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Non-coding DNA

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This is an old revision of this page, as edited by Evolution and evolvability (talk | contribs) at 05:12, 27 February 2023 (→Junk DNA: "ENCODE PROJECT" was probably not a useful section title any more. I have attempted to separate out into different broad methodological frameworks, but it could certainly use some refinement.). The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.

Non-coding DNA (ncDNA) sequences are components of an organism's DNA that do not encode protein sequences. Some non-coding DNA is transcribed into functional non-coding RNA molecules (e.g. transfer RNA, microRNA, piRNA, ribosomal RNA, and regulatory RNAs). Other functional regions of the non-coding DNA fraction include regulatory sequences that control gene expression; scaffold attachment regions; origins of DNA replication; centromeres; and telomeres. Some non-coding regions appear to be mostly nonfunctional such as introns, pseudogenes, intergenic DNA, and fragments of transposons and viruses.

Fraction of non-coding genomic DNA

In bacteria, the coding regions typically take up 88% of the genome. The remaining 12% consists largely of non-coding genes and regulatory sequences, which means that almost all of the bacterial genome has a function.[1] The amount of coding DNA in eukaryrotes is usually a much smaller fraction of the genome because eukaryotic genomes contain large amounts of repetitive DNA not found in prokaryotes. The human genome contains somewhere between 1–2% coding DNA.[2][3] The exact number is not known because there are disputes over the number of functional coding exons and over the total size of the human genome. This means that 98–99% of the human genome consists of non-coding DNA and this includes many functional elements such as non-coding genes and regulatory sequences.

Genome size in eukaryotes can vary over a wide range, even between closely related sequences. This puzzling observation was originally known as the C-value Paradox where "C" refers to the haploid genome size.[4] The paradox was resolved with the discovery that most of the differences were due to the expansion and contraction of repetitive DNA and not the number of genes. Some researchers speculated that this repetitive DNA was mostly junk DNA. The reasons for the changes in genome size are still being worked out and this problem is called the C-value Enigma.[5]

This led to the observation that the number of genes does not seem to correlate with perceived notions of complexity because the number of genes seems to be relatively constant, an issue termed the G-value Paradox.[6] 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 (i.e. more than 600 billion pairs of bases vs a bit more than 3 billion in humans).[7] 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. Genes take up about 30% of the pufferfish genome and the coding DNA is about 10%. (Non-coding DNA = 90%.) The reduced size of the pufferfish genome is due to a reduction in the length of introns and less repetitive DNA.[8][9]

Utricularia gibba, a bladderwort plant, has a very small nuclear genome (100.7 Mb) compared to most plants.[10][11] It likely evolved from an ancestral genome that was 1,500 Mb in size.[11] The bladderwort genome has roughly the same number of genes as other plants but the total amount of coding DNA comes to about 30% of the genome.[10][11]

The remainder of the genome (70% non-coding DNA) consists of promoters and regulatory sequences that are shorter than those in other plant species.[10] The genes contain introns but there are fewer of them and they are smaller than the introns in other plant genomes.[10] There are noncoding genes, including many copies of ribosomal RNA genes.[11] The genome also contains telomere sequences and centromeres as expected.[11] Much of the repetitive DNA seen in other eukaryotes has been deleted from the bladderwort genome since that lineage split from those of other plants. About 59% of the bladderwort genome consists of transposon-related sequences but since the genome is so much smaller than other genomes, this represents a considerable reduction in the amount of this DNA.[11] The authors of the original 2013 article note that claims of additional functional elements in the non-coding DNA of animals do not seem to apply to plant genomes.[10]

According to a New York Times piece, during the evolution of this species, "... genetic junk that didn’t serve a purpose was expunged, and the necessary stuff was kept."[12] According to Victor Albert of the University of Buffalo, the plant is able to expunge its so-called junk DNA and "have a perfectly good multicellular plant with lots of different cells, organs, tissue types and flowers, and you can do it without the junk. Junk is not needed."[13]

Types of non-coding DNA sequences

Further information: Conserved non-coding sequence

Noncoding genes

Further information: Non-coding RNA

There are two types of genes: protein coding genes and noncoding genes.[14] Noncoding genes are an important part of non-coding DNA and they include genes for transfer RNA and ribosomal RNA. These genes were discovered in the 1960s. Prokaryotic genomes contain genes for a number of other noncoding RNAs but noncoding RNA genes are much more common in eukaryotes.

