Mobile DNA and the TE-Thrust hypothesis: supporting evidence from the primates

  • Keith R Oliver1Email author and

    Affiliated with

    • Wayne K Greene2

      Affiliated with

      Mobile DNA20112:8

      DOI: 10.1186/1759-8753-2-8

      Received: 23 February 2011

      Accepted: 31 May 2011

      Published: 31 May 2011

      Abstract

      Transposable elements (TEs) are increasingly being recognized as powerful facilitators of evolution. We propose the TE-Thrust hypothesis to encompass TE-facilitated processes by which genomes self-engineer coding, regulatory, karyotypic or other genetic changes. Although TEs are occasionally harmful to some individuals, genomic dynamism caused by TEs can be very beneficial to lineages. This can result in differential survival and differential fecundity of lineages. Lineages with an abundant and suitable repertoire of TEs have enhanced evolutionary potential and, if all else is equal, tend to be fecund, resulting in species-rich adaptive radiations, and/or they tend to undergo major evolutionary transitions. Many other mechanisms of genomic change are also important in evolution, and whether the evolutionary potential of TE-Thrust is realized is heavily dependent on environmental and ecological factors. The large contribution of TEs to evolutionary innovation is particularly well documented in the primate lineage. In this paper, we review numerous cases of beneficial TE-caused modifications to the genomes of higher primates, which strongly support our TE-Thrust hypothesis.

      Introduction

      Building on the groundbreaking work of McClintock [1] and numerous others [214], we further advanced the proposition of transposable elements (TEs) as powerful facilitators of evolution [15] and now formalise this into 'The TE-Thrust hypothesis'. In this paper, we present much specific evidence in support of this hypothesis, which we suggest may have great explanatory power. We focus mainly on the well-studied higher primate (monkey, ape and human) lineages. We emphasize the part played by the retro-TEs, especially the primate-specific non-autonomous Alu short interspersed element (SINE), together with its requisite autonomous partner long interspersed element (LINE)-1 or L1 (Figure 1A). In addition, both ancient and recent endogenizations of exogenous retroviruses (endogenous retroviruses (ERVs)/solo long terminal repeats (sLTRs) have been very important in primate evolution (Figure 1A). The Alu element has been particularly instrumental in the evolution of primates by TE-Thrust. This suggests that, at least in some mammalian lineages, specific SINE-LINE pairs have a large influence on the trajectory and extent of evolution on the different clades within that lineage.
      http://static-content.springer.com/image/art%3A10.1186%2F1759-8753-2-8/MediaObjects/13100_2011_Article_33_Fig1_HTML.jpg
      Figure 1

      Summary of the effect of TEs on primate evolution. (A) Transposable elements (TEs) implicated in the generation of primate-specific traits. (B) Types of events mediated by TEs underlying primate-specific traits. Passive events entail TE-mediated duplications, inversions or deletions. (C) Aspects of primate phenotype affected by TEs. Based on the published data shown in Tables 3 to 6.

      The TE-Thrust Hypothesis

      The ubiquitous, very diverse, and mostly extremely ancient TEs are powerful facilitators of genome evolution, and therefore of phenotypic diversity. TE-Thrust acts to build, sculpt and reformat genomes, either actively by TE transposition and integration (active TE-Thrust), or passively, because after integration, TEs become dispersed homologous sequences that facilitate ectopic DNA recombination (passive TE-Thrust). TEs can cause very significant and/or complex coding, splicing, regulatory and karyotypic changes to genomes, resulting in phenotypes that can adapt well to biotic or environmental challenges, and can often invade new ecological niches. TEs are usually strongly controlled in the soma, where they can be damaging [16, 17], but they are allowed some limited mobility in the germline and early embryo [1820], where, although they can occasionally be harmful, they can also cause beneficial changes that can become fixed in a population, benefiting the existing lineage, and sometimes generating new lineages.

