Segmental Duplications

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Segmental Duplications
and Genetic Disease
Feyza Yilmaz, Department of Integrative Biology and School of Medicine, Univer-
sity of Colorado Denver, Aurora, Colorado, USA
Tamim H Shaikh, School of Medicine, University of Colorado Denver, Aurora,
Colorado, USA
Beverly S Emanuel, Perelman School of Medicine and Children’s Hospital of
Philadelphia, Philadelphia, Pennsylvania, USA
Based in part on the previous versions of this eLS article ‘Segmental
Duplications and Genetic Disease’ (2006, 2008).
Advanced article
Article Contents
• Introduction
• Genomic Disorders Mediated by Segmental
Duplications (SDs)
• Organisation and Structure of SDs
• Chromosomal Rearrangements Mediated
by Segmental Duplications (SDs)
• Mechanisms for SD-mediated and SD-stimulated
Chromosomal Rearrangements
• Evolution of SDs
• Conclusions
Online posting date: 31st October 2017
The human genome contains many different types
of repetitive DNA elements that vary by size and
copy number. Segmental duplications (SDs) are one
such class of repetitive elements that are relatively
large in size, have low copy number in the genome
and their copies share high levels of sequence iden-
tity with each other. These characteristic features
of SDs make them excellent substrates for genomic
rearrangements, resulting from aberrant recombi-
nation between the highly identical copies. Several
of the genomic rearrangements mediated by SDs
lead to copy number variations of large genomic
regions containing many genes. Consequently,
SD-mediated rearrangements are often associated
with genetic diseases that manifest as syndromes
characterised by multiple congenital anomalies
due to dosage imbalance of one or more genes.
Introduction
A significant proportion of human genome is composed of repeti-
tive deoxyribonucleic acid (DNA) elements (Lander et al., 2001).
Recent studies have estimated that repetitive elements may com-
prise 66–69% of the genome (de Koning et al., 2011). These
repetitive DNA elements are classified into different categories
based on several criteria including their size, copy number and
modes of dispersal within the genome. Segmental duplications
(SDs) (or low copy repeats – LCRs) are one such class of
repetitive elements that were first identified as a result of the
human genome project, estimated to comprise approximately 5%
eLS subject area: Genetics & Disease
How to cite:
Yilmaz, Feyza; Shaikh, Tamim H; and Emanuel, Beverly S
(October 2017) Segmental Duplications and Genetic Disease.
In: eLS. John Wiley & Sons, Ltd: Chichester.
DOI: 10.1002/9780470015902.a0006230.pub3
of the human genome (Lander et al., 2001). By definition, SDs
are ≥1 kilobase (kb) in size, with paralogous copies (paralogs)
sharing ≥90% sequence identity; however, SDs are often >100
kb sharing 96–99% sequence identity.
SDs have been shown to coincide with regions that are fre-
quently involved in genomic rearrangements associated with
genetic disease (Lupski, 1998; Bailey et al., 2002). The pres-
ence of highly identical SDs flanking genomic regions pre-
disposes these regions to genomic rearrangements as a result
of misalignment followed by recombination between nonallelic
SDs on homologous chromosomes. This mechanism referred to
as nonallelic homologous recombination (NAHR) is known to
mediate genomic rearrangements associated with several genetic
syndromes (Eichler, 2001; Emanuel and Shaikh, 2001; Bailey
et al., 2002; Carvalho and Lupski, 2016). In addition to medi-
ating recurrent genomic rearrangements via NAHR, recent evi-
dence has suggested that SDs may also ‘stimulate’ genomic
rearrangements by generating unstable DNA structures that can
initiate DNA breakage followed by repair via nonhomologous
end-joining (NHEJ) or replication-based mechanisms (RBMs)
(Carvalho and Lupski, 2016). The chromosomal rearrangements
mediated by SDs include deletions, duplications, translocations,
inversions and other complex rearrangements (Carvalho and Lup-
ski, 2016). Thus, SDs play a significant role in the formation of
structural variations, including copy number variations (CNVs).
CNVs can also lead to dosage imbalance of one or more genes
either by direct gene disruption or as a result of copy number
alterations, resulting in genetic disorders. Since a change at the
genomic level is involved, many SD-mediated disorders have also
been referred to as genomic disorders (Lupski, 1998).
Genomic Disorders Mediated
by Segmental Duplications (SDs)
The completion of the reference human genome first revealed the
presence of SDs near the breakpoints of deletions/duplications
associated with several previously known genetic disorders such
as Williams–Beuren syndrome (WBS) on 7q11.23 (Merla et al.,
2010), Prader–Willi syndrome (PWS)/Angelman syndrome
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Segmental Duplications and Genetic Disease
(AS) on 15q11–q13 (Cheon, 2016), Charcot–Marie–Tooth dis-
ease type 1A (CMT1A)/hereditary neuropathy with liability
to pressure palsies (HNPP) on 17p11.2 (Timmerman et al.,
2014), Smith–Magenis syndrome (SMS)/Potocki–Lupski syn-
drome (Potocki et al., 2007), neurofibromatosis type 1 (NF1)
on 17q11.2 (Dorschner et al., 2000), DiGeorge syndrome
(DGS)/velocardiofacial syndrome (VCFS) now collectively
referred to as the 22q11.2 deletion syndrome (22q11.2DS)
and cat-eye syndrome (CES) on 22q11 (Shaikh et al., 2000;
McDonald-McGinn et al., 2015). One important characteristic
common to these disorders is that affected individuals have
multiple congenital anomalies that can include intellectual dis-
ability (ID), developmental delay (DD), dysmorphic features,
cardiac defects, limb and digital abnormalities and seizures. The
subsequent mapping of the rearrangement breakpoints within
flanking SDs in all of these disorders demonstrated that they also
shared a common mechanism underlying the associated genomic
rearrangements, namely SD-mediated NAHR.
