In genomics and related disciplines, noncoding
DNA sequences are
components of an organism's
DNA that do not encode protein sequences.
DNA is transcribed into functional non-coding RNA
molecules (e.g. transfer RNA, ribosomal RNA, and regulatory RNAs).
Other functions of noncoding
DNA include the transcriptional and
translational regulation of protein-coding sequences, scaffold
attachment regions, origins of
DNA replication, centromeres and
The amount of noncoding
DNA varies greatly among species. Often, only
a small percentage of the genome is responsible for coding proteins,
but a rising percentage is being shown to have regulatory functions.
When there is much non-coding DNA, a large proportion appears to have
no biological function, as predicted in the 1960s. Since that time,
this non-functional portion has controversially been called "junk
The international Encyclopedia of
DNA Elements (ENCODE) project
uncovered, by direct biochemical approaches, that at least 80% of
DNA has biochemical activity. Though this was not
necessarily unexpected due to previous decades of research discovering
many functional noncoding regions, some scientists criticized
the conclusion for conflating biochemical activity with biological
function. Estimates for the biologically functional
fraction of our genome based on comparative genomics range between 8
and 15%. However, others have argued against relying
solely on estimates from comparative genomics due to its limited
DNA has been found to be involved in epigenetic
activity and complex networks of genetic interactions, and is being
explored in evolutionary developmental biology.
1 Fraction of noncoding genomic DNA
2 Types of noncoding
2.1 Noncoding functional RNA
2.2 Cis- and trans-regulatory elements
2.5 Repeat sequences, transposons and viral elements
3 Junk DNA
4 Evidence of functionality
5 Regulating gene expression
5.1 Transcription factors
6.2 Long range correlations
6.3 Forensic anthropology
7 See also
9 Further reading
10 External links
Fraction of noncoding genomic DNA
Utricularia gibba has only 3% noncoding 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. For example, it was originally suggested that over
98% of the human genome does not encode protein sequences, including
most sequences within introns and most intergenic DNA, whilst 20%
of a typical prokaryote genome is noncoding.
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. 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
Takifugu genome is noncoding DNA. The extensive variation in
nuclear genome size among eukaryotic species is known as the C-value
C-value paradox. Most of the genome size difference
appears to lie in the noncoding DNA.
In 2013, a new "record" for the most efficient eukaryotic genome was
discovered with Utricularia gibba, a bladderwort plant that has only
DNA and 97% of coding DNA. Parts of the noncoding DNA
were being deleted by the plant and this suggested that noncoding DNA
may not be as critical for plants, even though noncoding
DNA is useful
for humans. Other studies on plants have discovered crucial
functions in portions of noncoding
DNA that were previously thought to
be negligible and have added a new layer to the understanding of gene
Types of noncoding
Main article: Conserved non-coding sequence
Noncoding functional RNA
Transfer RNA and ribosomal
RNA are not translated into protein, but
they are functional, synthesising proteins by translating the coding
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.
Cis- and trans-regulatory elements
Cis-regulatory elements are sequences that control the transcription
of a nearby gene. Many such elements are involved in the evolution and
control of development. Cis-elements may be located in 5' or 3'
untranslated regions or within introns. Trans-regulatory elements
control the transcription of a distant gene.
Promoters facilitate the transcription of a particular gene and are
typically upstream of the coding region. Enhancer sequences may also
exert very distant effects on the transcription levels of genes.
Simple illustration of an unspliced m
RNA precursor, with two introns
and three exons (top). After the introns have been removed via
splicing, the mature m
RNA sequence is ready for translation (bottom).
Introns are non-coding sections of a gene, transcribed into the
RNA sequence, but ultimately removed by
RNA splicing during
the processing to mature messenger RNA. Many introns appear to be
mobile genetic elements.
Studies of group I introns from
Tetrahymena protozoans 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. Some introns appear to have significant
biological function, possibly through ribozyme functionality that may
RNA and r
RNA 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.
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
nonfunctional 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. Pseudogenes resulting from the retrotransposition of
RNA intermediate are known as processed pseudogenes; pseudogenes
that arise from the genomic remains of duplicated genes or residues of
inactivated genes are nonprocessed pseudogenes.
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 and a substantial number of pseudogenes are actively
transcribed. Because pseudogenes are presumed to change
without evolutionary constraint, they can serve as a useful model of
the type and frequencies of various spontaneous genetic mutations.
Repeat sequences, transposons and viral elements
Mobile genetic elements
Mobile genetic elements in the cell (left) and how they can be
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.
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
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.
