Pig H3K4me3,H3K27ac,and gene expression profiles reveal reproductive tissue-specific activity of transposable elements

Regulatory sequences and transposable elements(TEs)account for a large proportion of the genomic sequences of species;however,their roles in gene transcription,especially tissue-specific expression,remain largely unknown.Pigs serve as an excellent animal model for studying genomic sequence biology due to the extensive diversity among their wild and domesticated populations.Here,we conducted an integrated analysis using H3K27ac ChIP-seq,H3K4me3 ChIP-seq,and RNA-seq data from 10 different tissues of seven fetuses and eight closely related adult pigs.We aimed to annotate the regulatory elements and TEs to elucidate their associations with histone modifications and mRNA expression across different tissues and developmental stages.Based on correlation analysis between mRNA expression and H3K27ac and H3K4me3 peak activity,results indicated that H3K27ac exhibited stronger associations with gene expression than H3K4me3.Furthermore,1.45%of TEs overlapped with either the H3K27ac or H3K4me3 peaks,with the majority displaying tissue-specific activity.Notably,a TE subfamily(LTR4C_SS),containing binding motifs for SIX1 and SIX4,showed specific enrichment in the H3K27ac peaks of the adult and fetal ovaries.RNA-seq analysis also revealed widespread expression of TEs in the exons or promoters of genes,including 4688 TE-containing transcripts with distinct development stage-specific and tissue-specific expression.Of note,1967 TE-containing transcripts were enriched in the testes.We identified a long terminal repeat(LTR),MLT1F1,acting as a testis-specific alternative promoter in SRPK2(a cell cycle-related protein kinase)in our pig dataset.This element was also conserved in humans and mice,suggesting either an ancient integration of TEs in genes specifically expressed in the testes or parallel evolutionary patterns.Collectively,our findings demonstrate that TEs are deeply embedded in the genome and exhibit important tissue-specific biological functions,particularly in the reproductive organs.

Histone H3K27me3 methylation regulates the expression of secreted proteins distributed at fast-evolving regions through transcriptional repression of transposable elements

The fine-tuned expression dynamics of the effector genes are pivotal for the transition from vegetative growth to host colonization of pathogenic filamentous fungi.However,mechanisms underlying the dynamic regulation of these genes remain largely unknown.Here,through comparative transcriptome and chromatin immunoprecipitation sequencing(ChIP-seq)analyses of the methyltransferase PoKmt6 in rice blast fungus Pyricularia oryzae(syn.Magnaporthe oryzae),we found that PoKmt6-mediated H3K27me3 deposition was enriched mainly at fast-evolving regions and contributed to the silencing of a subset of secreted proteins(SP)and transposable element(TE)families during the vegetative growth of P.oryzae.Intriguingly,we observed that a group of SP genes,which were depleted of H3K27me3 modification,could also be silenced via the H3K27me3-mediated repression of the nearby TEs.In conclusion,our results indicate that H3K27me3 modification mediated by PoKmt6 regulates the expression of some SP genes in fast-evolving regions through the suppression of nearby TEs.

Dynamic evolution of transposable elements,demographic history,and gene content of paleognathous birds

Palaeognathae includes ratite and tinamou species that are important for understanding early avian evolution.Here,we analyzed the whole-genome sequences of 15 paleognathous species to infer their demographic histories,which are presently unknown.We found that most species showed a reduction of population size since the beginning of the last glacial period,except for those species distributed in Australasia and in the far south of South America.Different degrees of contraction and expansion of transposable elements(TE)have shaped the paleognathous genome architecture,with a higher transposon removal rate in tinamous than in ratites.One repeat family,AviRTE,likely underwent horizontal transfer from tropical parasites to the ancestor of little and undulated tinamous about 30 million years ago.Our analysis of gene families identified rapid turnover of immune and reproductionrelated genes but found no evidence of gene family changes underlying the convergent evolution of flightlessness among ratites.We also found that mitochondrial genes have experienced a faster evolutionary rate in tinamous than in ratites,with the former also showing more degenerated W chromosomes.This result can be explained by the Hill-Robertson interference affecting genetically linked W chromosomes and mitochondria.Overall,we reconstructed the evolutionary history of the Palaeognathae populations,genes,and TEs.Our findings of co-evolution between mitochondria and W chromosomes highlight the key difference in genome evolution between species with ZW sex chromosomes and those with XY sex chromosomes.