However, the large number of SDs identified in the human
genome predicted that SD-mediated NAHR is likely to be
associated with additional, yet unidentified disorders (Emanuel
and Shaikh, 2001; Bailey et al., 2002). Indeed, over the past
several years, the list of SD-mediated genomic disorders has
been expanding with the discovery of novel disorders including
deletions/duplications on 1q21 (Brunetti-Pierri et al., 2008),
deletions/duplications on 5q35 associated with Sotos syndrome
(Novara et al., 2014) and deletions/duplications on 15q24
(El-Hattab et al., 2009), to name a few of the many newly
identified disorders (Table 1). These new SD-mediated disorders
are also characterised by multiple congenital anomalies.
In addition to NAHR, SDs have also been shown to pro-
mote or stimulate genomic rearrangements via alternative mech-
anisms including NHEJ and RBMs (described below). These
alternative SD-stimulated mechanisms have been observed in
nonrecurrent duplications within Xq28 including MECP2. The
majority (77%) of these Xq28 duplications have distal break-
points that localise to one of two groups of SDs (Carvalho et al.,
2009); however, the rearrangements are not mediated by NAHR.
Similarly, nonrecurrent deletions of the PLP1 gene, associated
with Pelizaeus–Merzbacher disease (PMD), have rearrangement
breakpoints that are surrounded by SDs, but are not mediated by
NAHR (Zhang et al., 2009). More interestingly, it has been shown
that SDs associated with Smith–Magenis and Potocki–Lupski
syndromes (SMS-REPs) can mediate recurrent, NAHR-based as
well as nonrecurrent SD-stimulated rearrangement in a few indi-
viduals with SMS who have variant deletions in 17p11.2 (Potocki
et al., 2007).
Organisation and Structure of SDs
SDs are distributed between pericentromeric, subtelomeric and
interstitial regions of most chromosomes (Eichler, 2001; Bai-
ley et al., 2002). Further, SDs can either be interchromosomal,
with paralogs on nonhomologous chromosomes, or intrachromo-
somal, with paralogs mainly present on a single chromosome
or within a single chromosomal band (Lupski, 1998; Emanueland Shaikh, 2001). Further, SDs contain truncated gene seg-
ments/pseudogenes with intron–exon structures and high copy
number repeats such as Alu and LINE-1 elements as well as
other sequence motifs that promote chromosomal breakage and
rearrangement (Eichler, 2001; Emanuel and Shaikh, 2001; Bailey
et al., 2002).
There is a high level of variability in the organisation and
structure of SDs. The CMT1A-REP, the SD that mediates the
interstitial duplication/deletion associated with CMT1A/HNPP,
respectively, demonstrates a less complex structure and organ-
isation. There are two copies of the CMT1A-REP, each being
∼24 kb in size, sharing 98.7% sequence identity flanking the
duplicated/deleted region on either side (Timmerman et al.,
2014). Similarly, the SDs mediating rearrangements associated
with X-linked ichthyosis (Li et al., 1992) and hemophilia A
(Dittwald et al., 2013) are also less complex. However, a majority
of the larger SDs demonstrate a complex arrangement of dupli-
cated modules (Emanuel and Shaikh, 2001). These complex SDs
can consist of multiple smaller, duplicated modules and clusters
of paralogous sequences of diverse genomic origin, which are
organised in hierarchical groups of direct and inversely orientated
sequences (Dittwald et al., 2013).
The complex SDs range in size from 100 to 500 kb and con-
sist of multiple smaller, duplicated modules arranged in com-
plex configurations. Therefore, different copies of the complex
SDs may differ from each other in size, content and organisa-
tion of the duplicated modules within them. The modules that
are shared between any two given copies of these SDs share
95–98% nucleotide sequence identity. This complex architec-
ture of SDs makes them excellent substrates for misalignment,
followed by aberrant recombination leading to chromosomal
rearrangements. Genomic disorders mediated by large and com-
plex SDs include WBS (Merla et al., 2010), PWS/AS (Cheon,
2016), SMS/Potocki–Lupski syndromes (Potocki et al., 2007)
and the 22q11.2DS (Shaikh et al., 2000; McDonald-McGinn
et al., 2015). Although not associated with a specifically ‘named’
and historically known syndrome, the SDs in 1q21.1 also have
a complex arrangement of duplicated modules within four SD
blocks, ranging in size from 270 kb to 2.2 Mb, and most of these
regions are polymorphic in the general population (Sharp et al.,
2006).
