Kapranov, Philipp

St. Laurent, Georges

English

PubMed

Philipp Kapranov

Georges St. Laurent

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Genomic “dark matter”: implications for understanding 
human disease mechanisms, diagnostics, and cures
Philipp Kapranov* and Georges St. Laurent*
St. Laurent Institute, Cambridge, MA, USA
*Correspondence: philippk08@gmail.com; georgest98@yahoo.com
What is genomic “dark matter?”
The realization that protein-coding genes use only a tiny frac-
tion of the three billion base pairs that make up the human 
genome has given birth to perhaps the largest and most per-
sistent question in modern genetics: of what use, if any, is the 
vast non-coding sequences that we all carry in each of our cells. 
Is it really non-functional “junk” DNA as referred to by some, 
or does it provide the basis for the blueprint for organismal 
complexity and cellular information processing, as argued by 
others? The massive expanse of the non-coding portion of the 
genome, combined with the current technological and analytical 
limitations inherent to its functional analysis, has resulted in a 
mass of conflicting ideas and conclusions. Collectively this has 
created an aura of mystery and doubt surrounding it, leading 
to the label of genomic “dark matter.” In a manner analogous 
to the “dark matter” of the universe, it is something that we can 
neither easily detect nor understand, but that nonetheless exists 
and is open to careful experimental queries.
does it have function?
Classical approaches, such as sequence conservation and mutagen-
esis, have been unable to address the question of the functional-
ity in the non-coding realm. The simplest explanation for these 
observations is that the non-coding portion of the genome lacks 
function, but is instead a neutral passenger on the evolutionary 
journey. However, this leaves us with the intellectually unsatisfying 
conclusion that most of our genome exists for no reason. Function 
resonates well with an important aspect of the mysteries surround-
ing genomic “dark matter” – most of it is used to produce RNA. 
Moreover, this “dark matter” RNA is not just a minor fraction of 
the cell’s RNA, but rather makes up a majority of it (not counting 
the ribosomal or mitochondrial RNAs). RNA production is a sign 
of a functional DNA sequence and even more so if such RNA is 
abundant. While encouraging, our knowledge of the “dark mat-
ter” RNA is still rather limited in large measure due to the fact 
that most RNA analysis endeavors so far have focused on polyA 
+ RNA, while detection of “dark matter” transcripts requires total 
RNA presumably because they either tend to be polyA − or some-
how lost during polyA-selection process. Thus, this realm is ripe 
for discoveries, with brain and embryonic tissues likely (based on 
analysis of protein-coding mRNAs) harboring some of the richest 
reservoirs of novel “dark matter” transcripts. It is also worth noting 
that exons of well-characterized protein-coding transcripts can be 
found in unusual arrangements linking for example very distant 
genes, potentially due to trans-splicing, adding to the repertoire 
of un-annotated transcripts whose function we only now begin 
to understand.
hoW could it function?
It is generally assumed that “dark matter” RNAs do not code for 
proteins and function via regulation of expression of other loci. 
Two very general themes of non-coding RNA-mediated regulation 
became prominent in the recent decade: modulation of chromatin 
state via association with chromatin modulator complexes and, 
the production of small RNAs from longer non-coding RNAs to 
regulate various layers of transcript expression. Discovery of RNA-
mediated non-Mendelian inheritance of an epigenetic change in 
mammals uncovered a new tantalizing possibility for RNA func-
tion. It is worth noting that the basic assumption has been chal-
lenged recently by evidence suggesting existence of plethora of short 
peptides produced by the “dark matter” RNAs, even though they 
could conceivably be products of non-functional translation of 
bona fide non-coding RNAs. However, if the last decade has taught 
us anything, its that a given locus can produce a variety of different 
RNAs, that can be thought of as a “transcriptional forest” as coined 
by the FANTOM consortium researchers, and such RNAs could 
well have different functions in a cell.
does it boost human nervous system complexity?
The genomes of humans and flies have approximately the same 
information complexity – on the order of ∼20K protein-coding 
genes, just a couple fold higher than that of yeast. Some addi-
tional reservoir of complexity should exist. The human nervous 
system contains widespread expression of “dark mater” RNAs, 
distributed in highly articulated intracellular and cell specific 
patterns. Over this decade, investigations have revealed a stream 
of more and more striking functions in the nervous system, 
including the recent demonstration that LINE1 transposons 
result in somatic diversity within the neurons of individual 
humans.
could it have implications for human health?
Even if one were to assume the worst-case scenario where most 
of the “dark matter” RNA is not functional at all, we now know 
that it is highly cell-type specific and this opens a wide area of 
additional diagnostic biomarkers based on these RNAs. Indeed, 
first reports showing that profiling “dark matter” RNAs offers 
superior diagnostic and prognostic information compared to 
protein-coding genes are now starting to appear, particularly in 
the cancer field which is leading others in development of these 
RNAs as biomarkers. However, if some or all, of the “dark matter” 
RNA is indeed functional then we can only imagine the plethora 
of secrets that are locked within that can shed light on basic 
mechanisms of development, homeostasis, and disease that still 
await exploration. For example, its very curious that a (very) long 
www.frontiersin.org May 2012 | Volume 3 | Article 95 | 1
Editorial
published: 2  May 2012
doi: 10.3389/fgene.2012.00095
9
have. Still, the possibility that almost entirely unexplored treasure-
trove of biological information is buried within our reach is too 
tantalizing to ignore.
Received: 19 April 2012; accepted: 09 May 2012; published online: 2  May 2012.
Citation: Kapranov P and St. Laurent G (2012) Genomic “dark matter”: implications for 
understanding human disease mechanisms, diagnostics, and cures. Front. Gene. 3:95. doi: 
10.3389/fgene.2012.00095
This article was submitted to Frontiers in Non-Coding RNA, a specialty of Frontiers in 
Genetics.
Copyright © 2012 Kapranov and St. Laurent. This is an open-access article distributed 
under the terms of the Creative Commons Attribution Non Commercial License, which 
permits non-commercial use, distribution, and reproduction in other forums, provided the 
original authors and source are credited.
non-coding RNA could be highly restricted to a particular type of 
cancer and begs a  question of why that would be the case if it had 
no functional role in the disease. Illuminating these mechanisms 
may help approach the contemporary challenge of understanding 
molecular and cellular biology from a new, holistic perspective, 
potentially revealing novel key aspects of cellular systems inte-
gration pathways. And, this is not necessarily limited to human 
cells, as other organisms, including those medically important 
to our health also likely possess their “dark matter” RNAs and its 
mysteries. However, one cannot over-emphasize the fact that we 
are the very beginning of the process of understanding what kind 
of RNAs are produced by a cell and what functionality they may 
Kapranov and St. Laurent Implications of genomic “dark matter”
Frontiers in Genetics | Non-Coding RNA  May 2012 | Volume 3 | Article 95 | 2
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Genomic “Dark Matter”: Implications for Understanding Human Disease Mechanisms, Diagnostics, and Cures

Philipp eKapranov

Georges eSt. Laurent

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Genomic dark matter: implications for understanding human disease mechanisms, diagnostics, and cures

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Genomic “Dark Matter”: Implications for Understanding Human Disease Mechanisms, Diagnostics, and Cures

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