High genetic variation and recombination events in the vicinity of non-autonomous transposable elements from ‘Candidatus Liberibacter asiaticus'

Two miniature inverted-repeat transposable elements（MITEs）, MCLas-A and MCLas-B, were recently identified from ‘Candidatus Liberibacter asiaticus＇ known to be associated with citrus Huanglongbing（HLB, yellow shoot disease）. MCLas-A was suggested as an active MITE because of its mobility. The immediate upstream gene of the two MITEs was predicted to be a putative transposase. The goal of this study is to analyze the sequence variation in the upstream putative transposase of MITEs and explore the possible correlation between sequence variation of transposase gene and MITE activity. PCR and sequence analysis showed that 12 sequence types were found in six major amplicon types from 43 representative ‘Ca. L. asiaticus＇ isolates from China, the United States and Brazil. Out of the 12 sequence types, three（T4, T5-2, T6） were reported for the first time. Recombination events were found in the two unique sequence types（T5-2 and T6） which were detected in all Brazilian isolates. Notably, no sequence variation or recombination events were detected in the upstream putative transposase gene of MCLas-A, suggesting the conservation of the transposase gene might be closely related with the MITE activity. Phylogenetic analysis demonstrated two well supported clades including five subclades were identified, clearly reflecting the geographical origins of isolates, especially that of Ruili isolates, S？o Paulo isolates and a few Florida isolates.

Gapless indica rice genome reveals synergistic contributions of active transposable elements and segmental duplications to rice genome evolution

The ultimate goal of genome assembly is a high-accuracy gapless genome.Here,we report a new assembly pipeline that is used to produce a gapless genome for the indica rice cultivar Minghui 63.The resulting 397.71-Mb final assembly is composed of 12 contigs with a contig N50 size of 31.93 Mb.Each chromosome is represented by a single contig and the genomic sequences of all chromosomes are gapless.Quality evaluation of this gapless genome assembly showed that gene regions in our assembly have the highest completeness compared with the other 15 reported high-quality rice genomes.Further comparison with the japonica rice genome revealed that the gapless indica genome assembly contains more transposable elements(TEs)and segmental duplications(SDs),the latter of which produce many duplicated genes that can affect agronomic traits through dose effect or sub-/neo-functionalization.The insertion of TEs can also affect the expression of duplicated genes,which may drive the evolution of these genes.Furthermore,we found the expansion of nucleotide-binding site with leucine-rich repeat disease-resistance genes and cis-zeatin-O-glucosyltransferase growth-related genes in SDs in the gapless indica genome assembly,suggesting that SDs contribute to the adaptive evolution of rice disease resistance and developmental processes.Collectively,our findings suggest that active TEs and SDs synergistically contribute to rice genome evolution.

Transposable elements play an important role during cotton genome evolution and fiber cell development

Transposable elements(TEs)usually occupy largest fractions of plant genome and are also the most variable part of the structure.Although traditionally it is hallmarked as"junk and selfish DNA",today more and more evidence points out TE’s participation in gene regulations including gene mutation,duplication,movement and novel gene creation via genetic and epigenetic mechanisms.The recently sequenced genomes of diploid cottons Gossypium arboreum(AA)and Gossypium raimondii(DD)together with their allotetraploid progeny Gossypium hirsutum(At At Dt Dt)provides a unique opportunity to compare genome variations in the Gossypium genus and to analyze the functions of TEs during its evolution.TEs accounted for 57%,68.5%and67.2%,respectively in DD,AA and At At Dt Dt genomes.The 1,694 Mb A-genome was found to harbor more LTR(long terminal repeat)-type retrotransposons that made cardinal contributions to the twofold increase in its genome size after evolution from the 775.2 Mb D-genome.Although the 2,173 Mb At At Dt Dt genome showed similar TE content to the A-genome,the total numbers of LTR-gypsy and LTR-copia type TEs varied significantly between these two genomes.Considering their roles on rewiring gene regulatory networks,we believe that TEs may somehow be involved in cotton fiber cell development.Indeed,the insertion or deletion of different TEs in the upstream region of two important transcription factor genes in At or Dt subgenomes resulted in qualitative differences in target gene expression.We suggest that our findings may open a window for improving cotton agronomic traits by editing TE activities.

