ENCODE - Code within the code

Pillars of Creation (Eagle nebula M16; image by NASA)

The code is getting more enigmatic as scientists have begun to unwind it, now raising more curiosity and challenges to understand the beautiful life! The National Human Genome Research Institute (NHGRI)'s project ENCODE, the Encyclopedia Of DNA Elements, started in September 2003 is a multi-institutional, multiphasic, collaborative project has just finished its pilot phase, first of planned three phases (now remaining, a technology development phase and a planned production phase) which aims towards identification of functional elements and organization of entire genome rather genes of particular interest and thereby, having clear insight of human genome and linked expression. ENCODE team is conducting series of experimental procedures to identify not only genes that code for proteins but also for non-protein coding genes, regulatory elements controlling transcription of genes; and elements that maintain the structure of chromosomes and mediate the dynamics of their replication.

In the pilot phase, researchers focused on 44 targets, which together cover 29,998 kilobases (kb) of the human genome, equivalent to about 1 percent of the human genome sequence, or about 30 million of 3 billion DNA base pairs. Results of pilot project are challenging the established fundamentals, particularly of non-protein coding genes and their overlapping on protein-coding loci, lack of evolutionary constraint (that is, the rejection of mutations at a particular location) of genes and dynamism in DNA replication and structure of its supporting proteins (i.e. histone) influencing transcription and gene expression. As ENCODE is advancing further, better understanding of genome and importantly its functional structure would eventually helpful to sidestep current obstacles of applied genetics. Below are few lines from the original article (see citation) that may make you dream to see glimpse of dynamics within the pillars of creation!

The protein-coding component of these genes makes up just a small fraction of the human genome - 1.5 percent to 2 percent. Evidence exists that other parts of the genome also have important functions.

The majority of DNA in the human genome is transcribed into functional molecules, called RNA, and that these transcripts extensively overlap one another. This broad pattern of transcription challenges the long-standing view that the human genome consists of a relatively small set of discrete genes, along with a vast amount of so-called junk DNA that is not biologically active.

Simple view of the genome as having a defined set of isolated loci transcribed independently does not seem to be accurate.

ENCODE effort found about half of functional elements in the human genome do not appear to have been obviously constrained during evolution, at least when examined by current methods used by computational biologists. This lack of evolutionary constraint may indicate that many species' genomes contain a pool of functional elements, including RNA transcripts, that provide no specific benefits in terms of survival or reproduction. As this pool turns over during evolutionary time, researchers speculate it may serve as a "warehouse for natural selection" by acting as a source of functional elements unique to each species and of elements that perform the similar functions among species despite having sequences that appear dissimilar.

Regulatory sequences are just as likely to be located downstream of a transcription start site on a DNA strand as upstream.

Chromatin accessibility and histone modification patterns are highly predictive of both the presence and activity of transcription start sites.

Critical questions are raised by the presence of a large amount of unannotated transcription with respect to how the corresponding sequences are organized in the genome - do these reflect longer transcripts that include known loci, do they link known loci, or are they completely separate from known loci?

Original article:

Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project
The ENCODE Project Consortium
Nature 2007;447:799-816 (14 June 2007)
doi:10.1038/nature05874

Reference:

1. ENCODE at NHGRI
2. Press release from NHGRI: New Findings Challenge Established Views on Human Genome ENCODE Research Consortium Uncovers Surprises Related to Organization and Function of Human Genetic Blueprint 13 June 2007
3. Image courtesy: Pillars of Creation: Eagle nebula M16 by NASA Accessed 6-Aug-2007
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