Chromosomal Rearrangements
Mediated by Segmental
Duplications (SDs)
SDs have been associated with both recurrent and nonrecur-
rent chromosomal rearrangements including microdeletions,
microduplications, translocations, inversions and other complex
rearrangements. The most frequent microdeletions associated
with SDs include the 1.6 Mb microdeletion in 7q11.23 associ-
ated with WBS (Merla et al., 2010), the approximately 4 Mb
microdeletions of 15q11–q13 (del(15)(q11–q13)) associated
with PWS/AS (Cheon, 2016) and the 3 Mb microdeletion in
22q11.2 associated with the 22q11.2DS (Shaikh et al., 2000,
Emanuel and Shaikh, 2001). SD-mediated NAHR is expected
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Segmental Duplications and Genetic Disease
Table 1 SD-mediated genomic disorders
Genomic region
syndrome
Type (Del-Dup) size The most common phenotypes Reference
1q21 (TAR
syndrome)
Del, ∼200–500 kb Upper extremity abnormalities,
hypomegakaryocytic thrombocytopenia
Klopocki et al. (2007)
1q21.1 Del/Dup, ∼1.35 Mb Variable ID, cataracts, MCA (del)
Heart defects (del/dup) Brunetti-Pierri et al. (2008)
2q11.2 Del, ∼1.25 Mb ID, congenital heart defect(del) Rudd et al. (2009)
Dup, ∼1.47 Mb DD, hypotonia, macrocephaly (dup)
2q13 Del, ∼1.62 Mb ID, DD, anxiety, hypotonia Rudd et al. (2009)
3q29 Del, ∼1.4–1.6 Mb Dysmorphic features, microcephaly (del)
Dup, ∼1.6 Mb Variable ID (both) Ballif et al. (2008)
5q35.3 (Sotos
syndrome)
Del/Dup, ∼2 Mb (not
in all cases)
Prominent forehead, hypertelorism,
hypotonia, DD, speech delay, microcephaly
Novara et al. (2014)
7q11.23 (WBS) Del, ∼1.6 Mb DD, ID, congenital heart disease, bulbous
nasal tip (del)
Mild growth retardation, subtle facial
dysmorphism (dup)
Merla et al. (2010)
7q36.1 Del, ∼2.35 Mb Feeding difficulties, speech delay, DD Rudd et al. (2009)
8p23.1 Del, ∼2.9–6 Mb Congenital heart disease, DD, hyperactivity,
impulsiveness (del)
Ciccone et al. (2006)
Dup, ∼3.75 Mb Adrenal insufficiency, partial 2/3 syndactyly
of the toes and cleft palate(dup)
10q22–q23 Del, ∼7.2 Mb
Dup, ∼7.4 Mb
ID, behavioural abnormalities, hyperactivity van Bon et al. (2011)
12q14.2 Del, ∼200 Kb Spermatogenic failure 9 Coutton et al. (2013)
15q11–q13 – PWS,
AS
Del, ∼4 Mb Severe DD, ID, speech impairment,
microcephaly, hypopigmentation
Cheon (2016)
15q13.3 Del/Dup, ∼1.5 Mb DD, mild-to-moderate learning disability,
seizures
Behavioural abnormalities
van Bon et al. (2009)
15q24 Del, ∼1.7–3.9 Mb
Dup, ∼2.6 Mb
ID, dysmorphic features, growth problems,
digital abnormalities
El-Hattab et al. (2009)
16p11.2 Del/Dup, ∼600 kb Macrocephaly (del)
Microcephaly (dup)
Learning disability, speech delay, congenital
anomaly (both)
Rosenfeld et al. (2010)
16p11.2p12.2 Del, ∼7.1–8.7 Mb ID, DD, dysmorphic facial features Ballif et al. (2007)
16p12.1 Del, ∼520 kb Learning disability, multiple congenital
anomaly
Girirajan and Eichler (2010);
Antonacci et al. (2010)
16p13.11 Del/Dup, ∼1 Mb Multiple congenital anomaly (del) Ullmann et al. (2007)
Learning disability (dup)
17p11.2 – CMT1A/
HNPP
Del/Dup, ∼1.5 Mb Recurrent focal pressure nerve palsies,
decreased motor nerve conduction velocity,
learning disability
Timmerman et al. (2014)
17p11.2 – SMS
(del), PLS (dup)
Del, ∼3.7 Mb DD, learning disability, infantile hypotonia,
short stature (del)
Dup, 3.6 Mb Cardiac anomalies, ID, DD, failure to thrive
(dup)
Potocki et al. (2007)
17q11.2 (NF1) Del, 1.5 Mb Variable facial dysmorphisms, mental
retardation, developmental delay
Dorschner et al. (2000)
(continued overleaf )
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Segmental Duplications and Genetic Disease
Table 1 (continued)
Genomic region
syndrome
Type (Del-Dup) size The most common phenotypes Reference
17q12 Del/Dup, ∼1.5 Mb Learning disability (Dup)
Seizures (Both)
Shchelochkov et al. (2010)
17q21.31 Del/Dup, ∼700 Kb Moderate DD, learning disability, neonatal
hypotonia, kidney/urological anomalies
Koolen et al. (2006);
Shchelochkov et al. (2010)
17q23.1q23.2 Del, ∼2.2–2.8 Mb Heart defects and limb abnormalities Rudd et al. (2009); Ballif et al.
(2010)
22q11.2
(22q11.2DS)
Del/Dup, ∼3 Mb ID, DD, outflow heart defects, immune
deficiency (del)
ID, DD, delayed psychomotor development,
growth retardation (dup)
Shaikh et al. (2000);
McDonald-McGinn et al.
(2015)
Distal 22q11.2 Del, ∼2.2 Mb Growth delay, ID, MCA (del) Ben-Shachar et al. (2008); Ou
et al. (2008)
Dup, ∼1.4 Mb Variable ID (dup)
Xp11.22–p11.23 Dup, ∼0.8–9.2 Mb ID, speech delay, EEG abnormalities Nizon et al. (2015)
Abbreviations: ID, intellectual disability; DD, developmental delay; MCA, multiple congenital anomalies; CMT1A, Charcot–Marie–Tooth disease type
1A; HNPP, hereditary neuropathy with liability to pressure palsies; TAR, thrombocytopenia absent radius; VCFS, velocardiofacial syndrome; WBS,
Williams–Beuron Syndrome; PWS, Prader–Willi syndrome; AS, Angelman syndrome.
