Mutation Research 616 (2007) 2433

Mobile element-based forensic genomics

David A. Ray
1,2
, Jerilyn A. Walker
1
, Mark A. Batzer

Department of Biological Sciences, Biological Computation and Visualization Center, Louisiana State University,
202 Life Sciences Building, Baton Rouge, LA 70803, USA
Available online 8 December 2006
Abstract
Mobile elements are commonly referred to as selsh repetitive DNA sequences. However, mobile elements represent a unique
and underutilized group of molecular markers. Several of their characteristics make them ideally suited for use as tools in forensic
genomic applications. These include their nature as essentially homoplasy-free characters, they are identical by descent, the ancestral
state of any insertion is known to be the absence of the element, and many mobile element insertions are lineage specic. In this
review, we provide an overview of mobile element biology and describe the application of certain mobile elements, especially the
SINEs and other retrotransposons, to forensic genomics. These tools include quantitative species-specic DNA detection, analysis
of complex biomaterials, and the inference of geographic origin of human DNA samples.
2006 Elsevier B.V. All rights reserved.
Keywords: Mobile element; Forensic genomics; SINEs
1. Introduction to mobile elements
Mobile elements are repetitive DNA sequences with
the unique ability to move and/or make copies of them-
selves. They can comprise between 40 and 90% of
genomes [13]. While individual insertions tend to
be either neutral or deleterious, their prevalence in
eukaryotic genomes indicates that their presence is,
on the whole, selectively advantageous. Several studies
suggest that they play important roles in genome struc-
ture, genome instability and gene expression [1,411].
For instance, the movement of these elements can
change genomes by insertion mutagenesis [9,1216],
insertion-mediated genomic deletions [15,17-20], and
transposition-mediated transduction [15,2124]. Fur-

Corresponding author. Tel.: +1 225 578 7102;

fax: +1 225 578 7113.
E-mail address: mbatzer@lsu.edu (M.A. Batzer).
1
These authors contributed equally to this work.
2
Current address: Department of Biology, West Virginia University,
53 Campus Dr., Morgantown, WV 26506, USA.
ther, the widespread presence of very similar DNA
sequences throughout a genome promotes recombina-
tion, including both equal and unequal crossover events
[9,15,25,26], segmental duplication [27], gene conver-
sion [2830], exon shufing [23,31] and chromosomal
rearrangements [32].
Mobile elements are divided into two classes based on
their method of mobilization (Fig. 1) [33]. Class I mobile
elements utilize a copy and paste method referred to
as retrotransposition. In this process, the original DNA
copy in the genome is rst transcribed to RNA. The tran-
script is used as a template to form a DNA molecule that
is then inserted into a new location in the genome via
a process known as target primed reverse transcription
[34]. Autonomous class I elements encode some or all
of the enzymes needed to accomplish their mobiliza-
tion. These retrotransposons are subdivided into several
subgroups based on autonomy and sequence characteris-
tics. The autonomous class I elements include LTR(long
terminal repeat) retrotransposons that share many char-
acteristics with retroviruses [35]. Also autonomous are
the non-LTR retrotransposons, which are usually 46 kb
0027-5107/$ see front matter 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.mrfmmm.2006.11.019
D.A. Ray et al. / Mutation Research 616 (2007) 2433 25
Fig. 1. General structure for the two classes of mobile elements. Class I elements of the LTRvariety are anked by both long terminal repeats (LTRs)
and target site duplications (TSDs), which are produced during integration into the genome. These autonomous retrotransposons encode several
polypeptides related to viruses. LINEs typically contain two open reading frames. Finally, SINEs do not contain any open reading frames. Instead,
they use the enzymatic machinery of LINEs to mobilize in a genome. They are transcribed by RNA polymerase III which recognizes the A and B
promoter sequences that make up part of the SINE sequence itself. SINEs also often have a repetitive motif at the 3

