Genome Organisation:
Human
David H Kass, Eastern Michigan University, Ypsilanti, Michigan, USA
Mark A Batzer, Louisiana State University, Baton Rouge, Louisiana, USA
Based in part on the previous version of this eLS article ‘Genome
Organization: Human’ (2001, 2004).
The human nuclear genome is organised into
a highly complex arrangement of two sets of
23 chromosomes comprised of various types of
deoxyribonucleic acid (DNA) sequences. With less
than 2% of the human genome consisting of
protein-encoding DNA sequence, the remainder of
the 3 × 109 bp of the haploid genome consists of a
multifaceted assortment of DNA sequence classifi-
cations. At the broadest level, the genome can be
divided into single-copy protein-encoding genes,
repetitive sequences and spacer DNA. Notably, the
!
categories of repetitive sequences are profoundly
intricate and may be further classified into func-
tional or functionally related groups such as gene
families and superfamilies, or groups with no
known function such as satellite DNA and trans-
posable elements. Their genomic organisation
may be dispersed, within localised regions, and/or
tandemly repeated. The generation of repetitive
sequences results from a variety of mechanisms
continually promoting a genome that is highly
dynamic.
Introduction
The human nuclear genome contains over 3000 million base pairs
(Mbp) of deoxyribonucleic acid (DNA) with profound organi-
sational complexity that can be classified to some degree based
on certain sets of characteristics. Most broadly, these include
the single-copy protein-encoding genes (representing roughly
2–4% of the total genomic sequences), repetitive sequences and
intergenic (spacer) DNA (Figure 1). The repetitive sequences
eLS subject area: Genetics & Disease
How to cite:
Kass, David H and Batzer, Mark A. Genome Organisation:
Human, eLS, Vol 2: 61–71, 2021.
DOI: 10.1002/9780470015902.a0029269
Volume 2, Issue 1, April 2021 eLS © 2021, John Wiley & Sons, Ltd. www.els.net
Advanced article
Article Contents
• Introduction
• Sequence Complexity
• Genome Organisation at the Chromosomal Level
• Genome Organisation of DNA Sequences
Representing the Differing Levels of Complexity
• Mitochondrial Genome
• Genome Dynamics and Evolution
• Acknowledgements
Published online: 20th April 2021
can be further classified as either gene superfamilies (func-
tionally related with weak sequence homology) or gene fami-
lies (related paralogous genes) some of which are functional.
These are found to be dispersed and/or tandemly repeated and
may encode functional proteins, noncoding functional ribonu-
cleic acid (RNA) genes or nonfunctional pseudogenes derived
from these sequences. Repetitive sequences with no known func-
tion include the various highly repeated satellite families, and
the dispersed, moderately repeated transposable element (TE)
families, though there has been some evidence of TE function
including involvement in immune response (Kassiotis and Stoye,
2016) and gene regulation (Platt II et al., 2018). The remain-
der of the genome consists of spacer DNA, representing a broad
category of undefined intergenic DNA sequences. Overall, the
human genome consists of 23 pairs of chromosomes, or 46 DNA
molecules, of differing sizes (Table 1). This review is designed to
provide a synopsis of the organisation, complexity and dynamics
of the human genome. A general overview of the genomic cate-
gories, examples and organisation is summarised in Table 2.
Sequence Complexity
The human genome contains various levels of complexity as
demonstrated by reassociation kinetics. This involves the random
shearing of DNA into small fragments averaging about 500 bp,
heat denaturation to separate the strands of the double helix and
slow cooling. During cooling, complementary sequences anneal;
the more copies there are of a particular sequence, the greater
the chance of finding a complement to anneal to. Therefore, the
reassociation is dependent on time (t), as well as the initial con-
centration of that sequence (C0 ) yielding what is referred to as a
C0 t value. Analysis of the human genome utilising this method-
ology has provided estimates of 60% of the DNA is present as
either single copy or in very low copies; 30% of the DNA is
moderately repetitive; and 10% is considered highly repetitive.
Genome Organisation at the
Chromosomal Level
Various chromosomal staining techniques present alterna-
tive banding patterns of mitotic chromosomes referred to as
61
 Genome Organisation: Human

Human genome

Single-copy DNA present in more than Spacer DNA

protein-encoding genes 1 copy (repetitive)

Coding sequence Introns and cis-regulation

sequences

Functional sequences:
interspersed and/or tandem Sequences with no known function

Gene superfamilies Highly

(structurally related, but functionally Gene families Interspersed
(paralogous genes) repeated
and evolutionarily distinct) sequences in tandem
(satellites)

Highly DNA- Retrocopies

Coding Identical
Coding Non-coding homologous mediated
genes genes RNA genes transposons
with Macro- Micro-
with (regulatory
conserved Copies Evolutionarily satellites satellites
conserved and
protein amino structurally of the and Retrotransposons
Mini-
domains acid motifs similar) same functionally
satellites
gene related

!
genes

Figure 1 Broad classification of DNA sequences in the human genome.

