-
Nucleic Acids Research Nov 2023SINE-VNTR-Alu (SVA) retrotransposons are evolutionarily young and still-active transposable elements (TEs) in the human genome. Several pathogenic SVA insertions have...
SINE-VNTR-Alu (SVA) retrotransposons are evolutionarily young and still-active transposable elements (TEs) in the human genome. Several pathogenic SVA insertions have been identified that directly mutate host genes to cause neurodegenerative and other types of diseases. However, due to their sequence heterogeneity and complex structures as well as limitations in sequencing techniques and analysis, SVA insertions have been less well studied compared to other mobile element insertions. Here, we identified polymorphic SVA insertions from 3646 whole-genome sequencing (WGS) samples of >150 diverse populations and constructed a polymorphic SVA insertion reference catalog. Using 20 long-read samples, we also assembled reference and polymorphic SVA sequences and characterized the internal hexamer/variable-number-tandem-repeat (VNTR) expansions as well as differing SVA activity for SVA subfamilies and human populations. In addition, we developed a module to annotate both reference and polymorphic SVA copies. By characterizing the landscape of both reference and polymorphic SVA retrotransposons, our study enables more accurate genotyping of these elements and facilitate the discovery of pathogenic SVA insertions.
Topics: Humans; Alu Elements; Genome, Human; Minisatellite Repeats; Retroelements; Short Interspersed Nucleotide Elements
PubMed: 37823611
DOI: 10.1093/nar/gkad821 -
Molecular Biology and Evolution Sep 2020The hormone progesterone is important for preparing the uterine lining for egg implantation and for maintaining the early stages of pregnancy. The gene encoding the...
The hormone progesterone is important for preparing the uterine lining for egg implantation and for maintaining the early stages of pregnancy. The gene encoding the progesterone receptor (PGR) carries introgressed Neandertal haplotypes with two missense substitutions and a mobile Alu element. These Neandertal gene variants have reached nearly 20% frequency in non-Africans and have been associated with preterm birth. Here, we show that one of the missense substitutions appears fixed in Neandertals, while the other substitution as well as the Alu insertion were polymorphic among Neandertals. We show that two Neandertal haplotypes carrying the PGR gene entered the modern human population and that present-day carriers of the Neandertal haplotypes express higher levels of the receptor. In a cohort of present-day Britons, these carriers have more siblings, fewer miscarriages, and less bleeding during early pregnancy suggesting that the Neandertal progesterone receptor alleles promote fertility. This may explain their high frequency in modern human populations.
Topics: Alleles; Alu Elements; Animals; Female; Fertility; Genetic Introgression; Haplotypes; Humans; Neanderthals; Pregnancy; Premature Birth; Receptors, Progesterone
PubMed: 32437543
DOI: 10.1093/molbev/msaa119 -
BioMed Research International 2014DNA methylation primarily occurs on CpG dinucleotides and plays an important role in transcriptional regulations during tissue development and cell differentiation. Over... (Review)
Review
DNA methylation primarily occurs on CpG dinucleotides and plays an important role in transcriptional regulations during tissue development and cell differentiation. Over 25% of CpG dinucleotides in the human genome reside within Alu elements, the most abundant human repeats. The methylation of Alu elements is an important mechanism to suppress Alu transcription and subsequent retrotransposition. Decades of studies revealed that Alu methylation is highly dynamic during early development and aging. Recently, many environmental factors were shown to have a great impact on Alu methylation. In addition, aberrant Alu methylation has been documented to be an early event in many tumors and Alu methylation levels have been associated with tumor aggressiveness. The assessment of the Alu methylation has become an important approach for early diagnosis and/or prognosis of cancer. This review focuses on the dynamic Alu methylation during development, aging, and tumor genesis. The cause and consequence of Alu methylation changes will be discussed.
