Publications by authors named "Steven Boeynaems"

21 Publications

  • Page 1 of 1

-derived arginine-containing dipeptide repeats associate with axonal transport machinery and impede microtubule-based motility.

Sci Adv 2021 Apr 9;7(15). Epub 2021 Apr 9.

KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), Leuven, Belgium.

A hexanucleotide repeat expansion in the gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). How this mutation leads to these neurodegenerative diseases remains unclear. Here, we show using patient stem cell-derived motor neurons that the repeat expansion impairs microtubule-based transport, a process critical for neuronal survival. Cargo transport defects are recapitulated by treating neurons from healthy individuals with proline-arginine and glycine-arginine dipeptide repeats (DPRs) produced from the repeat expansion. Both arginine-rich DPRs similarly inhibit axonal trafficking in adult neurons in vivo. Physical interaction studies demonstrate that arginine-rich DPRs associate with motor complexes and the unstructured tubulin tails of microtubules. Single-molecule imaging reveals that microtubule-bound arginine-rich DPRs directly impede translocation of purified dynein and kinesin-1 motor complexes. Collectively, our study implicates inhibitory interactions of arginine-rich DPRs with axonal transport machinery in -associated ALS/FTD and thereby points to potential therapeutic strategies.
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http://dx.doi.org/10.1126/sciadv.abg3013DOI Listing
April 2021

HDAC6 inhibition restores TDP-43 pathology and axonal transport defects in human motor neurons with TARDBP mutations.

EMBO J 2021 Apr 10;40(7):e106177. Epub 2021 Mar 10.

Department of Neurosciences, Experimental Neurology, Leuven Brain Institute (LBI), KU Leuven - University of Leuven, Leuven, Belgium.

TDP-43 is the major component of pathological inclusions in most ALS patients and in up to 50% of patients with frontotemporal dementia (FTD). Heterozygous missense mutations in TARDBP, the gene encoding TDP-43, are one of the common causes of familial ALS. In this study, we investigate TDP-43 protein behavior in induced pluripotent stem cell (iPSC)-derived motor neurons from three ALS patients with different TARDBP mutations, three healthy controls and an isogenic control. TARDPB mutations induce several TDP-43 changes in spinal motor neurons, including cytoplasmic mislocalization and accumulation of insoluble TDP-43, C-terminal fragments, and phospho-TDP-43. By generating iPSC lines with allele-specific tagging of TDP-43, we find that mutant TDP-43 initiates the observed disease phenotypes and has an altered interactome as indicated by mass spectrometry. Our findings also indicate that TDP-43 proteinopathy results in a defect in mitochondrial transport. Lastly, we show that pharmacological inhibition of histone deacetylase 6 (HDAC6) restores the observed TDP-43 pathologies and the axonal mitochondrial motility, suggesting that HDAC6 inhibition may be an interesting therapeutic target for neurodegenerative disorders linked to TDP-43 pathology.
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http://dx.doi.org/10.15252/embj.2020106177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013789PMC
April 2021

Designer Condensates: A Toolkit for the Biomolecular Architect.

J Mol Biol 2021 Feb 1:166837. Epub 2021 Feb 1.

Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address:

Protein phase separation has emerged as a novel paradigm to explain the biogenesis of membraneless organelles and other so-called biomolecular condensates. While the implication of this physical phenomenon within cell biology is providing us with novel ways for understanding how cells compartmentalize biochemical reactions and encode function in such liquid-like assemblies, the newfound appreciation of this process also provides immense opportunities for designing and sculpting biological matter. Here, we propose that understanding the cell's instruction manual of phase separation will enable bioengineers to begin creating novel functionalized biological materials and unprecedented tools for synthetic biology. We present FASE as the synthesis of the existing sticker-spacer framework, which explains the physical driving forces underlying phase separation, with quintessential principles of Scandinavian design. FASE serves both as a designer condensates catalogue and construction manual for the aspiring (membraneless) biomolecular architect. Our approach aims to inspire a new generation of bioengineers to rethink phase separation as an opportunity for creating reactive biomaterials with unconventional properties and to encode novel biological function in living systems. Although still in its infancy, several studies highlight how designer condensates have immediate and widespread potential applications in industry and medicine.
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http://dx.doi.org/10.1016/j.jmb.2021.166837DOI Listing
February 2021

repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization.

Brain Commun 2020 19;2(2):fcaa064. Epub 2020 May 19.

