Segmental Duplications:
A Source of Diversity,
Evolution and Disease
Claudia R Catacchio, University of Bari Aldo Moro, Bari, Italy
Giorgia Chiatante, University of Bari Aldo Moro, Bari, Italy
Fabio Anaclerio, University of Bari Aldo Moro, Bari, Italy
Mario Ventura, University of Bari Aldo Moro, Bari, Italy
Genome mutations represent a source of variability
on which selective pressure acts: negative changes
are purged from the populations, whereas posi-
tive and neutral changes may be fixed. Segmental
duplications (SDs) in the human genome trig-
ger mutations such as structural rearrangements
(duplications, deletions, inversions and transloca-
tions), thus playing a crucial role in human disease
and genome evolution. Several human diseases
(genomic disorders) are caused by non-allelic
homologous recombination (NAHR) between
highly similar SDs, as well as gene-containing SDs
were crucial to survival and adaptation of human
species during evolution. Moreover, both from a
pathological and an evolutionary point of view,
SDs represent critically important regions for acen-
tric fragment rescue during neocentromerization
process. In this light, disease and evolution can be
considered as ‘two sides of the same coin’, where
the coin represents the SD-mediated chromosomal
rearrangements.
Introduction
Genome duplication (GD) during evolution has played a criti-
cal role in increasing genome size and complexity. Since GD
discovery, 40 years ago, our knowledge and understanding of
the evolution of genes and genomes has hugely increased. Event
of duplications can involve full genome (Ohno et al., 1968) or
eLS subject area: Evolution & Diversity of Life
How to cite:
Catacchio, Claudia R; Chiatante, Giorgia; Anaclerio, Fabio; and
Ventura, Mario (January 2015) Segmental Duplications: A
Source of Diversity, Evolution and Disease. In: eLS. John Wiley &
Sons, Ltd: Chichester.
DOI: 10.1002/9780470015902.a0020838.pub2
eLS © 2015, John Wiley & Sons, Ltd. www.els.net
Advanced article
Article Contents
• Introduction
• Segmental Duplications and Copy Number
Variations
• Impact of Segmental Duplications on the Human
Genome
• Segmental Duplications and Evolution
• Conclusions
• Acknowledgments
Online posting date: 27th January 2015
narrow regions can be expanded, thus increasing the copy num-
ber of genes imbedded in them. In the latter case, the involved
sequences are generally named SDs.
SDs represent a ‘new’ genomic repetitive element class, com-
monly defined as highly identical duplicated DNA fragments
greater than 1 kb and distinguished from any other classic repet-
itive element such as LINEs, by the absence of any recurrent
element in them. Most of them show intersperse, rather than tan-
dem organization. SDs in humans do not cluster but are rather
enriched on regions such as pericentromeres and subtelomeres
and few chromosomes, such as 7, 15, 16, 17 and 22, thus creating
‘hot spots’ of NAHR events (Girirajan et al., 2010).
Since the discovery of SDs, a lot of data have been produced
on their involvement in genomic disorders and evolution. In par-
ticular, regions of, or enriched in, SDs, because of their high
identity and wide distribution in the genomes, are favourite sites
of copy number polymorphisms, genomic disorders and evolu-
tionary breakpoints. Rearrangements may create new genes with
different spatial and temporal expression, thus creating and dif-
ferentiating gene pools in the cells or organisms. In this light, SDs
are great substrates for genomic variability and represent excep-
tional examples of ‘two sides of the same coin’ effect: disease
versus evolution. In this article, we focus on how SDs in human,
primate and mammalian genomes have exerted the important role
in genome plasticity (See also: Segmental Duplications and
Their Role in the Evolution of the Human Genome).
Segmental Duplications and Copy
Number Variations
The high similarity shared between SDs creates ideal conditions
for NAHR leading to chromosomal rearrangements (CRs). The
outcome and impact of these NAHR events mainly depend on the
size, percentage of identity and orientation of the paralogous SDs
and the recombination activity of the involved region. Indeed,
structural polymorphisms and recurrent pathogenic human rear-
rangements are mostly caused by unequal crossover of paired,
≥10 kb, ≥95% identical, 50 kb–10 Mb distant SDs (Stankiewicz,
2010).
Recently, duplicated genomic regions, roughly 12% of the
human genome, have been reported as highly polymorphic in
1
 Segmental Duplications: A Source of Diversity, Evolution and Disease
NAHR
Time