Adapted from Deak et al. (2011); Vissers and Stankiewicz (2012); phenotypic information from Girirajan and Eichler (2010); Vissers and Stankiewicz
(2012).
to result in reciprocal microdeletions and microduplications
(Emanuel and Shaikh, 2001). However, for many of the genomic
disorders resulting from microdeletions, such as the 22q11.2DS,
reciprocal microduplications of the region associated with
abnormal syndromic phenotypes were rarely identified. The
advent of chromosomal microarrays and the genotype-first
approach in clinical diagnostics has led to the discovery of a
larger number of reciprocal microduplications associated with
previously known microdeletion syndromes (Carvalho and
Lupski, 2016). Subsequently, several recurrentSD-mediated
reciprocal microdeletion/microduplications have been reported
in the pathogenesis of disorders characterised by ID and multiple
congenital anomalies (Table 1).
Several studies have shown that interchromosomal SDs can
mediate translocations, another class of chromosomal rear-
rangement often associated with genetic disorders. SD-mediated
translocations include the recurrent t(4;8)(p16;p23), which
apparently results from a crossover between the olfactory
receptor–gene clusters of SDs on chromosome 4p16 and 8p23
(Maas et al., 2007); the der(4)t(4;11)(p16.2;p15.4), a recur-
rent unbalanced translocation, which results in segmental 4p
monosomy and 11p trisomy (Ou et al., 2011) with break-
points that cluster within 204 kb homologous SDs; and the
t(7;9)(q11.23;p24.3). Interestingly, SDs within 7q11.23 and
22q11.2, two genomic regions associated with microdele-
tion/microduplication syndromes, have also been associated
with recurrent and nonrecurrent translocations, even though the
mechanism does not appear to be via NAHR but more likely
the result of NHEJ (Shaikh et al., 2000; Portera et al., 2006). It
is likely that the SDs on these chromosomes contain unstable
sequence motifs that give rise to frequent double-stranded breaks
(DSBs), which in turn predisposes these regions to recurrent
translocations. This is true for the palindromic AT-rich repeats
(PATRRs) in LCR22-B, the SD that mediates the recurrent
translocations of chromosome 22 (Emanuel and Shaikh, 2001).
PATRRs, a form of SD, have also been implicated as causing
other recurrent translocations, such as the t(3;8) associated
with renal cell carcinoma (Kato et al., 2014). Thus, based
on the evidence of SD-mediated NAHR leading to transloca-
tions, Ou et al. (2011) generated an in silico map composed of
1143 interchromosomal SD pairs that are potential substrates
for NAHR-mediated translocations. One of these predicted
NAHR-mediated translocations, t(8;12)(p23.1;p13.31), was
later identified in two individuals (Ou et al., 2011). Thus, both
SD-mediated NAHR and SD and PATRR-stimulated genomic
instability can give rise to translocations.
SD-mediated NAHR has also been implicated in chromoso-
mal inversions. Inversion polymorphisms have been observed
in several regions associated with SD-mediated microdele-
tions/microduplications including a 1.5 Mb inversion of 7q11
in parents of children with WBS (Feuk, 2010), an inversion in
parents of 22q11.2DS individuals (Demaerel et al., 2017), a 1.9
Mb inversion of 3q29 (Antonacci et al., 2009); a 2 Mb inversion
on 15q13.3 (Antonacci et al., 2009); a 1.2 Mb inversion on
15q24 microdeletion region (Antonacci et al., 2009; Feuk, 2010)
and a 900 kb inversion on 17q21.31 microdeletion syndrome
(Antonacci et al., 2009). These inversions potentially appear to
be mediated by the same SDs that are also involved in the recipro-
cal microdeletions/microduplications of these genomic regions.
This has led to the suggestion that structural polymorphisms may
predispose the parental chromosomes to further rearrangement,
leading to reciprocal microdeletion/microduplication (Vergés
et al., 2017). Such inversion polymorphisms in parental chromo-
somes have been clearly demonstrated to be a predisposing factor
leading to the 7q11.23 microdeletion (Feuk, 2010), the 22q11.2
deletion associated with the 22q11.2DS (Demaerel et al., 2017)
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Segmental Duplications and Genetic Disease
and is also likely true for the inversion polymorphism observed
at 5q35.2–q35.3 associated with Sotos syndrome (Feuk, 2010).
Alternatively, SD-mediated recurrent inversions can directly
lead to a disease phenotype by disrupting one or more genes.
The disruption of the IDS gene, by an inversion resulting from
SD-mediated NAHR, is a common cause of Hunter syndrome
(Dittwald et al., 2013). SD-mediated inversions have also
been shown to disrupt the factor VIII gene on Xq28 leading
to hemophilia A (Dittwald et al., 2013). Thus, SD-mediated
inversions not only give rise to disease via direct disruption of
genes but can also predispose to genomic disorders.