Department of Neurology, Brain Center Rudolf Magnus, University Medical Center, Utrecht, University of Utrecht, 3508 GA, Utrecht, The Netherlands.

Increasingly, repeat expansions are being identified as part of the complex genetic architecture of amyotrophic lateral sclerosis. To date, several repeat expansions have been genetically associated with the disease: intronic repeat expansions in , polyglutamine expansions in and polyalanine expansions in . Together with previously published data, the identification of an amyotrophic lateral sclerosis patient with a family history of spinocerebellar ataxia type 1, caused by polyglutamine expansions in , suggested a similar disease association for the repeat expansion in . We, therefore, performed a large-scale international study in 11 700 individuals, in which we showed a significant association between intermediate repeat expansions and amyotrophic lateral sclerosis (=3.33 × 10). Subsequent functional experiments have shown that ATXN1 reduces the nucleocytoplasmic ratio of TDP-43 and enhances amyotrophic lateral sclerosis phenotypes in , further emphasizing the role of polyglutamine repeat expansions in the pathophysiology of amyotrophic lateral sclerosis.
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http://dx.doi.org/10.1093/braincomms/fcaa064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425293PMC
May 2020

C9orf72-generated poly-GR and poly-PR do not directly interfere with nucleocytoplasmic transport.

Sci Rep 2019 10 31;9(1):15728. Epub 2019 Oct 31.

KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), Leuven, Belgium.

Repeat expansions in the C9orf72 gene cause amyotrophic lateral sclerosis and frontotemporal dementia characterized by dipeptide-repeat protein (DPR) inclusions. The toxicity associated with two of these DPRs, poly-GR and poly-PR, has been associated with nucleocytoplasmic transport. To investigate the causal role of poly-GR or poly-PR on active nucleocytoplasmic transport, we measured nuclear import and export in poly-GR or poly-PR expressing Hela cells, neuronal-like SH-SY5Y cells and iPSC-derived motor neurons. Our data strongly indicate that poly-GR and poly-PR do not directly impede active nucleocytoplasmic transport.
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http://dx.doi.org/10.1038/s41598-019-52035-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823349PMC
October 2019

Axons Gonna Ride 'til They Can't No More.

Neuron 2019 10;104(2):179-181

Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address:

Prion-like domains have been implicated in protein phase separation and aggregation in cellular stress and neurodegeneration. In this issue of Neuron, Andrusiak et al. (2019) uncover a surprising role for a stress granule protein and phase separation in axon regeneration.
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http://dx.doi.org/10.1016/j.neuron.2019.09.029DOI Listing
October 2019

Spontaneous driving forces give rise to protein-RNA condensates with coexisting phases and complex material properties.

Proc Natl Acad Sci U S A 2019 04 29;116(16):7889-7898. Epub 2019 Mar 29.

Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305;

Phase separation of multivalent protein and RNA molecules underlies the biogenesis of biomolecular condensates such as membraneless organelles. In vivo, these condensates encompass hundreds of distinct types of molecules that typically organize into multilayered structures supporting the differential partitioning of molecules into distinct regions with distinct material properties. The interplay between driven (active) versus spontaneous (passive) processes that are required for enabling the formation of condensates with coexisting layers of distinct material properties remains unclear. Here, we deploy systematic experiments and simulations based on coarse-grained models to show that the collective interactions among the simplest, biologically relevant proteins and archetypal RNA molecules are sufficient for driving the spontaneous emergence of multilayered condensates with distinct material properties. These studies yield a set of rules regarding homotypic and heterotypic interactions that are likely to be relevant for understanding the interplay between active and passive processes that control the formation of functional biomolecular condensates.
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http://dx.doi.org/10.1073/pnas.1821038116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475405PMC
April 2019

Pour Some Sugar on TDP(-43).

Mol Cell 2018 09;71(5):649-651

Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address:

In this issue of Molecular Cell, McGurk et al. (2018) identify how poly(ADP-ribose) binding tunes the phase behavior of the ALS disease protein TDP-43, uncovering the molecular events underlying its aggregation in disease and illuminating a novel therapeutic target.
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http://dx.doi.org/10.1016/j.molcel.2018.08.032DOI Listing
September 2018

Molecular Dissection of FUS Points at Synergistic Effect of Low-Complexity Domains in Toxicity.

