. These findings provide a foundation for understanding the population variation within invasive species among the genus.
Topics: Genome, Chloroplast; Amaranthaceae; Phylogeny; Introduced Species; Plant Weeds; Chloroplasts; High-Throughput Nucleotide Sequencing; Evolution, Molecular
PubMed: 38790173
DOI: 10.3390/genes15050544 -
Current Issues in Molecular Biology May 2024Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive genetic defects in cortisol synthesis and shows elevated ACTH concentrations, which in turn has...
Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive genetic defects in cortisol synthesis and shows elevated ACTH concentrations, which in turn has downstream effects. The most common variant of CAH, 21-hydroxylase deficiency (21OHD), is the result of pathogenic variants in the gene and is one of the most common monogenic disorders. However, the genetics of 21OHD is complex and challenging. The gene is located in the RCCX copy number variation (CNV), a complex, multiallelic, and tandem CNV in the major histocompatibility complex (MHC) class III region on chromosome 6 (band 6p21.3). Here, and its pseudogene are located 30 kb apart and share a high nucleotide homology of approximately 98% and 96% in exons and introns, respectively. This high-sequence homology facilitates large structural rearrangements, copy number changes, and gene conversion through intergenic recombination. There is a good genotype-phenotype correlation in 21OHD, and genotyping can be performed to confirm the clinical diagnosis, predict long-term outcomes, and determine genetic counseling. Thus, genotyping in CAH is clinically relevant but the interpretations can be challenging for non-initiated clinicians. Here, there are some concrete examples of how molecular diagnosis can sometimes require the use of multiple molecular strategies.
PubMed: 38785559
DOI: 10.3390/cimb46050291 -
Nature Communications May 2024SLC22A10 is an orphan transporter with unknown substrates and function. The goal of this study is to elucidate its substrate specificity and functional characteristics....
SLC22A10 is an orphan transporter with unknown substrates and function. The goal of this study is to elucidate its substrate specificity and functional characteristics. In contrast to orthologs from great apes, human SLC22A10, tagged with green fluorescent protein, is not expressed on the plasma membrane. Cells expressing great ape SLC22A10 orthologs exhibit significant accumulation of estradiol-17β-glucuronide, unlike those expressing human SLC22A10. Sequence alignments reveal a proline at position 220 in humans, which is a leucine in great apes. Replacing proline with leucine in SLC22A10-P220L restores plasma membrane localization and uptake function. Neanderthal and Denisovan genomes show proline at position 220, akin to modern humans, indicating functional loss during hominin evolution. Human SLC22A10 is a unitary pseudogene due to a fixed missense mutation, P220, while in great apes, its orthologs transport sex steroid conjugates. Characterizing SLC22A10 across species sheds light on its biological role, influencing organism development and steroid homeostasis.
Topics: Animals; Humans; Amino Acid Sequence; Estradiol; HEK293 Cells; Hominidae; Mutation, Missense; Organic Cation Transport Proteins; Primates; Pseudogenes; Substrate Specificity
PubMed: 38782905
DOI: 10.1038/s41467-024-48569-7 -
Molecular Biology and Evolution Jun 2024Transglutaminases (TGMs) cross-link proteins by introducing covalent bonds between glutamine and lysine residues. These cross-links are essential for epithelial...
Transglutaminases (TGMs) cross-link proteins by introducing covalent bonds between glutamine and lysine residues. These cross-links are essential for epithelial cornification which enables tetrapods to live on land. Here, we investigated which evolutionary adaptations of vertebrates were associated with specific changes in the family of TGM genes. We determined the catalog of TGMs in the main clades of vertebrates, performed a comprehensive phylogenetic analysis of TGMs, and localized the distribution of selected TGMs in tissues. Our data suggest that TGM1 is the phylogenetically oldest epithelial TGM, with orthologs being expressed in the cornified teeth of the lamprey, a basal vertebrate. Gene duplications led to the origin of TGM10 in stem vertebrates, the origin of TGM2 in jawed vertebrates, and an increasing number of epithelium-associated TGM genes in the lineage leading to terrestrial vertebrates. TGM9 is expressed in the epithelial egg tooth, and its evolutionary origin in stem amniotes coincided with the evolution of embryonic development in eggs that are surrounded by a protective shell. Conversely, viviparous mammals have lost both the epithelial egg tooth and TGM9. TGM3 and TGM6 evolved as regulators of cornification in hair follicles and underwent pseudogenization upon the evolutionary loss of hair in cetaceans. Taken together, this study reveals the gain and loss of vertebrate TGM genes in association with the evolution of cornified skin appendages and suggests an important role of TGM9 in the evolution of amniotes.
