ADD: retrocopy.rst: Retrocopy in a nutshell

docs/index.rst

@@ -13,6 +13,7 @@ Welcome to sideRETRO's documentation!
    intro.rst
    install.rst
    usage.rst
+   retrocopy.rst
    method.rst
    authors.rst
 

docs/intro.rst

@@ -23,8 +23,8 @@ the genome.
    :align: center
 
 Got interested? For a more detailed explanation about what is
-a retrocopy at all, please see our section `Retrocopy in a
-nutshell <retrocopy.rst>`_.
+a retrocopy at all, please see our section :ref:`Retrocopy in a
+nutshell <chap_retrocopy>`.
 
 Functionalities
 ===============

docs/meson.build

@@ -5,11 +5,13 @@ doc_sources = files(
   'install.rst',
   'intro.rst',
   'method.rst',
+  'retrocopy.rst',
   'usage.rst'
 )
 
 doc_images = files(
   'images/DBSCAN.png',
+  'images/LINE1.png',
   'images/abnormal_alignment_chr.png',
   'images/abnormal_alignment_clustering.png',
   'images/abnormal_alignment_dist.png',
@@ -18,6 +20,8 @@ doc_images = files(
   'images/genotype.png',
   'images/indistinguishable_alignment.png',
   'images/logo_sideRETRO.png',
+  'images/orientation_opposite_strand.png',
+  'images/orientation_same_strand.png',
   'images/retrocopy.png'
 )
 

