Wednesday, November 13, 2013

Retroviral genome remnants influence Neural functions


    One of the points I constantly have been arguing in this blog site is, Microbial system has more role than infectious diseases (Read here and here). I was arguing that the great part of human is not human, but has a microbial component in it. The effect is very evident, to a genomic level. Almost half of our genome is composed of retroviral elements more famously known as "selfish jumping genes". In this blog-post am trying to get you a sense of the importance of these viral remnant elements.

    Transposable elements or more commonly known as "Jumping genes", represent a DNA sequence that can be moved around through the genome. Barbara McClintock discovered the first TEs in maize, Zea mays, at the Cold Spring Harbor Laboratory. The story reads. By genetic crossing experiments of maize for patterns of variegation, She was able to identify a series of genes on chromosome number 9 that determine pigmentation and other characteristics of the endosperm. The genetic material that was involved with switching was traced by advanced studies of the time and were called as "control elements". Reference

Fig 1: Classification of Transposons.
      Transposable elements can be divided into 2 major classes based on their replicative strategy. Class I (Retrotransposons), actively encode an RNA intermediate, which is reverse transcribed and with the use of an integrase is joined to the parental strand. The Class 2 (Transposons), simply detach from one part of genome and is integrated into other part of genome. The process may involve producing a DNA copy that transposes (replicative transposition) or a simple movement to a new locus (conservative transposition). An illustration is represented below in Fig 2.

   The transposition of DNA elements is achieved through enzymes- Transposase and integrase which carry a ribonuclease-like catalytic domain and can use the same target site to catalyze both DNA cleavage and DNA strand transfer. These enzymes are active only in a complex synaptic machinery called as transpososome machinery. There is a huge list of transposase enzyme seen in nature, classified under 5 major families- DDE transposases, Tyrosine (Y) transposases, Serine (S) transposases, Y2 transposases, RT/En types.
Fig 2: Illustration of transposition mechanism
   The mammalian retroelement content is dominated by L1 type of transposons (LINE member; long interspersed element) which is almost 17% of the genome, followed by Alu (SINE member; Short interspersed element, 10 %) and LTR (about 8%). These alone make up about 35% of genome, the rest of the types altogether contributes some more This means our genome is parasitized anywhere from 40-50%, (consisting of replicative DNA that isn't ours). That should blow your mind!!!

   The original thought of genetics is that our genome is unique. In addition we have the same genomic sequence through all our cells. This fact is tolerating the finding that we have multiple traces of genetic assault (such as mutations, DNA breaks joined by Non homologus recombination which cause genetic scars). By modern genetic view (based on single cell sequencing techniques), we are shown more genetic variation within a single individual. Which means cells to an extent is genetically distinct from our own "other cell". But the one cell type where this matters the most is Neuron. This is an active area of Neurogenetics research. Fred Gage published a recent landmark paper in science, explains "Contrary to what we once thought, the genetic makeup of neurons in the brain aren't identical, but are made up of a patchwork of DNA" and "There are quite a few unique deletions and amplifications in the genomes of neurons derived from one iPSC line". Source

   There is a pretty good reason to believe the mosaic genetic nature of neurons can be attributed to some extent at least, to transposable elements. How does that apply? Answer is Wnt pathway. Wnt proteins are a group of  highly conserved secreted molecules and is a key component of embryogenesis. Neurogenesis is a hot field of research. Till date there has been no absolute cure for neuronal damage. The importance of Line-1 elements in co-ordination with NeuroD1 , has been shown possibly important for adult neurogenesis and survival of neuronal progenitors. 

    Here is my catch. If TE are so important in neurons, then they got to have a role in some of the key functions of neurobiology and possibly in neural diseases. So, I started a literature search and found the following points of interest.

Fig 3: Insertions found for each family
    Based on a study published in nature, I found an article in Scientific american that highlights the ideas. The study found mapped genetic insertions sites in neurons of two brain regions—the hippocampus and caudate nucleus. The result was that they mapped a massive 25,000 different sites for the three main retrotransposon families ( 7,743 putative somatic L1 insertions, 13,692 somatic Alu insertions and 1,350 SVA insertions) . The point is the insertion sites are at many key genes. Some are associated with tumor-suppressor genes and genes related to schizophrenia, memory etc. Faulkner comments "It is tempting to speculate that genetic differences between individual neurons could impact memory, but we have no evidence yet that this is the case. It is entirely possible that retrotransposition is generally a good thing but sometimes contributes to disease."