The effect of transposable elements on phenotypic variation： insights from plants to humans

Transposable elements(TEs), originally discovered in maize as controlling elements, are the main components of most eukaryotic genomes. TEs have been regarded as deleterious genomic parasites due to their ability to undergo massive amplification. However, TEs can regulate gene expression and alter phenotypes. Also, emerging findings demonstrate that TEs can establish and rewire gene regulatory networks by genetic and epigenetic mechanisms. In this review, we summarize the key roles of TEs in fine-tuning the regulation of gene expression leading to phenotypic plasticity in plants and humans, and the implications for adaption and natural selection.

Codon Usage Biases of Transposable Elements and Host Nuclear Genes in Arabidopsis thaliana and Oryza sativa

Transposable elements （TEs） are mobile genetic entities ubiquitously distributed in nearly all genomes. High frequency of codons ending in A/T in TEs has been previously observed in some species. In this study, the biases in nucleotide composition and codon usage of TE transposases and host nuclear genes were investigated in the AT-rich genome of Arabidopsis thaliana and the GC-rich genome of Oryza sativa. Codons ending in A/T are more frequently used by TEs compared with their host nuclear genes. A remarkable positive correlation between highly expressed nuclear genes and C/G-ending codons were detected in O. sativa （r=0.944 and 0.839, respectively, P〈0.0001） but not in A. thaliana, indicating a close association between the GC content and gene expression level in monocot species. In both species, TE codon usage biases are similar to that of weakly expressed genes. The expression and activity of TEs may be strictly controlled in plant genomes. Mutation bias and selection pressure have simultaneously acted on the TE evolution in A. thaliana and O. sativa. The consistently observed biases of nucleotide composition and codon usage of TEs may also provide a useful clue to accurately detect TE sequences in different species.

Transposable elements at the center of the crossroads between embryogenesis, embryonic stem cells, reprogramming,and long non-coding RNAs

Transposable elements(TEs) are mobile genomic sequences of DNA capable of autonomous and nonautonomous duplication. TEs have been highly successful,and nearly half of the human genome now consists of various families of TEs. Originally thought to be non-functional,these elements have been co-opted by animal genomes to perform a variety of physiological functions ranging from TE-derived proteins acting directly in normal biological functions, to innovations in transcription factor logic and influence on epigenetic control of gene expression. During embryonic development, when the genome is epigenetically reprogrammed and DNA-demethylated, TEs are released from repression and show embryonic stage-specific expression, and in human and mouse embryos, intact TEderived endogenous viral particles can even be detected. Asimilar process occurs during the reprogramming of somatic cells to pluripotent cells: When the somatic DNA is demethylated, TEs are released from repression. In embryonic stem cells(ESCs), where DNA is hypomethylated, an elaborate system of epigenetic control is employed to suppress TEs, a system that often overlaps with normal epigenetic control of ESC gene expression. Finally, many long non-coding RNAs(lnc RNAs) involved in normal ESC function and those assisting or impairing reprogramming contain multiple TEs in their RNA. These TEs may act as regulatory units to recruit RNA-binding proteins and epigenetic modifiers. This review covers how TEs are interlinked with the epigenetic machinery and lnc RNAs, and how these links influence each other to modulate aspects of ESCs,embryogenesis, and somatic cell reprogramming.

PacBio Sequencing Reveals Transposable Elements as a Key Contributor to Genomic Plasticity and Virulence Variation in Magnaporthe oryzae

Dear Editor ：The sustainable cultivation of rice, which serves as staple food crop for more than half of the world＇s population, is under serious threat due to the huge yield losses inflicted by rice blast disease caused by the globally destructive fungus Magnaporthe oryzae （Pyricularia oryzae） （Dean et al., 2012; Nalley et al., 2016; Deng et al., 2017）. This filamentous ascomycete fungus is also capable of causing blast infection on other economically important cereal crops, including wheat, millet, and barley, making it the world＇s most important plant pathogenic fungus （Zhong et al., 2016）.

