Biology Reference
In-Depth Information
The variety of mutations induced by TEs in the human genome argues
for the importance of the multitude of defense mechanisms present within human
cells that target almost every step of the TE life cycle. It also underscores the
importance of the balanced long-term evolutionary existence between the host
genome and TEs.
V. IMPACT ON HUMAN HEALTH
L1 has long been regarded as one of the intrinsic factors contributing to genomic
instability; however, its effects, such as insertional mutagenesis and NAHR
between interspersed L1 or Alu repeats (L1-, Alu-, and SVA-induced diseases
are summarized in Belancio
, 2008a, 2010a), were considered to be restricted
to cancer and mendelian genetic disorders, such as hemophilia A & B. While
TE-associated risk to human health is accepted, it is extremely challenging to
estimate TE contribution to human disease because of the randomness of the TE-
associated mutagenesis, the diversity of mutations arising from TE activity, and
the lack of adequate high throughput methods for the identification and analysis
of these mutations [reviewed in Belancio
et al.
, 2009]. The discovery of the
ongoing endogenous L1 expression in human tissues (Asch
et al.
et al.
, 1996; Belancio
et al.
, 2004), L1's ability to damage human DNA not only
through retrotransposition and recombination but also via induction of DNA
DSBs (Belgnaoui
, 2010b; Ergun
et al.
et al.
, 2006; Farkash
et al.
, 2006; Gasior
et al.
, 2006), and
L1-induced toxicity (Gasior
, 2008b) provides the basis
for reevaluation of the L1 role in human somatic and germline diseases.
Based on the significant estimated variation in the combined L1 activity
in any given human genome (Seleme
et al.
, 2006; Wallace
et al.
, 2006), there is likely a gradient of
endogenous L1 activity in the population and as a result, a spectrum of the L1-
associated burden imposed on the host genome (Fig. 6.3). This estimated dis-
crepancy in the L1 activity is associated with the presence of polymorphic L1 loci
and a significant variation in the activity of the same L1 locus among individuals
on account of mutations that modulate their activity (Beck
et al.
et al.
, 2010; Brouha
et al.
, 2006). Persons
lacking polymorphic L1 elements (that are most likely to be the most active L1
loci in the genome) and containing inactive or the least active fixed L1 loci
would likely experience the least damage from the endogenous L1 activity
(Fig. 6.3). On the other hand, genomes expressing very active and polymorphic
L1 loci would probably be exposed to the highest L1 damage. Even though this
assumption is relatively straight forward, and it is supported by experimental
evidence, the transition from knowing the spectrum of functional L1 loci in any
given genome to predicting their impact on human health is not trivial. The
difficulty predominantly arises
, 2003; Huang
et al.
, 2010; Iskow
et al.
, 2010; Seleme
et al.
from the existence of numerous defense