Typical classes of noncoding genes in eukaryotes include genes for small nuclear RNAs (snRNAs), small nucleolar RNAs (sno RNAs), microRNAs (miRNAs), short interfering RNAs (siRNAs), PIWI-interacting RNAs (piRNAs), and long noncoding RNAs (lncRNAs). In addition, there are a number of unique RNA genes that produce catalytic RNAs.[15]

Noncoding genes account for only a few percent of prokaryotic genomes[16] but they can represent a vastly higher fraction in eukaryotic genomes.[17] In humans, the noncoding genes take up at least 6% of the genome, largely because there are hundreds of copies of ribosomal RNA genes.[citation needed] Protein-coding genes occupy about 38% of the genome; a fraction that is much higher than the coding region because genes contain large introns.[citation needed]

The total number of noncoding genes in the human genome is controversial. Some scientists think that there are only about 5,000 noncoding genes while others believe that there may be more than 100,000 (see the article on Non-coding RNA). The difference is largely due to debate over the number of lncRNA genes.[18]

Promoters and regulatory elements

Further information: Promoter (genetics)

Promoters are DNA segments near the 5' end of the gene where transcription begins. They are the sites where RNA polymerase binds to initiate RNA synthesis. Every gene has a noncoding promoter.

Regulatory elements are sites that control the transcription of a nearby gene. They are almost always sequences where transcription factors bind to DNA and these transcription factors can either activate transcription (activators) or repress transcription (repressors). Regulatory elements were discovered in the 1960s and their general characteristics were worked out in the 1970s by studying specific transcription factors in bacteria and bacteriophage.[citation needed]

Promoters and regulatory sequences represent an abundant class of noncoding DNA but they mostly consist of a collection of relatively short sequences so they don't take up a very large fraction of the genome. The exact amount of regulatory DNA in mammalian genome is unclear because it is difficult to distinguish between spurious transcription factor binding sites and those that are functional. The binding characteristics of typical DNA-binding proteins were characterized in the 1970s and the biochemical properties of transcription factors predict that in cells with large genomes the majority of binding sites will be fortuitous and not biologiacally functional.[citation needed]

Many regulatory sequences occur near promoters, usually upstream of the transcription start site of the gene. Some occur within a gene and a few are located downstream of the transcription termination site. In eukaryotes, there are some regulatory sequences that are located at a considerable distance from the promoter region. These distant regulatory sequences are often called enhancers but there is no rigorous definition of enhancer that distinguishes it from other transcription factor binding sites.[19][20]

Introns

Further information: Intron
Illustration of an unspliced pre-mRNA precursor, with five introns and six exons (top). After the introns have been removed via splicing, the mature mRNA sequence is ready for translation (bottom).

Introns are the parts of a gene that are transcribed into the precursor RNA sequence, but ultimately removed by RNA splicing during the processing to mature RNA. Introns are found in both types of genes: protein-coding genes and noncoding genes. They are present in prokaryotes but they are much more common in eukaryotic genomes.[citation needed]

Group I and group II introns take up only a small percentage of the genome when they are present. Spliceosomal introns (see Figure) are only found in eukaryotes and they can represent a substantial proportion of the genome. In humans, for example, introns in protein-coding genes cover 37% of the genome. Combining that with about 1% coding sequences means that protein-coding genes occupy about 39% of the human genome. The calculations for noncoding genes are more complicated because there's considerable dispute over the total number of noncoding genes but taking only the well-defined examples means that noncoding genes occupy at least 6% of the genome.[21][2]

Untranslated regions

Further information: Untranslated region

The standard biochemistry and molecular biology textbooks describe non-coding nucleotides in mRNA located between the 5' end of the gene and the translation initiation codon. These regions are called 5'-untranslated regions or 5'-UTRs. Similar regions called 3'-untranslated regions (3'-UTRs) are found at the end of the gene. The 5'-UTRs and 3'UTRs are very short in bacteria but they can be several hundred nucleotides in length in eukaryotes. They contain short elements that control the initiation of translation (5'-UTRs) and transcription termination (3'-UTRs) as well as regulatory elements that may control mRNA stability, processing, and targeting to different regions of the cell.[22][23][24]

Origins of replication

Further information: Origin of replication

DNA synthesis begins at specific sites called origins of replication. These are regions of the genome where the DNA replication machinery is assembled and the DNA is unwound to begin DNA synthesis. In most cases, replication proceeds in both directions from the replication origin.

