Saturday, February 19, 2011

Diversity from Jumping genes

The inner universe that controls the function of the visible one is a basket of deceit, overthrow, control, incarceration, submission and acceptance.

Staring at my mailbox, I found enormous amounts of spam mail. Most if not all was nonsense. There was an occasional one that piqued my curiosity, but not enough to open them for fear of the worms and viruses. It got me thinking about the genetic system that we have within us that drives us from birth to death. Similar in scope and behavior as it relates to information gathering and dissemination.

The inner universe that controls the function of the visible one is a basket of deceit, overthrow, control, incarceration, submission and acceptance. The Human Genome Project determined that human DNA, in its Watson-Crick double helical mode, breathes life through 23 (22 + sex pairs) pairs of chromosomes. Although the break up of the DNA into chromatin material and further subdivide into chromosomes is for the purpose of division so that the two ends of the “daughter-cells” can pull the equal numbers via tubules on each side in a dividing non-germinal cell. Once separated and enclosed in the newly divided cell the DNA resumes its original shape.

The progeny of two (such) sister cells are not alike with respect to the types of gene alteration that will occur. Differential mitoses also produce the alterations that allow particular genes to be reactive. Other genes, although present, may remain inactive. This inactivity or suppression is considered to occur because the genes are ‘covered' by other non-genic chromatin materials. Gene activity may be possible only when a physical change in this covering material allows the reactive components of the gene to be ‘exposed' and thus capable of functioning." -- Barbara McClintock

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The amazing thing is that it is the DNA and its programming that forms, modulates, modifies and renders senescent the vessel (the body) it is carried in by a set of 25,000-30,000 genes (Based on the Sanger Institute’s human genome information in the VEGA database, these remain as estimates). Genome is not a stationary entity, but rather it is subject to alteration and rearrangement.  Even more fascinating is that the DNA at its basic level is composed of four, count four nucleic acids; (A) Adenine, (T) Thymine, (C) Cytosine and (G) Guanine. These four are locked in predetermined set of twos in a permanent state of dance. The A always mates with T and G always with C.  So from this simplicity arises the most complex of life forms that exist on our planet.

Manifest within the genes is the code that makes us and every other living breathing being around us. These genes code for the color of the flowers, the blade of grass, and the fur on the poodle that sits at your feet and its eyes that look at you longingly and the wet nose that sniffs for discovery. The control and color and grandeur of the world’s inhabitants are predicated by the genetic expressions.

So the question can be asked what makes a small number of genes create such diversity? What makes the subtle or dramatic changes just looking at each other’s faces, to recognize the difference amongst us? Therein lies the beauty and majesty of the genetic workshop.


Gregor Mendel
Gregory Mendel And His Genetic Experiments On The Pea Plants

At it’s most basic Mendelian level (Gregory Mendel - July 20, 1822 – January 6, 1884) the genes from two parents are paired together each carrying its own sets of programmable codes. When the merger takes place the dominant genes will overshadow the recessive ones and express their abilities into the character. That was the widespread thought in the past. The present has unfolded the napkin of the genetic nuance and there is a whole lot of mischief going on within the folds.

Pea Plant
In 1952 a geneticist named Barbara McClintock awarded the Nobel Prize in 1983) discovered that there were genetic transpositions occurring through the genomic material of maize. She termed these transgressions as “Jumping Genes.” The technical name was “Transposons.”  It turns out that the genetic material does prefer a sense of variety. As the saying goes “Variety is the spice of life,” genes take that to heart. Within the genomic system is a silent but busy mechanism that is in full perennial blossom.

Here is a video that explains the functions of tranposons.  If you cannot see the embedded video here is the link: http://youtu.be/WRkfiUDajIE.