Table 1 DNA content of human chromosomes in megabases DNA. The C-banding technique yields dark-staining regions of
(EMSEMBL GRCh37) the chromosome (or C bands), referred to as heterochromatin.
These regions are highly coiled, contain highly repetitive DNA
Chromosome Amount of Chromosome Amount of
DNA (Mb) DNA (Mb) and are typically found at the centromeres, telomeres and on the
Y chromosome. They are composed of long arrays of tandem
1 249 13 108 repeats and therefore some may contain a nucleotide composi-
2 237 14 105 tion that differs significantly from the remainder of the genome
3 192 15 99 (approximately 40–42% GC). Therefore, these repeats can be
4 183 16 84 separated from the bulk of the genome by buoyant density (cae-
5 174 17 81 sium chloride) gradient centrifugation, with the identification of
6 165 18 75
a major band along with three minor bands referred to as satellite
7 153 19 69
bands, hence the term satellite DNA.
8 135 20 63
The G-banding technique yields a pattern of alternating light
9 132 21 54
and dark bands reflecting variations in base composition, time of
10 132 22 57
replication, chromatin conformation and the density of genes and
11 132 X 141
repetitive sequences. Therefore, the karyograms define chromo-
12 123 Y 60
somal organisation of DNA sequences and allow for the identi-
Data from EMSEMBL GRCh37, DNA content of human chromosomes fication of the different chromosomes. The darker bands, or G
in megabases. bands, are comparatively more condensed, more AT-rich, con-
tain relatively few genes, and replicate later than the DNA within
the pale bands, which correspond to the R bands by an alter-
karyograms. Although the three broad classes of DNA are native staining technique. More recently these alternative band-
scattered throughout the chromosome, chromosomal banding ing patterns have been correlated to the level of compaction of
patterns reflect notable levels of compartmentalisation of the scaffold-attachment regions (Craig et al., 1997).

Volume 2, Issue 1, April 2021 eLS © 2021, John Wiley & Sons, Ltd. www.els.net 62
 !
Table 2 Components and organisation of nuclear DNA sequences in the human genome
Genome organisation Category Subcategory Genome characteristic &/ or example(s) Location
level
I. Chromosomal C bands Highly heterochromatic alphoid satellite DNA Centromere
G bands Relatively heterochromatic, A-T rich, gene poor Large dispersed chromosomal regions
R Bands Relatively euchromatic, GC rich, gene rich Large dispersed chromosomal regions
corresponding to unstained G bands
Satellites Nucleolar organiser regions, rRNA gene families Near ends of short arm of acrocentric

Volume 2, Issue 1, April 2021

chromosomes 13, 14, 15, 21, 22
II. Sequence Single-copy Roughly 25 000 genetic loci comprising 2–4% of Individual sites dispersed throughout genome,
protein-coding gene the genome primarily in euchromatic regions
Repetitive DNA
Satellite Alphoid (Macro)satellite 170 bp tandem repeats, comprise up of 10 Mbp Centromere
Minisatellite 15–100 bp tandem repeats, comprise1-5 kbp Interspersed and telomeres
Microsatellite Tandem repeats 4 bp or less Interspersed
Gene family Noncoding RNA genes rRNA, tRNA (different anticodon families), Tandem clusters in several chromosomal locations
snRNA (U-rich)
5SrRNA Clustered, single location
miRNA Widely distributed, primarily intergenic and
intronic regions
Protein coding Histone genes Tandem clusters at few chromosomal sites
Actin Dispersed
Globin genes 𝛼-globin clustered on chromosome 16, 𝛽-globin
clustered on chromosome 11, myoglobin on
chromosome 22
Gene superfamily Protein coding Protooncogenes, for example, myc and ras Dispersed on different chromosomes
Homeodomain-containing proteins Dispersed among a subset of single-copy
protein-encoding genes
Immunoglobulin protein domains Dispersed

eLS © 2021, John Wiley & Sons, Ltd. www.els.net

DEAD box, F-box, or WD box motifs Dispersed in a specific subset of protein-encoding
genes
Noncoding RNA genes lncRNA Dispersed
Transposable Class I. retrotransposons SINEs (Alu) Interspersed; AT-rich preference
elements (TEs)
LINEs (L1) Interspersed; GC-rich
HERVs or isolated LTR of HERVs Interspersed primarily intergenic regions, plus
high recombination regions such as the MHC
Class II. transposons Charlie, Mariner, Tigger Interspersed
Genome Organisation: Human

