288
Anthology of Human Repetitive DNA
Table 9 compiles both
de novo
inser-
tions, such as in the case of L1-induced
Fukuyama muscular dystrophy, and inher-
ited insertions causing familial disorders,
such as an Alu insertion into the adeno-
matosis polyposis coli (APC) gene, causing
hereditary desmoid disease. The table also
contains one somatic L1 insertion that
inactivates APC, indicating that the L1
retrotransposition can take place in both
germline and somatic tissues. Most phe-
notypes caused by insertional inactivations
are negatively selected in the population
and subsequently eliminated. Neverthe-
less, in cases of nonessential genes with
mild defects, the insertions may eventu-
ally become ±xed in the population. For
example, an Alu insertion seems to have
inactivated the CMP-
N
-acetylneuraminic
acid hydroxylase (CMAH) in the human
lineage after the evolutionary separation
of human and chimp, since all primates
except humans contain a functional copy
of CMAH. In rare cases, insertions may
even produce a positive phenotype. For
instance, AluYa5 insertion into intron 16
of angiogenesin-converting enzyme (ACE)
seems to provide protection against my-
ocardial infarction and age-related macular
degeneration, since genotypes without the
insertion have a higher incidence of the
aforementioned diseases in comparison
to individuals having Alu insertion in
both alleles.
Table 10 shows a list of the genetic
defects attributed to recombination be-
tween interspersed repeats. Preliminary
indications for linkage between Alu poly-
morphisms and genetic diseases, based
solely on polymorphism studies, are not
included. While for some genes only a
single case of recombination between in-
terspersed repeats is known, other loci in-
cluding LDLR, C1NH, alpha-globin, APC,
HEXB or MLL represent hotspots for re-
combinations. Many independent cases of
such recombination have been reported.
As in the case of insertions, there is a
detection bias for recombinations in X-
linked genes. Twelve out of 54 (22%)
deletion/duplication loci are located on
chromosome X.
In mammalian cells, two major recom-
bination pathways exist:
homologous recom-
bination
and nonhomologous end joining,
also known as
nonhomologous recombina-
tion
. In the great majority of genes listed
in Table 10, homologous recombination
between TEs was detected, but nonhomol-
ogous recombination between one or more
TEs was also found in many genes.
The majority of known rearrangements
were reported for direct repeats located
within or near one gene. While some rear-
rangements listed in Table 10 are inherited
(i.e. passed through germline cells), others
occur primarily during mitosis in somatic
t
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-
or other cancer-related recombinations.
Figure 14 shows a model of mitotic in-
trachromosomal recombination between
direct repeats. Unequal sister chromatid
exchange produces one duplicated and one
deleted copy. Reciprocal intrachromatid
exchange, on the other hand, results in one
deletion and one circular episomal DNA,
which is frequently lost. The mechanism
is the same as for the creation of solo LTRs
(see Fig. 10). Mispairing and crossing-over
between repeats, leading to deletion, have
been reported in 54 genes, compared to
duplications in only ±ve.
Internal indels can result in altered
lengths of the protein, if the reading
frame is preserved, or in premature
stop codons within the reading frame.
Typical outcomes of internal exon/gene
deletions and duplications are shown in
Fig. 14. RNAs with premature stop codons
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