Cell Rep 2018 07;24(3):529-537.e4

Experimental Neurology, Department of Neurosciences, and Leuven Brain Institute (LBI), KU Leuven-University of Leuven, 3000 Leuven, Belgium; Laboratory of Neurobiology, Center for Brain & Disease Research, VIB, 3000 Leuven, Belgium. Electronic address:

RNA-binding protein aggregation is a pathological hallmark of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). To gain better insight into the molecular interactions underlying this process, we investigated FUS, which is mutated and aggregated in both ALS and FTLD. We generated a Drosophila model of FUS toxicity and identified a previously unrecognized synergistic effect between the N-terminal prion-like domain and the C-terminal arginine-rich domain to mediate toxicity. Although the prion-like domain is generally considered to mediate aggregation of FUS, we find that arginine residues in the C-terminal low-complexity domain are also required for maturation of FUS in cellular stress granules. These data highlight an important role for arginine-rich domains in the pathology of RNA-binding proteins.
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http://dx.doi.org/10.1016/j.celrep.2018.06.070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077250PMC
July 2018

Phosphorylation Leads the Way for Protein Aggregate Disassembly.

Dev Cell 2018 05;45(3):279-281

Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address:

Protein aggregation can be beneficial, with important biological functions, but must be somehow controlled. In this issue of Developmental Cell, Carpenter et al. (2018) uncover how a solid-like supermolecular protein assembly that regulates yeast meiosis is disassembled through phosphorylation of a disordered prion-like domain to control the timing of meiotic progression.
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http://dx.doi.org/10.1016/j.devcel.2018.04.017DOI Listing
May 2018

Protein Phase Separation: A New Phase in Cell Biology.

Trends Cell Biol 2018 06 27;28(6):420-435. Epub 2018 Mar 27.

MTA-DE Laboratory of Protein Dynamics, Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, Hungary. Electronic address:

Cellular compartments and organelles organize biological matter. Most well-known organelles are separated by a membrane boundary from their surrounding milieu. There are also many so-called membraneless organelles and recent studies suggest that these organelles, which are supramolecular assemblies of proteins and RNA molecules, form via protein phase separation. Recent discoveries have shed light on the molecular properties, formation, regulation, and function of membraneless organelles. A combination of techniques from cell biology, biophysics, physical chemistry, structural biology, and bioinformatics are starting to help establish the molecular principles of an emerging field, thus paving the way for exciting discoveries, including novel therapeutic approaches for the treatment of age-related disorders.
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http://dx.doi.org/10.1016/j.tcb.2018.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034118PMC
June 2018

Phasing in on the cell cycle.

Cell Div 2018 25;13. Epub 2018 Jan 25.

1Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven-University of Leuven, 3000 Leuven, Belgium.

Just like all matter, proteins can also switch between gas, liquid and solid phases. Protein phase transition has claimed the spotlight in recent years as a novel way of how cells compartmentalize and regulate biochemical reactions. Moreover, this discovery has provided a new framework for the study of membrane-less organelle biogenesis and protein aggregation in neurodegenerative disorders. We now argue that this framework could be useful in the study of cell cycle regulation and cancer. Based on our work on phase transitions of arginine-rich proteins in neurodegeneration, via combining mass spectroscopy with bioinformatics analyses, we found that also numerous proteins involved in the regulation of the cell cycle can undergo protein phase separation. Indeed, several proteins whose function affects the cell cycle or are associated with cancer, have been recently found to phase separate from the test tube to cells. Investigating the role of this process for cell cycle proteins and understanding its molecular underpinnings will provide pivotal insights into the biology of cell cycle progression and cancer.
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http://dx.doi.org/10.1186/s13008-018-0034-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785872PMC
January 2018

A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism.

Acta Neuropathol 2018 03 4;135(3):427-443. Epub 2018 Jan 4.

Department of Neurosciences, Experimental Neurology, KU Leuven-University of Leuven, 3000, Leuven, Belgium.

