{"id":1717,"date":"2010-11-24T07:13:53","date_gmt":"2010-11-24T07:13:53","guid":{"rendered":"http:\/\/thetravellerslastjourney.com\/shai\/2018\/11\/27\/461-revision-v1\/"},"modified":"2019-07-09T11:33:25","modified_gmt":"2019-07-09T11:33:25","slug":"line-1-retrotransposition-in-neurons-2","status":"publish","type":"post","link":"https:\/\/thetravellerslastjourney.com\/shai\/2010\/11\/24\/line-1-retrotransposition-in-neurons-2\/","title":{"rendered":"LINE-1 retrotransposition in neurons"},"content":{"rendered":"

LINE-1\u00a0retrotransposon<\/a>s are sections of\u00a0DNA<\/a>\u00a0which are capable of copying themselves into another part of the\u00a0genome<\/a>. Although traditionally considered to merely epitomize the concept of the\u00a0selfish gene<\/a>, more recently they have been suggested to have physiological functions. Here I discuss the\u00a0incredibly fascinating hypothesis<\/strong>\u00a0that\u00a0LINE-1<\/a>\u00a0retrotransposons may be important in generating\u00a0neuronal variation<\/a><\/strong>.<\/p>\n

Selfish genes and retrotransposons<\/h3>\n

Personally, I think that there’s something\u00a0problematic<\/a>\u00a0about\u00a0Dawkins’<\/a>\u00a0reductionism in his book\u00a0The Selfish Gene<\/a><\/em>. In that book, Dawkins explains that the\u00a0gene<\/a>\u00a0can be considered as the smallest unit of\u00a0selection<\/a>, in which case the “purpose<\/a>” of every single gene is to independently copy itself as far as it can. We are vehicles for our genes, who share a common interest – the\u00a0organism<\/a>\u00a0– in order to propagate themselves.<\/p>\n

Don’t get me wrong, I agree that it’s practically a\u00a0truism<\/a>\u00a0to say that genes that can contribute to their own survival will, as a result, be better at replicating. My problem is with the conceptualisation of genes as\u00a0monads<\/a>. Dawkins seems to believe that the survival of the organism can be calculated as the sum of its genes.<\/p>\n

The most\u00a0important<\/a>\u00a0lesson of\u00a0developmental biology<\/a>\u00a0has been that there is no function without context. I can’t elaborate too much at this point, but suffice to say that in the same way that it would be impossible to read an alien language without some sort of\u00a0reference<\/a>, and in the same way that a protein could not be assigned a function without a cellular context, so too a gene has no survival-index without the context of its host organism, (and taking a step further back, without the context of its host organism’s environment).<\/p>\n

It is now interesting to consider unique cases like\u00a0transposons<\/a>. Transposons are segments of DNA which are capable of “jumping” around the host organism’s genome. A category of the transposon is the\u00a0retrotransposons<\/a>, which are segments of DNA which jump around the genome by copying themselves and then inserting the copy into another part of the genome. Transposons, including retrotransposons, are often considered to be classical selfish genes. They don’t\u00a0seem<\/em>\u00a0to contribute to the organism’s well-being at all, and their entire purpose is to replicate as much as possible\u00a0irrespective<\/em>\u00a0of the organism.<\/p>\n

As you can probably guess, the picture is far more interesting than all that. But first I need to say a few words about the different aspects and mechanisms of variation in neurons.<\/p>\n

Neuronal variation<\/h3>\n

It’s common when trying to communicate the incredibility of the human brain to quote the number of neurons or the number of connections, and then to try and quantitatively compare that with an electronic computer. That’s all well and good, but it’s not enough. Discussing the brain as a network of nodes connected in parallel ignores the complexity of that system. It ignores the manner in which individual neurons process information inputs, how that processing affects future processing, and the type of signals involved. It also ignores the fact that neurons are not a homogeneous population. There are various convenient ways to differentiate neurons, for instance, their\u00a0morphology<\/a>, what\u00a0receptors<\/a>\u00a0they present, what\u00a0neurotransmitters<\/a>\u00a0they use to signal, and so forth.<\/p>\n

An extraordinary diversity is found within the neuronal population. There might be as many as 10,000 types of neuron, although the definition of neuronal type is debated. Diversity exists between individual cells within a neuronal subtype, highlighting the importance of single neurons in the network. Even neurons with a similar morphology can differ in important molecular details, expressing different combinations of ion channels, for instance, providing cells with various excitation thresholds and distinctive firing patterns. However, how and when neuronal diversity is generated remains unknown.<\/em>\u00a0(Muotri & Gage 2006)<\/strong><\/small><\/p><\/blockquote>\n