Gene capture by transposable elements leads to epigenetic conflict in maize

Transposable elements(TEs)regularly capture fragments of genes.When the host silences these TEs,siRNAs homologous to the captured regions may also target the genes.This epigenetic crosstalk establishes an intragenomic conflict:silencing the TEs has the cost of silencing the genes.If genes are important,however,natural selection may maintain function by moderating the silencing response,which may also advantage the TEs.In this study,we examined this model by focusing on Helitrons,Pack-MULEs,and Sirevirus LTR retrotransposons in the maize genome.We documented 1263 TEs containing exon fragments from 1629 donor genes.Consistent with epigenetic conflict,donor genes mapped more siRNAs and were more methylated than genes with no evidence of capture.However,these patterns differed between syntelog versus translocated donor genes.Syntelogs appeared to maintain function,as measured by gene expression,consistent with moderation of silencing for functionally important genes.Epigenetic marks did not spread beyond their captured regions and 24nt crosstalk siRNAs were linked with CHH methylation.Translocated genes,in contrast,bore the signature of silencing.They were highly methylated and less expressed,but also overrepresented among donor genes and located away from chromosomal arms,which suggests a link between capture and gene movement.Splitting genes into potential functional categories based on evolutionary constraint supported the synteny-based findings.TE families captured genes in different ways,but the evidence for their advantage was generally less obvious;nevertheless,TEs with captured fragments were older,mapped fewer siRNAs,and were slightly less methylated than TEs without captured fragments.Collectively,our results argue that TE capture triggers an intragenomic conflict that may not affect the function of important genes but may lead to the pseudogenization of less-constrained genes.

Detection transposable elements in Botrytis cinerea in latent infection stage from symptomless apples

Objective:To detect Botrytis cinerea(B.cinerea)latent infections on apples before storage,which is essential for effective control strategies in the fruit postharvest industry.Methods:In the present study,a polymerase chain reaction detection method,based on primers designed on B.cinerea transposable elements(boty and flipper)and intergenic spacer region as internal control,were utilized to reveal the presence of symptomless infections on apple fruits.This molecular method proved to be highly specific and sensitive in detecting latent infections.It revealed the presence of the pathogen in 83%of the samples from infected apples with 104 conidia/mL,whereas those infected with 106 conidia/mL detected 94%as compared to the traditional method that revealed the pathogen in 40%and 66%of the samples inoculated with 10^(4)and 10^(6)conidia/mL respectively.Furthermore,the method characterized B.cinerea as subpopulation transposa-type by the presence of the transposable elements boty and flipper Results:The results obtained from DNA quantification method were compared with enzyme-linked immunosorbent assay and these studies showed good correlation.Therefore our method has important advantages compared with others detection methods for B.cinerea,because the proposed methodology allowed distinguishes between its two subpopulations(vacuma and transposa)and this would allow establish possible appropriate control strategies.Conclusions:Finally,the method can be an interesting alternative for its possible application in the phytosanitary programs of the fruit industry worldwide.

Construction of a transposase accessible chromatin landscape reveals chromatin state of repeat elements and potential causal variant for complex traits in pigs

Background:A comprehensive landscape of chromatin states for multiple mammalian tissues is essential for elucidating the molecular mechanism underlying regulatory variants on complex traits.However,the genome-wide chromatin accessibility has been only reported in limited tissue types in pigs.Results:Here we report a genome-wide landscape of chromatin accessibility of 20 tissues in two female pigs at ages of 6 months using ATAC-seq,and identified 557,273 merged peaks,which greatly expanded the pig regulatory ele-ment repository.We revealed tissue-specific regulatory elements which were associated with tissue-relevant biologi-cal functions.We identified both positive and negative significant correlations between the regulatory elements and gene transcripts,which showed distinct distributions in terms of their strength and distances from corresponding genes.We investigated the presence of transposable elements(TEs)in open chromatin regions across all tissues,these included identifications of porcine endogenous retroviruses(PERVs)exhibiting high accessibility in liver and homology of porcine specific virus sequences to universally accessible transposable elements.Furthermore,we prior-itized a potential causal variant for polyunsaturated fatty acid in the muscle.Conclusions:Our data provides a novel multi-tissues accessible chromatin landscape that serve as an important resource for interpreting regulatory sequences in tissue-specific and conserved biological functions,as well as regula-tory variants of loci associated with complex traits in pigs.

