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Non-coding DNA

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In genetics, noncoding DNA describes components of an organism's DNA sequences that do not encode for protein sequences. In many eukaryotes, a large percentage of an organism's total genome size is noncoding DNA, although the amount of noncoding DNA, and the proportion of coding versus noncoding DNA varies greatly between species.

Much of this DNA has no known biological function and is sometimes referred to as "Junk DNA". However, many types of noncoding DNA sequences do have known biological functions, including the transcriptional and translational regulation of protein-coding sequences. Other noncoding sequences have likely but as-yet undetermined function, an inference from high levels of homology and conservation seen in sequences that do not encode proteins but appear to be under heavy selective pressure.

Fraction of noncoding genomic DNA

The amount of total genomic DNA varies widely between organisms, and the proportion of coding and noncoding DNA within these genomes varies greatly as well. More than 98% of the human genome does not encode protein sequences, including most sequences within introns and most intergenic DNA.[1]

While overall genome size, and by extension the amount of noncoding DNA, are correlated to organism complexity, there are many exceptions. For example, the genome of the unicellular Polychaos dubium (formerly known as Amoeba dubia) has been reported to contain more than 200 times the amount of DNA in humans.[2] The pufferfish Takifugu rubripes genome is only about one eighth the size of the human genome, yet seems to have a comparable number of genes; approximately 90% of the Takifugu genome is noncoding DNA[1] and most of the genome size difference appears to lie in the noncoding DNA. The extensive variation in nuclear genome size among eukaryotic species is known as the C-value enigma or C-value paradox.[3]

About 80% of the nucleotide bases in the human genome may be transcribed,[4] but transcription does not necessarily imply function.[5]

Types of noncoding DNA sequences

Noncoding functional RNA

Noncoding RNAs are functional RNA molecules that are not translated into protein. Examples of noncoding RNA include ribosomal RNA, transfer RNA, Piwi-interacting RNA and microRNA.

MicroRNAs are predicted to control the translational activity of approximately 30% of all protein-coding genes in mammals and may be vital components in the progression or treatment of various diseases including cancer, cardiovascular disease, and the immune system response to infection.[6]

Cis-regulatory elements

Cis-regulatory elements are sequences that control the transcription of a gene. Cis-elements may be located in 5' or 3' untranslated regions or within introns. Promoters facilitate the transcription of a particular gene and are typically upstream of the coding region.

Enhancer sequences may exert very distant effects on the transcription levels of genes.[7]

Introns

Introns are non-coding sections of a gene, transcribed into the precursor mRNA sequence, but ultimately removed by RNA splicing during the processing to mature messenger RNA. Many introns appear to be mobile genetic elements.[8]

Studies of group I introns from Tetrahymena indicate that some introns appear to be selfish genetic elements, neutral to the host because they remove themselves from flanking exons during RNA processing and do not produce an expression bias between alleles with and without the intron.[8] Some introns do appear to have significant biological function, possibly through ribozyme functionality that may regulate tRNA and rRNA activity as well as protein-coding gene expression, evident in hosts that have become dependent on such introns over long periods of time; for example, the trnL-intron is found in all green plants and appears to have been vertically inherited for several billions of years, including more than a billion years within chloroplasts and an additional 2–3 billion years prior in the cyanobacterial ancestors of chloroplasts.[8]

Pseudogenes

Pseudogenes are DNA sequences, related to known genes, that have lost their protein-coding ability or are otherwise no longer expressed in the cell. Pseudogenes arise from retrotransposition or genomic duplication of functional genes, and become "genomic fossils" that are nonfuctional due to mutations that prevent the transcription of the gene, such as within the gene promoter region, or fatally alter the translation of the gene, such as premature stop codons or frameshifts.[9] Pseudogenes resulting from the retrotransposition of an RNA intermediate are known as processed pseudogenes; pseudogenes that arise from the genomic remains of duplicated genes or residues of inactivated are nonprocessed pseudogenes.[9]

While Dollo's Law suggests that the loss of function in pseudogenes is likely permanent, silenced genes may actually retain function for several million years and can be "reactivated" into protein-coding sequences[10] and a substantial number of pseudogenes are actively transcribed.[9] Because pseudogenes are presumed to evolve without evolutionary constraint, they can serve as a useful model of the type and frequencies various spontaneous genetic mutations.[11]