The main features of replication origins are sequences where specific initiation proteins are bound. A typical replication origin covers about 100-200 base pairs of DNA. Prokaryotes have one origin of replication per chromosome or plasmid but there are usually multiple origins in eukaryotic chromosomes. The human genome contains about 100,000 origins of replication representing about 0.3% of the genome.[25][26][27]

Centromeres

Schematic karyogram of a human, showing an overview of the human genome on G banding, wherein non-coding DNA is present at the centromeres (shown as narrow segment of each chromosome), and also occurs to a greater extent in darker (GC poor) regions.[28]
Further information: Karyotype
Further information: Centromere

Centromeres are the sites where spindle fibers attach to newly replicated chromosomes in order to segregate them into daughter cells when the cell divides. Each eukaryotic chromosome has a single functional centromere that's seen as a constricted region in a condensed metaphase chromosome. Centromeric DNA consists of a number of repetitive DNA sequences that often take up a significant fraction of the genome because each centromere can be millions of base pairs in length. In humans, for example, the sequences of all 24 centromeres have been determined[29] and they account for about 6% of the genome. However, it's unlikely that all of this noncoding DNA is essential since there is considerable variation in the total amount of centromeric DNA in different individuals.[30] Centromeres are another example of functional noncoding DNA sequences that have been known for almost half a century and it's likely that they are more abundant than coding DNA.

Telomeres

Further information: Telomere

Telomeres are regions of repetitive DNA at the end of a chromosome, which provide protection from chromosomal deterioration during DNA replication. Recent studies have shown that telomeres function to aid in its own stability. Telomeric repeat-containing RNA (TERRA) are transcripts derived from telomeres. TERRA has been shown to maintain telomerase activity and lengthen the ends of chromosomes.[31]

Scaffold attachment regions

Further information: Scaffold/matrix attachment region

Both prokaryotic and eukarotic genomes are organized into large loops of protein-bound DNA. In eukaryotes, the bases of the loops are called scaffold attachment regions (SARs) and they consist of stretches of DNA that bind an RNA/protein complex to stabilize the loop. There are about 100,000 loops in the human genome and each one consists of about 100 bp of DNA. The total amount of DNA devoted to SARs accounts for about 0.3% of the human genome.[32]

Pseudogenes

Further information: Pseudogene

Pseudogenes are mostly former genes that have become non-functional due to mutation but the term also refers to inactive DNA sequences that are derived from RNAs produced by functional genes (processed pseudogenes). Pseudogenes are only a small fraction of noncoding DNA in prokaryotic genomes because they are eliminated by negative selection. In some eukaryotes, however, pseudogenes can accumulate because selection isn't powerful enough to eliminate them (see Nearly neutral theory of molecular evolution).

The human genome contains about 15,000 pseudogenes derived from protein-coding genes and an unknown number derived from noncoding genes.[33] They may cover a substantial fraction of the genome (~5%) since many of them contain former intron sequences, .

Pseudogenes are junk DNA by definition and they evolve at the neutral rate as expected for junk DNA.[34] Some former pseudogenes have secondarily acquired a function and this leads some scientists to speculate that most pseudogenes are not junk because they have a yet-to-be-discovered function.[35]

Repeat sequences, transposons and viral elements

Further information: Repeated sequence (DNA)
Mobile genetic elements in the cell (left) and how they can be acquired (right)

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.[36][37][38]

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.[39]

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.[40] Genome size variation in at least two kinds of plants is mostly the result of retrotransposon sequences.[41][42]

Highly repetitive DNA

Highly repetitive DNA consists of short stretches of DNA that are repeated many times in tandem (one after the other). The repeat segments are usually between 2 bp and 10 bp but longer ones are known. Highly repetitive DNA is rare in prokaryotes but common in eukaryotes, especially those with large genomes. It is sometimes called satellite DNA.

Most of the highly repetitive DNA is found in centromeres and telomeres (see above) and most of it is functional although some might be redundant. The other significant fraction resides in short tandem repeats (STRs; also called microsatellites) consisting of short stretches of a simple repeat such as ATC. There are about 350,000 STRs in the human genome and they are scattered throughout the genome with an average length of about 25 repeats.[43][44]

Variations in the number of STR repeats can cause genetic diseases when they lie within a gene but most of these regions appear to be non-functional junk DNA where the number of repeats can vary considerably from individual to individual. This is why these length differences are used extensively in DNA fingerprinting.

Junk DNA

Although many non-coding regions have biological function,[45][46] some portion of non-coding DNA has also been described as "Junk DNA". Though exact definitions differ, this refers broadly to "any DNA sequence that does not play a functional role in development, physiology, or some other organism-level capacity."[47] The term "junk DNA" was used in the 1960s.[47][48][49] but it only became widely known in 1972 in a paper by Susumu Ohno.[9] Ohno noted that the mutational load from deleterious mutations placed an upper limit on the number of functional loci that could be expected given a typical mutation rate. He hypothesized that mammalian genomes could not have more than 30,000 loci under selection before the "cost" from the mutational load would cause an inescapable decline in fitness, and eventually extinction.[9] Similar calculations focusing on nucleotides rather than gene loci come to the similar conclusion that the functional portion of the human genome (given mutation rates, genome size and population size) can only be maintained up to approximately 15%.[50] The presence of junk DNA also explained the observation that even closely related species can have widely (orders-of-magnitude) different genome sizes (C-value paradox).[51]

