Potential impact of primate-specific SVA retrotransposons during the evolution of human cognitive function

Vasieva, Olga; Cetiner, Sultan; Savage, A.; Schumann, Gerald G.; Bubb, Vivien J.; Quinn, John P.

doi:10.4081/eb.2017.6514

Cited by 6 publications

(8 citation statements)

References 24 publications

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“…Despite transposable elements making up nearly half of the human genome, they remain relatively unexplored as sources of important genomic variation [ 1 ], as their repetitive nature makes them difficult to map to the human genome. The evolutionarily youngest SVA retrotransposons may be particularly important for human health and evolution since they have introduced hominid-specific elements with regulatory potential to specific genomic loci, a process that is ongoing for SVA subclasses D–F1 [ 32 ]. It should be noted that SVA regulatory influences need not be dramatic to be biologically important in individuals of certain genetic backgrounds—for example, in the study of genetically complex disease, it is generally accepted that disease can result from the cumulative effect of many low-contribution variants [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

“…Our observations therefore complement previous hypotheses that SVAs may be important sources of genomic variation in the central nervous system. As hominid-specific elements, SVAs may be implicated in the development of higher cognitive function and ongoing human-specific genome evolution [ 32 ]. It is also conceivable that transposable elements, particularly SVAs, which are currently filtered out of short-read WGS data represent an under-appreciated source of variation that may be relevant to genetically complex processes.…”

Section: Discussionmentioning

confidence: 99%

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A SINE-VNTR-Alu in the LRIG2 Promoter Is Associated with Gene Expression at the Locus

Hall

Moore

Hernandez

et al. 2020

IJMS

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The hominid SINE-VNTR-Alu (SVA) retrotransposons represent a repertoire of genomic variation which could have significant effects on genome function. A human-specific SVA in the promoter region of the gene leucine-rich repeats and immunoglobulin-like domains 2 (LRIG2), which we termed SVA_LRIG2, is a common retrotransposon insertion polymorphism (RIP), defined as an element which is polymorphic for its presence or absence in the genome. We hypothesised that this RIP might be associated with differential levels of expression of LRIG2. The RIP genotype of SVA_LRIG2 was determined in a subset of frontal cortex DNA samples from the North American Brain Expression Consortium (NABEC) cohort and was imputed for a larger set of that cohort. Utilising available frontal cortex total RNA-seq and CpG methylation data for this cohort, we observed that increased allele dosage of SVA_LRIG2 was non-significantly associated with a decrease in transcription from the region and significantly associated with increased methylation of the CpG probe nearest to SVA_LRIG2, i.e., SVA_LRIG2 is a significant methylation quantitative trait loci (mQTL) at the LRIG2 locus. These data are consistent with SVA_LRIG2 being a transcriptional regulator, which in part may involve epigenetic modulation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A SINE-VNTR-Alu in the LRIG2 Promoter Is Associated with Gene Expression at the Locus

Hall

Moore

Hernandez

et al. 2020

IJMS

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“…Although they are found in many eukaryote species, present day interest has focused on their role in hominid evolution and their contribution to the development of human-specific traits in the evolution of modern humans and in particular neural function. 2 – 4 In modern humans, TR DNA has been associated both with traits such as aggression and addictive behaviors, reviewed by literature 5 – 8 and implicated in the increased susceptibility to, and risk of developing, a wide variety of neurological diseases such as motor neuron disease 9 – 11 and Alzheimer’s disease 12 , 13 mental health conditions such as bipolar disorder, depression, and schizophrenia. 14 , 15 To date, 1584 such repeats have been found to be human specific and it has been proposed that they contribute to human-specific traits.…”

Section: Consequences and Genetic Nature Of Tandem Repeat Dnamentioning

confidence: 99%

“…2700), SVAs are hominid-specific elements with almost 50% of those characterized in the reference genome found to be human specific and have been postulated to correlate with the development of hominid lineage-specific traits. 2 They are composite regulatory DNA domains containing multiple regulatory components ( Figure 2 ) that affect reporter gene expression. 72 Several of these domains are tandem repeats, specifically the CT hexamer flanking domain and a central large VNTR domain.…”