Figure 1 Model representing the formation of copy number variants
(CNVs, striped rectangles) and segmental duplications (SDs, solid colour
rectangles). Regions harbouring highly identical SDs (green/blue rectangles)
undergo NAHR. If not negatively selected, the created microdeletions and
microduplications (rectangles with star) represent new CNVs and can be
transmitted from generation to generation. The frequency of the duplicated
sequence in the population may increase until it becomes fixed, creating a
new SD (turquoise rectangle).
copy number in the normal population [copy number vari-
ants (CNVs)], thus increasing the complexity of the human
genome (Zhou and Mishra, 2005). CNVs have been considered
as the unsettled, polymorphic form of SDs, and SDs correspond
to CNVs that have been fixed in the human population (see
Figure 1) (Kim et al., 2008). However, at the moment, com-
plete repertoires distinguishing between SDs and CNVs do not
exist and some duplications annotated as SDs may not be fixed
in the population, being rather common CNVs. For this reason,
current efforts to sequence individual human genomes, such as
the 1000 Genomes Project are focused on bringing greater cer-
tainty about which SDs are fixed and which are polymorphic,
revealing significant differences on genomic disorders prevalence
among different human populations (Mulle et al., 2010) (See
also: Segmental Duplications and Genetic Disease).
2 eLS © 2015, John Wiley & Sons, Ltd. www.els.net
Impact of Segmental Duplications
on the Human Genome
SDs can mediate unbalanced (microdeletions and microduplica-
tions) and balanced (translocations and inversions) genomic rear-
rangements that in turn can increase the susceptibility to human
disease or, at worst, directly engender a clinical phenotype (Wain
et al., 2009).
The role of SDs in the susceptibility to infectious and inflam-
matory diseases has been demonstrated, as a result of the fact
that regions of SDs are enriched in genes involved in immune
response. One of the first studies to provide precedents for a
link between SD distribution and variability in the phenotypic
response to disease showed that the variation of a CCL3L1
(a potent human immunodeficiency virus-1 (HIV-1)-suppressive
chemokine and ligand for the HIV co-receptor CCR5) copy
number is significantly associated with considerably enhanced
HIV/acquired immunodeficiency syndrome (AIDS) susceptibil-
ity. In particular, evidence of lower CCL3L1 copy number among
the HIV-positive individuals compared with HIV-negative sub-
jects suggested that people who carry a CCL3L1 copy number
lower than the population average have higher risk of HIV infec-
tion (Gonzalez et al., 2005).
Recent studies have provided evidence for the involvement of
specific CNVs also in cancer susceptibility. A common CNV
at chromosome 1q21.1 contributes to neuroblastoma suscepti-
bility, by altering the expression of the NBPF23 gene (Diskin
et al., 2009). Similarly, Marotta et al. (2012) hypothesized that a
large (300 kb), complex block of duplicated segments (sequence
similarity >90%) was involved in the initiating mechanisms of
ERBB2 amplification, found in breast cancers and associated with
advanced stages, recurrence and poor patient survival. This sug-
gests that deletion polymorphisms of such repeated sequences
might affect the initiation and thus the frequency of ERBB2
amplification.
Microdeletions and microduplications
There are numerous examples of SD-mediated polymorphic CNV
formation but when the region changing copy number contains
dosage-sensitive or imprinted genes, CNVs are responsible for
the genomic alterations underlying genetic syndromes (genomic
disorders) (see Table 1).
As deletions and duplications caused by NAHR are recip-
rocal events, the assumption that their rates were similar has
been a common misconception for a long time. Nevertheless,
recently, it has been showed that at least in male meiosis, dele-
tions occur approximately twice as frequently as duplications on
autosomes (Turner et al., 2008). Up to 2012, 211 microdeletion
versus 79 microduplication syndromes had been reported. Only
for 56 of these loci (21%), reciprocal/co-localising microdeletion
and microduplication syndromes (MMSs) are described (Weise
et al., 2012). Moreover, it is a general observation that microdu-
plications result in a milder or no clinical phenotype compared
to the reciprocal microdeletions, as shown by duplications ver-
sus deletions of 22q11.2 (Ensenauer et al., 2003) and 1q21.1
(Brunetti-Pierri et al., 2008).
 Segmental Duplications: A Source of Diversity, Evolution and Disease