Repeat sequences, transposons and viral elements

Transposons and retrotransposons are mobile genetic elements. Retrotransposon repeated sequences, which include long interspersed nuclear elements (LINEs) and short interspersed nuclear elements (SINEs), account for a large proportion of the genomic sequences in many species. Alu sequences, classified as a short interspersed nuclear element, are the most abundant mobile elements in the human genome. Some examples have been found of SINEs exerting transcriptional control of some protein-encoding genes.[12][13][14]

Endogenous retrovirus sequences are the product of reverse transcription of retrovirus genomes into the genomes of germ cells. Mutation within these retro-transcribed sequences can inactivate the viral genome.

Over 8% of the human genome is made up of (mostly decayed) endogenous retrovirus sequences, as part of the over 42% fraction that is recognizably derived of retrotransposons, while another 3% can be identified to be the remains of DNA transposons. Much of the remaining half of the genome that is currently without an explained origin is expected to have found its origin in transposable elements that were active so long ago (> 200 million years) that random mutations have rendered them unrecognizable.[15] Genome size variation in at least two kinds of plants is mostly the result of retrotransposon sequences.[16]

Telomeres

Telomeres are regions of repetitive DNA at the end of a chromosome, which provide protection from chromosomal deterioration during DNA replication.

Functions of noncoding DNA

Many noncoding DNA sequences have very important biological functions. Comparative genomics reveals that some regions of noncoding DNA are highly conserved, sometimes on time-scales representing hundreds of millions of years, implying that these noncoding regions are under strong evolutionary pressure and positive selection.[17] For example, in the genomes of humans and mice, which diverged from a common ancestor 65–75 million years ago, protein-coding DNA sequences account for only about 20% of conserved DNA, with the remaining majority of conserved DNA represented in noncoding regions.[18] Linkage mapping often identifies chromosomal regions associated with a disease with no evidence of functional coding variants of genes within the region, suggesting that disease-causing genetic variants lie in the noncoding DNA.[18]

Some noncoding DNA sequences are genetic "switches" that do not encode proteins, but do regulate when and where genes are expressed.[19] According to a comparative study of over 300 prokaryotic and over 30 eukaryotic genomes,[20] eukaryotes appear to require a minimum amount of non-coding DNA. This minimum amount can be predicted using a growth model for regulatory genetic networks, implying that it is required for regulatory purposes. In humans the predicted minimum is about 5% of the total genome.

Some specific sequences of noncoding DNA may be features essential to chromosome structure, centromere function and homolog recognition in meiosis.[21]

Some noncoding DNA sequences determine the expression levels of various genes.[22] Other sequences of noncoding DNA determine where transcription factors attach.[22]

Noncoding DNA and evolution

Shared sequences of apparently non-functional DNA are a major line of evidence for common descent.[23]

Pseudogene sequences appear to accumulate mutations more rapidly than coding sequences due to a loss of selective pressure.[11] This allows for the creation of mutant alleles that incorporate new functions that may be favored by natural selection; thus, pseudogenes can serve as raw material for evolution and can be considered "protogenes".[24]

Junk DNA

Junk DNA, a term that was introduced in 1972 by Susumu Ohno,[25] was a provisional label for the portions of a genome sequence for which no discernible function had been identified. According to a 1980 review in Nature by Leslie Orgel and Francis Crick, junk DNA has "little specificity and conveys little or no selective advantage to the organism".[26] The term is currently, however, a somewhat outdated concept, being used mainly in popular science and in a colloquial way in scientific publications, and may have slowed research into the biological functions of noncoding DNA.[27] Several lines of evidence indicate that many "junk DNA" sequences have likely but unidentified functional activity, and other sequences may have had functions in the past.[28]

Still, a large amount of sequence in these genomes falls under no existing classification other than "junk". For example, one experiment removed 0.1% of the mouse genome with no detectable effect on the phenotype.[29] This result suggests that the removed DNA was largely nonfunctional. In addition, these sequences are enriched for the heterochromatic histone modification H3K9me3 [30].

See also

References

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