DNA Damage-Induced Transcription of Transposable Elements and Long Non-coding RNAs in Arabidopsis Is Rare and ATM-Dependent

Induction and mobilization of transposable elements （TEs） following DNA damage or other stresses has been reported in prokaryotes and eukaryotes. Recently it was discovered that eukaryotic TEs are frequently associated with long non-coding RNAs （IncRNAs）, many of which are also upregulated by stress. Yet, it is unknown whether DNA damage-induced transcriptional activation of TEs and IncRNAs occurs sporadically or is a synchronized, genome-wide response. Here we investigated the transcriptome of Arabidopsis wild- type （WT） and ataxia telangiectasia mutated （atm） mutant plants 3 h after induction of DNA damage. In WT, expression of 5.2% of the protein-coding genes is 〉 2-fold changed, whereas in atm plants, only 2.6% of these genes are regulated, and the response of genes associated with DNA repair, replication, and cell cy- cle is largely lost. In contrast, only less than 0.6% of TEs and IncRNAs respond to DNA damage in WT plants, and the regulation of 〉95% of them is ATM-dependent. The ATM-downstream factors BRCA1, DRM1, JMJ30, AGO2, and the ATM-independent AGO4 participate in the regulation of individual TEs and IncRNAs. Remarkably, protein-coding genes located adjacent to DNA damage-responsive TEs and IncRNAs are frequently coexpressed, which is consistent with the hypothesis that TEs and IncRNAs located close to genes commonly function as controlling elements.

Silencing of Transposable Elements by piRNAs in Drosophila:An Evolutionary Perspective

Transposable elements （TEs） are DNA sequences that can move within the genome. TEs have greatly shaped the genomes, transcriptomes, and proteomes of the host organisms through a variety of mechanisms. However, TEs generally disrupt genes and destabilize the host genomes, which substantially reduce fitness of the host organisms. Understanding the genomic distribution and evolutionary dynamics of TEs will greatly deepen our understanding of the TE-mediated bio- logical processes. Most TE insertions are highly polymorphic in Drosophila melanogaster, providing us a good system to investigate the evolution of TEs at the population level. Decades of theoretical and experimental studies have well established ＂transposition-selection＂ population genetics model, which assumes that the equilibrium between TE replication and purifying selection determines the copy number of TEs in the genome. In the last decade, P-element-induced wimpy testis （PIW1）- interacting RNAs （piRNAs） were demonstrated to be master repressors of TE activities in Droso- phila, The discovery of piRNAs revolutionized our understanding of TE repression, because it reveals that the host organisms have evolved an adaptive mechanism to defend against TE invasion. Tremendous progress has been made to understand the molecular mechanisms by which piRNAs repress active TEs, although many details in this process remain to be further explored. The inter- action between piRNAs and TEs well explains the molecular mechanisms underlying hybrid dysge- nesis for the IoR and P-M systems in Drosophila, which have puzzled evolutionary biologists for decades. The piRNA repression pathway provides us an unparalleled system to study the co-evolutionary process between parasites and host organisms.

Nitrogen starvation induces genome-wide activation of transposable elements in Arabidopsis

Nitrogen(N)availability is a major limiting factor for plant growth and agricultural productivity.Although the gene regulation network in response to N starvation has been extensively studied,it remains unknown whether N starvation has an impact on the activity of transposable elements(TEs).Here,we report that TEs can be transcriptionally activated in Arabidopsis under N starvation conditions.Through genetic screening of idm1-14 suppressors,we cloned GLU1,which encodes a glutamate synthase that catalyzes the synthesis of glutamate in the primary N assimilation pathway.We found that glutamate synthase 1(GLU1)and its functional homologs GLU2 and glutamate transport 1(GLT1)are redundantly required for TE silencing,suggesting that N metabolism can regulate TE activity.Transcriptome and methylome analyses revealed that N starvation results in genome-wide TE activation without inducing obvious alteration of DNA methylation.Genetic analysis indicated that N starvationinduced TE activation is also independent of other well-established epigenetic mechanisms,including histone methylation and heterochromatin decondensation.Our results provide new insights into the regulation of TE activity under stressful environments in planta.

Diversity and association analysis of important agricultural trait based on miniature inverted-repeat transposable element specific marker in Brassica napus L.

Miniature inverted-repeat transposable elements(MITEs)are a group of DNA transposable element(TE)which preferentially distributed with gene associated regions.Tens of MITEs families have been revealed in Brassica napus genome,they scatter across the genome with tens of thousands copies and produce polymorphisms both intra-and inter-species.Our previous studies revealed a Tourist-like MITE,Monkey King,associated with vernalization requirement of B.napus,however there are still few studies reveal MITE association with agricultural traits in B.napus.In the present study,80 polymorphic markers were developed from 55 MITEs,and used to evaluate genetic diversity in a panel of B.napus accessions consisting of 101 natural and 25 synthetic genotypes.Five agricultural traits,oil content,glucosinolate content,erucic acid content,weight of thousand seeds(WTS)and plant height,were investigated across 3-years field experiments,in addition,two traits,hypocotyl length and root length,were evaluated at the 4-leaf stage in the laboratory.Correlations between the MITE-based markers and seven traits were analyzed,finally,10 polymorphic markers produced by 6 pairs of MITE specific primers were revealed relatively high correlation with 5 traits.Two polymorphic markers were anchored with two candidate genes,BnaA02g13530D and BnaA08g20010D,respectively,which may contribute to glucosinolate content and WTS.This research may contribute to genetic improvement through utilization of MITE-induced polymorphisms in Brassica species.