      There is generally no Darwinian selection for individual TEs or TE families, although there may be exceptions, such as the primate-specific Alu SINEs in gene-rich areas [21, 22]. Instead, according to the TE-Thrust hypothesis, there is differential survival of those lineages that contain or can acquire suitable germline repertoires of TEs, as these lineages can more readily adapt to environmental or ecological changes, and can potentially undergo, mostly intermittently, fecund radiations. We hypothesize that lineages lacking a suitable repertoire of TEs are, if all else is equal, are liable to stasis, possibly becoming 'living fossils' or even becoming extinct.

      TE activity is usually intermittent [2327], with periodic bursts of transposition due to interplay between various cellular controls, various stresses, de novo syntheses, de novo modifications, new infiltrations of DNA-TEs (by horizontal transfer), or new endogenizations of retroviruses. However, the vast majority of viable TEs usually undergo slow mutational decay and become non-viable (incapable of activity), although some superfamilies have remained active for more than 100 Myr. Episodic TE activity and inactivity, together with differential survival of lineages, suggests an explanation for punctuated equilibrium, evolutionary stasis, fecund lineages and adaptive radiations, all found in the fossil record, and for extant 'fossil species' [15, 28].

      TE-Thrust is expected to be optimal in lineages in which TEs are active and/or those that possess a high content of homogeneous TEs, both of which can promote genomic dynamism [15]. We hypothesize four main modes of TE-Thrust (Table 1), but as these are extremes of continuums, many intermediate modes are possible.
      Table 1

      Hypothesized major modes of transposable element (TE)-thrust

      Mode

      TE activity

      TE homogeneity

      TE population size

      Evolutionary outcome

      Type of TE thrust

      1

      Viable and intermittently active

      Heterogeneous

      Large

      Stasis with punctuation events

      Active

         

      Small

      Stasis with punctuation events

      Active

      2

      Viable and intermittently active

      Homogeneous

      Large

      Gradualism with punctuation events

      Active and passive

         

      Small

      Stasis with punctuation events

      Active

      3

      Non-viable/Inactive

      Heterogeneous

      Large

      Stasisa,b

      Minimalc

         

      Small

      Stasisa,b

      Minimalc

      4

      Non-viable/Inactive

      Homogeneous

      Large

      Gradualisma

      Passivec

         

      Small

      Stasisa,b

      Minimalc

      aUnless new infiltrations or reactivation of TEs occur.

      bFossil taxa are a possible outcome of prolonged stasis.

      cInactive/non-viable TEs can be exapted in a delayed fashion, which could cause some resumption of active TE-Thrust.

      Mode 1: periodically active heterogeneous populations of TEs result in stasis with the potential for intermittent punctuation events.

      Mode 2: periodically active homogenous populations of TEs result in: 1) gradualism as a result of ectopic recombination, if the TE population is large, with the potential for periodic punctuation events, or 2) stasis with the potential for periodic punctuation events if the TE population is small.

      Mode 3: non-viable heterogeneous populations of TEs, in the absence of new infiltrations, result in prolonged stasis, which can sometimes result in extinctions and/or 'living fossils'.

      Mode 4: non-viable homogenous populations of TEs, in the absence of new infiltrations, can result in: 1) gradualism as a result of ectopic recombination, if the TE population is large or 2) stasis if the TE population is small.

      These modes of TE-Thrust are in agreement with the findings of palaeontologists [29] and some evolutionary biologists [30] that punctuated equilibrium is the most common mode of evolution, but that gradualism and stasis also occur. Many extant 'living fossils' are also known.

      We acknowledge that TE-Thrust acts by enhancing evolutionary potential, and whether that potential is actually realized is heavily influenced by environmental, ecological and other factors. Moreover, there are many other 'engines' of evolution besides TE-Thrust, such as point mutation, simple sequence repeats, endosymbiosis, epigenetic modification and whole-genome duplication [3135], among others. These often complement TE-Thrust; for example, point mutations can endow duplicated or retrotransposed genes with new functions [36, 37]. There may also be other, as yet unknown, or hypothesized but unconfirmed, 'engines' of evolution.