Table 1 Recurrent SD-mediated microdeletion/duplications

Locus Microdeletion-associated MIM code Locus Microduplication-associated MIM code
syndromes syndromes
1q21.1 Chromosome 1q21.1 deletion 612474 1q21.1 Chromosome 1q21.1 duplication 612475
syndrome, 1.35-mb syndrome
2q21.1 Attention deficit hyperactivity 612311 2q21.1 NI –
disorder, susceptibility to
Attention deficit hyperactivity 143465 NI –
disorder (ADHD)
3q29 3q29 deletion syndrome 609425 3q29 3q29 microduplication syndrome 611936
7q11.23 Williams-Beuren syndrome 194050 7q11.23 Williams-Beuren region 609757
(WBS) duplication syndrome
10q23.3 Prostate cancer 176807 10q23.3 NI –
15q11-q13 Angelman syndrome (if 105830 15q11-q13 15q11-q13 duplication syndrome 608636
maternally derived)
Prader-Willi syndrome (if 176270
paternally derived)
15q13.3 15q13.3 deletion syndrome 612001 15q13.3 NI –
Schizophrenia 13; sczd13 613025 15q13.3 NI –
15q24 15q24 deletion syndrome 613406 15q24 NI –
16p11.2 Chromosome 16p11.2 deletion 611913 16p11.2 Chromosome 16p11.2 614671
syndrome, 593 kb duplication syndrome
16p11.2-p12.2 16p11.2p12.2 deletion syndrome 613604 16p11.2p12.2 NI –
16p12.1 Chromosome 16p12.1 deletion 136570 16p12.1 NI –
syndrome, 520-KB
17p11.2 Smith-Magenis syndrome (SMS)a 182290 17p11.2 Potocki-Lupski syndrome 610883
(PTLS)
17p12 Hereditary neuropathy with 162500 17p12 Charcot–Marie–Tooth type 1A 604563
liability to pressure palsies (CMT1A)
syndrome (HNPP)
17q11.2 Neurofibromatosis type 1 613675 17q11.2 NI –
microdeletion syndrome
(NF1)
17q12 Chromosome 17q12 deletion 614527 17q12 Chromosome 17q12 duplication 614526
syndrome syndrome
17q21.31 Koolen-De Vries syndrome 610443 17q21.31 17q21.31 duplication syndrome 613533
22q11.2 DiGeorge syndrome (DGS) 188400 22q11.2 22q11.2 duplication syndrome 608363
Velocardiofacial syndrome 192430
(VCFS)
Chromosome 22q11.2 deletion 611867
syndrome, distal
Xp11.22-p11.23 NI – Xp11.23-p11.22 Chromosome Xp11.23-p11.22 300801
duplication syndrome
Xp22 X-linked ichthyosis 308100 Xp22 NI –
NI, not identified.
a The first evidence of a genomic disorder in a chimpanzee with features resembling to Smith-Magenis syndrome (see text for details).

Recent studies have consistently coupled SD-mediated
NAHR causing genomic structural rearrangements to com-
plex phenotypes associated to mental illnesses, such as autism
spectrum disorders (ASD), schizophrenia, mental retarda-
tion and intellectual disability (Beckmann et al., 2007) (see
Table 1).
The genotype/phenotype correlation and variability in
penetrance and expression regarding the genetics of mental
illnesses mainly depend on the role of genes contained in the
deleted/duplicated interval. However, the parental origin of the
CNV, as well as the presence of variations in the wild-type allele,
has also been shown to play an important role. Preliminary
evidence has also been provided on the contribution of genes
or expressed pseudogenes contained in the SDs (besides those
located in the single region between the SD blocks) to the clinical
phenotype (Merla et al., 2010).

eLS © 2015, John Wiley & Sons, Ltd. www.els.net 3

 Segmental Duplications: A Source of Diversity, Evolution and Disease

The knowledge on the basic features of the SDs mediating
NAHR events causing genomic disorders allowed the utiliza-
tion of an inverse strategy to detect genomic regions involved
in the aetiology of mental retardation: a map of potential ‘rear-
rangement hotspots’ in the human genome has been generated,
highlighting regions of genomic instability. On the basis of
this map, several genomic abnormalities on 17q21.31, 1q21.1,
15q13.1–13.3 and 15q24.1–q24.3 were detected using a cus-
tomized array (Sharp et al., 2006).
Inversions and translocations
Inversions generated by meiotic or mitotic intrachromatidic mis-
alignment between the inverted homologous SDs can be consid-
ered a benign polymorphism because carriers are phenotypically
normal (Tam et al., 2008). However, polymorphic chromoso-
mal microinversions have been found as putative susceptibil-
ity or resistance variants for some of the previously mentioned
MMSs. Indeed, these structural events can predispose or pro-
tect to further genomic rearrangements, enhancing or lowering
the disease risk in carriers. Two extended haplotypes, designated
H1 and H2, have been identified on 17q21.31 hotspot region,
with the H2 being inverted compared to the reference genome.
The inverted haplotype is rare in Africans, almost absent in East
Asians but is found at a frequency of 20% in Europeans. The 900
kb inversion haplotype is the only one that carries SD in direct
orientation at both breakpoints of the 17q21.31 microdeletion
region and therefore has a tendency to undergo NAHR leading
to the 17q21.31 microdeletion syndrome (MIM 610433) (Itsara
et al., 2012). These results bear striking similarity to another
region of the human genome: heterozygosity for a polymorphic
∼2 Mb chromosomal microinversion in 7q11.23 is thought to
lead to abnormal meiotic pairing and therefore an increased sus-
ceptibility to unequal recombination causing the William-Beuren
syndrome deletion. Similarly, paracentric microinversions have
been found as putative susceptibility variants for other recurrent
genomic rearrangements, such as the deletions causing Angelman
and Sotos syndromes (Cusco et al., 2008).
NAHR between interchromosomal SDs (i.e. on non-
homologous chromosomes) results in chromosomal translo-
cations (Stankiewicz and Lupski, 2002) whose stability depends
on the orientation of the SDs and the chromosome arms involved.
Only when SDs map in the same orientation and on the same
chromosome arms (i.e. p-arm of one chromosome versus the
p-arm of the other) or they show opposite orientation on different
chromosome arms (i.e. p-arm from one chromosome versus
q-arm of the other), the interchromosomal NAHR produces
stable, monocentric reciprocal translocation chromosomes. In
contrast, SDs in opposite orientation on the same chromosome
arms or those in the same orientation on opposite chromosome
arms are predicted to result in either unstable dicentric or acen-
tric chromosomes (see Figure 2) (Ou et al., 2011). It has been
demonstrated that two pairs of the many olfactory receptor
(OR) gene clusters located close to each other, on chromosomes
4p16 and 8p23, are involved in the origin of the t(4;8)(p16;p23)
translocation by mediating interchromosomal NAHR (Giglio
et al., 2002). Likewise, from 10% to 20% of the translocations
between chromosomes 9 and 22 occurred between the 76 kb
interchromosomal SDs that are located at the centromere proxi-
mal to ABL gene on chromosome 9 and at the centromere distal
to BCR gene on chromosome 22, t(9;22)(q34;q11) creating the
BCR/ABL fusion gene that is the underlying aetiology of chronic
myeloid leukaemia (CML) (Albano et al., 2010). Recently, it
has been provided further molecular evidence to support NAHR
between interchromosomal SDs as a potential major mechanism
for recurrent reciprocal translocations (Ou et al., 2011).
The understanding of the NAHR mechanism combined with
the availability of the human genome sequence (International
Human Genome Sequencing Consortium, 2004) paved the way
to massive in silico analyses to predict hotspots for genomic

