Biology Reference
In-Depth Information
Batzer, 2009]. All active human retroelements (L1,Alu, and SVA) contributedwith
different frequencies to the variety of human disease ranging from hemophilia to
cancer [reported human diseases are summarized in Belancio
, 2008a, 2010a].
Despite the continuously growing list of the TE-induced human diseases, the rate of
TE-associated mutagenesis, including retrotransposition and recombination, in
humans is likely significantly underestimated due to the difficulty in detection of
TE-caused mutations by conventionally used diagnostic methods of screening
[reviewed in Belancio
et al.
,2009]. New studies, however, leveraging 2
nd
generation
sequencing are improving our estimates of baseline transposition rates (Beck
et al.
et al.
,
2010; Ewing and Kazazian, 2010; Huang
,2010).
In addition to insertional mutagenesis resulting in disease, retrotranspo-
sition of L1, Alu, and most likely SVA elements can have less drastic phenotypic
effects on cell survival or function. Integration of these elements within human
intronic regions most of the time does not prevent gene expression, but may reduce
cell fitness or function under certain stress conditions or in combination with
other genomic alterations [reviewed in Kines and Belancio, 2011]. Because L1 and
SVAelements contain functional splice and polyadenylation sites (Belancio
et al.
, 2010; Iskow
et al.
et al.
,
2006, 2008b; Hancks
, 2009; Perepelitsa-Belancio and Deininger, 2003) and
Alu elements are prone to acquiring functional splice sites through random
mutations long after the integration process is completed. Intronic integration
events are known to interfere with expression of genes in which they integrate
(Belancio
et al.
et al.
, 2006; Han
et al.
, 2004; Lin
et al.
, 2008; Perepelitsa-Belancio and
Deininger, 2003; Sorek
, 2005).
Full-length L1 insertions in forward orientation have the most pronounced effect
on gene expression most likely due to the presence of the functional promoter in
addition to the highest content of the splice and polyA sites (Boissinot
et al.
, 2004; Ustyugova
et al.
, 2006; Wheelan
et al.
et al.
, 2001,
2006; Chen
et al.
, 2006; Ustyugova
et al.
, 2006). Intronic Alu integration events
can influence alternative splicing (Sorek
, 2002) and the presence of inverted
Alu sequences within 3
0
UTRs of genes can alter nuclear retention of mRNAs and
strongly represses gene expression (Chen andCarmichael, 2008, 2009; Chen
et al.
,
2008). As discussed below, occasionally, retrotransposition provides genomic
rearrangements or cis-acting signals that convey positive benefits to the host
organism (Babushok
et al.
et al.
, 2007; Xing
et al.
, 2006)
C. Issues in repair and recombination
Another significant contribution of human TEs to genomic instability is through
nonallelic homologous recombination (NAHR). Due to their very nature, TEs
typically exist in multiple interspersed copies within a given host genome.
Depending on their age, the various genomic copies will diverge at the level of
nucleotide identity from one another. The longer elements reside in the genome,
the more likely that random genetic mutation will level the level of nucleotide