      Higher primate genomes are very suited to TE-Thrust as they possess large homogeneous populations of TEs

      Human and other extant higher primate genomes are well endowed with a relatively small repertoire of TEs (Table 2). These TEs, which have been extensively implicated in engineering primate-specific traits (Table 3; Table 4; Table 5; Table 6), are largely relics of an evolutionary history marked by periodic bursts of TE activity [25, 38, 39]. TE activity is presently much reduced, but extant simian lineage genomes remain well suited for passive TE-Thrust, with just two elements, Alu and L1, accounting for over 60% of the total TE DNA sequence [21, 40, 41]. In humans, there are 10 times as many mostly homogeneous class I retro-TEs as there are very heterogeneous class II DNA-TEs [21]. Only L1, Alu, SVA (SINE-R, variable number of tandem repeats (VNTR), Alu) and possibly some ERVs, remain active in humans [42].
      Table 2

      Summary of the major transposable elements (TEs) found in humans

       

      Family

      Percentage of genome

      Number in genome

      Average length, bp

      Maximum length, kb

      Viable

      Potentially autonomous

      Type I: retro-TEs

      LTRa/ERVb

      8.3

      443,000

      510

      10

      No

      Yes (via reverse transcriptase)

       

      LINE1c

      16.9

      516,000

      900

      6

      Some

      Yes (via reverse transcriptase)

       

      LINE2

      3.2

      315,000

      280

      5

      No

      Yes (via reverse transcriptase)

       

      Alu SINEd

      10.6

      1,090,000

      270

      0.3

      Yes

      No

       

      MIRe SINE

      2.2

      393,000

      150

      0.26

      No

      No

       

      SVAf SINE-like composite

      0.2

      3,000

      1,400

      3

      Yes

      No

      Type II: DNA-TEs

      Many

      2.8

      294,000

      260

      3

      No

      Some (via transposase)

      aLTR = long terminal repeat

      bERV = endogenous retrovirus

      cLINE = long interspersed nuclear element

      dSINE = short interspersed nuclear element

      eMIR = mammalian-wide interspersed repeat

      fSVA = SINE-VNTR-Alu

      Table 3

      Specific examples of transposable elements (TEs) implicated in primate-specific traits: brain and sensory

      TE generated trait

      Gene affected

      Gene function

      TE responsible

      Distributiona

      Type of event

      Effect

      Tissue expression

      Type of TE-Thrust

      Reference

       

      snaRs

      Cell growth and translational regulation

      Alu

      Afr. great ape/ human

      Domestication

      Novel genes

      Brain, testis

      Active

      Parrott and Mathews, 2009 [105]

       

      BCYRN1

      Translational regulation of dendritic proteins

      Alu

      Simian

      Domestication

      Novel gene

      Brain

      Active

      Watson and Sutcliffe, 1987 [106]

       

      FLJ33706

      Unknown

      Alu

      Human

      Domestication

      Novel gene

      Brain

      Active

      Li et al., 2010 [107]

      Neuronal stability?

      SETMAR

      DNA repair and replication

      Hsmar1

      Simian

      Exonization

      Novel fusion gene

      Brain, various

      Active

      Cordaux et al., 2006 [108]

       

      Survivin

      Anti-apoptotic/brain development

      Alu

      Ape

      Exonization

      Novel isoform

      Brain, spleen

      Active

      Mola et al., 2007 [109]

       

      ADARB1

      RNA editing/neurotransmitter receptor diversity

      Alu

      >Human

      Exonization

      Novel isoform

      Brain, various

      Active

      Lai et al., 1997 [110]

       

      CHRNA1

      Synaptic transmission

      MIRb

      Great ape

      Exonization

      Novel isoform

      Neuromuscular

      Active

      Krull et al., 2007 [47]

       

      ASMT

      Melatonin synthesis

      LINE-1c

      >Human

      Exonization

      Novel isoform

      Pineal gland

      Active

      Rodriguez et al., 1994 [111]

       

      CHRNA3

      Synaptic transmission

      Alu

      Great ape

      Regulatory

      Major promoter

      Nervous system

      Active

      Fornasari et al., 1997 [112]

       

      CHRNA6

      Synaptic transmission

      Alu

      >Human

      Regulatory

      Negative regulation

      Brain

      Active

      Ebihara et al., 2002 [113]

       

      NAIP

      Anti-apoptosis (motor neuron)

      Alu

      >Human

      Regulatory

      Alternative promoters

      CNS, various

      Active

      Romanish et al., 2009 [114]

       

      CNTNAP4

      Cell recognition/adhesion

      ERVd

      >Human

      Regulatory

      Alternative promoter

      Brain, testis

      Active

      van de Lagemaat et al., 2003 [73]

       

      CCRK

      Cell cycle-related kinase

      Alu

      Simian

      Regulatory

      CpG island

      Brain

      Active

      Farcas et al., 2009 [86]

      Enhanced cognitive capacity/memory?