Stable reciprocal
Unstable reciprocal translocations
translocations

p q q p

p q p q

(a) (c)

q p q p

p q q p

(b) (d)

Figure 2 Outcomes of interchromosomal NAHR mediated by SDs. Non-homologous chromosomes are coloured differently with the centromeres shown
as black box. Blue and yellow boxes indicate highly identical segmental duplications and arrows indicate their orientation. Stable reciprocal translocations
are originated by NAHR between interchromosomal SDs located on the same chromosomal arms (i.e. q-arm to q-arm) directly orientated (a) or on different
chromosomal arms with inverted orientation (i.e. p-arm to q-arm) (b). Conversely, SDs located on the same chromosomal arms in inverted orientation (c)
or on different chromosomal arms directly orientation (d) would lead to unstable dicentric and acentric chromosomes, resulting in chromosome breakage
and loss, respectively.

4 eLS © 2015, John Wiley & Sons, Ltd. www.els.net

 Segmental Duplications: A Source of Diversity, Evolution and Disease
instability that may be prone to recurrent translocations, identi-
fying 1902 sequences that correspond to interchromosomal SDs
of >5 kb in length and >94% DNA sequence identity. Inter-
estingly, some of the potential interchromosomal NAHR pairs
represent olfactory receptor gene repeats. Some of the predicted
recurrent translocations, however, may be underrepresented as
derivative chromosomes with longer segments of imbalance are
more likely to be incompatible with life. High-resolution genome
analyses of additional balanced and unbalanced translocations
will be required to further confirm the utility of this ‘recurrent
translocation map’ (Ou et al., 2011).
Segmental Duplications
and Evolution
To date, sequencings of 12 primate genomes have been pub-
lished including human (International Human Genome Sequenc-
ing Consortium, 2001), chimpanzee (Chimpanzee Sequencing
and Analysis Consortium, 2005), gorilla (Scally et al., 2012),
orangutan (Locke et al., 2011), gibbon (Carbone et al., 2014),
marmoset (Consortium, 2014) and macaque (Rhesus Macaque
Genome Sequencing and Analysis Consortium, 2007). Moreover,
36 other mammalian genomes have been sequenced at various
levels of coverage; most of them have been resolved from whole
genome shotgun (WGS) approaches using different technologies
such as classical capillary methods and next-generation sequenc-
ings (NGS).
Despite extensive progress in genome sequencing, SDs are
complex parts of genomes to be assembled mostly due to their
repetitive nature, similarity and mosaic organization, thus rep-
resenting a challenging task in finishing genome assemblies.
For this reason, most of the research has been focused in
finding new methods to discover and genotype SDs including
experimental approaches using hybridization-based microarrays,
single-molecule analyses and sequencing-based computational
approaches. Noteworthy, different experimental methods and
computational analyses of NGS data sets applied to the same
genome show low levels of overlap showing that there does not
exist a single approach to detect all the SDs at once (see Table 2)
(Alkan et al., 2011).
Recent comparative works, using multiple genomic
approaches, have shown that human and great ape lineages
are particularly enriched for interspersed duplications with a
suggested burst occurring in the common ancestor of the humans
and African great apes, in contrast to the hominid slowdown of
single base-pair mutations (Marques-Bonet et al., 2009). Excep-
tionally, in gorilla, events of duplicative transpositions created
complex pattern of SDs unique to this lineage and syntenic
neither to human nor to chimpanzee (Ventura et al., 2011).
When compared to other sequenced primates such as marmoset
and gibbon and to mammalian genomes, human and great ape
SDs tend to be more complex, more interspersed and bigger.
In particular, in mammals, SDs are mostly organized in local
tandem duplication clusters as opposed to duplicative transpo-
sitions to new locations, and the distribution is not homoge-
neous, showing a preference for pericentromeric and subtelom-
eric regions (Clop et al., 2012). Despite the simpler structure
eLS © 2015, John Wiley & Sons, Ltd. www.els.net