Mechanisms for SD-mediated
and SD-stimulated Chromosomal
Rearrangements
SDs that flank regions associated with genomic disorders share
96–99% sequence identity over large spans (>10 Kb). These
highly identical SDs can promote recurrent rearrangements
via a process of NAHR (Lupski, 1998). NAHR between SDs
on homologous chromosomes, which are in the same orien-
tation, is the accepted mechanism underlying the recurrent
deletions/duplications associated with the 22q11.2DS, WBS,
PWS/AS and other genomic disorders (Carvalho and Lupski,
2016). However, intrachromosomal NAHR between paralogous
SDs that are in opposite orientation has also been observed
in some cases including deletions in 17q11.2 associated with
NF1 and atypical deletions associated with the 22q11.2DS
(Emanuel and Shaikh, 2001; Dorschner et al., 2000). These
types of intrachromosomal events may also explain the para-
centric inversions within the factor VIII gene associated with
hemophilia A, the polymorphic but benign inversion found close
to the EMD gene and the inversions associated with Hunter
syndrome (Emanuel and Shaikh, 2001; Carvalho and Lupski,
2016). NAHR between interchromosomal SDs has also been
implicated in recurrent translocation (Ou et al., 2011). Thus,
a majority of the SD-mediated rearrangements are believed to
result from NAHR.
However, recent evidence has suggested that SDs may also
‘stimulate’ or promote nonrecurrent rearrangements via mech-
anisms other than NAHR, including NHEJ and RBMs (Car-
valho and Lupski, 2016). NHEJ is normally used to repair
DSBs in organisms ranging from bacteria to mammals. Although
NHEJ does not require SDs, several NHEJ-mediated deletions
have been identified in patients with PMD in which one of
the deletion breakpoints was within a 32 Kb SD (Inoue et al.,
2002). Similarly, other apparently NHEJ-mediated rearrange-
ment breakpoints have been identified within SDs in patients
with nonrecurrent rearrangements associated with SMS (Shaw
and Lupski, 2005). The use of higher resolution techniques for
breakpoint mapping suggested that many rearrangements associ-
ated with genomic disorders could not be explained by NAHR
or NHEJ (Zhang et al., 2009). This led to the proposal of
RBMs, including break-induced replication (BIR), fork stalling
and template switching (FoSTeS) and microhomology-mediated
break-induced replication (MMBIR) (Zhang et al., 2009; Car-
valho and Lupski, 2016). SDs may stimulate RBMs due to the
presence of sequence motifs that can promote cruciform or other
unstable secondary structures, which in turn can lead to repli-
cation fork stalling or collapse leading to DNA breakage. The
subsequent replicative repair of the broken DNA can lead to the
formation of deletions, duplications and other rearrangements
(Carvalho and Lupski, 2016). Duplications of Xq28 including
MECP2 appear to result from RBM-based mechanisms with the
distal rearrangement breakpoints localising within SDs (Carvalho
et al., 2009).
Evolution of SDs
Duplicated sequences have played an important role in the evo-
lution of new gene function (Ohno et al., 1968). Thus, SDs
are not only involved in promoting genomic instability asso-
ciated with disease but have also played a role in the emer-
gence of new genes (Marques-Bonet and Eichler, 2009). SDs
were first identified in human and later in other nonhuman pri-
mate genomes. As the number of genome sequences from dif-
ferent species have become available, it is clear that SDs are
not limited to primates but are also present in the genomes of
other mammals such as mouse, rat, dog and domestic animals
including cattle (Cheung et al., 2003; She et al., 2008; Nicholas
et al., 2009; Feng et al., 2017). However, the SDs in nonpri-
mate, mammalian genomes differ in their structure and organi-
sation from the ones in human and nonhuman primate genomes
(Marques-Bonet and Eichler, 2009; Marques-Bonet et al., 2009).A comparison of human and mouse genomes showed that almost
all mouse SDs are tandemly organised, whereas ∼60% of human
SDs are interspersed (Marques-Bonet et al., 2009). Furthermore,
SDs have rapidly expanded and have developed a more complex
architecture of duplicated modules in the genomes of humans,
chimp and gorilla (African great apes) after their divergence from
orangutan (Asian great ape) (Marques-Bonet and Eichler, 2009;
Marques-Bonet et al., 2009).
SDs associated with genomic disorders appear to have origi-
nated during the evolution of the primate genome and expanded
in size and complexity in the genomes of great apes and humans.
Molecular analysis of the SDs associated with CMT1A suggests
that the duplication of the CMT1A-REP occurred after the diver-
gence of chimpanzee and humans because the gorilla genome has
just one copy of this sequence (Kiyosawa and Chance, 1996).
Similarly, the SDs associated with 22q11.2DS expanded after the
divergence of hominoids from Old World monkeys (Shaikh et al.,
2000; Babcock et al., 2007). The comparative sequence analy-
sis of primate genomes suggests that the complex SDs associated
with the majority of genomic disorders have evolved relatively
recently (<12 million years ago) (Marques-Bonet and Eichler,
2009).
In addition to their role in genomic disorders, SDs have played
a significant role in human evolution and adaptation (see also:
Segmental Duplications: A Source of Diversity, Evolution and
Disease). Human-specific SDs in the genome are enriched for
genes associated with brain development and neuronal apoptosis.
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Segmental Duplications and Genetic Disease
Several of these SDs are also associated with neurodevelopmen-
tal disease and recurrent chromosomal rearrangements (Cooper
et al., 2014). There is also a strong correlation between genomic
regions containing SDs and evolutionary breakpoints, suggesting
that SDs may have played an important role in evolutionary rear-
rangements in mammalian genomes (Bailey et al., 2004). SDs
have been localised to the breakpoints of six out of nine peri-
centric inversions that distinguish the karyotype of human and
chimpanzee as well as species-specific inversions in the genomes
of humans and chimpanzees (Marques-Bonet and Eichler, 2009).