      GLUD2

      Neurotransmitter recycling

      Unknown

      Ape

      Retrotransposition

      Novel gene

      Brain

      Active

      Burki and Kaessmann, 2004 [37]

      Altered auditory perception?

      CHRNA9

      Cochlea hair development/ modulation of auditory stimuli

      Alu

      Human

      Deletion

      Exon loss

      Cochlea, sensory ganglia

      Passive

      Sen et al., 2006 [62]

      Trichromatic colour vision

      OPN1LW

      Cone photoreceptor

      Alu

      Old World primate

      Duplication

      Novel gene

      Retina

      Passive

      Dulai et al., 1999 [36]

      a > = Maximum known distribution.

      bMIR = mammalian-wide interspersed repeat

      cLINE = long interspersed nuclear element

      dERV = endogenous retrovirus

      Table 4

      Specific examples of transposable elements (TEs) implicated in primate-specific traits: reproduction and development

      TE generated trait

      Gene affected

      Gene function

      TE responsible

      Distributiona

      Type of event

      Effect

      Tissue expression

      Type of TE-Thrust

      Reference

      Placental morphogenesis

      Syncytin-1

      Trophoblast cell fusion

      ERVb

      Ape

      Domestication

      Novel gene

      Placenta

      Active

      Mi et al., 2000 [92]

      Placental morphogenesis

      Syncytin-2

      Trophoblast cell fusion

      ERV

      Simian

      Domestication

      Novel gene

      Placenta

      Active

      Blaise et al., 2003 [93]

       

      HERVV1

      Unknown

      ERV

      Simian

      Domestication

      Novel gene

      Placenta

      Active

      Kjeldbjerg et al., 2008 [115]

       

      HERVV2

      Unknown

      ERV

      Simian

      Domestication

      Novel gene

      Placenta

      Active

      Kjeldbjerg et al., 2008 [115]

       

      ERV3

      Development and differentiation?

      ERV

      Old World primate

      Domestication

      Novel gene

      Placenta, various

      Active

      Larsson et al., 1994 [116]

       

      DNMT1

      DNA methylation

      Alu

      >Afr. great ape

      Exonization

      Novel isoform

      Fetal, various

      Active

      Hsu et al., 1999 [117]

       

      LEPR

      Leptin receptor

      SVA

      Human

      Exonization

      Novel isoform

      Fetal liver

      Active

      Damert et al., 2004 [118]

       

      IL22RA2

      Regulation of inflammatory responses/interleukin-22 decoy receptor

      LTRc

      Great ape

      Exonization

      Novel isoform

      Placenta

      Active

      Piriyapongsa et al., 2007 [119]

       

      PPHLN1

      Epithelial differentiation/nervous-system development

      ERV/Alu/LINE-1d

      Ape

      Exonization

      Novel isoforms

      Fetal, various

      Active

      Huh et al., 2006 [120]

       

      CGB1/2

      Chorionic gonadotropin

      Alu (snaR-G1/2)

      Afr. great ape

      Regulatory

      Major promoter

      Testis

      Active

      Parrott and Mathews, 2009 [105]

       

      GSDMB

      Epithelial development

      Alu

      Ape

      Regulatory

      Major promoter

      Stomach

      Active

      Komiyama et al., 2010 [121]

       

      HYAL4

      Hyaluronidase

      LINE-1/Alu

      >Human

      Regulatory

      Major promoter

      Placenta

      Active

      van de Lagemaat et al., 2003 [73]