docs/retrocopy.rst

@@ -0,0 +1,141 @@
+.. _chap_retrocopy:
+
+***********************
+Retrocopy in a nutshell
+***********************
+
+In the late 1940s, Barbara McClintock discovered the controlling elements,
+later known as transposons [1]_.
+
+.. figure:: images/barbara.jpg
+   :scale: 20%
+   :align: center
+
+   Image of Barbara McClintock. Cold Spring Harbor Laboratory Archives.
+   Copyright © 2016 by the Genetics Society of America
+
+These elements, also called transposable elements (TEs), collectively comprise more
+than half of mammals’ genome [2]_ and for humans, approximately two-thirds
+of the 3 billion base pair genome are the outcome of TEs activity [3]_.  TEs are
+subdivided in DNA-transposons and retrotransposons, and the latter being the result
+of retrotransposition process [4]_ [5]_. Those classes of TEs can be autonomous or
+non-autonomous according to the presence or absence of their own enzymatic machinery
+of (retro)transposition, respectively. In retrotransposons, the most prominent autonomous
+elements are LINEs (Long Interspersed Nuclear Elements), and from the non-autonomous class,
+they are SINEs (Short Interspersed Nuclear Elements) together with processed pseudogenes
+or retrocopies of mRNAs (retrotransposed protein-coding genes).
+
+LINE
+====
+
+LINEs became the most frequent transposable element, in number of nucleotides,
+corresponding to approximately 17% of the human genome [6]_. In our genome, the most
+numerous family of LINEs is LINE-1 (L1) and when its sequence is full-lenght (about 6 kb),
+this element has: i) one promoter region; ii) a 5’UTR region; iii) two coding regions (ORF1p
+and ORF2p); iv) a 3’UTR region; v) a poly-A tail inside its transcript; vi) and recently a
+distinct ORF (ORF0, which is 70 amino acids in length, but still with unknown function) was
+found in primates [7]_ [8]_.
+
+.. image:: images/LINE1.png
+   :scale: 30%
+   :align: center
+
+ORF1p encodes a RNA-binding protein, responsible for the mRNA
+binding specificity, and ORF2p encodes a dual function protein working as reverse transcriptase
+and endonuclease. Together, the coding regions of L1s are accountable for shaping the
+retrotransposase and this machinery can operate in cis making retrocopies of the element itself,
+or in trans retrocopying non-autonomous repetitive elements, like SINEs and mRNAs transcripts
+[9]_ [10]_. In this process, from mRNA, a cDNA is generated (by retrotranscription) and then
+randomly inserted back to the nuclear genome, giving birth to a (retro)copy from the
+original/parental element.
+
+SINE
+====
+
+SINEs, one of the elements retrotransposed by L1 retrotransposase, account for approximately 11%
+of the human genome and its most frequent family is Alu with average length of 300bp [11]_. Alu is
+a primate-specific element and has (when in full-length mode) 5’ end with internal hallmarks of RNA
+polymerase III linked by an A-rich region to a 3’ end with an oligo-dA-rich sequence that acts as
+target to the reverse transcription [12]_. As well as SINEs, retrocopies of coding genes depend on
+L1 machinery and they are one of the major sources of de novo genetic variations [13]_, potentially
+contributing also to genetic diseases [14]_. Nowadays, we know that retrotransposition events are very
+frequent in many organisms, with more than 1 million copies of Alu [9]_ and more than 7,800
+retroduplication events of coding genes in our genome [15]_ [16]_.
+
+Retrocopy and diseases
+======================
+
+In somatic cells, retrotransposition events are repressed by post-transcriptional and epigenetics
+modifications, but the temporary loss of these controls can lead to new insertions resulting in
+structural modifications accountable for diseases, as colorectal and lung cancers [17]_ [18]_ [19]_.
+Recently, some authors showed that, in tumorigenic process, there is a strong correlation between
+colorectal cancer (CRC) progression and the loss of methylation in regions containing LINEs, from
+the most methylated (normal mucosa) to the least methylated (CRC metastasis), suggesting that LINEs
+could act as an important marker for CRC progression [20]_ [21]_.  Alu elements are also rich in CpG
+residues and, as in LINEs, the methylation of these elements appears to decrease in many tumors
+contributing to the development of diseases by either altering the expression of some genes in several
+ways, disrupting a coding region or splice signal [11]_. In 2016, Clayton et al. [22]_ showed a
+potentially tumorigenic Alu insertion in the enhancer region of the tumor suppressor gene CBL in a
+breast cancer sample [22]_. However, although many studies have highlighted Alu elements as sources of
+genetic instability and their contribution to carcinogenesis [23]_ [24]_, other high throughput studies
+have hidden Alu elements due to the difficulties in developing efficient methods to identify these
+elements in a tumorigenic context [11]_.  Retrocopies were also described in tumorigenic context, as
+the classical case of PTEN and its retrocopy PTEN1 [25]_. In this paper, Poliseno and others show the
+critical consequences of the interaction between PTEN and PTENP1, where the retrocopy (pseudogene) is
+active, regulates coding gene expression by regulating cellular levels of PTEN and is also selectively
+deleted in cancer. Therefore, finding these retrotranscribed elements became very important in
+understanding their potential functions in tumorigenesis and tumor heterogeneity.
+
+
+References and Further Reading
+==============================
+
+.. [1] McCLINTOCK, 1950.
+
+.. [2] BURNS, 2017.
+
+.. [3] DE KONING et al., 2011.
+
+.. [4] KAESSMANN, 2010.
+
+.. [5] HELMAN et al., 2014.
+
+.. [6] LANDER et al., 2001.
+
+.. [7] HANCKS and KAZAZIAN, 2016.
+
+.. [8] DENLI et al. 2015.
+
+.. [9] BATZER and DEININGER, 2002.
+
+.. [10] KAESSMANN et al., 2009.
+
+.. [11] DEININGER, 2011.
+
+.. [12] BAKSHI et al. 2016.
+
+.. [13] BECK et al., 2010.
+
+.. [14] LEE et al., 2012.
+
+.. [15] NAVARRO and GALANTE, 2013.
+
+.. [16] NAVARRO and GALANTE, 2015.
+
+.. [17] MIKI et al., 1992.
+
+.. [18] SOLYOM et al., 2012.
+
+.. [19] COOKE et al., 2014.
+
+.. [20] SUNAMI et al. 2011.
+
+.. [21] HUR et al., 2014.
+
+.. [22] CLAYTON et al. 2016
+
+.. [23] DEININGER and BATZER, 1999.
+
+.. [24] BELANCIO et al. 2010.
+
+.. [25] POLISENO et al, 2010.