end ((XX)
n
). Autonomous class
II elements, the DNA transposons contain an open reading frame for transposase and are typically anked by inverted terminal repeats (ITRs) and
direct repeats (DRs).
long. Atypical example is the LINE-1 (long interspersed
element-1) repeat of mammals. LINE-1elements contain
two open reading frames (ORFs). The rst, short ORF
encodes a protein thought to have a nucleic acid binding
function [3639]. The second ORF encodes a protein
with both endonuclease and reverse-transcriptase prop-
erties [40,41]. It is via this enzymatic machinery that
a LINE is able to mobilize after transcription by RNA
polymerase II [42]. The endonuclease of LINE-1 and
other non-LTR retrotransposons recognize specic tar-
get sequences in order to initiate the insertion process
[43,44].
Class II elements, the DNA transposons and their
derivatives, are common in many organisms from bacte-
ria to humans. First discovered by Barbara McClintock
in maize [45], DNA transposons differ from class I ele-
ments in that they utilize a DNA intermediate when
mobilizing. They may utilize a cut and paste (con-
servative) or copy and paste method (replicative). In
the former case, an entire DNA segment that includes
the coding sequences and associated non-coding regions
is excised from where it resides and reinserted into the
genome at a different location. This process is mediated
by the action of transposase, which is encoded by the
autonomous element. Usually, transposase binds to both
the inverted repeats of the transposon and a target site
in the genome where the transposon will reinsert. The
target site is cut and the transposon is then inserted.
Non-autonomous versions exist for both classes
I and II elements. These elements lack the coding
sequences typical of autonomous elements. Instead, they
are believed to hijack the machinery of autonomous
elements to accomplish their mobilization [46,47].
Several examples include TRIMs (terminal-repeat
retrotransposons in miniature) and LARDs (large retro-
transposon derivatives) that are both recently described
non-autonomous elements derived from LTR retrotrans-
posons [48,49]. SINEs (short interspersed elements) are
non-autonomous, non-LTR retrotransposons that occur
in large numbers in a wide variety of vertebrate genomes
[14,5053]. Class II non-autonomous mobile elements
include the MITEs (minature inverted terminal repeat
elements), Mers, and Acrobat elements among others
[5456].
This review will focus on SINEs. The widespread
presence of SINEs in eukaryotes [14,50] and their rela-
tively small size (usually between 100 and 500 bp) make
themuseful for a varietyof different forensic approaches.
Below, we will discuss some of them. The approaches
that have been attempted include the simple identica-
tion of the taxon present in an unknown DNA sample to
the identication of ancestry within a specic taxon.
2. Identication and quantitation of
species-specic DNA
As various SINEs and LINEs expanded throughout
the genomes of different organisms, generating over
100,000 mobile elements in many, genome-specic fam-
ilies with characteristic diagnostic mutations have arisen
[10]. These large dispersed gene families serve as novel
markers that identify the DNA from each species, thus
26 D.A. Ray et al. / Mutation Research 616 (2007) 2433
Fig. 2. Species DNA detection using PCR and agarose gel elec-
trophoresis. Lanes: (1) 100 bp ladder, (2) cow, (3) pig, (4) chicken,
(5) horse, (6) sheep, (7) deer, (8) antelope, (9) rabbit, (10) duck, (11)
dog, (12) cat, (13) rat, (14) mouse, (15) human and (16) NTC (no tem-
plate control). (A) Cow-specic; (B) pig-specic; (C) chicken-specic;
(D) amplies in all ruminants.
providing specic genomic tags that can be used in