Topics: Aging; Alu Elements; Carcinogenesis; DNA Methylation; Female; Humans; Male
PubMed: 25243180
DOI: 10.1155/2014/784706 -
Nucleus (Austin, Tex.) 2014Alus are transposable elements belonging to the short interspersed element family. They occupy over 10% of human genome and have been spreading through genomes over the... (Review)
Review
Alus are transposable elements belonging to the short interspersed element family. They occupy over 10% of human genome and have been spreading through genomes over the past 65 million years. In the past, they were considered junk DNA with little function that took up genome volumes. Today, Alus and other transposable elements emerge to be key players in cellular function, including genomic activities, gene expression regulations, and evolution. Here we summarize the current understanding of Alu function in genome and gene expression regulation in human cell nuclei.
Topics: Alu Elements; Cell Nucleus; DNA Damage; DNA Transposable Elements; Humans; Transcription, Genetic
PubMed: 24637839
DOI: 10.4161/nucl.28005 -
G3 (Bethesda, Md.) May 2022Alu elements are one of the most successful groups of RNA retrotransposons and make up 11% of the human genome with over 1 million individual loci. They are linked to...
Alu elements are one of the most successful groups of RNA retrotransposons and make up 11% of the human genome with over 1 million individual loci. They are linked to genetic defects, increases in sequence diversity, and influence transcriptional activity. Still, their RNA metabolism is poorly understood yet. It is even unclear whether Alu elements are mostly transcribed by RNA Polymerase II or III. We have conducted a transcription shutoff experiment by α-amanitin and metabolic RNA labeling by 4-thiouridine combined with RNA fragmentation (TT-seq) and RNA-seq to shed further light on the origin and life cycle of Alu transcripts. We find that Alu RNAs are more stable than previously thought and seem to originate in part from RNA Polymerase II activity, as previous reports suggest. Their expression however seems to be independent of the transcriptional activity of adjacent genes. Furthermore, we have developed a novel statistical test for detecting the expression of quantitative trait loci in Alu elements that relies on the de Bruijn graph representation of all Alu sequences. It controls for both statistical significance and biological relevance using a tuned k-mer representation, discovering influential sequence features missed by regular motif search. In addition, we discover several point mutations using a generalized linear model, and motifs of interest, which also match transcription factor-binding motifs.
Topics: Alu Elements; Humans; RNA; RNA Polymerase II; Retroelements; Transcription, Genetic
PubMed: 35253846
DOI: 10.1093/g3journal/jkac054 -
Scientific Reports Aug 2022Long interspersed nucleotide element-1 (LINE-1) and Alu elements are retrotransposons whose abilities cause abnormal gene expression and genomic instability. Several...
Long interspersed nucleotide element-1 (LINE-1) and Alu elements are retrotransposons whose abilities cause abnormal gene expression and genomic instability. Several studies have focused on DNA methylation profiling of gene regions, but the locus-specific methylation of LINE-1 and Alu elements has not been identified in autism spectrum disorder (ASD). Here we interrogated locus- and family-specific methylation profiles of LINE-1 and Alu elements in ASD whole blood using publicly-available Illumina Infinium 450 K methylation datasets from heterogeneous ASD and ASD variants (Chromodomain Helicase DNA-binding 8 (CHD8) and 16p11.2del). Total DNA methylation of repetitive elements were notably hypomethylated exclusively in ASD with CHD8 variants. Methylation alteration in a family-specific manner including L1P, L1H, HAL, AluJ, and AluS families were observed in the heterogeneous ASD and ASD with CHD8 variants. Moreover, LINE-1 and Alu methylation within target genes is inversely related to the expression level in each ASD variant. The DNA methylation signatures of the LINE-1 and Alu elements in ASD whole blood, as well as their associations with the expression of ASD-related genes, have been identified. If confirmed in future larger studies, these findings may contribute to the identification of epigenomic biomarkers of ASD.
Topics: Alu Elements; Autism Spectrum Disorder; Autistic Disorder; DNA Methylation; Humans; Long Interspersed Nucleotide Elements
PubMed: 35978033
DOI: 10.1038/s41598-022-18232-6 -
Cellular and Molecular Life Sciences :... Jul 2007Alu elements are the most abundant repetitive elements in the human genome; they have amplified by retrotransposition to reach the present number of more than one... (Review)
Review
Alu elements are the most abundant repetitive elements in the human genome; they have amplified by retrotransposition to reach the present number of more than one million copies. Alu elements can be transcribed in two different ways, by two independent polymerases. 'Free Alu RNAs' are transcribed by Pol III from their own promoter, while 'embedded Alu RNAs' are transcribed by Pol II as part of protein- and non-protein-coding RNAs. Recent studies have demonstrated that both free and embedded Alu RNAs play a major role in post transcriptional regulation of gene expression, for example by affecting protein translation, alternative splicing and mRNA stability. These discoveries illustrate how a part of the 'junk DNA' content of the human genome has been recruited to important functions in regulation of gene expression.