      Placental oestrogen synthesis

      HSD17B1

      Oestrogen synthesis

      ERV

      >Human

      Regulatory

      Major promoter

      Ovary, placenta

      Active

      Cohen et al., 2009 [122]

      Placental development

      INSL4

      Regulation of cell growth and metabolism

      ERV

      Old World primate

      Regulatory

      Major promoter

      Placenta

      Active

      Bieche et al., 2003 [123]

       

      DSCR4

      Unknown reproductive function

      ERV

      Ape

      Regulatory

      Major promoter

      Placenta, testis

      Active

      Dunn et al., 2006 [124]

       

      DSCR8

      Unknown reproductive function

      ERV

      >Ape

      Regulatory

      Major promoter

      Placenta, testis

      Active

      Dunn et al., 2006 [124]

       

      CGA

      Common subunit of chorionic gonadotropin, luteinizing, follicle-stimulating and thyroid-stimulating hormones

      Alu

      >Simian

      Regulatory

      Negative regulation

      Placenta, pituitary gland

      Active

      Scofield et al., 2000 [125]

      Globin switching

      HBE1

      Embryonic oxygen transport

      Alu

      >Human

      Regulatory

      Negative regulation

      Fetal

      Active

      Wu et al., 1990 [126]

       

      GH

      Growth hormone

      Alu

      >Human

      Regulatory

      Negative regulation

      Pituitary gland

      Active

      Trujillo et al., 2006 [127]

       

      WT1

      Urogenital development

      Alu

      >Human

      Regulatory

      Negative regulation

      Urogenital

      Active

      Hewitt et al., 1995 [128]

      Efficient placental gas exchange

      HBG1

      Fetal oxygen transport

      LINE-1

      Old World primate

      Regulatory

      Tissue-specific enhancer

      Fetal

      Active

      Johnson et al., 2006 [91]

      Placental leptin secretion

      LEP

      Metabolic regulatory hormone

      LTR

      >Human

      Regulatory

      Tissue-specific enhancer

      Placenta

      Active

      Bi et al., 1997 [129]

       

      MET

      Hepatocyte growth-factor receptor

      LINE-1

      > Afr. great ape

      Regulatory

      Alternative promoter

      Liver, Pancreas, Lung

      Active

      Nigumann et al., 2002 [71]

       

      BCAS3

      Embryogenesis/erythropoiesis

      LINE-1

      > Afr. great ape

      Regulatory

      Alternative promoter

      Fetal, various

      Active

      Wheelan et al., 2005 [130]

       

      CHRM3

      Synaptic transmission

      LINE-1

      Human

      Regulatory

      Alternative promoter

      Placenta

      Active

      Huh et al., 2009 [131]

       

      CLCN5

      Chloride transporter

      LINE-1

      >Human

      Regulatory

      Alternative promoter

      Placenta

      Active

      Matlik et al., 2006 [132]

       

      SLCO1A2

      Organic anion transporter

      LINE-1

      >Human

      Regulatory

      Alternative promoter

      Placenta

      Active

      Matlik et al., 2006 [132]

       

      CHRM3

      Synaptic transmission

      LTR

      Human

      Regulatory

      Alternative promoter

      Testis

      Active

      Huh et al., 2009 [131]

       

      IL2RB

      Growth-factor receptor

      LTR

      >Human

      Regulatory

      Alternative promoter

      Placenta

      Active

      Cohen et al., 2009 [122]

      Placental development

      ENTPD1

      Thromboregulation

      LTR

      >Human

      Regulatory

      Alternative promoter

      Placenta

      Active

      van de Lagemaat et al., 2003 [73]

       

      MKKS

      Molecular chaperone

      LTR/LINE-2

      >Human

      Regulatory

      Alternative promoter

      Testis, fetal

      Active

      van de Lagemaat et al., 2003 [73]

       

      NAIP

      Anti-apoptosis

      ERV

      >Human

      Regulatory

      Alternative promoter

      Testis

      Active

      Romanish et al., 2007 [133]

       

      EDNRB

      Placental development/circulation

      ERV

      >Human

      Regulatory

      Alternative promoter

      Placenta

      Active

      Medstrand et al., 2001 [134]