Nonfunctional genes DNA pseudogenes Adjacent to functional gene

63
𝛽-globin pseudogenes
Processed pseudogenes Hmg, actin, tRNA Dispersed
 Genome Organisation: Human
The human genome may also be compartmentalised into large
segments of DNA with distinctive GC richness referred to as ‘GC
content domains’ (Lander et al., 2001). There is a distinct corre-
lation between GC-richness and gene density. This is consistent
with the association of CpG islands, which are the 500–1000-bp
GC-rich segments flanking (usually at the 5′ end), with most
housekeeping and many tissue-specific genes. The clustering of
CpG islands, as demonstrated by FISH (Craig and Bickmore,
1994), further depicts gene-poor and gene-rich chromosomal seg-
ments.
Another organisational feature of the human genome at the
chromosomal level is a thin bridge with rounded ends at the termi-
nus of five acrocentric human chromosomes (13, 14, 15, 21, 22),
which are referred to as chromosomal satellites. These contain
repeats of genes coding for ribosomal ribonucleic acid (rRNA)
and ribosomal proteins that coalesce to form the nucleolus and
are known as nucleolar organising regions (NORs).
Genome Organisation of DNA
Sequences Representing
the Differing Levels of Complexity
Single-copy sequences
Although originally defined as a functional unit of heredity, a
gene may be defined as a protein-encoding segment of DNA with
!
various noncoding regulatory elements or a segment of DNA
encoding a functional RNA molecule. Venter et al. (2001) esti-
mated that there are at least 26 588 protein-encoding transcripts,
consistent with the 30 000–40 000 estimate of the International
Human Genome Sequencing Consortium (Lander et al., 2001), as
well as a more recent estimate of roughly 21 000 protein-coding
loci based on the GENCODE Project (Harrow et al., 2012).
With alternative splicing for these genes, it is estimated that
100 000 different proteins can be generated. Based on the 21 000
estimate, the proportion of the genome consisting of genes is
roughly 10–11% assuming an average gene size of 15 kb. How-
ever, approximately 90% of the DNA from protein-encoding
genes is noncoding, including the upstream and downstream
regulatory sequences, as well as the introns. Therefore, only
1.5–2% (45–60 Mb) of DNA has coding function. Cis-acting
regulatory sequences include common promoters such as the
TATA, CCAAT and GC boxes which are recognised by tran-
scription factors, and are located at specific upstream distances
from the transcription start site. There are also tissue-specific
cis-acting DNA sequences, such as hormone response elements
(HREs) in various orientations within or near a gene that serve as
either enhancers or silencers to up or downregulate gene expres-
sion, respectively. Many coding sequences may be included as
members of gene families as described below. In addition, there
may be single-copy sequences in the spacer DNA with no known
(determinable) function.
Repetitive sequences
The human genome contains various sized stretches of repeated
DNA sequences with differing numbers of copies. These
Volume 2, Issue 1, April 2021 eLS © 2021, John Wiley & Sons, Ltd. www.els.net
repetitive sequences may be in a tandem orientation and/or
dispersed throughout the genome. Repetitive sequences may be
classified by function, dispersal patterns and sequence identity.
Satellite DNA typically refers to highly repetitive sequences
with no known function; gene families are DNA sequences, with
at least one functional gene, with members related by sequence
homology and/or function; and interspersed repeat sequences
are typically the products of TE integrations but may include
retropseudogene copies (retrocopies) of a functional gene.
Repetitive sequences I. Satellites, minisatellites
and microsatellites
Satellites (or macrosatellites) are very long arrays, up to hun-
dreds of kilobases, of tandemly repeated DNA. The three satel-
lite bands observed by buoyant density centrifugation represent
sections of the human genome containing highly repeated DNA
that differ in GC richness in relation to the overall genomic com-
position. However, not all satellite sequences are resolved by
density gradient centrifugation. Alpha satellite DNA or alphoid
DNA (in humans) constitutes the bulk of centromeric heterochro-
matin on all chromosomes. The alphoid DNA consists of 170 bp
tandemly repeated sequences that can vary in number, constitut-
ing 0.5–10 Mb of DNA. The interchromosomal sequence diver-
gence of the alpha satellite families allows the different chromo-
somes to be distinguished by fluorescence in situ hybridisation
(FISH).
Minisatellites are tandemly repeated sequences of 15–100 bp
of DNA, yielding a total length ranging from less than 1 kbp
up to 15 kbp. One subset of minisatellites comprises the highly
polymorphic arrays of variable number tandem repeats (VNTRs).
These have no known function but can serve as useful DNA mark-
ers (Jeffreys et al., 1985) for generating DNA profiles as tools
for forensics, paternity analysis, and so on. Several minisatel-
lites, scattered throughout the genome share a core sequence with
enough similarity to be analysed using a single probe in Southern
blotting, yielding highly informative DNA profiles. An example
is a 10–15-bp almost invariant core sequence (GGGCAGGANG)
of myoglobin minisatellites, identified among several polymor-
phic VNTR loci.
Telomeric DNA contains 10–15 kb stretches of sequences rep-
resenting a unique subset of minisatellites, which in the human
genome are TTAGGG hexanucleotide tandem repeats located at
the termini of the chromosomes. These sequences are added by
telomerase to ensure complete replication of the chromosome.
Telomeres of somatic cells are generally shorter than in germ
cells, illustrated by their decreasing size within human B cells
and skin cells with increasing age. In humans, it has been postu-
lated that telomeric sequence loss is associated with ageing and
assorted genetic disorders (Turner et al., 2019).
Microsatellites are small arrays of short simple tandem repeats,
primarily 4 bp or less. Different arrays are found dispersed
throughout the genome, although dinucleotide CA/TG repeats
are most common, yielding 0.5% of the genome. Runs of A’s
and T’s are common as well. Microsatellites typically have no
known functions. However, CA/TG dinucleotide pairs can form
the Z-DNA conformation in vitro, which is possibly indicative
of function. Repeat unit copy number variation of microsatellites
64