of SDs in mammals, breed-specific differences have been iden-
tified in mammals such as in cow (Nelore breed) where excellent
gene candidates (CATHL4, ULBPT7 and KRTAP9-2) embedded
in SDs have been reported for pathogen and parasite resistance
(Bickhart et al., 2012).
Massive sequencing at high coverage of 97 great ape individ-
uals has been recently used to create a comprehensive assess-
ment of fixed deletions and duplications between humans and
great apes. In particular, demographic effects have been hypoth-
esized as main contributors in larger gene-rich deletions in the
chimpanzee lineage, one of them being responsible for the first
reported case of a Smith-Magenis-like syndrome phenotype in
chimpanzee (see Table 1) (Sudmant et al., 2013).
Many efforts have been focused on understanding the struc-
ture and organization of human SDs and their formation. To
date, SDs in humans have resulted in organized patchworks
of several regions arranged around “core” elements that usu-
ally show greater EST and exon density when compared to
flanking SDs (see Figure 3). In several primates, the cores
have been copied to other locations in the genome, thus cre-
ating a totally different set of SDs all centred on the same
core duplication (Marques-Bonet and Eichler, 2009). In par-
ticular, the genomic distribution of great ape SDs is highly
non-random with the presence of ancestral duplications being a
strong predictor of “new”, lineage-specific events. For example,
45% of human–chimpanzee shared duplications map within 5 kb
of SDs shared among human–chimpanzee–orangutan, whereas
31% of human–chimpanzee–orangutan duplications map adja-
cent to human–chimpanzee–orangutan–macaque duplications.
These observations emphasize that unique sequences flanking
more ancient duplications have a much higher probability to
duplicate and the duplication process itself is not random. This
phenomenon is named duplication shadowing (Cheng et al.,
2005).
Neocentromeres and fusion genes
As previously reported for human genomic disorders in the
species evolution, SDs represent a source of structural novelty
triggering CRs that play a crucial role in neocentromere forma-
tion and create new genes by gene shuffling.
Comparative studies on chromosome 15 (low copy repeats,
LCR15) have highlighted specific chromosomal duplications as
preferential sites of chromosomal breakage and rearrangement
and of recurrent evolutionary events of expansion and local dupli-
cation. Noteworthy, the same duplications that resulted trigger
not only the CR through NAHR but also SD accumulation at
specific loci in response to a “feedback mechanism” to the chro-
mosomal breakage. After the evolutionary breakage, additional
DNA material transposed from other loci to recover the damage
caused by the breakage, thus creating local duplications (Gian-
nuzzi et al., 2013a). Breakpoints of several evolutionary inver-
sions and translocations have been recently associated to SDs.
Often, the presence of SDs at these rearrangement breakpoints
prevents them to be resolved at the base-pair level (Ventura et al.,
2011; Dennis et al., 2012).
CRs mediated by SDs, such as interstitial deletions and inver-
sions, can result in the formation of a chromosomal fragment
5
6
Table 2 Comparison of SD discovery methods.
Method Type Rearrangements Time Throughput Cost Advantages Limitations
(days)
Deletions Duplications Balanced
Microarray CGH array • • 2–3 High Low Complex phenotypes Lack of standardisation, no
SNP array • • analysis, multiple information on the
breakpoints definition localisation
FISH Interphase-nuclei FISH • • • 2–3 Low Medium Copy number prediction/ Low breakpoint resolution
Metaphases FISHa • • • validation, chromosomal
localization of the
rearrangementa
PCR-based MLPA • • <1 Medium Low Low amount of starting Small number of analysable
Segmental Duplications: A Source of Diversity, Evolution and Disease

MAPH • • material, high feasibility loci, sequence availability

Sequencing- Read-pair technologiesw • • • 2–7b High High Copy number prediction, High storage space and
based Read-depth methods • • high breakpoint resolution, computing capacity
Split-read approaches • • whole-genome analysis

