alu insertion
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2022 ◽  
Author(s):  
Albano Pinto ◽  
Catarina Cunha ◽  
Raquel Chaves ◽  
Matthew ER Butchbach ◽  
Filomena Adega

Abstract Transposable elements (TEs) are interspersed repetitive DNA sequences with the ability to mobilize in the genome. The recent development of improved tools for evaluating TE-derived sequences in genomic studies has enabled an increasing attention to the contribution of TEs to human development and disease. Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease that is caused by deletions or mutations in the Survival Motor Neuron 1 (SMN1) gene. SMN2 gene is a nearly perfect duplication of SMN1. Both genes (collectively known as SMN1/SMN2) are highly enriched in TEs. A comprehensive analysis of TEs insertions in the SMN1/2 loci of SMA carriers, patients and healthy/control individuals was completed to perceive TE dynamics in SMN1/2 and try to establish a link between these elements and SMA.We found an Alu insertion in the promoter region and one L1 element in the 3’UTR that likely play an important role as an alternative promoter and as an alternative terminator to the gene, respectively. Additionally, the several Alu repeats inserted in the genes’ introns influence splicing, giving rise to alternative splicing events that cause RNA circularization and the birth of new alternative exons. These Alu repeats present throughout the genes are also prone to recombination events that can lead to SMN1 exons deletions, that ultimately lead to SMA. The many good and bad implications associated with the presence of TEs inside SMN1/2 make this genomic region ideal for understanding the implications of TEs on genomic evolution as well as on human genomic disease.


2021 ◽  
Author(s):  
Lindsay M. Payer ◽  
Jared P. Steranka ◽  
Maria S. Kryatova ◽  
Giacomo Grillo ◽  
Mathieu Lupien ◽  
...  

Alu are high copy number interspersed repeats that have accumulated near genes during primate and human evolution. They are a pervasive source of structural variation in modern humans. Impacts that Alu insertions may have on gene expression are not well understood, although some have been associated with expression quantitative trait loci (eQTLs). Here, we directly test regulatory effects of polymorphic Alu insertions in isolation of other variants on the same haplotype. To screen insertion variants for those with such effects, we used ectopic luciferase reporter assays and evaluated 110 Alu insertion variants, including more than 40 with a potential role in disease risk. We observed a continuum of effects with significant outliers that up- or down-regulate luciferase activity. Using a series of reporter constructs, which included genomic context surrounding the Alu, we can distinguish between instances in which the Alu disrupts another regulator and those in which the Alu introduces new regulatory sequence. We next focused on three polymorphic Alu loci associated with breast cancer that display significant effects in the reporter assay. We used CRISPR to modify the endogenous sequences, establishing cell lines varying in the Alu genotype. Our findings indicate that Alu genotype can alter expression of genes implicated in cancer risk, including PTHLH, RANBP9, and MYC. These data show that commonly occurring polymorphic Alu elements can alter transcript levels and potentially contribute to disease risk.


Author(s):  
Zijun Zhou ◽  
Iris Hollink ◽  
Arjan Bouman ◽  
Mirthe Lourens ◽  
Rik Brooimans ◽  
...  

Background: Defects in IFN–gamma receptor (IFN-γR) signaling via STAT1 leads to susceptibility to infection by otherwise weak pathogenic mycobacteria, resulting in mendelian susceptibility to mycobacterial disease. We identified three patients presented with disseminated mycobacterial infections caused by M. avium, M. persicum or M. bovis BCG respectively. Whole-exome sequencing (WES) was used as the first line diagnostic approach, however in all patients additional analysis was crucial to make the definite diagnosis. Method: WES, SNP array and long range PCR were performed to identify the genetic defects. Expression of IFNGR1, STAT1, CD64, SOCS1 and phosphorylation of STAT1 were determined after stimulation with IFN-α or IFN-γ. Results: In Patient 1, only one heterozygous variant p.(Val63Gly) in the IFNGR1 gene was identified by WES. Additional genetic analysis identified a second complex Alu-insertion in IFNGR1. Patient 2 was compound heterozygous for the null p.(Val68Lysfs*6) variant and the hypomorphic p.(Ile37Thr) variant in IFNGR1. In Patient 3 a novel variant in the STAT1 gene p.(Asn460Ile) was identified. Patients 1 and 2 had reduced expression of IFN-γR1. All patients had reduced phosphorylation of STAT1 and absent induction of SOCS1 after IFN-γ stimulation. While STAT1 phosphorylation was normal after IFN–α stimulation in Patient 1 and 2, and mildly reduced in Patient 3. Conclusion: We conclude that functional assays are crucial to assess the extent of IFN-γR signaling defects when new combinations of bi-allelic or non-conclusive genetic variants are found, which is important in the determination of clinical treatment.