apparently occurs by replication slippage yielding highly poly-
morphic DNA markers referred to as short tandem repeat poly-
morphisms (STRPs). STRPs are commonly used in commercial
DNA fingerprinting kits for ancestry studies. In addition, STRPs
are used as a forensic tool in crime investigations by generat-
ing profiles used to screen the combined deoxyribonucleic acid
index system (CODIS) to identify an individual. In addition, the
expansion of trinucleotide repeats within genes has been associ-
ated with genetic disorders such as Huntington disease, myotonic
muscular dystrophy, spinocerebellar ataxias, Friedreich ataxia,
fragile-X syndrome and fragile XE mental retardation (Paulson,
2018).
Repetitive sequences II. Gene families
Gene families generally consist of a set of genes with high
sequence identity over their entire length, primarily in the exons
of protein-encoding gene families. Members of gene families,
or possibly separate clusters of the same gene family, are con-
sidered paralogous and are derived from an ancestral gene or
locus by duplication, therefore, are evolutionarily and function-
ally related. The duplication of a gene, however, may alternatively
yield a nonfunctional pseudogene. In addition, there are groups
of genes with weak overall sequence identity that are homolo-
gous at conserved domains or short amino acid motifs, that may
have diverged to have no overlapping functions and collectively
termed gene superfamilies. Only a limited number of examples
will be discussed.
! miRNA genes with a distribution of 52% in intergenic regions,
II A. Noncoding gene families with essentially identical or
highly homologous products. If a cell requires abundant
amounts of particular proteins or RNA molecules, one logical
solution might be the production of multiple functional copies
of the same gene. The human genome and eukaryotic genomes,
in general, have amplified a number of genes whose products
are responsible for general-purpose functions such as DNA
replication (e.g. histones) and protein synthesis (e.g. transfer
ribonucleic acid (tRNA) and rRNA).
Genes that encode rRNA, inclusive of the spacer units, total
about 0.4% of the DNA in the human genome. The individ-
ual genes of a particular rRNA family are essentially identical.
The 28S, 5.8S and 18S rRNA genes are clustered, with both
external transcribed spacer (ETS) units and internal transcribed
spacer (ITS) units, in tandem arrays of approximately 60 copies
each yielding about 2 Mbp of DNA. These clusters are present
on the short arms of five acrocentric chromosomes consequently
totalling approximately 300 copies, and form the nucleolar organ-
iser regions (NORs). These three rRNA genes are transcribed as
a single unit (yielding 41S rRNA) and then cleaved. 5S rRNA
genes are clustered on chromosome 1q.
There are an estimated 51 human tRNA gene families estab-
lished by their anticodon sequence (Iben and Maraia, 2014).
In contrast to the distribution of rRNA genes, the more than
500 tRNA genes demonstrate variable clustering patterns with
differing copy number variations (CNVs). Dispersal of tRNA
pseudogenes may have occurred via RNA-mediated retroposition
(McBride et al., 1989) and is consistent with the postulation that
various families of short interspersed DNA elements (discussed
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Genome Organisation: Human
below) have been derived from tRNA-like genes (Deininger and
Batzer, 1993).
Small nuclear ribonucleic acid (snRNA) molecules are consid-
ered to function in RNA processing. There are six families of
related snRNA genes, termed U1 to U6, that are dispersed among
the chromosomes. However, differing cluster patterns have been
observed for these genes. For example 35–100 functional U1
genes, all sharing 20 kb of nearly identical 5′ and 3′ flank-
ing sequences, are loosely clustered on chromosome 1p36 and
contain over 44 kb of intergenic sequences, whereas 10–20 U2
genes are clustered in a tight, virtually perfect 6-kb repeat unit
on 17q21–q22 (Lindgren et al., 1985). In addition, more than
one subfamily of a U snRNA has been identified; U3 com-
prises at least two subfamilies, which differ in their flanking
sequences. Also, pseudogenes of snRNA have been identified
and are thought to be dispersed in the genome by retrotransposi-
tion. tRNA genes are also found clustered with U RNA genes; for
example, chromosomal band 1p36 contains 15–30 copies each of
U1, Glu-tRNA and Asn-tRNA genes (van der Drift et al., 1994).
snRNA additionally includes the noncoding gene family of
micro (mi)RNA. MicroRNAs are individually expressed genes
that posttranscriptionally regulate the expression of genes. If
the miRNA sequence, in which the final product is about 22
nucleotides long, closely resembles the antisense sequence
(reverse complement) of an mRNA transcript (sense sequence),
then it may bind and prevent translation of the mRNA. As a
result of an incomplete match to the mRNA, a single miRNA can
regulate several genes. Hsu et al. (2006) estimated 762 human
40% in introns and 8% in exons, comprising approximately
1% of all predicted genes in mammals and other eukaryotes.
In addition, many human miRNA genes appear to have been
derived from TEs (Piriyapongsa et al., 2007), particularly
medium reiterated frequency repeats (MERs), mammalian-wide
interspersed repeats (MIRs) and L1 elements, thereby forming
distinct miRNA gene families. Over 3700 miRNA binding
sites have been identified in long noncoding ribonucleic acid
(lncRNA) genes.
II B. Coding gene families with high sequence identity.
There are numerous families of homologous genes in the human
genome sharing extensive intra-family sequence identity. These
are generally dispersed but occasionally contain linked mem-
bers. Histone genes are highly conserved among eukaryotes and
have a fundamental role in chromatin structure. The histone
family consists of five genes that tend to be linked, although
in differing arrays of variable copy numbers dispersed in the
human genome. The individual genes of a particular histone
family encode essentially identical products (i.e. H4 genes yield
the same H4 protein). Clusters of two or more tandemly repeated
histone genes, including all five (H3-H4-H1-H2A-H2B) have
been identified on human chromosomes 1, 6 and 12 (Tripputi
et al., 1986). In addition, histone genes lack introns; a rare feature
for eukaryotic genes.
Another gene family with a generalised important role in all
cells is represented by the actin genes, which comprise the cellu-
lar cytoskeleton and are involved in a variety of functions includ-
ing intracellular movement, stability and contraction. There are
65
 Genome Organisation: Human
six different actin genes dispersed in the human genome, encod-
ing six different isoforms with greater than 90% amino acid