      Placental development

      PTN

      Growth factor

      ERV

      Ape

      Regulatory

      Alternative promoter

      Trophoblast

      Active

      Schulte et al. 1996 [135]

       

      MID1

      Cell proliferation and growth

      ERV

      Old World primate

      Regulatory

      Alternative promoter

      Placenta, fetal kidney

      Active

      Landry et al., 2002 [136]

       

      NOS3

      Endothelial nitric oxide synthesis

      ERV

      >Human

      Regulatory

      Alternative promoter

      Placenta

      Active

      Huh et al., 2008 [137]

       

      GSDMB

      Epithelial development

      ERV

      Ape

      Regulatory

      Alternative promoter

      Various

      Active

      Sin et al., 2006 [138]

      Placental oestrogen synthesis

      CYP19

      Oestrogen synthesis

      ERV

      Simian

      Regulatory

      Alternative promoter

      Placenta

      Active

      van de Lagemaat et al., 2003 [73]

       

      AMACs

      Fatty-acid synthesis

      SVA

      Afr. great ape

      Retrotransposition

      Novel genes

      Placenta, testis

      Active

      Xing et al., 2006 [139]

       

      POTEs

      Pro-apoptosis/spermatogenesis

      LINE-1

      Ape

      Retrotransposition

      Novel fusion genes

      Testis, ovary, prostate, placenta

      Active

      Lee et al., 2006 [140]

       

      PIPSL

      Intracellular protein trafficking

      LINE-1

      >Great ape

      Retrotransposition

      Novel fusion gene

      Testis

      Active

      Babushok et al., 2007 [141]

       

      CDYs

      Chromatin modification

      Unknown

      Simian

      Retrotransposition

      Novel genes

      Testis

      Active

      Lahn and Page, 1999 [142]

       

      ADAM20/21

      Membrane metalloprotease

      Unknown

      >Human

      Retrotransposition

      Novel genes

      Testis

      Active

      Betran and Long, 2002 [143]

      Placental growth hormone secretion

      GH

      Placental growth hormone

      Alu

      Simian

      Duplication

      Novel genes

      Placenta

      Passive

      De Mendoza et al., 2004 [88]

       

      Chr19 miRNAs

      Unknown

      Alu

      Simian

      Duplication

      Novel genes

      Placenta

      Passive

      Zhang et al., 2008 [144]

      Enhanced immune tolerance at fetal-maternal interface

      LGALS13/14/16

      Carbohydrate recognition/immune regulation

      LINE-1

      Simian

      Duplication

      Novel genes

      Placenta

      Passive

      Than et al., 2009 [145]

      Efficient placental gas exchange

      HBG2

      Fetal oxygen transport

      LINE-1

      Simian

      Duplication

      Novel gene

      Fetal

      Passive

      Fitch et al., 1991 [90]

      a > = Maximum known distribution.

      bERV = endogenous retrovirus

      cLTR = long terminal repeat

      dLINE = long interspersed nuclear element

      Table 5

      Specific examples of transposable elements (TEs) implicated in primate-specific traits: immune defence

      TE generated trait

      Gene affected

      Gene function

      TE responsible

      Distributiona

      Type of event

      Effect

      Tissue expression

      Type of TE-Thrust

      Reference

      Soluble CD55

      CD55

      Complement regulation

      Alu

      >Human

      Exonization

      Novel isoform

      Various

      Active

      Caras et al., 1987 [146]

      Intracellular TNFR

      P75TNFR

      Tumour necrosis factor receptor

      Alu

      Old World primate

      Exonization

      Novel isoform

      Various

      Active

      Singer et al., 2004 [147]

      Altered infectious-disease resistance?

      IRGM

      Intracellular pathogen resistance

      ERVb

      Afr. Great Ape

      Regulatory

      Major promoter

      Various

      Active

      Bekpen et al., 2009 [148]

      Altered infectious-disease resistance?