Isolating the Mutator Transposable Element Insertional Mutant Gene mio16 of Maize Using Double SelectedAmplification of Insertion Flanking Fragments (DSAIFF)

Mutator transposable element （Mu） has been used as an effective tool to clone maize （Zea mays L.） genes. One opaque endosperm mutant （miol6） was identified in a pool of Mu inserted mutants. A modified method, termed the double selected amplification of insertion flanking fragments （DSAIFF）, was employed to isolate the Mu flanking fragments （MFFs） of miol6. The target site duplications （TSDs） isolated from the Msp I and Mse I digested MFFs had a same 9-bp sequence and were confirmed to be the flanking sequence of one identically inserted gene. Co-segregation analysis suggested that the MFFs were associated with the mutant opaque endosperm, and miol6 was mapped in silico onto the physical position ranged from 229 965 021 to 229 965 409 bp of the maize chromosome 4.09 bin. The full-length cDNA of the wild-type gene was obtained by an RT-PCR primer-scanning technique, and Mio16 was found to putatively encode a homolog of the Arabidopsis MAP3K delta-1 protein kinase. RT-PCR result the mRNA expression of miol6 region anchored by primers Mu20 and af276 was not interrupted by Mu insertion. Further researches will be done to elucidate how the expression of miol6 is alternated by Mu insertion.

Study on the Homologous Sequences of copia-like Retrotransposons in a Twin ovary Mutant of Rice

A twin ovary mutant derived from the doubled haploid (DH) progeny of a cross,02428/Gui 630, was presumably related to the transposition of some transposable elements. Up to date, all reported the active transposable elements in rice (Oryza sativa L.) are copia like retrotransposons. In the present study, the reverse transcriptase domains of copia like retrotransposons were amplified from the total DNA isolated from the mutant plants with the degenerated oligonucleotide primers for the domain. Three cloned insert DNAs, R33 1, R33 4 and R33 8, representing putative different copia like retrotransposons were screened out. Two of them displayed high polymorphism between “Zhaiyeqing 8” and “Jingxi 17”. Nine of the polymorphic bands were mapped on seven rice chromosomes. Sequencing analysis revealed that stop codons frequently occur in the sequence of R33 8, while both R33 1 and R33 4 contain a continuous coding region for 81 putative amino acid residues. No significant variation in hybridization patterns was found between indica and japonica rice or among 26 varieties of indica rice when R33 1 was used as a probe. Nevertheless, when R33 4 was used as a probe, high polymorphisms were detected both between indica and japonica rice and among 26 indica varieties, implying that this element might still be active in rice genomes.

DNA plasticity and damage in amyotrophic lateral sclerosis

The pathophysiology of amyotrophic lateral sclerosis （ALS） is particularly challenging due to the heteroge- neity of its clinical presentation and the diversity of cellular, molecular and genetic peculiarities involved. Molecular insights unveiled several novel genetic factors to be inherent in both familial and sporadic dis- ease entities, whose characterizations in terms of phenotype prediction, pathophysiological impact and putative prognostic value are a topic of current researches. However, apart from genetically well-defined high-confidence and other susceptibility loci, the role of DNA damage and repair strategies of the genome as a whole, either elicited as a direct consequence of the underlying genetic mutation or seen as an autono- mous parameter, in the initiation and progression of ALS, and the different cues involved in either process are still incompletely understood. This mini review summarizes current knowledge on DNA alterations and counteracting DNA repair strategies in ALS pathology and discusses the putative role of unconventional DNA entities including transposable elements and extrachromosomal circular DNA in the disease process. Focus is set on SODl-related pathophysiology, with extension to FUS, TDP-43 and C90RF72 mutations. Advancing our knowledge in the field will contribute to an improved understanding of this relentless dis- ease, for which therapeutic options others than symptomatic approaches are almost unavailable.