sequence conservation (Parker et al., 2020). The actin proteins
are differentially expressed in various cell types and interact with
several different proteins. In addition, there are over 16 identified
actin pseudogenes thereby forming a multipseudogene family
(Ng et al., 1985).
One of the most comprehensively studied gene families is the
haemoglobin family. Human haemoglobin is a tetrameric pro-
tein consisting of two 𝛼-globin and two 𝛽-globin subunits. There
are several possible polypeptides constructing the haemoglobin
molecule with differing physiological properties and ontological
regulation. This probably occurred as a result of gene dupli-
cation allowing for divergence of sequences for procuring new
function. The two globin families exist as clusters of genes
and pseudogenes on separate chromosomes. The 𝛼-globin gene
cluster is on human chromosome 16 and the 𝛽-globin cluster
is on 11. Although related in sequence, there is greater intra-
than inter-cluster homology. Therefore, intra-cluster duplications
postdate the duplication of the ancestral gene yielding 𝛼- and
𝛽-globin. The ontological regulation is apparently coordinated
on each cluster by upstream sequences, providing the expres-
sion of the gene best suited for the oxygen need (a foetus, for
example, exists in a relatively hypoxic environment). Predating
haemoglobin divergence is the evolution of haemoglobin and
myoglobin from an ancestral gene. Myoglobin is a monomeric
protein encoded by a single gene on human chromosome 22 and
!
stores oxygen in muscle, whereas haemoglobin is the oxygen car-
rier in blood.
Protooncogones, the genes associated with signal transduction
pathways, additionally are comprised of gene families. Muta-
tions in these genes yield a dominant gain-of-function activity,
becoming oncogenes and disrupting regulation of the cell cycle
thus leading to the progression of tumours. One such family is
represented by the MYC genes, in which the protein products
contain the basic helix-loop-helix domain of transcription factors.
Functional members, including C-MYC, L-MYC and N-MYC, are
not linked genetically, with the latter two demonstrating more
restricted patterns of expression, but they share a three exon, two
intron structure. A detailed sequence analysis of MYC genes sug-
gests that the progenitor of the N-MYC and L-MYC genes was a
duplicated C-MYC gene (Atchley and Fitch, 1995).
Repeat sequences III. Gene superfamilies
III A. Gene families with low sequence identity but function-
ally conserved domains or short motifs. DNA superfamilies
are represented by genetic loci derived from a common ances-
tral gene that have diverged to the extent in which the proteins
encoded for may be structurally related but ‘develop’ nonover-
lapping functions, with members having different patterns of
expression (see also: Gene Families: Multigene Families and
Superfamilies). However, characteristically, the members of a
gene superfamily have conserved protein domains or motifs. A
notable example is the large genomically dispersed homeobox
superfamily. The protein products are associated with embryonic
development and characterised by a conserved homeodomain
Volume 2, Issue 1, April 2021 eLS © 2021, John Wiley & Sons, Ltd. www.els.net
typically 60 amino acids long that serve as transcription fac-
tors in regulating gene expression. In a comprehensive study by
Holland et al. (2007), 300 homeobox loci were identified in the
human genome of which 235 are likely to be functional. These
authors classified this superfamily as having 11 homeobox gene
classes further divided into 102 homeobox gene families based
on molecular phylogenetic analysis. The complexity of this gene
family with individual genes having diverse roles is consistent
with the complexity of human development. Additional large
gene superfamilies are listed in Gene Families: Multigene Fam-
ilies and Superfamilies and include the RAS family, the SRC
homology 3 domain and the immunoglobulin domain associ-
ated with the immune response. Genes of the immunoglobulin
superfamily encode proteins that form dimers consisting of extra-
cellular variable domains at the N-terminus and constant domains
at the C-terminus. Members of the immunoglobulin superfamily
include immunoglobulin, human leucocyte antigen (HLA), T-cell
receptor (TCR), T4 and T8 genes.
A gene superfamily may lack sequence identity, therefore, dis-
playing an overall low amount of similarity for the length of the
gene, but contain highly conserved short amino acid motifs. For
example, the DEAD box (Asp-Glu-Ala-Asp) is a motif within
a gene family that encode proteins with helicase activity (Lin-
der et al., 1989). Another supergene family encode proteins
containing an F-box, often found in the amino-terminal half,
which is a 50 amino acid motif that functions in protein-protein
interactions (Kipreos and Pagano, 2000), coupling with motifs
such as leucine-rich repeats (LRRs) and WD repeats in the
carboxyl-terminal region. The WD box genes are characterised
by between four and eight tandem repeats of a core sequence of
fixed length terminating in a WD dipeptide.
III B. Noncoding gene superfamily. Long noncoding ribonu-
cleic acid (lcnRNA) genes are, at this point, more complex to
characterise. They have been defined as a class of genes divided
into four different functional archetypes based on modes of action
(Wang and Chang, 2011). For this review, we have currently clas-
sified lcnRNA as a noncoding gene superfamily based on shared
characteristics including most notably the RNA transcripts being
greater than 200 nucleotides in length that are primarily tran-
scribed by RNA polymerase II utilising regulatory features simi-
lar to protein-coding genes (Derrien et al., 2012), having struc-
tural similarity in which the predominant transcript form con-
sists of two exons, and the suggestion of shared structural motifs
(Bhartiya et al., 2013). In addition, unlike a gene family, there
is a lack of sequence conservation among individual loci, plus
they serve a variety of functions. The GENCODE Consortium,
the reference for human genome annotation for the ENCODE
Project (www.gencodegenes.org), has provided for the identi-
fication of 9640 lcnRNA loci dispersed throughout the human
genome (Harrow et al., 2012). Development of an lncRNome
(Bhartiya et al., 2013) has yielded 18 000 lcnRNA annotated tran-
scripts that include intergenic noncoding RNA, antisense RNA
and processed pseudogenes, with differential patterns of expres-
sion. The lncRNA represents 68% of the human transcriptome
(Iyer et al., 2015). Biological processes of lncRNA include chro-
matin organisation and remodelling associated with gene regula-
tion. Examples include the XIST gene in X-inactivation and the
66
 Genome Organisation: Human