conjunction with PCR to amplify specic subsets of
genomic sequences unique to the genome or species
of interest (for recent reviews see [57,58]). Mobile
element-based PCR assays have been developed for the
sensitive identication and quantitation of DNA from
many different classes, orders and species [59,60]. To
date, class-specic intra-element PCR assays are avail-
able for birds, order-specic assays are available for
primates, ruminants and rodents, and species-specic
assays are available for humans, cows, horses, pigs, dogs,
cats, hamsters, guinea pigs, rats, rabbits, and chickens
(Fig. 2).
3. Quantitative detection of species DNA in
meats
Documented cases of mad cow disease (bovine
spongiform encephalopathy) have received high public-
ity in recent years. The risk associated with infectious
transmissible spongiformencephalopathy in humans has
discouraged many individuals around the globe from
consuming beef. Hindu populations also choose not to
eat beef, while Jewish and Muslim populations choose
to avoid consumption of pork, even in minute quantities,
due to their religious beliefs. Many consumers prefer to
include more chicken in their diet instead of beef or pork.
In addition to infectious disease and religious concerns,
many individuals are altering their eating behavior to
include more chicken simply to reduce dietary fat intake
in accordance with health trends. Physicians routinely
recommend such dietary changes to patients with heart
disease, diabetes or obesity, for example.
Previously, species-specic SINE-based and LINE-
based PCRassays have been reported for the detection of
ruminant-, pig-, and chicken-derived materials [59,60].
Quantitative SINE-based PCR assays have been devel-
oped for the sensitive detection and quantitation of
bovine, porcine, chicken and ruminant species DNA
frommixedsources andfoodproducts [60]. For example,
the bovine SINE-satellite 1.711B is thought to occupy
7.1% of the bovine genome [61] and the intra-SINE-
based PCR assay using this repeat element can detect
0.005% bovine DNA from a mixed DNA sample [60].
The porcine SINE PRE-1 has an estimated 100,000
copies in the pig genome [62] and the intra-PRE-1-
based PCR assay is able to detect even trace quantities
(0.0005%) of porcine DNA from within a mixed-DNA
sample [60]. A randomly selected food product labeled
chicken sausage was determined to contained about
8% pork [60]. The chicken intra-CR1 SINE-based PCR
assay can detect down to 0.05% chicken DNA and the
intra-Bov-tA2 SINE-based PCRassay can detect as little
as 0.1% ruminant species DNA (cow, sheep, deer, ante-
lope, etc.) frommixed sources [60]. This highly sensitive
species specicity makes these assays ideal for identi-
cation of beef, pork, chicken, and ruminant materials
from human foods and animal feed mixtures.
4. Identication and quantitation of animal DNA
In addition to agricultural meat species intended for
human consumption, certain situations make determin-
ing the source of a tissue, blood or DNA sample a
necessity. For example, some violent crime scenes may
include blood stains from not only human victims but
from our animal companions as well. Other events such
as earthquakes, tornadoes, and terrorist attacks create
such volatile conditions that the biological evidence
available for post-event genomic analysis may include a
human and a nonhuman component. Thus, there is a need
for sensitive detection and quantitation of other common
domestic species from multi-species or unknown DNA
samples.
D.A. Ray et al. / Mutation Research 616 (2007) 2433 27
Fig. 3. The typical Alu element consists of two monomers, with the right monomer containing an additional 31-bp insertion (not shown) relative
to the left monomer. Each Alu is 300 bp, depending on the length of the 3