Conclusions
SD-mediated genomic rearrangements represent a significant
source of genetic variation associated with human disease. The
presence of complex, highly identical SDs in specific regions
of the genome leads to instability, creating ‘hot spots’ for chro-
mosomal rearrangements associated with genetic disorders. The
advances in genomic technologies have greatly improved our
ability to detect all forms of variation within the human genome.
The higher resolution analysis of the human genome has led
to the observation that in addition to their role in mediating
disease-associated rearrangements, SD-mediated genetic varia-
tions also play an important role in generating genetic diversity
within the human population.
Glossary
Copy number variation A structural variation that results in
loss or gain of a genomic segment, leading to changes in its
copy number.
Genomic disorder A clinically recognizable disorder resulting
from a genomic rearrangement mediated by segmental
duplications or other unstable genomic architecture.
Inversion A rearrangement in which a genomic segment is
reversed end to end.
Microdeletion A loss via deletion of a genomic segment that is
too small (< 5 million base pairs) to be detected by
conventional cytogenetics.
Microduplication A gain via duplication of a genomic segment
that is too small (< 5 million base pairs) to be detected by
conventional cytogenetics.
Non-allelic homologous recombination An aberrant form of
homologous recombination that can occur between regions of
the genome that are not alleles, but share a high level of
sequence identity (e.g. segmental duplications).
Segmental duplication A type of DNA element greater than
1000 base pairs, which is repeated in the human genome at
low copy number with the copies sharing greater than 90%
sequence identity with one another. Many are chromosome
specific.
Structural variation A genomic change or difference between
individual genomes resulting from a chromosomal
rearrangement such as a microdeletion, microduplication,
insertion, inversion or translocation.
Translocation A rearrangement in which genomic segments
are exchanged between two non-homologous chromosomes.
References
Antonacci F, Kidd J, Marques-Bonet T, et al. (2009) Characterization
of six human disease-associated inversion polymorphisms. Human
Molecular Genetics 18 (14): 2555–2566.
Antonacci F, Kidd J, Marques-Bonet T, et al. (2010) A large and com-
plex structural polymorphism at 16p12.1 underlies microdeletion
disease risk. Nature Genetics 42 (9): 745–750.
Babcock M, Yatsenko S, Hopkins J, et al. (2007) Hominoid lin-
eage specific amplification of low-copy repeats on 22q11. 2
(LCR22s) associated with velo-cardio-facial/digeorge syndrome.
Human Molecular Genetics 16 (21): 2560–2571.
Bailey JA, Gu Z, Clark RA, et al. (2002) Recent segmental duplica-
tions in the human genome. Science 297 (5583): 1003–1007.
Bailey JA, Church DM, Ventura M, Rocchi M and Eichler EE (2004)
Analysis of segmental duplications and genome assembly in the
mouse. Genome Research 14 (5): 789–801.
Ballif BC, Hornor SA, Jenkins E, et al. (2007) Discovery of a pre-
viously unrecognized microdeletion syndrome of 16p11.2-p12.2.
Nature Genetics 39 (9): 1071–1073.
Ballif BC, Theisen A, Coppinger J, et al. (2008) Expanding the clini-
cal phenotype of the 3q29 microdeletion syndrome and characteri-
zation of the reciprocal microduplication. Molecular Cytogenetics
1 (1): 8.
Ballif BC, Theisen A, Rosenfeld JA, et al. (2010) Identification of
a recurrent microdeletion at 17q23.1q23.2 flanked by segmental
duplications associated with heart defects and limb abnormalities.
American Journal of Human Genetics 86 (3): 454–461.
Ben-Shachar S, Ou Z, Shaw CA, et al. (2008) 22q11.2 distal deletion:
a recurrent genomic disorder distinct from DiGeorge syndrome and
velocardiofacial syndrome. American Journal of Human Genetics
82 (1): 214–221.
Brunetti-Pierri N, Berg JS, Scaglia F, et al. (2008) Recurrent recip-
rocal 1q21.1 deletions and duplications associated with micro-
cephaly or macrocephaly and developmental and behavioral abnor-
malities. Nature Genetics 40 (12): 1466–1471.
Carvalho CM, Zhang F, Liu P, et al. (2009) Complex rearrange-
ments in patients with duplications of MECP2 can occur by fork
stalling and template switching. Human Molecular Genetics 18
(12): 2188–2203.
Carvalho CM and Lupski JR (2016) Mechanisms underlying struc-
tural variant formation in genomic disorders. Nature Reviews
Genetics 17 (4): 224–238.
Cheon CK (2016) Genetics of Prader-Willi syndrome and
Prader-Will-Like syndrome. Annals of Pediatric Endocrinology &
Metabolism 21 (3): 126–135.
Cheung J, Wilson M, Zhang J, et al. (2003) Recent segmental and
gene duplications in the mouse genome. Genome Biology 4 (8):
1–12.
Ciccone R, Mattina T, Giorda R, et al. (2006) Inversion polymor-
phisms and non-contiguous terminal deletions: the cause and the
(unpredicted) effect of our genome architecture. Journal of Medi-
cal Genetics 43 (5): e19.
Cooper G, Coe B, Girirajan S, et al. (2014) A copy number variation
morbidity map of developmental delay. Nature Genetics 43 (9):
838–846.
6 eLS © 2017, John Wiley & Sons, Ltd. www.els.net
Segmental Duplications and Genetic Disease
Coutton C, Abada F, Karaouzene T, et al. (2013) Fine characterisa-
tion of a recombination hotspot at the DPY19L2 locus and resolu-
tion of the paradoxical excess of duplications over deletions in the
general population. PLoS Genetics 9 (3): e1003363.