     A little bit of digression here. I had known for sometime, we have active mechanisms in our genome to suppress the genetic parasites and that most of the TE's are well controlled by us in our early stages. I recall a recent paper in cell titled "The Frustrated Gene". The essay basically argues, eukaryotic genetic controls are too complex and tight cause it evolved to be so, to combat the genetic parasites.

   A recent study has shows that our cellular ability to fight genetic parasites diminshes with age. John Sedivy an author in the paper says "We seem to be barely winning this high-stakes warfare, given that these molecular parasites make up over 40 percent of our genomes". Source This information gives me a leap in understanding. Consider the following points. TE's takeover as we age and TE's are more active in Neurons. So is age related neuronal problems (Classical example is Alzheimer's), something to do with TE? Again I searched for literature and answer is it does. Here are some examples

    A protein called TDP-43 (known to bind to both DNA and RNA) silence or repress the expression of potentially harmful transposons. Loss of TP-43 is associated with amyotrophic lateral sclerosis (ALS), mean to say TE's can effect ALS. Alzheinmer's is associated with PGBD1 (piggyBac transposable element derived 1). But am skeptic of commenting cause Alzheimers is multifactorial condition, falling into realm of genetics and Prions. There are positive and negative studies in this case. Nevertheless there is a clear possibility. Another paper, suggests "Transposition in the human brain can influence the biosynthesis of more than 250 metabolites, including dopamine, serotonin and glutamate, shows large inter-individual variability in metabolic effects, and may contribute to the development of Parkinson’s disease and schizophrenia".

     In conclusion, TE's are not just mere jumping genes that wander inside cells (especially neurons). They are actively implicated in process such as neurogenesis, memory and a plethora of neurologic conditions. So in future if a paper arrives suggesting PKM-ζ (Main protein in long-term memory formation) is connected with TE's, it wouldn't surprise me at all. I still am willing to debate Microbial products (In this case remnants of Retroviral genome), still influence every part of us. Hilariously speaking, we are less human than are microbes.
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McConnell MJ, Lindberg MR, Brennand KJ, Piper JC, Voet T, Cowing-Zitron C, Shumilina S, Lasken RS, Vermeesch JR, Hall IM, & Gage FH (2013). Mosaic copy number variation in human neurons. Science (New York, N.Y.), 342 (6158), 632-7 PMID: 24179226

Kuwabara T, Hsieh J, Muotri A, Yeo G, Warashina M, Lie DC, Moore L, Nakashima K, Asashima M, & Gage FH (2009). Wnt-mediated activation of NeuroD1 and retro-elements during adult neurogenesis. Nature neuroscience, 12 (9), 1097-105 PMID: 19701198

Baillie JK, Barnett MW, Upton KR, Gerhardt DJ, Richmond TA, De Sapio F, Brennan PM, Rizzu P, Smith S, Fell M, Talbot RT, Gustincich S, Freeman TC, Mattick JS, Hume DA, Heutink P, Carninci P, Jeddeloh JA, & Faulkner GJ (2011). Somatic retrotransposition alters the genetic landscape of the human brain. Nature, 479 (7374), 534-7 PMID: 22037309

Madhani HD (2013). The frustrated gene: origins of eukaryotic gene expression. Cell, 155 (4), 744-9 PMID: 24209615

Li W, Jin Y, Prazak L, Hammell M, & Dubnau J (2012). Transposable elements in TDP-43-mediated neurodegenerative disorders. PloS one, 7 (9) PMID: 22957047

Bertram, L. (2009-10-15) Genome-wide association studies in Alzheimer. , 18(R2), R137-R145. DOI: 10.1093/hmg/ddp406

Ohnuma T, Nakamura T, Takebayashi Y, Hanzawa R, Kitazawa M, Higashiyama R, Takeda M, Thompson K, Komatsu M, Shimazaki H, Shibata N, & Arai H (2012). No Associations Found between PGBD1 and the Age of Onset in Japanese Patients Diagnosed with Sporadic Alzheimer's Disease. Dementia and geriatric cognitive disorders extra, 2 (1), 496-502 PMID: 23277782

Abrusán G (2012). Somatic transposition in the brain has the potential to influence the biosynthesis of metabolites involved in Parkinson's disease and schizophrenia. Biology direct, 7 PMID: 23176288

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