eLS © 2015, John Wiley & Sons, Ltd. www.els.net

Sequence assembly • • •
a Type-specific advantages.
b Depending on the platform used (MiSeq, HiSeq or newer).
 Segmental Duplications: A Source of Diversity, Evolution and Disease
Duplication
CD
event 1
Time
Duplication
event 2
Time
Duplication
event 3
Figure 3 Core duplicon model for segmental duplication formation.
Duplicative transposition (Duplication event 1) creates a copy of the ancestral
locus (core duplicon, CD, in green) to a new locus on the same chromo-
some, thus generating an intrachromosomal duplication. A following event
of duplicative transposition (Duplication event 2) involving the CD and flank-
ing single sequences (empty orange squares) moves these regions to a new
locus on a non-homologous chromosome, thus creating interchromosomal
duplications. This step results in an increase of the segmental duplication
size now composed by the CD (filled green square) plus flanking sequences
(filled orange squares). An additional round of duplication (Duplication event
3) involving further flanking single sequences may create bigger and more
complex intra- or interchromosomal segmental duplications. The new par-
alogous sequences share high similarity and can now promote non-allelic
homologous recombination. These events take place at multiple points dur-
ing the speciation process (before and after) generating both lineage-specific
and shared duplication blocks between closely related species.
lacking the centromere. If a new ectopic centromere (neocen-
tromere) devoid of alpha satellite is formed, this fragment can be
inherited as supernumerary marker chromosome during cell divi-
sion. Several cases of human neocentromeres (HNs) have been
reported (Marshall et al., 2008).
The enrichment in SDs described in pericentromeric regions
and ancestral pericentromeric regions can either represent a tem-
poral evolutionary consequence of centromere positioning or SDs
might precede the neocentromere formation and play an active
role in the new centromere repositioning and function. Four of
eLS © 2015, John Wiley & Sons, Ltd. www.els.net
six evolutionary new human centromeres (ENCs), on chromo-
somes 6, 11, 15 and 21, are among the highest in SD content (She
et al., 2004), underlining how SD enrichment in pericentromeric
regions is not only a temporal consequence of centromere posi-
tioning.
HNs give the possibility to study the connection between
SDs and neocentromerization without the time-action that con-
trariwise, operating over millions of years from centromere
positioning to nowadays, have changed the organization of peri-
centromeric regions in ENCs. Since 1993, 15 HNs have been
described on human region 15q24–26, therefore considered a
hotspot of neocentromerization. Chromosomes 14 and 15 derived
from an ancestral chromosome after a fission event. After the fis-
sion on chromosome 15, the ancestral centromere was inactivated
and a new centromere emerged.
Comparative studies have mapped the ancestral centromeric
locus to 15q24–26, a chromosomal region enriched in SDs. The
evidence that this region still preserves its ability to act as a cen-
tromere, despite both the inactivation occurring at about 25 mya
followed by rapid loss of alphoid sequences, suggests that SDs
play a crucial role in triggering centromeric positioning (Ventura
et al., 2003).
Besides the role in changing the structural organization of a
genome mediating CRs, SDs play an essential role in remodelling
transcriptionally active parts of the genome through both full-size
or partial duplication of genes.
While full-size duplication of genes is the basis for gene family
creation, partial duplication or deletion creates the potential for
new chimeric genes (Francis et al., 2012).
Round of duplications were responsible for the creation of the
BTNL gene family whose members, located on human chromo-
somes 1, 5 and 6, are involved in immune response. On chro-
mosome 5, the close proximity of BTNL8 and BTNL3 genes is
the result of a tandem duplication. An NAHR event between
these highly identical duplications is responsible of a 56 kb
CNV deletion from BTNL8 and BTNL3 that creates the new
chimeric BTNL8*3 fusion gene. It has been demonstrated that
BTNL8*3del allele is responsible for the different regulation of
BTNL9 and other genes involved in immune response and can-
cer. The different stratification of this CNV in the major ethnical
continental groups is the corroboration that CNVs and SDs play
a fundamental role in adaptive evolution, increasing variability in
expression levels (Aigner et al., 2013).
The link between gene duplication and evolution has been
recently demonstrated by the human SRGAP2 gene. This gene is
extremely conserved, with single copy in mammals and specifi-
cally duplicated in humans. Gene expression studies showed that
paralogs (SRGAP2B, C and D) show similar broad patterns of
expression, including expression in the developing human foetal
brain concurrently with SRGAP2A (ancestral gene) and often
display higher expression in multiple regions of the human cor-
tex and cerebellum when compared to other tissues including
lung, kidney and testis. In particular, it has been shown that
SRGAP2C encodes a functional protein antagonist of SRGAP2A
and is among the most fixed human-specific duplicate genes.
Very interestingly, comparative-sequencing studies showed that
the duplication occurred 2–3 mya at the transition from Australo-