Terminology

The term "junk DNA" is contentious and different exact definitions (and associated methods) yield widely different estimates of its prevalence.[52] Some authors assert that the term occurs mainly in popular science and is no longer used in serious research articles.[53] It has also been pointed out that the term 'junk' can imply that its accumulation is disadvantageous, whereas the majority of non-functional sequence is likely merely neutral.[54] Strong reactions to the term "junk DNA" have also lead some to recommend more neutral terminology, such as "nonfunctional DNA."[51]

Measurement and estimates

Different methodologies rest on different implicit definitions yield different estimates of the non-functional fraction of the genome.[52]

For example, 20% of human genomic DNA shows no detectable biochemical activity,[55] but comparative genomics methods estimate a nonfunctional fraction of 85-92%.[56][57][58] Consequently, different exact definitions of Junk DNA would yield different exact proportions. Each method has limitations, for example, genetic approaches may miss functional elements that do not manifest physically on the organism, evolutionary approaches have difficulties using accurate multispecies sequence alignments since genomes of even closely related species vary considerably, and biochemical signatures do not always automatically signify a function.[57] Ultimately genetic, evolutionary, and biochemical approaches can all be used in a complementary way to identify regions that may be functional in human biology and disease.[57]

Biochemical activity

Detectable biochemical activity (e.g. transcription, transcription factor association, chromatin structure, and histone modification) was observed for at least 80% of human genomic DNA by the Encyclopedia of DNA Elements (ENCODE) project.[55] This forms an upper estimate of the functional portion of the human genome since biochemical activity is not necessarily biological function or selective advantage.[59][51][60][47][61] For example, transcription factor binding sites are short and can be found by chance over the whole genome[62] and 70% of transcribed sequences are below 1 transcript per cell[57] and so may be spurious background transcription.[57]Genetic function

Contributing to the debate is that there is no consensus on what constitutes a "functional" element in the genome since geneticists, evolutionary biologists, and molecular biologists employ different approaches and definitions of "function",[57] often with a lack of clarity of what they mean in the literature.[63] Due to the ambiguity in the terminology, there are different schools of thought over this matter.[64]

However, widespread transcription and splicing in the human genome has been discussed as another indicator of genetic function in addition to genomic conservation which may miss poorly conserved functional sequences.[57] And much of the apparent junk DNA is involved in epigenetic regulation and appears to be necessary for the development of complex organisms.[65][66][67]

Some critics have argued that functionality can only be assessed in reference to an appropriate null hypothesis. In this case, the null hypothesis would be that these parts of the genome are non-functional and have properties, be it on the basis of conservation or biochemical activity, that would be expected of such regions based on our general understanding of molecular evolution and biochemistry. According to these critics, until a region in question has been shown to have additional features, beyond what is expected of the null hypothesis, it should provisionally be labelled as non-functional.[68]

Evolutionary impact

One indication of functionality of a genomic region is if that sequence has been maintained by purifying selection (or if mutating away the sequence is deleterious to the organism). Estimates for the functionally constrained fraction of the human genome based on evolutionary conservation using comparative genomics range between 8 and 15%.[56][57][58] These may still be an underestimate when lineage-specific constraints are included. However, others have argued against relying solely on estimates from comparative genomics due to its limited scope since non-coding DNA has been found to be involved in epigenetic activity and complex networks of genetic interactions and is explored in evolutionary developmental biology.[65][57][66][67]

Biologically functional sequences may also have different evolutionary impacts on the sequence itself or the organism that it is found in. Much of the DNA in large genomes originates from selfish amplification of transposable elements. Some of this sequence has biological function (transposition and self replication in the host genome) but does not provided a selective advantage to the host organism.[69]

An additional complication is that the large body of nonfunctional background transcripts produced by non-function sequences can evolve into functional elements de novo.[70][71] Therefore a sequence fitting a strict defining of junk as having no biological function and no fitness effect can still have long-term evolutionary significance.[72][73]

Genome-wide association studies (GWAS) and non-coding DNA

Genome-wide association studies (GWAS) identify linkages between alleles and observable traits such as phenotypes and diseases. Most of the associations are between single-nucleotide polymorphisms (SNPs) and the trait being examined and most of these SNPs are located in non-functional DNA. The association establishes a linkage that helps map the DNA region responsible for the trait but it doesn't necessarily identify the mutations causing the disease or phenotypic difference.[74][75][76][77][78]

SNPs that are tightly linked to traits are the ones most likely to identify a causal mutation. (The association is referred to as tight linkage disequilibrium.) About 12% of these polymorphisms are found in coding regions; about 40% are located in introns; and most of the rest are found in intergenic regions, including regulatory sequences.[75]

See also

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Further reading

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