INTRONS, vital roles revealed

Insulin resistance and diseases
Fragile X Syndrome, and stem cell research
Bacteria & Cardiovascular Disease
STEM CELLs--Scientific American
Serotonin--a detailed overview
Hedgehog genes & embryo development
DNA Repair--Mechanism Revealed
Immune response to cancer observed
CANCER, Classification of cell types
INTRONS, vital roles revealed
Sex-linked Brain Differences--Scientific American
Gene For Diabetes Found
Why People Have Different Blood Types
Dupuytren's Contracture: most common connective tissue disease
New Technique for observing superoxides

The Hidden Genetic Program of Complex Organisms


John Mattick, Scientific American, p.61-67, Nov. 04


Biologists assumed that proteins alone regulate the genes of complex organisms because they had not until recently discovered the regulatory system based upon the introns in DNA.  The standard dogma in molecular biology for the past half a century has stated that genetic information encoded in DNA is transcribed as intermediary molecules of RNA, which are in turn translated into the amino acid sequences that make up proteins.  The prevailing assumption was one gene, one protein.  A corollary has been that proteins, in addition to their structural and enzymatic roles in cells, must be the primary agents for regulating the expression and activation of genes. 


Introns, “junk DNA” are absent in prokaryotes.  Less than 1.5% of the human genome code for protein.  Some amoebaes have 1,000 more DNA than humans; some amphibians have 5x more DNA as mammals do.  The nematode work Caenorhababditis elegan (made of about 1,000 cells) has about 19,000 protein-coding genes, almost as much as the human’s 25,000.  Around 99% of the proteins in humans have recognizable protein equivalents in mice, and vice versa


Many genes in complex organisms do not encode protein but instead give rise to RNAs with direct regulatory function.  Thousands of RNAs that never get translated into protein (noncoding RNAs) have been identified in recent analyses of transcription in mammals.  Between half & 3/4th of all RNA transcripts fit this category.  Hundreds of “microRNAs derived from introns and larger nonprotein-coding RNA transcripts have recently been identified in plants, animals, and fungi.  Many of them control the timing of processes that occur during development, such as tem cell maintenance, cell proliferation, and apoptosis.  These RNA signals, by finding targets on other RNAs, DNA, and proteins, could influence a cell’s genetic program in many ways.  They could inform various genes that a particular protein coding sequence has been transcribed, and that feedback could trigger a host of parallel adjustments.  Other could control trajectories of gene expression. 


Chromatin—what makes up chromosomes-- consists of DNA complexed with proteins.  Within cells, small chemical tags (such as methyl and acetyl groups) can attach to segments of DNA and to chromatin proteins and thereby determine whether the genes in the associated DNA will be accessible for transcription or will stay silent.  Recent results indicate that RNA signaling directs the tagging of the chromatin and thus gene expression. 


RNA can encode short, sequence specific signals which can direct RNA molecules precisely to receptive targets in other RNAs and DNA.   When intron RNA is spliced out of a gene’s transcript, the protein-coding RNA regions may be assembled in more than one way to yield more than one type of protein.  Multiple structurally similar forms of the same protein are thus possible without having a gene for each form.  Only a few times has protein factors been responsible for these alternate forms, the other instances it is from introns.  Generating complexity; (variations in a protein) is easy; however, controlling them so that best ones can be duplicated in the right situation is difficult


In prokaryotes the regulatory function was performed by DNA (genes); thus limiting the complexity of such systems because regulatory genes themselves need regulating.  Eukaryotes however developed a regulatory system using RNA.  This development helps (along with 3 embryonic tissue systems up from just 2) to explain the Cambrian explosion.  Even though the overall rate of change (mutation) of introns in greater than exons, there are parts of the introns that have persisted virtually unaltered for many millions of years.  These unchanging islands of sequence play a vital role, obviously.


A number of genetic diseases such as cystic fibrosis and thalassemia are caused by coding damage which thus makes a defective protein.  Noncoding RNAs have recently been linked with several conditions, including B cell lymphoma, lung cancer, prostate cancer, autism, and schizophrenia. 


About 40% of the genome comprises transponson and other repetitive elements.  Their contribution is not well understood.  Another process not well understood is the A-to-I editing (adenosine-to-inosine) editing, in which an RNA sequence changes at very specific sites.  It was demonstrated recently that this editing of RNA transcripts is two orders of magnitude more widespread in humans than previously thought and overwhelmingly occurs in repeat sequences called Alu elements that reside in noncoding RNA sequences.  A-to-I editing is particularly active in the brain, and aberrant editing has been associated with a range of abnormal behaviors, including epilepsy and depression.  Although RNA editing occurs to some extent in all animals, Alu elements are unique to primates.  An intriguing possibility is that the colonization of primate lineage by Alu elements make it possible for a new level of complexity to arise in RNA processing and allowed programming for neural circuitry7 to become more dynamic and flexible.  That versatility may have in turn laid the foundation for the emergence of memory and higher-order cognition in the human species. 



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