2021 ◽  
Author(s):  
Yoshihito Kishita ◽  
Masaru Shimura ◽  
Masakazu Kohda ◽  
Takuya Fushimi ◽  
Kazuhiro R. Nitta ◽  
...  

2021 ◽  
Author(s):  
Zijun Zhou ◽  
Iris H.I.M. Hollink ◽  
Arjan Bouman ◽  
Mirthe S. Lourens ◽  
Rik A. Brooimans ◽  
...  

Abstract IFN–gamma receptor (IFNGR) signaling via STAT1 is crucial in the defense against intracellular pathogens. Defects in this pathway enhance the susceptibility to infection by otherwise weak pathogenic mycobacteria, resulting in a primary immunodeficiency called mendelian susceptibility to mycobacterial disease (MSMD). Here we describe three patients with MSMD caused by variants in the IFNGR1 or STAT1 genes. All three patients presented with disseminated non-tuberculous mycobacterial infections caused by M. avium , M. persicum or M. bovis BCG respectively. Whole-exome sequencing (WES) was used as the first line diagnostic approach, however in all patients additional analysis was crucial to make the definite diagnosis. In Patient 1, only one heterozygous autosomal recessive variant p.(Val63Gly) in the IFNGR1 gene was identified. Patient 2 was compound heterozygous for the pathogenic null p.(Val68Lysfs*6) variant and the hypomorphic p.(Ile37Thr) variant in IFNGR1. In Patient 3 a novel variant in the STAT1 gene c.1379A>T, p.(Asn460Ile) was identified. Additional genetic analysis identified a second novel complex Alu-insertion in the IFNGR1 gene in Patient 1. Functional analysis showed that Patients 1 and 2 had reduced expression of IFNGR1. All patients had reduced phosphorylation of STAT1 and absent induction of SOCS1 mRNA after IFN-γ stimulation. While STAT1 phosphorylation was normal after IFN–α stimulation in Patient 1 and 2, it was mildly reduced in Patient 3. We conclude that functional assays are crucial to assess the extent of IFNGR signaling defects when new combinations of bi-allelic or non-conclusive genetic variants are found, which is important in the determination of clinical treatment.


Author(s):  
Annum Ishfaq ◽  
Ejaz Ali ◽  
Warda Fatima ◽  
Nageen Hussain

Breast cancer presents a serious public health risk in both developed and developing countries. The ACE gene, which is located in chromosome 17q23, has many polymorphisms. The most commonly studied is a 287 bp Alu insertion/deletion (I/D) polymorphism in intron 16 that accounts for 50% of the variability in circulating ACE levels. The main aim of this study is to find out the association of ACE gene with breast cancer in Pakistani population. Experimental and cross-sectional. A total of 186 samples were collected. Of the 186, 93 were taken as healthy controls and 93 were the female patients suffering from breast cancer. First DNA was isolated and then further genotypes II, ID and DD were identified by Nested PCR. Chi-square (χ2) test was applied to check the association level between ACE I/D polymorphism and breast cancer. The DD genotype showed (76) 81.7% and ID showed (17) 18.2% whereas II was not found (0) 0% in breast cancer patients. In controls, the frequency of DD is (80) 86%, ID (13) 13.9% and (0) 0 percent for II genotype. It is concluded that there is no significant association of ACE I/D polymorphisms with the breast cancer (p < 0.05) in Pakistani population.


2020 ◽  
Author(s):  
Sylvia De Brakeleer ◽  
Jacques De Grève ◽  
Erik Teugels

ABSTRACTBackgroundRetrotransposons are genetic elements that jump within the genome via an RNA intermediate. Although they had a strong impact on human genome evolution, only a very tiny fraction of them can be reactivated nowadays, most often with neutral or detrimental consequences. The pathological outcomes associated with such genetic alterations are poorly investigated in the clinic, merely due to their difficult detection.ResultsWe developed a strategy to detect rare retrotransposon mediated insertions in Whole Exome Sequencing data from 65 familial breast cancer patients. When restricting our search to high confidence retrotransposition events occurring in less than 10% of the samples, we identified only ten different Alu elements, two L1 elements, one SVA and two processed pseudogenes. Only two of these insertions occurred within protein coding sequences and interestingly, several of the targeted genes have been previously linked to cancer, in three cases even to increased breast cancer risk (GHR, DMBT1 and NEK10). When investigating the molecular consequences of four Alu insertions at the mRNA level, we found that the element present in the 3’UTR of GHR repressed expression of the corresponding allele. oMreover, the analysis of a near exonic Alu insertion in PTPN14 (a mediator of P53 tumor suppressor activity) revealed that this gene was imprinted and that the presence of an intronic Alu element can lead to loss of imprinting.ConclusionsOur data underline the relevance of incorporating the search for uncommon retrotransposition events in Next Generation Sequencing pipelines when analyzing patients with a suspected genetic disease.


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