poly-A tail. An A-rich central region also exists between the two
monomers. The 5

half of each Alu element contains an RNA-polymerase-III promoter (A and B boxes).

To address this need, a series of class-specic (Aves),
order-specic (Rodentia), and species-specic (equine,
canine, feline, rat, hamster, guinea pig, and rabbit)
PCR-based assays were developed using intra-element
amplicationof genome-specic SINEs andLINEs [63].
The minimum effective quantitation levels of these
assays ranged from1 to 0.001%in 10 ng of starting DNA
template. Thus, even when small amounts of DNA are
available, it is possible for forensic investigators to deter-
mine who may have been present at a scene whether
that individual is human or non-human.
5. The Alu element
The most abundant class of SINE in the human
genome is the Alu element (Fig. 3). This SINE family
is derived from the 7SL gene and is specic to primate
genomes. Alu elements are only 300 bp long but, with
more than one million copies, they account for more
than 10%of the mass of the human genome [1,14]. Most
Alu elements are xed in the human genome, mean-
ing that all individuals are homozygous for the insertion
at a particular locus in the genome in which it resides.
The expansion of Alu elements throughout primate evo-
lution has created several recently integrated young
subfamilies that are present in the human genome but
are largely absent from nonhuman primates [14]. Some
members of these young Alu subfamilies have inserted
in the human genome recently enough that individu-
als remain polymorphic for insertion presence/absence
[14,6468]. Both xed and polymorphic Alu elements
have been utilized quite successfully as forensic tools
for a variety of applications [69,70].
6. Mobile element-based human gender
identication
One important forensic use for Alu elements is human
gender identication [70]. Determination of gender from
human DNA samples is a common problem in forensic
laboratories. The most widely used approach is based
on the Amelogenin locus, which yields different-sized
PCR (polymerase chain reaction) amplicons for the X
and Y chromosome versions of the Amelogenin gene
[71]. However, this method can misidentify males as
females in some cases due to a deletion in the AMEL
Y region [7274]. While the frequency of the deletion is
relatively low, the crucial nature of forensic test results
in circumstances such as rape and prenatal gender deter-
mination where there is risk for male-specic inherited
disorders makes any source of error a legitimate cause
for concern. This has led several researchers to recom-
mend that Amelogenin should not be relied upon as the
sole determinant of gender [7275].
Fixed Alu insertions on either the X or the Y chro-
mosome provide a way of identifying the respective
chromosome. Loci AluSTXa and AluSTYa demonstrate
100% accuracy in gender identication (X and Y chro-
mosome identication) in 778 human DNA samples
fromdiverse populations [70]. The combination of these
two markers provides added assurance that gender test
results are accurate since independent mutations would
have to occur in two separate genomic locations to affect
the outcome of the test. This Alu-based method may also
be useful as a precursor to more extensive Y chromo-
some marker analysis, such as Y-Plex
TM
12 (ReliaGene
Technologies, Inc., NewOrleans, LA). In addition, since
AluSTXa is xed on the X chromosome and AluSTYa is
xed on the Ychromosome, uorescent-based detection
of these markers allows for quantitative resolution of
male and female contributions to mixed DNA samples,
such as might be found in sexual assault cases.
7. Human DNA identication and quantitation
Just as in the examples for other species described
above, the identication of human DNA in a com-
plex mix may also be required. The vast majority of
humanforensic caseworkinvolves the analysis of nuclear
loci, making the quantitation of human nuclear DNA a
paramount issue [76]. Alu elements have amplied to a
copy number of over 1 million elements throughout pri-
mate evolution producing a series of subfamilies of Alu
elements that appear to be of different ages [14]. Because
of their high copy number, Alu elements are a rich source
of human genetic markers. Several systems have been
developed to quantify human DNA using PCR primers
designed to amplify the core Alu sequence [7781]. Dur-
28 D.A. Ray et al. / Mutation Research 616 (2007) 2433
ing intra-Alu PCR, primers are designed within the core
body of the element to amplify multiple target copies of
the Alu family. Most of these systems are specic to the
primate lineage and are not necessarily human specic.
Intra-Alu-based PCR assays have been developed
for human-specic DNA identication and quantita-
tion based on Alu subfamiliesYb8 and Yd6 [69], taking
advantage of the large diagnostic insertion or deletion
characteristic of these respective subfamilies. The intra-
Yb8-based PCR assay has a linear quantitation range of
100.001 ng of DNAand is capable of detecting 10 pg of
human DNAfroma mixed source sample [69]. The intra-
Yd6-based PCR assay is less sensitive quantitatively
with a detection limit of 100 pg of human DNA. But
the intra-Yd6-based PCR assay is specic to humans,
no background amplication occurs from non-human
primate templates, and has proven useful as an initial
screening tool [69]. The collective use of primate specic
and human specic Alu-based PCR assays in forensic
genomics provides a powerful tool for sensitive human
DNAidenticationandquantitationfrommixedsources.
8. Alu insertion polymorphisms and inference of