Genome size variation in at least
two kinds of plants is mostly the result of retrotransposon
Telomeres are regions of repetitive
DNA at the end of a chromosome,
which provide protection from chromosomal deterioration during DNA
The term "junk DNA" became popular in the 1960s. According to
T. Ryan Gregory, the nature of junk
DNA was first discussed explicitly
in 1972 by a genomic biologist, David Comings, who applied the term to
all noncoding DNA. The term was formalized that same year by
Susumu Ohno, who 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. Ohno hypothesized
that mammal 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. This
prediction remains robust, with the human genome containing
approximately 20,000 genes. Another source for Ohno's theory was the
observation that even closely related species can have widely
(orders-of-magnitude) different genome sizes, which had been dubbed
C-value paradox in 1971.
Though the fruitfulness of the term "junk DNA" has been questioned on
the grounds that it provokes a strong a priori assumption of total
non-functionality and though some have recommended using more neutral
terminology such as "noncoding DNA" instead; "junk DNA" remains a
label for the portions of a genome sequence for which no discernible
function has been identified and that through comparative genomics
analysis appear under no functional constraint suggesting that the
sequence itself has provided no adaptive advantage. Since the late 70s
it has become apparent that the majority of non-coding
DNA in large
genomes finds its origin in the selfish amplification of transposable
elements, of which W.
Ford Doolittle and Carmen Sapienza in 1980 wrote
in the journal Nature: "When a given DNA, or class of DNAs, of
unproven phenotypic function can be shown to have evolved a strategy
(such as transposition) which ensures its genomic survival, then no
other explanation for its existence is necessary." The amount of
DNA can be expected to depend on the rate of amplification of
these elements and the rate at which non-functional
DNA is lost.
In the same issue of Nature,
Leslie Orgel and
Francis Crick wrote that
DNA has "little specificity and conveys little or no selective
advantage to the organism". The term occurs mainly in popular
science and in a colloquial way in scientific publications, and it has
been suggested that its connotations may have delayed interest in the
biological functions of noncoding DNA.
Several lines of evidence indicate that some "junk DNA" sequences are
likely to have unidentified functional activity and that the process
of exaptation of fragments of originally selfish or non-functional DNA
has been commonplace throughout evolution. In 2012, the ENCODE
project, a research program supported by the National
Research Institute, reported that 76% of the human genome's noncoding
DNA sequences were transcribed and that nearly half of the genome was
in some way accessible to genetic regulatory proteins such as
However, the suggestion by
ENCODE that over 80% of the human genome is
biochemically functional has been criticized by other scientists,
who argue that neither accessibility of segments of the genome to
transcription factors nor their transcription guarantees that those
segments have biochemical function and that their transcription is
selectively advantageous. Furthermore, the much lower estimates of
functionality prior to
ENCODE were based on genomic conservation
estimates across mammalian lineages.
In response to such views, other scientists argue that the wide spread
transcription and splicing that is observed in the human genome
directly by biochemical testing is a more accurate indicator of
genetic function than genomic conservation because conservation
estimates are relative due to incredible variations in genome sizes of
even closely related species, it is partially tautological, and these
estimates are not based on direct testing for functionality on the
genome. Conservation estimates may be used to provide clues to
identify possible functional elements in the genome, but it does not
limit or cap the total amount of functional elements that could
possibly exist in the genome since elements that do things at the
molecular level can be missed by comparative genomics.
Furthermore, much of the apparent junk
DNA is involved in epigenetic
regulation and appears to be necessary for the development of complex
In a 2014 paper,
ENCODE researchers tried to address "the question of
whether nonconserved but biochemically active regions are truly
functional". They noted that in the literature, functional parts of
the genome have been identified differently in previous studies
depending on the approaches used. There have been three general
approaches used to identify functional parts of the human genome:
genetic approaches (which rely on changes in phenotype), evolutionary
approaches (which rely on conservation) and biochemical approaches
(which rely on biochemical testing and was used by ENCODE). All three
have limitations: 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
with biochemical approaches, though having high reproducibility, the
biochemical signatures do not always automatically signify a
They noted that 70% of the transcription coverage was less than 1
transcript per cell. They noted that this "larger proportion of genome
with reproducible but low biochemical signal strength and less
evolutionary conservation is challenging to parse between specific
functions and biological noise". Furthermore, assay resolution often
is much broader than the underlying functional sites so some of the
reproducibly “biochemically active but selectively neutral”
sequences are unlikely to serve critical functions, especially those
with lower-level biochemical signal. To this they added, "However, we
also acknowledge substantial limitations in our current detection of
constraint, given that some human-specific functions are essential but
not conserved and that disease-relevant regions need not be
selectively constrained to be functional." On the other hand, they
argued that the 12–15% fraction of human
DNA under functional
constraint, as estimated by a variety of extrapolative evolutionary
methods, may still be an underestimate. They concluded that in
contrast to evolutionary and genetic evidence, biochemical data offer
clues about both the molecular function served by underlying DNA
elements and the cell types in which they act. 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.
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.