This complexity is presumably required by the\u00a0brain<\/a>\u00a0in order to manifest its higher-order capacities, including perhaps\u00a0self-awareness<\/a>. Different mechanisms are responsible for generating the neuronal variation, including alternative\u00a0transcription<\/a>\u00a0start sites and\u00a0RNA<\/a>\u00a0splicing. Retrotransposition may also contribute to neuronal variation.<\/p>\n

L1 and somatic mosaicism<\/h3>\n

The next paragraph, and the next paragraph alone depends on evidence heard second hand; my “source” heard Fred Gage give a talk. Gage is a leader in this particular sub-field and is the primary investigator<\/a>\u00a0on almost all of the papers referenced for this write-up.<\/small><\/p>\n

The story begins with Fred Gage and colleagues studying neuronal precursor cells. These are cells that aren’t quite neurons yet but can mature into the various forms of neurons. As part of their experiments, the group\u00a0sequenced<\/a>\u00a0their cells, but something strange kept occurring: the more times these precursor cells divided the bigger their genomes got! After ruling out some sort of\u00a0contamination<\/a>, they took a look at what the cells were transcripting, and realised that these cells had a lot of retrotransposon activity. In particular, the retrotransposon called\u00a0Long interspersed repetitive element-1<\/strong>, which abbreviates to\u00a0LINE-1<\/strong>\u00a0which abbreviates to\u00a0L1<\/strong>.<\/p>\n

The very first paper showing that L1 could contribute to neuronal heterogeneity was published in\u00a02005<\/a>\u00a0in the prestigious science journal\u00a0Nature<\/a><\/em>. The paper demonstrated that when precursor cells begin to\u00a0transform<\/a>\u00a0into neurons, they reduce the amount of\u00a0Sox2<\/a>\u00a0(transcription factor<\/a>). Sox2 normally binds to the DNA near L1 elements to prevent them from copying themselves, so when there is less Sox2 then there is increased L1 retrotransposition. This seems to be a phenomenon restricted somewhat to neuron development and might involve those precursor cells remodelling their\u00a0chromatin<\/a>\u00a0(DNA) to alter L1 availability. Finally, the paper demonstrated the L1 is active during neuron development in actual\u00a0animals<\/a>.<\/p>\n

Big deal? Yes<\/strong>. First of all, the facts until now had said that transposon activity is\u00a0only<\/em>\u00a0present in\u00a0germ line<\/a>\u00a0cells (ie. those that produce sperm and ovum), but is soon\u00a0turned<\/a>\u00a0off<\/a>. This paper shows that\u00a0normal<\/a>\u00a0cells have the potential for transposon activity, and more-so, that neurons preferentially allow it! It also implies that even inside the same brain, different areas are not completely genetically identical. Different neurons may have experienced different transposon activities, in which L1 was copied a different number of times and to different locations in the genome. And as a consequence, where those L1 insertions affect genes, the actual neurons’\u00a0gene activity<\/a>\u00a0may differ.<\/p>\n

These results were followed up with publications reporting that L1 is similarly active in humans, and can even be found in adult brains, although it’s not yet clear whether how this relates to adult\u00a0neurogenesis<\/a>\u00a0(Coufal 2009)<\/small>; a third paper elaborated on the molecular mechanisms involved in L1 activation\u00a0(Moutri 2010)<\/small>.<\/p>\n

L1<\/a>, the\u00a0brain<\/a>, and\u00a0life<\/a><\/h3>\n

If valid, the implications of\u00a0physiological<\/em>\u00a0retrotransposition in neurons could be huge. I stress “physiological” because that would imply that this feature of neuronal development has been selected for. If that were the case it would highlight the fact that although transposons considered in and of themselves display a parasitic function, without regard for their host, this is not the whole story. L1 as a DNA parasite and L1 as a mechanism for variation are both “selfish”. They both result in increasing the capacity of L1 to propagate. The difference is whether we call L1 selfish in its capacity as a gene, or as an organism. Because I hold that genes have no meaning, no natural function, without their host context,\u00a0I’d suggest<\/a>\u00a0that only the second possibility is meaningful.<\/p>\n

\n<\/span>\n

Even in a perfectly controlled experiment some animal traits, like fear and learning, appear to display an unavoidable variation. This\u00a0variation<\/a>\u00a0results in the well-known\u00a0bell curve<\/a>\u00a0response and has been termed\u00a0intangible variance<\/a><\/strong>. This intangible variance might be partially explained by appealing to L1: “L1-mediated retrotransposition could be a mechanism that alters neuronal function in individuals, thereby broadening the spectrum of behavioural phenotypes that can originate from any single genome<\/em>”\u00a0(Singer 2010)<\/small>.<\/p>\n

