Repetitive DNA sequence detection and its role in the human genome

Communications Biology, Год журнала: 2023, Номер 6(1)

Опубликована: Сен. 19, 2023

Abstract Repetitive DNA sequences playing critical roles in driving evolution, inducing variation, and regulating gene expression. In this review, we summarized the definition, arrangement, structural characteristics of repeats. Besides, introduced diverse biological functions repeats reviewed existing methods for automatic repeat detection, classification, masking. Finally, analyzed type, structure, regulation human genome their role induction complex diseases. We believe that review will facilitate a comprehensive understanding provide guidance annotation in-depth exploration its association with

Язык: Английский

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Polygenic burden of short tandem repeat expansions promotes risk for Alzheimer’s disease

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 28, 2025

Studies of the genetics Alzheimer's disease (AD) have largely focused on single nucleotide variants and short insertions/deletions. However, most heritability has yet to be uncovered, suggesting that there is substantial genetic risk conferred by other forms variation. There are over one million tandem repeats (STRs) in genome, their link AD not been assessed. As pathogenic expansions STR cause 30 neurologic diseases, it important ascertain whether STRs may also implicated risk. Here, we genotype 312,731 polymorphic tracts genome-wide using PCR-free whole genome sequencing data from 2981 individuals (1489 case 1492 control individuals). We implement an approach identify as with tract lengths outliers population. then test for differences aggregate burden versus individuals. patients harbor a 1.19-fold increase compared healthy elderly controls (p = 8.27×10-3, two-sided Mann-Whitney test). Individuals carrying >30 3.69-fold higher odds having more severe neuropathology. highly enriched within active promoters post-mortem hippocampal brain tissues particularly SINE-VNTR-Alu (SVA) retrotransposons. Together, these results demonstrate expanded promoter regions associate AD. The authors explore how DNA sequences affect disease. They find who carry high than three-fold increased

Язык: Английский

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Genetic features and genomic targets of human KRAB-zinc finger proteins

Genome Research, Год журнала: 2023, Номер 33(8), С. 1409 - 1423

Опубликована: Авг. 1, 2023

Krüppel-associated box (KRAB) domain-containing zinc finger proteins (KZFPs) are one of the largest groups transcription factors encoded by tetrapods, with 378 members in human alone. KZFP genes often grouped clusters reflecting amplification gene and segment duplication since family first emerged more than 400 million years ago. Previous work has revealed that many KZFPs recognize transposable element (TE)-embedded sequences as genomic targets, facilitate co-option regulatory potential TEs for benefit host. Here, we present a comprehensive survey genetic features targets KZFPs, notably completing past analyses adding data on close to hundred members. General principles emerge from our study TE-KZFP system, which point multipronged evolutionary mechanisms underlaid highly complex combinatorial modes action strong influences speciation.

Язык: Английский

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Epigenomic insights into common human disease pathology

Cellular and Molecular Life Sciences, Год журнала: 2024, Номер 81(1)

Опубликована: Апрель 11, 2024

Abstract The epigenome—the chemical modifications and chromatin-related packaging of the genome—enables same genetic template to be activated or repressed in different cellular settings. This multi-layered mechanism facilitates cell-type specific function by setting local sequence 3D interactive activity level. Gene transcription is further modulated through interplay with factors co-regulators. human body requires this epigenomic apparatus precisely installed throughout development then adequately maintained during lifespan. causal role epigenome pathology, beyond imprinting disorders tumour suppressor genes, was brought into spotlight large-scale sequencing projects identifying that mutations machinery genes could critical drivers both cancer developmental disorders. Abrogation providing new molecular insights pathogenesis. However, deciphering full breadth implications these changes remains challenging. Knowledge accruing regarding disease mechanisms clinical biomarkers, pathogenically relevant surrogate tissue analyses, respectively. Advances include consortia generated reference epigenomes, high-throughput DNA methylome association studies, as well ageing-related diseases from biological ‘clocks’ constructed machine learning algorithms. Also, 3rd-generation beginning disentangle complexity modification haplotypes. Cell-free methylation a biomarker has clear utility potential assess organ damage across many Finally, understanding aetiology brings it opportunity for exact therapeutic alteration CRISPR-activation inhibition.

Язык: Английский

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The Role of Transposable Elements of the Human Genome in Neuronal Function and Pathology

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(10), С. 5847 - 5847

Опубликована: Май 23, 2022

Transposable elements (TEs) have been extensively studied for decades. In recent years, the introduction of whole-genome and whole-transcriptome approaches, as well single-cell resolution techniques, provided a breakthrough that uncovered TE involvement in host gene expression regulation underlying multiple normal pathological processes. Of particular interest is increased activity neuronal tissue, specifically hippocampus, was repeatedly demonstrated experiments. On other hand, numerous neuropathologies are associated with dysregulation. Here, we provide comprehensive review literature about role TEs neurons published over last three The first chapter present describes known mechanisms interaction genomes general, focus on mammalian human TEs; second provides examples exaptation including differentiation plasticity; lists TE-related neuropathologies. We sought to specific molecular neuron-specific processes whenever possible; however, many cases, only phenomenological reports were available. This underscores importance further studies this area.