Evidence of functionality
DNA sequences must have some important biological
function. This is indicated by comparative genomics studies that
report highly conserved regions of noncoding DNA, sometimes on
time-scales of hundreds of millions of years. This implies that these
noncoding regions are under strong evolutionary pressure and positive
selection. For example, in the genomes of humans and mice, which
diverged from a common ancestor 65–75 million years ago,
DNA sequences account for only about 20% of conserved
DNA, with the remaining 80% of conserved
DNA represented in noncoding
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. The significance of
DNA mutations in cancer was explored in April 2013.
Noncoding genetic polymorphisms play a role in infectious disease
susceptibility, such as hepatitis C. Moreover, noncoding genetic
polymorphisms contribute to susceptibility to Ewing sarcoma, an
aggressive pediatric bone cancer.
Some specific sequences of noncoding
DNA may be features essential to
chromosome structure, centromere function and homolog recognition in
According to a comparative study of over 300 prokaryotic and over 30
eukaryotic genomes, eukaryotes appear to require a minimum amount
of non-coding DNA. The 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.
Over 10% of 32 mammalian genomes may function through the formation of
RNA secondary structures. The study used comparative
genomics to identify compensatory
DNA mutations that maintain RNA
base-pairings, a distinctive feature of
RNA molecules. Over 80% of the
genomic regions presenting evolutionary evidence of
conservation do not present strong
DNA sequence conservation.
DNA separate genes from each other with long gaps, so
mutation in one gene or part of a chromosome, for example deletion or
insertion, does not have a frameshift effect on the whole chromosome.
When genome complexity is relatively high, like in the case of human
genome, not only between different genes, but also inside many genes,
there are gaps of introns to protect the entire coding segment and
minimise the changes caused by mutation. Non-coding
DNA may perhaps
serve to decrease the probability of gene disruption during
Regulating gene expression
Main article: Regulation of gene expression
DNA sequences determine the expression levels of
various genes, both those that are transcribed to proteins and those
that themselves are involved in gene regulation.
Main article: Transcription factor
DNA sequences determine where transcription factors
attach. A transcription factor is a protein that binds to specific
DNA sequences, thereby controlling the flow (or
transcription) of genetic information from
DNA to mRNA.
Main article: Operator (biology)
An operator is a segment of
DNA to which a repressor binds. A
repressor is a DNA-binding protein that regulates the expression of
one or more genes by binding to the operator and blocking the
RNA polymerase to the promoter, thus preventing
transcription of the genes. This blocking of expression is called
Main article: Enhancer (genetics)
An enhancer is a short region of
DNA that can be bound with proteins
(trans-acting factors), much like a set of transcription factors, to
enhance transcription levels of genes in a gene cluster..
Main article: Silencer (DNA)
A silencer is a region of
DNA that inactivates gene expression when
bound by a regulatory protein. It functions in a very similar way as
enhancers, only differing in the inactivation of genes.
Main article: Promoter (biology)
A promoter is a region of
DNA that facilitates transcription of a
particular gene when a transcription factor binds to it. Promoters are
typically located near the genes they regulate and upstream of
Main article: Insulator (genetics)
A genetic insulator is a boundary element that plays two distinct
roles in gene expression, either as an enhancer-blocking code, or
rarely as a barrier against condensed chromatin. An insulator in a DNA
sequence is comparable to a linguistic word divider such as a comma in
a sentence, because the insulator indicates where an enhanced or
repressed sequence ends.
Shared sequences of apparently non-functional
DNA are a major line of
evidence of common descent.
Pseudogene sequences appear to accumulate mutations more rapidly than
coding sequences due to a loss of selective pressure. 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".
Long range correlations
A statistical distinction between coding and noncoding
has been found. It has been observed that nucleotides in non-coding
DNA sequences display long range power law correlations while coding
sequences do not.
Police sometimes gather
DNA as evidence for purposes of forensic
identification. As described in Maryland v. King, a 2013 U.S. Supreme
The current standard for forensic
DNA testing relies on an analysis of
the chromosomes located within the nucleus of all human cells. 'The
DNA material in chromosomes is composed of "coding" and "noncoding"
regions. The coding regions are known as genes and contain the
information necessary for a cell to make proteins. . . . Non-protein
coding regions . . . are not related directly to making proteins,
[and] have been referred to as "junk" DNA.' The adjective "junk" may
mislead the lay person, for in fact this is the
DNA region used with
near certainty to identify a person.
Conserved non-coding sequence
Eukaryotic chromosome fine structure
Gene-centered view of evolution
Gene regulatory network
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the other hand, gave what must be considered the first explicit
discussion of the nature of "junk DNA," and was the first to apply the
term to all noncoding DNA."; "For this reason, it is unlikely that any
one function for noncoding
DNA can account for either its sheer mass
or its unequal distribution among taxa. However, dismissing it as no
more than "junk" in the pejorative sense of "useless" or "wasteful"
does little to advance the understanding of genome evolution. For this
reason, the far less loaded term "noncoding DNA" is used throughout
this chapter and is recommended in preference to "junk DNA" for future
treatments of the subject."
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