Gag Pol Env

Retrovirus

P ORF1 ORF2 -AN

Non-LTR retrotransposon (L1)

A B 31 -AN

Dimeric SINE (Alu)

IR Transposase IR

Transposon

Figure 2 Transposable elements in the human genome. Each contains the characteristic flanking direct repeats (red arrows). The human endogenous
retrovirus (or LTR retrotransposon) contains long terminal repeats (LTRs) (pale green regions), gag (group-specific antigen gene), pol (polymerase gene) and
possibly env (envelope gene). The non-LTR LINE (L1) retrotransposon contains internal RNA polymerase II promoter sequences (P), two open reading frames
and a poly(A) tail. The SINE retrotransposon (Alu element) has a dimeric structure of homologous halves separated by a middle A-rich region (blue), with
the left half containing A- and B-box RNA polymerase III promoter sequences, and the right half containing an additional internal 31 bp. For L1 and Alu
elements, pale green and mauve regions are sequences unique to these elements.

H19 gene involvement in embryogenesis. In addition, roughly
! 20% of lncRNA transcripts contain sites for miRNA binding.
Repeat Sequences IV. Transposable Elements
Throughout the human genome are interspersed repeat sequences
that have largely amplified in copy number by movement (jump-
ing) into new genomic locations. These sequences referred to
collectively as TEs include class I elements (retrotransposons or
retroposons) that mobilise via an RNA intermediate, and class II
elements (transposons) (Figure 2) that are strictly DNA medi-
ated. Both TE classes contain flanking direct repeats (FDRs) as
a result of the integration event. Although the human genome
contains roughly 300 000 class II DNA transposons (e.g. Char-
lie, Mariner and Tigger), there is a lack of evidence that these
have been active in the human genome, with the youngest fam-
ilies (MER75 and MER85) most recently active in an ancestral
species of humans and new world monkeys (Lander et al., 2001).
Short and long interspersed DNA elements (SINEs and LINEs,
respectively) are the primary TE families of the human genome.
These lack the long terminal repeats (LTRs) of endogenous
retroviral sequences (ERVs) and are, therefore, referred to
as non-LTR retrotransposons. LINEs are autonomous retro-
transposons encoding proteins necessary for retrotransposition
through a process termed target primed reverse transcrip-
tion (TPRT) (Luan and Eickbush, 1996); whereas SINEs are
nonautonomous and have been experimentally demonstrated to
mobilise using available LINE machinery (Moran et al., 1999;
Dewannieux et al., 2003).
L1 elements represent the primary LINE family in mam-
malian genomes, with humans estimated to contain over 500 000
copies and are predominately found in chromosomal G bands.
A full-length LINE is approximately 6.1 kbp, although most
are truncated retropseudogenes with various 5′ ends due to
incomplete reverse transcription. There are only an estimated
80–100 L1 loci considered retrotranspositionally competent; and
referred to as source or master genes (Brouha et al., 2003),
with allelic variations associated with retrotransposition capa-
bility (Seleme et al., 2006). Source loci represent a subgroup
of full-length L1 elements that contain two intact open reading
frames (ORFs), one encoding for a protein (ORF1p) involved in
L1 ribonucleoprotein (RNP) formation and the other (ORF2p)
encoding both an endonuclease and reverse transcriptase (Figure
2). Individual LINEs contain an internal RNA polII promoter, 5′
and 3′ untranslated regions and a poly (A) tail each contributing
to autonomous mobilisation in both germinal and somatic tissues.
The Alu element is estimated at over one million copies in
the human genome representing the primary SINE family (Lan-
der et al., 2001). Sequence comparisons suggest that Alu repeats
were derived from the 7SL RNA gene. Each Alu element is about
280 bp, has a rare dimeric structure, contains internal RNA poly-
merase III promoter sequences and typically includes an A-rich
tail (Figure 2). Approximately 5000 Alu elements have inte-
grated within the human genome subsequent to the divergence
of humans from the great apes. About 25% of the more recent
Alu integrations have yielded presence/absence insertion poly-
morphisms that are useful as DNA markers for the study of
forensics and human population genetics (Xing et al., 2007).
Alu elements predominate in chromosomal R bands and pref-
erentially insert into A-rich sequences including the A-tails of
previous Alu integrations. Of the one million plus Alu elements
in the human genome, only 143 loci have been deemed putatively