Язык: Английский

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SAFB restricts contact domain boundaries associated with L1 chimeric transcription

Molecular Cell, Год журнала: 2024, Номер 84(9), С. 1637 - 1650.e10

Опубликована: Апрель 10, 2024

Язык: Английский

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Transposable elements may enhance antiviral resistance in HIV-1 elite controllers

Genome biology, Год журнала: 2025, Номер 26(1)

Опубликована: Фев. 23, 2025

Less than 0.5% of people living with HIV-1 are elite controllers (ECs)—individuals who maintain undetectable plasma viremia without antiretroviral therapy, despite having replication-competent viral reservoirs. While EC CD4+ T cells have been investigated for gene expression signatures associated resistance, the and regulatory activity transposable elements (TEs) remain unexplored. TEs can directly impact host immune responses to pathogens, including HIV-1, suggesting their activities could contribute control. To begin testing this hypothesis, we conduct a TE-centric analysis public multi-omics data from ECs other populations. We find cell transcriptome retrotranscriptome distinct healthy controls, on viremic progressors. However, there is substantial transcriptomic heterogeneity among ECs. categorize into four clusters chromatin accessibility profiles antiviral factors. Several TE families known immuno-regulatory differentially expressed Their positively correlates in negatively KRAB zinc-finger (KZNF) repressors. This coordinated, locus-level variation forms network putative cis-regulatory genes involved restriction. propose that phenotype driven part by reduced KZNF-mediated repression specific TE-derived genes, heightening resistance against HIV-1. Our study reveals transcriptome, variable KZNF controllers, must be considered when deciphering control mechanisms.

Язык: Английский

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Young transposable elements rewired gene regulatory networks in human and chimpanzee hippocampal intermediate progenitors

Development, Год журнала: 2022, Номер 149(19)

Опубликована: Сен. 2, 2022

ABSTRACT The hippocampus is associated with essential brain functions, such as learning and memory. Human hippocampal volume significantly greater than expected compared that of non-human apes, suggesting a recent expansion. Intermediate progenitors, which are able to undergo multiple rounds proliferative division before final neurogenic division, may have played role in evolutionary To investigate the evolution gene regulatory networks underpinning neurogenesis we leveraged differentiation human chimpanzee induced pluripotent stem cells into TBR2 (or EOMES)-positive intermediate progenitor (hpIPCs). We found active hpIPCs different between humans chimpanzees, ∼2500 genes being differentially expressed. demonstrate species-specific transposon-derived enhancers contribute these transcriptomic differences. Young transposons, predominantly endogenous retroviruses SINE-Vntr-Alus (SVAs), were co-opted manner. Human-specific SVAs provided substrates for thousands novel TBR2-binding sites, CRISPR-mediated repression attenuated expression ∼25% upregulated progenitors relative same cell population chimpanzee.

Язык: Английский

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Regulation of expression quantitative trait loci by SVA retrotransposons within the major histocompatibility complex

Experimental Biology and Medicine, Год журнала: 2023, Номер unknown

Опубликована: Ноя. 30, 2023

Genomic and transcriptomic studies of expression quantitative trait loci (eQTL) revealed that SINE-VNTR-Alu (SVA) retrotransposon insertion polymorphisms (RIPs) within human genomes markedly affect the co-expression many coding noncoding genes by coordinated regulatory processes. This study examined polymorphic SVA modulation gene major histocompatibility complex (MHC) genomic region where more than 160 are involved in innate adaptive immunity. We characterized RIPs utilizing sequencing data obtained from whole blood 1266 individuals Parkinson’s Progression Markers Initiative (PPMI) cohort included an analysis leukocyte antigen ( HLA) -A regulation a subpopulation cohort. The properties eight SVAs located class I II MHC regions were associated with differential 71 different 75 outside region. Some same affected two or SVA. Five annotated reference sequence GRCh38.p14/hg38, whereas other three novel insertions individuals. also found distinct structural effects (long short variants CT internal variants) for one R_SVA_24) on HLA-A (550 individuals) PPMI is first time HLA non-HLA (multilocus units) splicing mechanisms have been shown to be regulated structurally applying precise statistical RNA derived samples population. shows important regulators rheostats might potential roles diversity, health, disease.

Язык: Английский

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A SINE-VNTR-Alu at the LRIG2 locus is associated with proximal and distal gene expression in CRISPR and population models

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Янв. 8, 2024

Abstract SINE-VNTR- Alu (SVA) retrotransposons represent mobile regulatory elements that have the potential to influence surrounding genome when they insert into a locus. Evolutionarily recent mobilisation has resulted in loci human where given retrotransposon might be observed present or absent, termed insertion polymorphism (RIP). We previously an SVA RIP ~ 2 kb upstream of LRIG2 on chromosome 1, ‘LRIG2 SVA’, was associated with differences local gene expression and methylation, two were correlated. Here, we used CRISPR-mediated deletion cell line model validate presence is directly affecting provide evidence suggestive modest role for modulating nearby methylation. Additionally, leveraging available Hi-C dataset also involved long-range chromatin interactions cluster genes 300 away, these varying degrees dosage both CRISPR population models. Altogether, data support SVAs modulation expression, latter potentially involving looping, consistent RIPs may contribute interpersonal transcriptional networks.

Язык: Английский

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