284
Anthology of Human Repetitive DNA
contractions, and occur primarily in GC-
rich genes.
Centromeric and telomeric repeats can
also
trigger
chromosomal
instabilities
in the human genome. Recombinations
between both centromeric and telom-
eric satellites were reported in cases
of chromosome rearrangements, chromo-
some fragility, or jumping chromosomal
translocations.
Gene
pol II
e1
e3
e2
i1
i2
e6
e4
i4
i4
SA
SD
&
mRNA
mRNA
mRNA
(a)
Alternative
splicing
(b)
Insertion
into exon
(c)
Insertion into intron,
exon skipping
e1
e2
e3
(A)
n
(A)
n
(A)
n
(A)
n
(A)
n
(A)
n
(A)
n
(A)
n
(A)
n
(A)
n
(A)
n
e1
e1
e1
e1
e2
e1
e2
e1
e2
e1
e2
e3
i5
e5
e1
e3
e2
e4
e6
e5
e1
e3
e2
e4
e6
e5
e1
e2
e3
e6
e5
Premature stop codon
(NMD sensitive?)
Frameshift
Exon
Intron
Different reading
frame
Downstream to stop
(noncoding part)
TE
e1
i1
Fig. 13
Transposable elements and human
disease. Three different mechanisms of
TE-mediated disruptions affecting the gene
functionality: (a) intronic repeats that contain
splice donor (SD) and splice acceptor (SA) sites,
can provide a new exon. (b) Insertion of
transposable element into exon. (c) Insertion of
transposable element into intron, disrupting
proper splicing can lead to exon skipping. All
three disruptions lead to similar changes on the
mRNAleve
l.Insertionorde
letionincod
ing
sequences may change the reading frame, if the
indel length is not a multiple of three. Long
frameshifts are likely to induce premature stop
codon(s) into mRNA (case 1). mRNAs with
premature stop codon (i.e. located more than
50–55 bp upstream of the last exon–exon
junction) are likely to be destroyed by the
nonsense-mediated RNA decay (NMD), and the
corresponding protein is not produced. In some
cases, particularly for short frameshifts, the
random stop codon is found close enough to the
last exon–exon boundary and the protein can be
synthesized, albeit with an aberrant C-terminal
domain (case 2). Note that mRNAs completely
lacking stop codons are also destroyed by the
cellular RNA control, although by a different
pathway than the nonsense-mediated RNA
decay. Insertions containing stop codon without
change in the reading frame (case 3). Again, if
the stop is more than 50 to 55 bp 5
0
from the last
exon–exon junction, the RNA is likely to be
NMD-sensitive and the protein is not produced.
Finally, if neither frameshifts nor new premature
stop codons are induced, insertions lead to
creation of a protein with a new repeat derived
domain. Exon-skippings induce deletions of
some domains. These new proteins may or may
not be functional.
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