Volume 2, Issue 1, April 2021 eLS © 2021, John Wiley & Sons, Ltd. www.els.net 67
 Genome Organisation: Human
active source genes (Cordaux et al., 2006). These contain diag-
nostic nucleotides which account for the generation of different
subfamilies of Alu elements. A recent large scale pedigree study
based estimates of new mobile element integrations in humans to
occur at rates of 1/20 to 1/200 births (Feusier et al., 2019).
Direct integration events of SINEs and LINEs into genes
have contributed to human disorders (reviewed in Deininger and
Batzer, 1999; Kass, 2001), but also post-integration of several
elements within a gene have disrupted genes by serving as sites
for unequal homologous recombination. For example, within the
low-density lipoprotein receptor (LDLR) gene alone there have
been several alterations attributed to recombination between var-
ious Alu elements resulting in familial hypercholesterolemia. In
addition, SINEs and LINEs contribute to the dynamics of the
genome by serving as DNA methylation sites that alter the regu-
lation of adjacent genes.
The human genome also contains families of retroviral-related
sequences. These elements are characterised by sequences encod-
ing enzymes for retrotransposition and contain LTRs (Figure 2).
However, most of these sequences are defunct truncated and/or
mutated retrovirus-like elements that may or may not contain
an env gene. Human endogenous retrovirus (HERV) loci are
found predominantly in intergenic regions, though high densities
have been identified in genetic regions undergoing high levels of
recombination, such as with the human class I and class II major
histocompatibility complexes (Jern and Coffin, 2008). In addi-
tion, solitary LTRs of these elements may be located throughout
!
the genome. There are several low abundant (10–1000 copies)
HERV families, with individual elements ranging from 6 to 10 kb.
In addition, sequences within HERVs as well as HERV-derived
proteins have been associated with serving a role in human devel-
opment but also contributing to various ailments (Kazazian and
Moran, 2017). Overall, LTR elements encompass approximately
8% of the genome (Lander et al., 2001).
V. Pseudogenes and retropseudogenes
Pseudogenes are nonfunctional copies of a gene containing all
or part of the original sequence. Pseudogenes may arise by tan-
dem (segmental) duplication, accumulating mutations as a result
of the lack of selection pressure, and although structurally sim-
ilar to the functional gene (e.g. maintaining introns) are usually
recognisable by a lack of an open reading frame. These include
the globin pseudogenes.
Processed pseudogenes, aka retropseudogenes or retrocopies,
are generated through an RNA intermediate using TPRT, thereby
displaying the characteristic features of lacking introns that
were spliced out during processing, are flanked by short tan-
dem repeats and are distant in genomic locations from the source
gene (Richardson et al., 2014). In addition, they lack regulatory
sequences and therefore are normally incapable of expression.
There may be as many as 20–30 retropseudogenes that have
arisen from a parental functional gene, for example ribosomal
protein L32, and glyceraldehyde-3-phosphate dehydrogenase, as
well as a multipseudogene family, derived from different mem-
bers of the 𝛽-actin gene family (Ng et al., 1985). Processed pseu-
dogenes may be derived from noncoding RNA genes as well. In
Volume 2, Issue 1, April 2021 eLS © 2021, John Wiley & Sons, Ltd. www.els.net
addition to FDRs, tRNA retrocopies include the posttranscrip-
tionally added CCA sequences at the 3′ end. Overall, there are
roughly 15 000 pseudogenes, of which approximately 11 000 are
processed retrocopies (www.gencodegenes.org).
Retropseudogenes continue to shape the human genome. Anal-
yses of the 1000 Genomes Project by different laboratory groups
have identified 58 new retrocopy sequences in relation to the
human reference sequence, (Richardson et al., 2014). In addition,
among over 200 high mobility group (Hmg) nonhistone chromo-
somal protein retrotropseudogenes in the human genome, there is
evidence for recent mobilisation based on sequence similarity to
cDNA as well as the identification of human-specific integrations
(Tecle et al., 2006). The Hmg retrocopies exhibit traits suggest-
ing mobilisation via L1 machinery, including A-tails, FDRs and
notably the preferential TT/AAAA consensus sequence of L1
integration sites. Furthermore, it has been suggested that mobil-
isation of cellular mRNA by L1 elements has generated an esti-
mated 8000–17 000 retrocopies (Richardson et al., 2014) provid-
ing notable contributions to the dynamics of the human genome.
Should fortuitous landings of retrocopies occur into sites that
allow for the copy to be expressed, then these would be referred
to as retrogenes.
Mitochondrial Genome
The mitochondrion contains an autonomously replicating
genome. The human mitochondrial genome is circular and
contains 16 569 bp encoding for 37 genes, including tRNA and
rRNA genes used for mitochondrial protein synthesis. Mitochon-
drial deoxyribonucleic acid (mtDNA) is maternally inherited
and generally there are thousands of copies of mtDNA in the
cytoplasm of a cell.
Genome Dynamics and Evolution
The considerable variations of genomes among different organ-
isms as well as just between individual humans are indicative of
the highly complex and dynamic nature of the genome. How-
ever, comparisons of human and chimpanzee DNA demonstrate
98–99% sequence identity. This poses an interesting question as
to what makes us human. By analysis of chromosomes via FISH
and karyograms, it is evident that a shuffling of different segments
of the genome between humans and chimpanzees has occurred,
although there is conservation of synteny of genes, that is sets of
genes that are linked in humans are also linked in chimpanzees.
However, genomic rearrangements may alter temporal or spatial
expression of genes, as a result of the chromosomal location of
the gene(s), or possibly as a function of a shift in gene imprinting,
consequently yielding phenotypic variation.
TEs have had a considerable role in the construction and
organisation of the human genome, as TE sequences repre-
sent nearly half of the three billion base pairs (Lander et al.,
2001). Although TE activity has considerably decreased over
time, rare fortuitous retrotransposon integrations have the poten-
tial to become newly established source genes capable of further
generating retrocopies, which provides an explanation for the
68