Topics: Alternative Splicing; Alu Elements; Base Sequence; DNA, Intergenic; Gene Expression Regulation; Genome, Human; Humans; MicroRNAs; Molecular Sequence Data; Protein Biosynthesis; RNA Stability; Transcription, Genetic
PubMed: 17514354
DOI: 10.1007/s00018-007-7084-0 -
Biochemical Society Transactions Dec 2013The cost of DNA sequencing is decreasing year by year, and the era of personalized medicine and the $1000 genome seems to be just around the corner. In order to link... (Review)
Review
The cost of DNA sequencing is decreasing year by year, and the era of personalized medicine and the $1000 genome seems to be just around the corner. In order to link genetic variation to gene function, however, we need to learn more about the function of the non-coding genomic elements. The advance of high-throughput sequencing enabled rapid progress in mapping the functional elements in our genome. In the present article, I discuss how intronic mutations acting at Alu elements enable formation of new exons. I review the mutations that cause disease when promoting a major increase in the inclusion of Alu exon into mature transcripts. Moreover, I present the mechanism that represses such a major inclusion of Alu exons and instead enables a gradual evolution of Alu elements into new exons.
Topics: Alu Elements; Disease; Evolution, Molecular; Exons; Humans
PubMed: 24256249
DOI: 10.1042/BST20130157 -
Cell May 2012Mobile DNAs have had a central role in shaping our genome. More than half of our DNA is comprised of interspersed repeats resulting from replicative copy and paste... (Review)
Review
Mobile DNAs have had a central role in shaping our genome. More than half of our DNA is comprised of interspersed repeats resulting from replicative copy and paste events of retrotransposons. Although most are fixed, incapable of templating new copies, there are important exceptions to retrotransposon quiescence. De novo insertions cause genetic diseases and cancers, though reliably detecting these occurrences has been difficult. New technologies aimed at uncovering polymorphic insertions reveal that mobile DNAs provide a substantial and dynamic source of structural variation. Key questions going forward include how and how much new transposition events affect human health and disease.
Topics: Alu Elements; Animals; Base Sequence; Biological Evolution; DNA Transposable Elements; Genome, Human; Humans; Molecular Sequence Data
PubMed: 22579280
DOI: 10.1016/j.cell.2012.04.019 -
Cellular and Molecular Life Sciences :... Nov 2015The human genome is under constant invasion by retrotransposable elements. The most successful of these are the Alu elements; with a copy number of over a million, they... (Review)
Review
The human genome is under constant invasion by retrotransposable elements. The most successful of these are the Alu elements; with a copy number of over a million, they occupy about 10 % of the entire genome. Interestingly, the vast majority of these Alu insertions are located in gene-rich regions, and one-third of all human genes contains an Alu insertion. Alu sequences are often embedded in gene sequence encoding pre-mRNAs and mature mRNAs, usually as part of their intron or UTRs. Once transcribed, they can regulate gene expression as well as increase the number of RNA isoforms expressed in a tissue or a species. They also regulate the function of other RNAs, like microRNAs, circular RNAs, and potentially long non-coding RNAs. Mechanistically, Alu elements exert their effects by influencing diverse processes, such as RNA editing, exonization, and RNA processing. In so doing, they have undoubtedly had a profound effect on human evolution.
Topics: Alu Elements; Animals; Apoptosis; Evolution, Molecular; Exons; Gene Expression Regulation; Genome, Human; Humans; MicroRNAs; Primates; RNA; RNA Editing; RNA Processing, Post-Transcriptional; RNA, Circular; Untranslated Regions
PubMed: 26223268
DOI: 10.1007/s00018-015-1990-3