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Transposons are genetic materials that move or transpose from one part of the DNA to another. They comprise of at least two main groups, the DNA Transposons and the Retrotransposons (RNA Transposons)
  1. DNA Transposons
  2. LTR or Long Tandem Repeats
  3. LINEs or Long Interspersed Nuclear elements
  4. SINEs or Short Interspersed Nuclear Elements.
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The DNA Transposons encode the protein transposase, which they require for insertion and excision of the DNA material/fragment that are clipped from within the linear DNA material of the entire genome and inserted into another part of the genome. It is a “cut-and-paste” biological technology at work. The question is why? Why does the DNA partake in this promiscuity? The answer for this and all the other transpositional mechanistic fragments is for “Diversity.” The “jump” of a gene from one part to another favors diversity and as Charles Darwin maintained evolution favors “survival of the fittest.” There is an evolutionary programming within the DNA to maintain itself through adversity. It therefore tries to continue the evolutionary experiment to make itself robust against extinction based on the “Soma Theory.” (The Soma or body has to be maintained for propagation of the genome and once replicated, the Some or body can be disposed of).

So what happens with each transpositioned genetic material? Interestingly when a material transposes itself to another site it would by necessity, depending on its new location -especially if it happens to be near a functional gene, cause it to either over-function, under-function or just stop functioning.

The fact that transposable elements do not always excise perfectly and can take genomic sequences along for the ride has also resulted in a phenomenon scientists call exon  shuffling. Exon shuffling results in the juxtaposition of two previously unrelated exons, usually by transposase, thereby potentially creating novel gene products (Moran et al., 1999).

Lets look at few examples of inter-genetic mischief:

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 1. Deletion
 2. Duplication 
 3. Translocation

  1. 9:22 Translocation leads to Chronic Myeloid Leukemia.
  2. 11:14 Translocation leads to Malignant Lymphoma.
  3. 15:17 Translocation leads to Acute Promyelocytic Leukemia.
  4. 9p21 Polymorphism leads to heart disease.
  5. Insertions of L1 into the factor VIII gene caused hemophilia (Kazazian et al., 1988).
  6. Researchers found L1 in the APC genes in colon cancer cells but not in the APC genes in healthy cells in the same individuals. This confirms that L1 transposes in somatic cells in mammals, and that this element might play a causal role in disease development (Miki et al., 1992).
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Addition, Translocation
Transposons have been labeled as "spam" by some and rightly so. Most of the time spam is relegated to spam archives and does not interfere with workings of the computer, but some times it can insert a "computer virus" or "worm" in it's hidden code, "crash" the computer system and infrequently it may provide valid information. The Transposons work mostly as promoters and when this promoter effect gets juxtaposed to a functional gene that codes for proliferation of a particular cell type, malignancy ensues. Fortunately just like the Antiviral Software that exists for computer also exists in the human body. If the Transposons cause an adverse event it can be deselected or rendered inactive. Question is how?

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The genetic "antiviral software" is called the siRNA (small interfering RNA) or RNAi (RNA interference). These RNA fragments are snippets of the messenger RNA that derives its information from the DNA. These snippets can lay themselves on the Transposons and neutralize them by a methylation process or simply by suppressing the gene function. It is the body's own defense mechanism to fight internal revolt. Even though the Transposon material are perfectly intact and capable of moving, yet they are kept inactive by epigenetic defense mechanisms such as DNA methylation, chromatin remodeling, and miRNAs.

Consider the issue of a quiescent gene used specifically for proliferation of cells in organ (liver, lung, kidney etc.) growth during in-utero phase, which is then mutated during adult life as for instance the gene that codes for pluripotential cells that liberate CEA (Carcinoma Embryonic Antigen) or AFP (Alpha Feto Protein)  between the 12-28 weeks of life. That mutation in later life would lead to unrestricted cell growth and cancer formation with liberation of these proteins CEA (found in gastrointestinal malignancies) and AFP (hepatocellular carcinoma or liver cancer). These serum proteins become guides for disease monitoring and response to therapy by an oncologist. The switch that gets turned on later in life was not supposed to happen, but it happens when the specific gene goes awry. The gene mutation may occur due to many causes both environmental genetic stressors to these mischievous Transposons.