concurrent amplification of elements representing distinguish-
able subfamilies of L1 and Alu (Deininger et al., 1992). Retro-
transposon integration can also potentially yield new families of
elements, as exemplified by the SINE-VNTR-Alu (SVA) com-
posite element, proposed to have been generated by two distinct
events (Ono et al., 1987). Presumably, the first step involved
the RNA-mediated transposition of a partial HERV-K element
polyadenylated at the 3′ end becoming a source gene for a new
retrotransposon family referred to as SINE-R, followed by an
individual SINE-R integration downstream of a region consist-
ing of CCCTCT hexamer repeats, an Alu homologous region and
a VNTR. Two of six SVA subfamilies are limited to the human
genome predominantly located in GC-rich regions, with roughly
one third found to be insertion polymorphisms (Wang et al., 2005)
and supporting continued evolution of the human genome result-
ing from more recently derived TEs.
Phenotypic changes may result from the discussed genomic
alterations including genomic rearrangements, TE integrations,
as well as various types of common nucleotide mutations caus-
ing alterations such as in the biochemical nature of the protein
product or the regulation of expression of the protein product.
In addition, genomic alterations have the potential to generate
new proteins/gene families that are composites of differing func-
tional domains as outlined in this review, plus can occur by means
of exon shuffling. One mechanism of exon shuffling is unequal
homologous recombination at sites of differing introns, occur-
ring as a result of shared repetitive sequences. Exon shuffling has
!
been proposed to be a reason for the existence and maintenance
of introns (Gilbert, 1978). More recently there has been evidence
supporting the process of both 5′ and 3′ transduction mediated
by L1 and SVA elements contributing to multiple exon shuffling
events (Moran et al., 1999; Boeke and Pickeral, 1999; Ostertag
et al., 2003; Szak et al., 2003; Damert et al., 2009; Tica et al.,
2016) generating new functional genes (Xing et al., 2006), and
further supporting the contributions of TEs to the dynamics of
genomes and consequently considered accelerators of evolution
(Nishihara, 2019).
Acknowledgements
David H Kass was supported by an Eastern Michigan University
Provost Research Support Award and a Faculty Research Fellow-
ship
Mark A Batzer was supported by National Institutes of Health
Grant RO1 GM59290.
Glossary
Gene family Set of paralogous genes with related function that
is identical or very similar.
Gene Superfamily Group of genes diverged from a common
ancestral gene resulting in nonoverlapping functions but
sharing a common domain or motif.
Genome The total DNA in a cell.
Homologous genes Related genes sharing common ancestry.
Volume 2, Issue 1, April 2021 eLS © 2021, John Wiley & Sons, Ltd. www.els.net
Genome Organisation: Human
Karyogram Representation of an entire chromosome set that
has been stained by one of several possible methods yielding
discrete banding patterns.
Paralogous genes Genes descended from a common ancestral
gene arising as a result of gene duplications.
Retrotransposon source (master) genes The limited number of
retrotransposon loci capable of generating copies integrated
into new chromosomal sites.
Sequence identity The number of characters that match exactly
between two sequences.
Sequence similarity Likeness or resemblance between two
sequences.
SINEs and LINEs Short and long interspersed repeat elements
representing a subclass of class I elements that lack LTR
sequences, and are nonautonomous and autonomous,
respectively, utilising an RNA intermediate to generate
genomic copies.
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