pithecus to Homo, at the same time of the neocortex expansion
7
 Segmental Duplications: A Source of Diversity, Evolution and Disease
and the use of stone tools. Overall, these data strongly support a
role of these genes in human brain evolution (Dennis et al., 2012).
SDs may influence gene expression by moving regulatory
elements, such as promoters, close to genes. An example is
the LRRC37 gene family, where its expression evolved from a
testis-specific to a more complex pattern because of the increase
in gene copy number and the juxtaposition of promoters (Gian-
nuzzi et al., 2013b). The acquisition of new promoters via SD
formation in the common ancestor of human and great apes was
also responsible for the ‘resurrection’ of the IRGM gene other-
wise not expressed due to an ALU retrotransposition disrupting
the open reading frame in the early stage of primate evolution
(Bekpen et al., 2009).
Conclusions
Since their discovery, there has been growing interest on the struc-
ture, distribution and influence of SDs on human and mammalian
genome plasticity, but many questions are still open. For example,
what is their role in mediating structural rearrangements responsi-
ble for genomic disorders? What are the structures and functions
of the genes created by SD shuffling?
Although massive sequencing has helped in defining the loca-
tion and distribution of SDs in the analyzed genomes, still SDs
are difficult to be assembled, thus remaining ambiguous regions
of human and mammalian genomes that need systematic analy-
ses to be accurately decoded in terms of genotype, copy number
content and structure.
Additional comparative high-quality sequences of SDs among
primates and mammals will provide useful insights into their
diffusion and diversification in different lineages and into the way
selection shapes these regions of the genome, thus explaining the
dual effect (genomics disorders vs. evolution) that SDs have on
the human genome.
It is now clear that SDs represent an impressive source of
genomic variation, essential from an evolutionary point of view.
They balance negative selection of disease-causing microdele-
tions and microduplications versus positive selection of newly
minted gene families embedded in core duplications and dis-
tributed to new locations. Most of these genes, both in humans
and in mammals, are involved in immunity and are critically
important for individual/species survival. Despite their impor-
tance, very little is known about the role of SDs and CNVs in
the mechanisms for adaptation and diversification of responses
for both host and pathogen. Gaining more insights on SDs is then
necessary to fully understand the genetics and biology of infec-
tious diseases pathogenesis.
Acknowledgments
We thank Dr. Francesca Antonacci for valuable comments and
help in the preparation of this manuscript. The authors declare no
conflicts of interest. Our work is supported by Futuro in Ricerca
2010 (RBFR103CE3).
8 eLS © 2015, John Wiley & Sons, Ltd. www.els.net
References
Aigner J, Villatoro S, Rabionet R, et al. (2013) A common
56-kilobase deletion in a primate-specific segmental duplication
creates a novel butyrophilin-like protein. BMC Genetics 14: 61.
Albano F, Anelli L, Zagaria A, et al. (2010) Genomic segmental
duplications on the basis of the t(9;22) rearrangement in chronic
myeloid leukemia. Oncogene 29: 2509–2516.
Alkan C, Coe BP and Eichler EE (2011) Genome structural variation
discovery and genotyping. Nature Reviews. Genetics 12: 363–376.
Beckmann JS, Estivill X and Antonarakis SE (2007) Copy number
variants and genetic traits: closer to the resolution of phenotypic to
genotypic variability. Nature Reviews. Genetics 8: 639–646.
Bekpen C, Marques-Bonet T, Alkan C, et al. (2009) Death and res-
urrection of the human IRGM gene. PLoS Genetics 5: e1000403.
Bickhart DM, Hou Y, Schroeder SG, et al. (2012) Copy number vari-
ation of individual cattle genomes using next-generation sequenc-
ing. Genome Research 22: 778–790.
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: 1466–1471.
Carbone L, Alan Harris R, Gnerre S, et al. (2014) Gibbon genome
and the fast karyotype evolution of small apes. Nature 513 (7517):
195–201.
Cheng Z, Ventura M, She X, et al. (2005) A genome-wide comparison
of recent chimpanzee and human segmental duplications. Nature
437: 88–93.
Chimpanzee Sequencing and Analysis Consortium (2005) Initial
sequence of the chimpanzee genome and comparison with the
human genome. Nature 437: 69–87.
Clop A, Vidal O and Amills M (2012) Copy number variation in the
genomes of domestic animals. Animal Genetics 43: 503–517.
Consortium (2014) The common marmoset genome provides insight
into primate biology and evolution. Nature Genetics 46: 850–857.
Cusco I, Corominas R, Bayes M, et al. (2008) Copy number variation
at the 7q11.23 segmental duplications is a susceptibility factor for
the Williams-Beuren syndrome deletion. Genome Research 18:
683–694.
Dennis MY, Nuttle X, Sudmant PH, et al. (2012) Evolution of
human-specific neural SRGAP2 genes by incomplete segmental
duplication. Cell 149: 912–922.
Diskin SJ, Hou C, Glessner JT, et al. (2009) Copy number variation
at 1q21.1 associated with neuroblastoma. Nature 459: 987–991.
Ensenauer RE, Adeyinka A, Flynn HC, et al. (2003) Microdu-
plication 22q11.2, an emerging syndrome: clinical, cytogenetic,
and molecular analysis of thirteen patients. American Journal of
Human Genetics 73: 1027–1040.
Francis NJ, McNicholas B, Awan A, et al. (2012) A novel hybrid