Deak KL, Horn SR and Rehder CW (2011) The evolving picture of
microdeletion/microduplication syndromes in the age of microar-
ray analysis:variable expressivity and genomic complexity. Clinics
in Laboratory Medicine 31 (4): 543–564.
Demaerel W, Hestand MS, Vergaelen E, et al. (2017) Nested inver-
sion polymorphisms predispose for chromosome 22q11.2 rear-
rangements. American Journal of Human Genetics (in press).
Dittwald P, Gambin T, Gonzaga-Jauregui C, et al. (2013) Inverted
low-copy repeats and genome instability–a genome-wide analysis.
Human Mutation 34 (1): 210–220.
Dorschner MO, Sybert VP, Weaver M, Pletcher BA and Stephens
K (2000) NF1 microdeletion breakpoints are clustered at flanking
repetitive sequences. Human Molecular Genetics 9 (1): 35–46.
Eichler EE (2001) Recent duplication, domain accretion and the
dynamic mutation of the human genome. Trends in Genetics 17
(11): 661–669.
El-Hattab AW, Smolarek AW, Walker ME, et al. (2009) Rede-
fined genomic architecture in 15q24 directed by patient dele-
tion/duplication breakpoint mapping. Human Genetics 126 (4):
589–602.
Emanuel BS and Shaikh TH (2001) Segmental duplications: an
‘expanding’ role in genomic instability and disease. Nature
Reviews Genetics 2 (10): 791–800.
Feng X, Jiang J, Padhi A, et al. (2017) Characterization of
genome-wide segmental duplications reveals a common genomic
feature of association with immunity among domestic animals.
BMC Genomics 18 (1): 293.
Feuk L (2010) Inversion variants in the human genome: role in
disease and genome architecture. Genome Medicine 2 (2): 11.
Girirajan S and Eichler EE (2010) Phenotypic variability and genetic
susceptibility to genomic disorders. Human Molecular Genetics 19
(R2): R176–R187.
Inoue K, Osaka H, Thurston VC, et al. (2002) Genomic rearrange-
ments resulting in PLP1 deletion occur by nonhomologous end
joining and cause different dysmyelinating phenotypes in males
and females. The American Journal of Human Genetics 71 (4):
838–853.
Kato T, Franconi CP, Sheridan MB, et al. (2014) Analysis of the t
(3; 8) of hereditary renal cell carcinoma: a palindrome-mediated
translocation. Cancer Genetics 207 (4): 133–140.
Kiyosawa H and Chance PF (1996) Primate origin of
the CMT1A-REP repeat and analysis of a putative
transposon-associated recombinational hotspot. Human Molecular
Genetics 5 (6): 745–753.
Klopocki E, Schulze H, Strauß G, et al. (2007) Complex inheri-
tance pattern resembling autosomal recessive inheritance involv-
ing a microdeletion in thrombocytopenia-absent radius syndrome.
American Journal of Human Genetics 80 (2): 232–240.
de Koning AP, Gu W, Castoe TA, Batzer MA and Pollock DD (2011)
Repetitive elements may comprise over two-thirds of the human
genome. PLoS Genetics 7 (12): e1002384.
Koolen DA, Vissers LE, Pfundt R, et al. (2006) A new chromo-
some 17q21.31 microdeletion syndrome associated with a com-
mon inversion polymorphism. Nature Genetics 38 (9): 999–1001.
Lander ES, Linton LM, Birren B, et al. (2001) Initial sequencing and
analysis of the human genome. Nature 409 (6822): 860–921.
Li XM, Yen PH and Shapiro LJ (1992) Characterization of a low
copy repetitive element S232 involved in the generation of frequent
deletions of the distal short arm of the human X chromosome.
Nucleic Acids Research 20 (5): 1117–1122.
Lupski JR (1998) Genomic disorders: structural features of the
genome can lead to DNA rearrangements and human disease traits.
Trends in Genetics 14 (10): 417–422.
Maas NM, Van Vooren S, Hannes F, et al. (2007) The t(4;8) is
mediated by homologous recombination between olfactory recep-
tor gene clusters, but other 4p16 translocations occur at random.
Genetic Counseling (Geneva, Switzerland) 18 (4): 357–365.
Marques-Bonet T and Eichler EE (2009) The evolution of human
segmental duplications and the core duplicon hypothesis. Cold
Spring Harbor Symposia on Quantitative Biology 74: 355–362.
Marques-Bonet T, Girirajan S and Eichler EE (2009) The origins and
impact of primate segmental duplications. Trends in Genetics 25
(10): 443–454.
McDonald-McGinn D, Sullivan K, et al. (2015) 22q11.2 deletion
syndrome. Nature Reviews Disease Primers 1: 15071.
Merla G, Brunetti-Pierri N, Micale L and Fusco C (2010) Copy
number variants at Williams-Beuren syndrome 7q11.23 region.
Human Genetics 128 (1): 3–26.
Nicholas T, Cheng Z, Ventura M, et al. (2009) The genomic architec-
ture of segmental duplications and associated copy number variants
in dogs. Genome Research 19 (3): 491–499.
Nizon M, Andrieux J, Rooryck C, et al. (2015) Phenotype-genotype
correlations in 17 new patients with an Xp11.23p11.22 microdu-
plication and review of the literature. American Journal of Medical
Genetics Part A 167 (1): 111–122.
Novara F, Stanzial F, Rossi E et al. (2014) Defining the phenotype
associated with microduplication reciprocal to Sotos syndrome
microdeletion. American Journal of Medical Genetics Part A 164
(8): 2084–2090.