Topics: Animals; Transglutaminases; Vertebrates; Evolution, Molecular; Phylogeny; Biological Evolution; Skin
PubMed: 38781495
DOI: 10.1093/molbev/msae100 -
Science Advances May 2024We present a draft genome of the little bush moa ()-one of approximately nine species of extinct flightless birds from Aotearoa, New Zealand-using ancient DNA recovered...
We present a draft genome of the little bush moa ()-one of approximately nine species of extinct flightless birds from Aotearoa, New Zealand-using ancient DNA recovered from a fossil bone from the South Island. We recover a complete mitochondrial genome at 249.9× depth of coverage and almost 900 megabases of a male moa nuclear genome at ~4 to 5× coverage, with sequence contiguity sufficient to identify more than 85% of avian universal single-copy orthologs. We describe a diverse landscape of transposable elements and satellite repeats, estimate a long-term effective population size of ~240,000, identify a diverse suite of olfactory receptor genes and an opsin repertoire with sensitivity in the ultraviolet range, show that the wingless moa phenotype is likely not attributable to gene loss or pseudogenization, and identify potential function-altering coding sequence variants in moa that could be synthesized for future functional assays. This genomic resource should support further studies of avian evolution and morphological divergence.
Topics: Animals; Birds; Genome; Extinction, Biological; Cell Nucleus; Phylogeny; Fossils; Genome, Mitochondrial; Flight, Animal; New Zealand; Male; DNA Transposable Elements; Genomics
PubMed: 38781323
DOI: 10.1126/sciadv.adj6823 -
Microbial Pathogenesis Jul 2024Limosilactobacillus fermentum is an isolate obtained from oral gingival samples of healthy human individuals. The whole genome of Lb. fermentum GD5MG is composed of a...
Limosilactobacillus fermentum is an isolate obtained from oral gingival samples of healthy human individuals. The whole genome of Lb. fermentum GD5MG is composed of a circular DNA molecule containing 1,834,134 bp and exhibits a GC content of 52.80 %. The sequencing effort produced 38.6 million reads, each 150 bp in length, resulting in a sequencing depth of 2912.48x. Our examination unveiled a total of 1961 protein-coding genes, 27 rRNA genes, 24 tRNA genes, 3 non-coding RNA genes, and 63 pseudogenes with the use of gene annotations in NCBI Prokaryotic Genome Annotation tool. RAST revealed 1863 coding genes distributed across 209 subsystems, with a predominant involvement in amino acid, carbohydrate, and protein metabolism. Phylogenetic analysis infers that the Lb. fermentum GD5MG shares 281 gene clusters. Furthermore, the genome features showed a single CRISPR locus of 45 bp in length. Three genes associated with adhesion ability (strA, dltD, and dltA) and 26 genes related to acid tolerance, digestive enzyme secretion, and bile salt resistance were identified. Numerous genes associated with oral probiotic properties, comprising adhesion, acid and bile salt tolerance, oxidative stress tolerance, and sugar metabolism, were identified in the genome. Our findings shed light on the genomic characteristics of Lb. fermentum GD5MG, which are probable probiotics with functional benefits in humans.
Topics: Probiotics; Limosilactobacillus fermentum; Genome, Bacterial; Phylogeny; Humans; Multigene Family; Molecular Sequence Annotation; Base Composition; Bacterial Proteins; Sequence Analysis, DNA; Bacterial Adhesion; Clustered Regularly Interspaced Short Palindromic Repeats; Pseudogenes; DNA, Bacterial; Genes, Bacterial
PubMed: 38750775
DOI: 10.1016/j.micpath.2024.106686