CFH/CFHR3 gene generated by a microhomology-mediated dele-
tion in familial atypical hemolytic uremic syndrome. Blood 119:
591–601.
Giannuzzi G, Pazienza M, Huddleston J, et al. (2013a) Hominoid fis-
sion of chromosome 14/15 and the role of segmental duplications.
Genome Research 23: 1763–1773.
Giannuzzi G, Siswara P, Malig M, et al. (2013b) Evolutionary
dynamism of the primate LRRC37 gene family. Genome Research
23: 46–59.
 Segmental Duplications: A Source of Diversity, Evolution and Disease
Giglio S, Calvari V, Gregato G, et al. (2002) Heterozygous submicro-
scopic inversions involving olfactory receptor-gene clusters medi-
ate the recurrent t(4;8)(p16;p23) translocation. American Journal
of Human Genetics 71: 276–285.
Girirajan S, Rosenfeld JA, Cooper GM, et al. (2010) A recurrent
16p12.1 microdeletion supports a two-hit model for severe devel-
opmental delay. Nature Genetics 42: 203–209.
Gonzalez E, Kulkarni H, Bolivar H, et al. (2005) The influence of
CCL3L1 gene-containing segmental duplications on HIV-1/AIDS
susceptibility. Science 307: 1434–1440.
International Human Genome Sequencing Consortium (2001) Ini-
tial sequencing and analysis of the human genome. Nature 409:
860–921.
Itsara A, Vissers LE, Steinberg KM, et al. (2012) Resolving
the breakpoints of the 17q21.31 microdeletion syndrome with
next-generation sequencing. American Journal of Human Genetics
90: 599–613.
Kim PM, Lam HY, Urban AE, et al. (2008) Analysis of copy num-
ber variants and segmental duplications in the human genome:
Evidence for a change in the process of formation in recent evo-
lutionary history. Genome Research 18: 1865–1874.
Locke DP, Hillier LW, Warren WC, et al. (2011) Comparative
and demographic analysis of orang-utan genomes. Nature 469:
529–533.
Marotta M, Chen X, Inoshita A, et al. (2012) A common
copy-number breakpoint of ERBB2 amplification in breast cancer
colocalizes with a complex block of segmental duplications. Breast
Cancer Research 14: R150.
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, Kidd JM, Ventura M, et al. (2009) A burst of
segmental duplications in the genome of the African great ape
ancestor. Nature 457: 877–881.
Marshall OJ, Chueh AC, Wong LH and Choo KH (2008) Neocen-
tromeres: new insights into centromere structure, disease devel-
opment, and karyotype evolution. American Journal of Human
Genetics 82: 261–282.
Merla G, Brunetti-Pierri N, Micale L and Fusco C (2010) Copy
number variants at Williams-Beuren syndrome 7q11.23 region.
Human Genetics 128: 3–26.
Mulle JG, Dodd AF, McGrath JA, et al. (2010) Microdeletions of
3q29 confer high risk for schizophrenia. American Journal of
Human Genetics 87: 229–236.
Ohno S, Wolf U and Atkin NB (1968) Evolution from fish to mam-
mals by gene duplication. Hereditas 59: 169–187.
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: 33–46.
Rhesus Macaque Genome Sequencing and Analysis Consortium
(2007) Evolutionary and biomedical insights from the rhesus
macaque genome. Science 316: 222–234.
eLS © 2015, John Wiley & Sons, Ltd. www.els.net
Scally A, Dutheil JY, Hillier LW, et al. (2012) Insights into hominid
evolution from the gorilla genome sequence. Nature 483: 169–175.
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: 1038–1042.
She X, Horvath JE, Jiang Z, et al. (2004) The structure and evolution
of centromeric transition regions within the human genome. Nature
430: 857–864.
Stankiewicz P and Lupski JR (2002) Genome architecture, rearrange-
ments and genomic disorders. Trends in Genetics 18: 74–82.
Stankiewicz P (2010) Structural variation in the human genome and
its role in disease. Annual Review of Medicine 61: 437–455.
Sudmant PH, Huddleston J, Catacchio CR, et al. (2013) Evolution
and diversity of copy number variation in the great ape lineage.
Genome Research 23: 1373–1382.
Tam E, Young EJ, Morris CA, et al. (2008) The common inversion of
the Williams-Beuren syndrome region at 7q11.23 does not cause
clinical symptoms. American Journal of Medical Genetics. Part A
146A: 1797–1806.
Turner DJ, Miretti M, Rajan D, et al. (2008) Germline rates of de
novo meiotic deletions and duplications causing several genomic
disorders. Nature Genetics 40: 90–95.
Ventura M, Catacchio CR, Alkan C, et al. (2011) Gorilla genome
structural variation reveals evolutionary parallelisms with chim-
panzee. Genome Research 21: 1640–1649.
Ventura M, Mudge JM, Palumbo V, et al. (2003) Neocentromeres in
15q24-26 map to duplicons which flanked an ancestral centromere
in 15q25. Genome Research 13: 2059–2068.
Wain LV, Armour JA and Tobin MD (2009) Genomic copy number
variation, human health, and disease. Lancet 374: 340–350.
Weise A, Mrasek K, Klein E, et al. (2012) Microdeletion and
microduplication syndromes. The Journal of Histochemistry and
Cytochemistry 60: 346–358.
Zhou Y and Mishra B (2005) Quantifying the mechanisms for seg-
mental duplications in mammalian genomes by statistical analysis
and modeling. Proceedings of the National Academy of Sciences
of the United States of America 102: 4051–4056.
Further Reading
Alkan C, Coe BP and Eichler EE (2011) Genome structural variation
discovery and genotyping. Nature Reviews. Genetics 12: 363–376.
Beckmann JS, Estivill X and Antonarakis SE (2007) Copy number
variants and genetic traits: closer to the resolution of phenotypic to
genotypic variability. Nature Reviews. Genetics 8: 639–646.
Stankiewicz P (2010) Structural variation in the human genome and
its role in disease. Annual Review of Medicine 61: 437–455.
9