Section: Vntrs In Non-long Terminal Repeat Retrotransposonsmentioning

confidence: 99%

Variable number tandem repeats – Their emerging role in sickness and health

Marshall

Lopez

Pfaff

et al. 2021

Exp Biol Med (Maywood)

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Understanding the mechanisms regulating tissue specific and stimulus inducible regulation is at the heart of understanding human biology and how this translates to wellbeing, the ageing process, and disease progression. Polymorphic DNA variation is superimposed as an extra layer of complexity in such processes which underpin our individuality and are the focus of personalized medicine. This review focuses on the role and action of repetitive DNA, specifically variable number tandem repeats and SINE-VNTR- Alu domains, highlighting their role in modification of gene structure and gene expression in addition to their polymorphic nature being a genetic modifier of disease risk and progression. Although the literature focuses on their role in disease, it illustrates their potential to be major contributors to normal physiological function. To date, these elements have been under-reported in genomic analysis due to the difficulties in their characterization with short read DNA sequencing methods. However, recent advances in long read sequencing methods should resolve these problems allowing for a greater understanding of their contribution to a host of genomic and functional mechanisms underlying physiology and disease.

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“…Ongoing mobilisation of SVAs has led to insertions being polymorphic for their presence or absence and are thus named retrotransposon insertion polymorphisms (RIPs) [13,14]. It should be noted that the evolutionarily youngest classes of SVAs (D-F1) may be of special interest for human physiology, health and evolution since they have introduced hominid-speci c insertions which can exert novel regulatory potential to speci c genomic loci [15].…”

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confidence: 99%

Characterisation of the Function of a SINE-VNTR-Alu Retrotransposon to Modulate Isoform Expression at the MAPT Locus

Fröhlich

Pfaff

Bubb

et al. 2021

Preprint

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Background: SINE-VNTR-Alu retrotransposons represent one class of transposable elements which contribute to the regulation and evolution of the primate genome and have the potential to be involved in genetic instability and disease progression. However, these polymorphic elements have not been extensively analysed when addressing the missing heritability of neurodegenerative diseases, including Parkinson´s disease (PD) and amyotrophic lateral sclerosis (ALS). SVA_67, a retrotransposon insertion polymorphism, is located in a 1.8 Mb region of high linkage disequilibrium, called the MAPT locus, which is known to contribute to increased risk of developing PD, frontotemporal dementia and other tauopathies. This study was conducted to investigate the role of SVA_67 in directing differential gene expression at this locus by characterising the impact of SVA_67 allele dosage on isoform expression of several genes in the MAPT locus.Methods:In this study, transcriptomic data from both the Parkinson’s Progression Markers Initiative and New York Genome Center Consortium Target ALS cohort were used. The Parkinson’s data was from gene expression in the blood and the ALS data from a variety of central nervous system (CNS) regions. The association of three different genotypes (AA, PA, PP) based on the presence (P) or absence (A) of SVA_67 was analysed. The unpaired Wilcoxon test was used to compare two independent groups of samples and to demonstrate statistical significance.Results: Using two different datasets for analysis, we could demonstrate that SVA_67 presence or absence was significantly associated with 1) changes in expression of multiple genes at this locus and 2) both differential isoform and tissue specific expression of these genes.Conclusions:This study highlights the importance of addressing SVA polymorphism in disease genetics to gain insight into a better understanding of the role of these regulatory domains to a variety of neurodegenerative diseases. Therefore, this study underlines an additional type of variation to be considered at the MAPT locus and an added layer of complexity when analysing the missing heritability of neurodegenerative diseases.

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Potential impact of primate-specific SVA retrotransposons during the evolution of human cognitive function

Cited by 6 publications

References 24 publications

A SINE-VNTR-Alu in the LRIG2 Promoter Is Associated with Gene Expression at the Locus

A SINE-VNTR-Alu in the LRIG2 Promoter Is Associated with Gene Expression at the Locus

Variable number tandem repeats – Their emerging role in sickness and health

Characterisation of the Function of a SINE-VNTR-Alu Retrotransposon to Modulate Isoform Expression at the MAPT Locus

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