The RNA Transposons work differently. They are also known as retrotransposons. In other words, retrotransposons do not encode transposase; rather, they produce RNA transcripts and then rely upon reverse transcriptase enzymes to reverse transcribe the RNA sequences back into DNA, which is then inserted into the target site. They therefore have codes for proteins that cleave specific portions of the RNA, and then via other enzymatic protein that they have co-opted or part of their own framework, entice the reverse transcriptase to get attached to the DNA. So in essence (the RNA) the messenger becomes (the DNA) the message creator.
Here is a video that may help you understand the process by which retrotransposons work.  If you cannot see the embedded video here is the link: http://youtu.be/eS1GODinO8w.


The two main types are the LINEs and SINEs.
SINEs constitute 10.4% of the human genome. LINEs constitute 17% of the genome.  Of the 17% of the LINE transposons only a 100 remain active in the human genome. 47% are LTRs (Long Terminal Repeats) and the DNA Transposons “cut-and-paste” only constitute 2-4% of the genome. 50% of the entire human genome is composed of these transposons.

Therefore not surprisingly this DNA/RNA Transposons behavior has been in vogue for millennia. Similar Transposons copies have been found in various primates such as the Alu (also present in humans) and in a large segment of common Transposons in animals that includes the whales, which helps better understand the mammalian evolutionary branch in the Tree of life.

Large segments of the human DNA contain various genetic materials from viruses that have inserted their own genetic materials. Most of this lies dormant as "junk DNA." some have gained respect as " proto-oncogenes" that can via various mechanisms convert to "oncogenes" and start the cancer process. These genes include the c-myc gene, src gene etc. Other primates and animals, indicating non-species specific manifestation, also share these viral genetic insertions.

Another interesting fact is our body's ability to generate a large diversity of immunological antibodies against various viral, bacterial, fungal agents. This diversity is believed to arise as a result of the Rag protein that smuggled it's way onto being reverse-coded onto our DNA millions of years ago. It survives and is functionally propagated because of its utility and benefit of its host! The robust human immune surveillance with its enormous diversity to generate disease specific antibodies is a magnificent example of the benefit of evolutionary “Jumps.”

This is a companion article to Hypothesis and Evidence, previously posted here.


Parvez Dara, MD FACP
Twitter: JediPD

References:

1. McClintock, B. (June 1950). "The origin and behavior of mutable loci in maize". Proc Natl Acad Sci U S A. 36 (6): 344–55

2. Wei-Jen Chung,Katsutomo Okamura,Raquel Martin, Eric C. Lai (3 June 2008). "Endogenous RNA Interference Provides a Somatic Defense against Drosophila Transposons". Current Biology 18 (11): 795–802

3. Yang, N., & Kazazian, H. H. L1 retrotransposition is suppressed by endogenously encoded small interfering RNAs in human cultured cells. Nature Structural and Molecular Biology 13, 763–771 (2006

4. Kazazian, H. H. Mobile elements: Drivers of genome evolution. Science 303, 1626–1632 (2004) doi:10.1126/science.1089670

5. Kazazian, H. H., et al. Haemophilia A resulting from de novo insertion of L1 sequences represents a novel mechanism for mutation in man. Nature 332, 164–166 (1988)

6. Kazazian, H. H., & Moran, J. V. The impact of L1 retrotransposons on the human genome. Nature Genetics 19, 19–24 (1998)

7. Moran, J. V., et al. Exon shuffling by L1 retrotransposition. Science 283, 1530–1534 (1999)

8. Miki, Y., et al. Disruption of the APC gene by a retrotransposal insertion of L1 sequence in colon cancer. Cancer Research 52, 643–645 (1992)

2 comments:

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Christopher said...

This is a very uncommon challenge to read by and understand but other than that it is a real amazing experience to see and read about. I would love to try this one day. Who ever knew that genes could jump? Thanks for the people who presented this information and I also hope other people will love it.