The exact mechanism underlying amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) associated with the GGGGCC repeat expansion in C9orf72 is still unclear. Two gain-of-function mechanisms are possible: repeat RNA toxicity and dipeptide repeat protein (DPR) toxicity. We here dissected both possibilities using a zebrafish model for ALS. Expression of two DPRs, glycine-arginine and proline-arginine, induced a motor axonopathy. Similarly, expanded sense and antisense repeat RNA also induced a motor axonopathy and formed mainly cytoplasmic RNA foci. However, DPRs were not detected in these conditions. Moreover, stop codon-interrupted repeat RNA still induced a motor axonopathy and a synergistic role of low levels of DPRs was excluded. Altogether, these results show that repeat RNA toxicity is independent of DPR formation. This RNA toxicity, but not the DPR toxicity, was attenuated by the RNA-binding protein Pur-alpha and the autophagy-related protein p62. Our findings demonstrate that RNA toxicity, independent of DPR toxicity, can contribute to the pathogenesis of C9orf72-associated ALS/FTD.
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http://dx.doi.org/10.1007/s00401-017-1796-5DOI Listing
March 2018

Anterior interosseous mononeuropathy associated with HEV infection.

Neurol Neuroimmunol Neuroinflamm 2018 Mar 22;5(2):e429. Epub 2017 Dec 22.

Department of Neurosciences, Experimental Neurology (B.S., S.B., P.V.D.), KU Leuven-University of Leuven; Laboratory of Neurobiology (B.S., S.B., P.V.D.), Center for Brain & Disease Research, VIB; Departments of Neurology (B.S., M.S., K.G.C., P.V.D.), and Laboratory Medicine (V.S.), University Hospitals Leuven; and Laboratory for Cognitive Neurology (M.S.), Department of Neurosciences, Department of Microbiology and Immunology (V.S.), Laboratory for Muscle Diseases and Neuropathies (K.G.C.), Department of Neurosciences, Experimental Neurology, KU Leuven-University of Leuven, Belgium.

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http://dx.doi.org/10.1212/NXI.0000000000000429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5745356PMC
March 2018

Phase Separation of C9orf72 Dipeptide Repeats Perturbs Stress Granule Dynamics.

Mol Cell 2017 Mar;65(6):1044-1055.e5

Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), Department of Neurosciences, KU Leuven - University of Leuven, 3000 Leuven, Belgium; Laboratory of Neurobiology, VIB, Center for Brain and Disease Research, 3000 Leuven, Belgium. Electronic address:

Liquid-liquid phase separation (LLPS) of RNA-binding proteins plays an important role in the formation of multiple membrane-less organelles involved in RNA metabolism, including stress granules. Defects in stress granule homeostasis constitute a cornerstone of ALS/FTLD pathogenesis. Polar residues (tyrosine and glutamine) have been previously demonstrated to be critical for phase separation of ALS-linked stress granule proteins. We now identify an active role for arginine-rich domains in these phase separations. Moreover, arginine-rich dipeptide repeats (DPRs) derived from C9orf72 hexanucleotide repeat expansions similarly undergo LLPS and induce phase separation of a large set of proteins involved in RNA and stress granule metabolism. Expression of arginine-rich DPRs in cells induced spontaneous stress granule assembly that required both eIF2α phosphorylation and G3BP. Together with recent reports showing that DPRs affect nucleocytoplasmic transport, our results point to an important role for arginine-rich DPRs in the pathogenesis of C9orf72 ALS/FTLD.
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http://dx.doi.org/10.1016/j.molcel.2017.02.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5364369PMC
March 2017

Inside out: the role of nucleocytoplasmic transport in ALS and FTLD.

Acta Neuropathol 2016 08 6;132(2):159-173. Epub 2016 Jun 6.

Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven-University of Leuven, 3000, Leuven, Belgium.

Neurodegenerative diseases are characterized by the presence of protein inclusions with a different protein content depending on the type of disease. Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are no exceptions to this common theme. In most ALS and FTLD cases, the predominant pathological species are RNA-binding proteins. Interestingly, these proteins are both depleted from their normal nuclear localization and aggregated in the cytoplasm. This key pathological feature has suggested a potential dual mechanism with both nuclear loss of function and cytoplasmic gain of function being at play. Yet, why and how this pathological cascade is initiated in most patients, and especially sporadic cases, is currently unresolved. Recent breakthroughs in C9orf72 ALS/FTLD disease models point at a pivotal role for the nuclear transport system in toxicity. To address whether defects in nuclear transport are indeed implicated in the disease, we reviewed two decades of ALS/FTLD literature and combined this with bioinformatic analyses. We find that both RNA-binding proteins and nuclear transport factors are key players in ALS/FTLD pathology. Moreover, our analyses suggest that disturbances in nucleocytoplasmic transport play a crucial initiating role in the disease, by bridging both nuclear loss and cytoplasmic gain of functions. These findings highlight this process as a novel and promising therapeutic target for ALS and FTLD.
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http://dx.doi.org/10.1007/s00401-016-1586-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4947127PMC
August 2016

Drosophila screen connects nuclear transport genes to DPR pathology in c9ALS/FTD.