One of the most incredible things about people is how much they vary. (The other incredible thing is obviously their similarity). It seems so obvious and commonsensical that people should be tweaked slightly differently in myriad ways that we don’t question it. Even when identical twins have differences we’re only mildly distracted, after all, each person is their own person. But maybe not. Maybe it is this inherent fallible randomness that makes us possible – that transforms us from an anonymous ego into a particular\u00a0you<\/a>\u00a0and\u00a0me<\/a>.<\/p>\n

\n<\/span>\n

Some other things that spring to mind as possibly being applicable to L1-mediated neuronal variance: adult neurogenesis, anti-depressants, and neuronal pruning during early development.<\/p>\n

References:<\/strong><\/p>\n

    \n
  • Muotri AR et al.\u00a0Somatic mosaicism in neuronal precursor cells mediated by L1 retrotransposition<\/strong>\u00a0(2005)\u00a0Nature<\/em><\/li>\n
  • Muotri AR & Gage FH\u00a0Generation of neuronal variability and complexity<\/strong>\u00a0(2006)\u00a0Nature<\/em><\/li>\n
  • Coufal NG et al.\u00a0L1 retrotransposition in human neural progenitor cells<\/strong>\u00a0(2009)\u00a0Nature<\/em><\/li>\n
  • Ma DK et al.\u00a0Epigenetic choreographers of neurogenesis in the adult mammalian brain<\/strong>\u00a0(2010)\u00a0Nat Neuro<\/em><\/li>\n
  • Muotri AR et al.\u00a0L1 retrotransposition in neurons is modulated by MeCP2<\/strong>\u00a0(2010)\u00a0Nature<\/em><\/li>\n
  • Singer T et al.\u00a0LINE-1 retrotransposons: mediators of somatic variation in neuronal genomes?<\/strong>\u00a0(2010)\u00a0Trends Neuro<\/em><\/li>\n<\/ul>\n

    Conflict of interest: None. I have not been associated with any of the authors cited. (Nov 2010).<\/p>\n

     <\/p>\n","protected":false},"excerpt":{"rendered":"

    LINE-1\u00a0retrotransposons are sections of\u00a0DNA\u00a0which are capable of copying themselves into another part of the\u00a0genome. Although traditionally considered to merely epitomize the concept of the\u00a0selfish gene, more recently they have been suggested to have physiological functions. Here I discuss the\u00a0incredibly fascinating hypothesis\u00a0that\u00a0LINE-1\u00a0retrotransposons may be important in generating\u00a0neuronal variation. Selfish genes and retrotransposons Personally, I think that […]<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_monsterinsights_skip_tracking":false,"_monsterinsights_sitenote_active":false,"_monsterinsights_sitenote_note":"","_monsterinsights_sitenote_category":0,"_jetpack_newsletter_access":"","_jetpack_dont_email_post_to_subs":false,"_jetpack_newsletter_tier_id":0,"_jetpack_memberships_contains_paywalled_content":false,"_jetpack_memberships_contains_paid_content":false,"footnotes":"","jetpack_publicize_message":"","jetpack_publicize_feature_enabled":true,"jetpack_social_post_already_shared":true,"jetpack_social_options":{"image_generator_settings":{"template":"highway","default_image_id":0,"font":"","enabled":false},"version":2},"jetpack_post_was_ever_published":false},"categories":[159,206,204,16],"tags":[],"metadata":[],"class_list":["post-1717","post","type-post","status-publish","format-standard","hentry","category-all-posts","category-biology","category-everything2","category-science"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"","jetpack-related-posts":[{"id":817,"url":"https:\/\/thetravellerslastjourney.com\/shai\/2016\/09\/13\/untitled\/","url_meta":{"origin":1717,"position":0},"title":"Untitled","author":"Pala","date":"September 13, 2016","format":false,"excerpt":"Editorial notes: This untitled post was found in 'Draft' mode in the original blog and may be incomplete. It is published here in its original state. It was last updated on 13\/09\/2016 Like a captain far from any familiar shore, gifted with a map without which he could only be\u2026","rel":"","context":"In "All Posts"","block_context":{"text":"All Posts","link":"https:\/\/thetravellerslastjourney.com\/shai\/all-posts\/"},"img":{"alt_text":"","src":"","width":0,"height":0},"classes":[]},{"id":2811,"url":"https:\/\/thetravellerslastjourney.com\/shai\/2013\/10\/08\/tuesday-october-8-2013\/","url_meta":{"origin":1717,"position":1},"title":"Tuesday October 8, 2013","author":"Pala","date":"October 8, 2013","format":false,"excerpt":"Meta1: Look at yesterday and realize that I seriously need to revise my ability to use whatever code {fyi: markdown} this site uses for formatting! 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