Ohno S, Wolf U and Atkin NB (1968) Evolution from fish to mam-
mals by gene duplication. Hereditas 59 (1): 169–187.
Ou Z, Berg JS, Yonath H, et al. (2008) Microduplications of 22q11.2
are frequently inherited and are associated with variable pheno-
types. Genetics in Medicine 10 (4): 267–277.
Ou Z, Stankiewicz P, Xia Z, et al. (2011) Observation and prediction
of recurrent human translocations mediated by NAHR between
nonhomologous chromosomes. Genome Research 21 (1): 33–46.
Portera G, Venturin M, Patrizi A, et al. (2006) Characterisation of a
non-recurrent familial translocation t(7;9)(q11.23;p24.3) points to
a recurrent involvement of the Williams-Beuren syndrome region
in chromosomal rearrangements. Journal of Human Genetics 51
(1): 68–75.
Potocki L, Bi W, Treadwell-Deering D, et al. (2007) Characteriza-
tion of Potocki-Lupski syndrome (dup(17)(p11.2p11.2)) and delin-
eation of a dosage-sensitive critical interval that can convey an
autism phenotype. American Journal of Human Genetics 80 (4):
633–649.
Rosenfeld JA, Coppinger J, Bejjani BA, et al. (2010) Speech delays
and behavioral problems are the predominant features in individ-
uals with developmental delays and 16p11.2 microdeletions and
microduplications. Journal of Neurodevelopmental Disorders 2
(1): 26–38.
Rudd MK, Keene J, Bunke B, et al. (2009) Segmental duplications
mediate novel, clinically relevant chromosome rearrangements.
Human Molecular Genetics 18 (16): 2957–2962.
Shaikh TH, Kurahashi H, Saitta SC, et al. (2000) Chromosome
22-specific low copy repeats and the 22q11.2 deletion syndrome:
eLS © 2017, John Wiley & Sons, Ltd. www.els.net 7
Segmental Duplications and Genetic Disease
genomic organization and deletion endpoint analysis. Human
Molecular Genetics 9 (4): 489–501.
Sharp AJ, Hansen S, Selzer RR, et al. (2006) Discovery of previously
unidentified genomic disorders from the duplication architecture of
the human genome. Nature Genetics 38 (9): 1038–1042.
Shaw CJ and Lupski JR (2005) Non-recurrent 17p11. 2 deletions
are generated by homologous and non-homologous mechanisms.
Human Genetics 116 (1): 1–7.
Shchelochkov OA, Cheung SW and Lupski JR (2010) Genomic and
clinical characteristics of microduplications in chromosome 17.
American Journal of Medical Genetics Part A 152 (5): 1101–1110.
She X, Cheng Z, Zöllner S, Church D and Eichler EE (2008) Mouse
segmental duplication and copy number variation. Nature Genetics
40 (7): 909–914.
Timmerman V, Strickland AV and Züchner S (2014) Genetics of
Charcot-Marie-Tooth (CMT) Disease within the frame of the
Human Genome Project success. Genes 5 (1): 13–32.
Ullmann R, Turner G, Kirchhoff M, et al. (2007) Array CGH iden-
tifies reciprocal 16p13.1 duplications and deletions that predis-
pose to autism and/pr mental retardation. Human Mutation 28 (7):
23–32.
Van Bon BW, Mefford HC, Menten B, et al. (2009) Further delin-
eation of the 15q13 microdeletion and duplication syndromes: a
clinical spectrum varying from non-pathogenic to a severe out-
come. Journal of Medical Genetics 46 (8): 511–523.
Van Bon BW, Balciuniene J, Fruhman G, et al. (2011) The pheno-
type of recurrent 10q22q23 deletions and duplications. European
Journal of Human Genetics 19 (4): 400–408.Vergés L, Vidal F, Geán E, et al. (2017) An exploratory study of pre-
disposing genetic factors for DiGeorge/velocardiofacial syndrome.
Scientific Reports 7: 40031.
Vissers LE and Stankiewicz P (2012) Microdeletion and microdupli-
cation syndromes. In: Feuk L. (eds) Genomic Structural Variants,
Methods and Protocols, pp. 29–75. Clifton, NJ: Springer.
Zhang F, Khajavi M, Connolly A, et al. (2009) The DNA replication
FoSTeS/MMBIR mechanism can generate genomic, genic and
exonic complex rearrangements in humans. Nature Genetics 41
(7): 849–853.
Further Reading
Dennis M and Eichler EE (2016) Human adaptation and evolution
by segmental duplication. Current Opinion in Genetics & Devel-
opment 41: 44–52.
Girirajan S, Campbell C and Eichler EE (2011) Human copy number
variation and complex genetic disease. Annual Review of Genetics
45 (1): 203–226.
Sheridan MB, Kato T, Haldeman-Englert C, et al. (2010) A
palindrome-mediated recurrent translocation with 3: 1 meiotic
nondisjunction: the t(8; 22)(q24. 13; q11. 21). The American Jour-
nal of Human Genetics 87 (2): 209–218.
Watson C, Marques-Bonet T, Sharp A and Mefford H (2014) The
genetics of microdeletion and microduplication syndromes: an
update. Annual Review of Genomics and Human Genetics 15 (1):
1–30.
Zhang F, Gu W, Hurles ME and Lupski JR (2009) Copy number
variation in human health, disease, and evolution. Annual Review
of Genomics and Human Genetics 10: 451–481.
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