Sci Rep 2016 Feb 12;6:20877. Epub 2016 Feb 12.

KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), B-3000 Leuven, Belgium.

Hexanucleotide repeat expansions in C9orf72 are the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) (c9ALS/FTD). Unconventional translation of these repeats produces dipeptide repeat proteins (DPRs) that may cause neurodegeneration. We performed a modifier screen in Drosophila and discovered a critical role for importins and exportins, Ran-GTP cycle regulators, nuclear pore components, and arginine methylases in mediating DPR toxicity. These findings provide evidence for an important role for nucleocytoplasmic transport in the pathogenic mechanism of c9ALS/FTD.
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http://dx.doi.org/10.1038/srep20877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4751451PMC
February 2016

Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS.

Nat Neurosci 2015 Sep;18(9):1226-9

Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.

C9orf72 mutations are the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Dipeptide repeat proteins (DPRs) produced by unconventional translation of the C9orf72 repeat expansions cause neurodegeneration in cell culture and in animal models. We performed two unbiased screens in Saccharomyces cerevisiae and identified potent modifiers of DPR toxicity, including karyopherins and effectors of Ran-mediated nucleocytoplasmic transport, providing insight into potential disease mechanisms and therapeutic targets.
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http://dx.doi.org/10.1038/nn.4085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4552077PMC
September 2015

Variable Glutamine-Rich Repeats Modulate Transcription Factor Activity.

Mol Cell 2015 Aug 6;59(4):615-27. Epub 2015 Aug 6.

Laboratory of Systems Biology, VIB, Gaston Geenslaan 1, 3001 Heverlee, Belgium; Laboratory of Genetics and Genomics, Centre of Microbial and Plant Genetics (CMPG), Department M2S, KU Leuven, Gaston Geenslaan 1, 3001 Heverlee, Belgium. Electronic address:

Excessive expansions of glutamine (Q)-rich repeats in various human proteins are known to result in severe neurodegenerative disorders such as Huntington's disease and several ataxias. However, the physiological role of these repeats and the consequences of more moderate repeat variation remain unknown. Here, we demonstrate that Q-rich domains are highly enriched in eukaryotic transcription factors where they act as functional modulators. Incremental changes in the number of repeats in the yeast transcriptional regulator Ssn6 (Cyc8) result in systematic, repeat-length-dependent variation in expression of target genes that result in direct phenotypic changes. The function of Ssn6 increases with its repeat number until a certain threshold where further expansion leads to aggregation. Quantitative proteomic analysis reveals that the Ssn6 repeats affect its solubility and interactions with Tup1 and other regulators. Thus, Q-rich repeats are dynamic functional domains that modulate a regulator's innate function, with the inherent risk of pathogenic repeat expansions.
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http://dx.doi.org/10.1016/j.molcel.2015.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4543046PMC
August 2015

Beyond junk-variable tandem repeats as facilitators of rapid evolution of regulatory and coding sequences.

Genes (Basel) 2012 Jul 26;3(3):461-80. Epub 2012 Jul 26.

Laboratory for Systems Biology, VIB, Gaston Geenslaan 1, B-3001 Heverlee, Belgium.

Copy Number Variations (CNVs) and Single Nucleotide Polymorphisms (SNPs) have been the major focus of most large-scale comparative genomics studies to date. Here, we discuss a third, largely ignored, type of genetic variation, namely changes in tandem repeat number. Historically, tandem repeats have been designated as non functional "junk" DNA, mostly as a result of their highly unstable nature. With the exception of tandem repeats involved in human neurodegenerative diseases, repeat variation was often believed to be neutral with no phenotypic consequences. Recent studies, however, have shown that as many as 10% to 20% of coding and regulatory sequences in eukaryotes contain an unstable repeat tract. Contrary to initial suggestions, tandem repeat variation can have useful phenotypic consequences. Examples include rapid variation in microbial cell surface, tuning of internal molecular clocks in flies and the dynamic morphological plasticity in mammals. As such, tandem repeats can be useful functional elements that facilitate evolvability and rapid adaptation.
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http://dx.doi.org/10.3390/genes3030461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3899988PMC
July 2012