of sine retrotransposition. effects of sine transposition insertion of a sine upstream of a coding region may result in exon shuffling or changes to the regulatory region of the gene. insertion of a sine into the coding sequence of a gene can have deleterious effects and unregulated transposition can cause genetic disease. the transposition and recombination of sines and other active nuclear elements is thought to be one of the major contributions of genetic diversity between lineages during speciation. common sines short-interspersed nuclear elements are believed to have parasitic origins in eukaryotic genomes. these sines have mutated and replicated themselves a large number of times on an evolutionary time-scale and thus form many different lineages. their early evolutionary origin has caused them to be ubiquitous in many eukaryotic lineages. alu elements, short-interspersed nuclear element of about 300 nucleotides, are the most common sine in humans, with >1,000,000 copies throughout the genome, which is over 10 percent of the total genome; this is not uncommon among other species. alu element copy number differences can be used to distinguish between and construct phylogenies of primate species. canines differ primarily in their abundance of sinec_cf repeats throughout the genome, rather than other gene or allele level mutations. these dog-specific sines may code for a splice acceptor site, altering the sequences that appear as exons or introns in each species. apart from mammals, sines can reach high copy numbers in a range of species, including nonbony vertebrates (elephant shark) and some fish species (coelacanths). in plants, sines are often restricted to closely related species and have emerged, decayed, and vanished frequently during evolution. nevertheless, some sine families such as the au-sines and the angio-sines are unusually widespread across many often unrelated plant species. diseases there are >50 human diseases associated with sines. when inserted near or within the exon, sines can cause improper splicing, become coding regions, or change the reading frame, often leading to disease phenotypes in humans and other animals. insertion of alu elements in the human genome is associated with breast cancer, colon cancer, leukemia, hemophilia, dent's disease, cystic fibrosis, neurofibromatosis, and many others. micrornas the role of short-interspersed nuclear elements in gene regulation within cells has been supported by multiple studies. one such study examined the correlation between a certain family of sines with micrornas (in zebrafish). the specific family of sines being examined was the anamnia v-sines; this family of short interspersed nuclear elements is often found in the untranslated region of the 3' end of many genes and is present in vertebrate genomes. the study involved a computational analysis in which the genomic distribution and activity of the anamnia v-sines in danio rerio zebrafish was examined; furthermore, these v-sines potential to generate novel microrna loci was analyzed. it was found that genes which were predicted to possess v-sines were targeted by micrornas with significantly higher hybridization e-values (relative to other areas in the genome). the genes that had high hybridization e-values were genes particularly involved in metabolic and signaling pathways. almost all mirnas identified to have a strong ability to hybridize to putative v-sine sequence motifs in genes have been identified (in mammals) to have regulatory roles. these results which establish a correlation between short-interspersed nuclear elements and different regulatory micrornas strongly suggest that v-sines have a significant role in attenuating responses to different signals and stimuli related to metabolism, proliferation and differentiation. many other studies must be undertaken to establish the validity and extent of short-interspersed nuclear element retrotransposons' role in regulatory gene-expression networks. in conclusion, though not much is known about the role and mechanism by which sines generate mirna gene loci it is generally understood that sines have played a significant evolutionary role in the creation of "rna-genes", this is also touched upon above in sines and pseudogenes. with such evidence suggesting that short-interspersed nuclear elements have been evolutionary sources for microrna loci generation it is important to further discuss the potential relationships between the two as well as the mechanism by which the microrna regulates rna degradation and more broadly, gene expression. a microrna is a non-coding rna generally 22 nucleotides in length. this non-protein coding oligonucleotide is itself coded by longer nuclear dna sequence usually transcribed by rna polymerase ii which is also responsible for the transcription of most mrnas and snrnas in eukaryotes. however, some research suggests that some micrornas that possess upstream short-interspersed nuclear elements are transcribed by rna polymerase iii which is widely implicated in ribosomal rna and trna, two transcripts vital to mrna translation. this provides an alternate mechanism by which short-interspersed nuclear elements could be interacting with or mediating gene-regulatory networks involving micrornas. the regions coding mirna can be independent rna-genes often being anti-sense to neighboring protein-coding genes, or can be found within the introns of protein-coding genes. the co-localization of microrna and protein-coding genes provides a mechanistic foundation by which microrna regulates gene-expression. furthermore, scarpato et al. reveals (as discussed above) that genes predicted to possess short-interspersed nuclear elements (sines) through sequence analysis were targeted and hybridized by micrornas significantly greater than other genes. this provides an evolutionarily path by which the parasitic sines were co-opted and utilized to form rna-genes (such as micrornas) which have evolved to play a role in complex gene-regulatory networks. the micrornas are transcribed as part of longer rna strands of generally about 80 nucleotides which through complementary base-pairing are able to form hairpin loop structures these structures are recognized and processed in the nucleus by the nuclear protein digeorge syndrome critical region 8 (dgcr8) which recruits and associates with the drosha protein. this complex is responsible for cleaving some of the hair-pin structures from the pre-microrna which is transported to the cytoplasm. the pre-mirna is processed by the protein dicer into a double stranded 22 nucleotide. thereafter, one of the strands is incorporated into a multi-protein rna-induced silencing complex (risc). among these proteins are proteins from the argonaute family which are critical to the complex's ability to interact with and repress the translation of the target mrna. understanding the different ways in which microrna regulates gene-expression, including mrna-translation and degradation is key to understanding the potential evolutionary role of sines in gene-regulation and in the generation of microrna loci. this, in addition to sines' direct role in regulatory networks (as discussed in sines as long non-coding rnas) is crucial to beginning to understand the relationship between sines and certain diseases. multiple studies have suggested that increased sine activity is correlated with certain gene-expression profiles and post-transcription regulation of certain genes. in fact, peterson et al. 2013 demonstrated that high sine rna expression correlates with post-transcriptional downregulation of brca1, a tumor suppressor implicated in multiple forms of cancer, namely breast cancer. furthermore, studies have established a strong correlation between transcriptional mobilization of sines and certain cancers and conditions such as hypoxia; this can be due to the genomic instability caused by sine activity as well as more direct-downstream effects. sines have also been implicated in countless other diseases. in essence, short-interspersed nuclear elements have become deeply integrated in countless regulatory, metabolic and signaling pathways and thus play an inevitable role in causing disease. much is still to be known about these genomic parasites but it is clear they play a significant role within eukaryotic organisms. sines and pseudogenes the activity of sines however has genetic vestiges which do not seem to play a significant role, positive or negative, and manifest themselves in the genome as pseudogenes. sines however should not be mistaken as rna pseudogenes. in general, pseudogenes are generated when processed mrnas of protein-coding genes are reverse-transcribed and incorporated back into the genome (rna pseudogenes are reverse transcribed rna genes). pseudogenes are generally functionless as they descend from processed rnas independent of their evolutionary-context which includes introns and different regulatory elements which enable transcription and processing. these pseudogenes, though non-functional may in some cases still possess promoters, cpg islands, and other features which enable transcription; they thus can still be transcribed and may possess a role in the regulation of gene expression (like sines and other non-coding elements). pseudogenes thus differ from sines in that they are derived from transcribed- functional rna whereas sines are dna elements which retrotranspose by co-opting rna genes transcriptional machinery. however, there are studies which suggest that retro-transposable elements such as short-interspersed nuclear elements are not only capable of copying themselves in alternate regions in the genome but are also able to do so for random genes too. thus sines can be playing a vital role in the generation of pseudogenes, which themselves are known to be involved in regulatory networks. this is perhaps another means by which sines have been able to influence and contribute to gene-regulation.