ancestry
Forensic DNA specimens are routinely matched to
alleged criminal suspects in modern law enforcement.
Frequently however, tools that narrow the potential pool
of suspects are essential precursors to a positive identi-
cation in investigative forensics. The inferred ancestral
origin of a DNA specimen is one type of predictor
evidence which can aid a criminal investigation. Poly-
morphic Alu insertions have been widely used to study
human genetic variation in world populations [82103].
These elements are ideal for studying human geo-
graphic origins because they are essentially homoplasy
free characters [57,104], they are identical by descent
[14,57,105], and the ancestral state of a mobile element
insertion polymorphism is known to be the absence of
the element at a particular genomic location [83]. These
features make the analysis of Alu elements a robust tool
for tracking human geographic ancestry.
The distribution and structure of human genetic diver-
sity has been systematically evaluated in a dataset of
100 Alu insertion polymorphisms, mined from existing
human genome databases and selected for the greatest
allele frequency variation between populations [106].
In this analysis, 710 individuals representing 31 differ-
ent populations across 4 continents were evaluated for
each of the 100 Alu insertion polymorphisms [85]. The
inferred geographic afliation of the samples was calcu-
lated using the Structure 2.0 software package [107,108].
The Markov Chain Monte Carlo methodology used by
Structure 2.0 incorporates a powerful analysis to group
all individuals into the selected number of populations
and then determine the probability that each individual
belongs to any given group. In addition, the software has
the ability to detect admixture between populations in
individual genotypes going back three generations.
This existing dataset is a powerful forensic tool to
ascertain the inferred geographic ancestry of unknown
forensic DNA samples. The methodology is simple,
requiring only standard thermal cyclers for PCR and
the ability to run agarose gel electrophoresis. In a study
conducted in collaboration with law enforcement of-
cials, forensic DNA specimens were evaluated using the
dataset of 100 Alu insertion polymorphisms and Struc-
ture 2.0. The system demonstrated accurate assignment
of each specimen to the correct geographic afliation
[109].
In addition to existing datasets, Alu elements have
continued to accumulate in various populations since
the human dispersal from Africa estimated to have
occurred 156,000 years ago [85]. Many of these new
Alu insertions are likely to be polymorphic and occur
in various world populations to different degrees. The
presence of these population-specic insertions will
allow for subsequent layers of subgroup afliation tests
to be conducted using a cascade-like approach in the
analyses. Thus, once the initial Structure 2.0 analysis
assigns the DNA specimen to a continental afliation
such as Europe, Africa, Asia or India, subsequent
Structure 2.0 analyses, using only insertion loci that are
useful within the sub-continental population groups, can
be used to further isolate the sub-continental region. The
inferred ancestral origin of a DNA specimen narrows
the pool of potential suspects and can successfully
impact a criminal investigation.
Forensic DNA samples are often only available in
trace quantities. This has previously been a limita-
tion to this type of multiple locus approach. Recent
advancements in whole genome amplication (WGA)
technologies which utilize 29 polymerase have vir-
tually eliminated this obstacle. In fact, successful
genotypes have been obtained using post-WGA DNA,
obtained from residual skin cells salvaged from a nger-
print [110]. Therefore, the inferred ancestral origin of a
human DNA sample can even be determined from trace
evidence.
9. Conclusion
Mobile elements represent novel tools within
the increasingly varied armamentarium available to
D.A. Ray et al. / Mutation Research 616 (2007) 2433 29
forensic scientists. Their utility ranges from sim-
ple detection schemes, such as gender and species
identication, to complex multi-locus systems for infer-
ence of human ancestry. Continued development of
mobile element-based genetic systems in combination
with high-throughput DNA analysis technologies will
undoubtedly further the application of these approaches
in the future.
Acknowledgements
This research was supported by the Louisiana Board
of Regents Governors Biotechnology Initiative GBI
(2002-005) (MAB), National Science Foundation EPS-
0346411 (M.A.B.) and the State of Louisiana Board of
Regents Support Fund (MAB).
This paper is dedicated to the memory of Tony Car-
rano. During my (MAB) years at Lawrence Livermore
National Laboratory I had the privilege of working in the
Human Genome Center under the guidance of Tony. At
that time Tony had the foresight to initiate a number
of the forensic genomics efforts at Lawrence Liver-
more National Laboratory in an effort to create future
areas of investigation for the Biology and Biotechnol-
ogy Research Program. These early initiatives proved to
be the underpinnings for many subsequent years of fruit-
ful scientic investigations by individuals at Lawrence
Livermore National Laboratory and elsewhere including
my own laboratory. Tony was an exceptional scientist
and was one of the best scientic administrators that I
have ever known. His mentoring, dedication, leadership,
and enthusiasm will be remembered and missed.
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