      IL29

      Antiviral cytokine

      Alu/LTRc

      >Human

      Regulatory

      Positive regulation

      Dendritic cells, epithelial cells

      Active

      Thomson et al., 2009 [149]

       

      FCER1G

      IgE/IgG Fc receptor/T cell antigen receptor

      Alu

      Ape

      Regulatory

      Positive/negative regulation

      T cells, basophils

      Active

      Brini et al., 1993 [150]

       

      CD8A

      T cell interaction with class I MHC

      Alu

      Ape

      Regulatory

      Tissue-specific enhancer

      T cells

      Active

      Hambor et al., 1993 [151]

      Red cell ABH antigen expression

      FUT1

      Fucosyltransferase

      Alu

      Ape

      Regulatory

      Alternative promoter

      Erythrocytes

      Active

      Apoil et al., 2000 [96]

       

      TMPRSS3

      Membrane serine protease

      Alu/LTR

      >Human

      Regulatory

      Alternative promoter

      Peripheral blood leukocytes

      Active

      van de Lagemaat et al., 2003 [73]

      Colon Le antigen expression

      B3GALT5

      Galactosyltransferase

      ERV

      Old World primate

      Regulatory

      Alternative promoter

      Colon, small intestine, breast

      Active

      Dunn et al., 2003 [152]

      Prolactin potentiation of the adaptive immune response

      PRL

      Regulation of lactation and reproduction

      ERV

      Old World primate

      Regulatory

      Alternative promoter

      Lymphocytes, endometrium

      Active

      Gerlo et al., 2006 [153]

       

      ST6GAL1

      Sialyltransferase

      ERV

      >Human

      Regulatory

      Alternative promoter

      B lymphocytes

      Active

      van de Lagemaat et al., 2003 [73]

      Vitamin D regulation of cathelicidin antimicrobial peptide gene

      CAMP

      Antimicrobial peptide

      Alu

      Simian

      Regulatory

      Vitamin D responsiveness

      Myeloid cells, various

      Active

      Gombart et al., 2009 [98]

       

      MPO

      Myeloperoxidase/microbicidal enzyme

      Alu

      >Human

      Regulatory

      Thyroid hormone/retinoic acid responsiveness

      Myeloid cells

      Active

      Piedrafita et al., 1996 [154]

      Altered infectious-disease resistance?

      IFNG

      Antiviral/immunoregulatory factor

      Alu

      Old World primate

      Retrotransposition

      Novel positive regulatory element

      Natural killer cells, T cells

      Active

      Ackerman et al., 2002 [155]

      Absence of N-glycolylneuraminic acid/altered infectious-disease resistance?

      CMAH

      N-glycolylneuraminic acid synthesis

      Alu

      Human

      Gene disruption

      Gene loss

      Various

      Active

      Hayakawa et al., 2001 [104]

       

      IRGM

      Intracellular pathogen resistance

      Alu

      Old and New World monkey

      Gene disruption

      Gene loss

      Various

      Active

      Bekpen et al., 2009 [148]

      Altered malaria resistance?

      HBA2

      Oxygen transport

      Alu

      >Ape

      Duplication

      Novel gene

      Erythrocytes

      Passive

      Hess et al., 1983 [156]

      a > = Maximum known distribution.

      bERV = endogenous retrovirus

      cLTR = long terminal repeat

      Table 6

      Specific Examples of transposable elements (TEs) implicated in primate-specific traits: metabolic and other

      TE generated trait

      Gene affected

      Gene function

      TE responsible

      Distributiona

      Type of event

      Effect

      Tissue expression

      Type of TE-Thrust

      Reference

       

      RNF19A

      Ubiquitin ligase

      Alu

      > Human

      Exonization

      Novel isoform

      Various

      Active

      Huh et al., 2008 [157]

       

      BCL2L11

      Pro-apoptotic

      Alu

      > Human

      Exonization

      Novel isoform

      Various

      Active

      Wu et al., 2007 [158]

       

      BCL2L13

      Pro-apoptotic

      Alu

      > Human

      Exonization

      Novel isoform

      Various (cytosolic instead of mitochondrial)

      Active

      Yi et al., 2003 [159]

       

      SFTPB

      Pulmonary surfactant

      Alu/ERVb

      Primate

      Exonization

      Novel isoform

      Various

      Active

      Lee et al., 2009 [160]

      Efficiency of ZNF177 transcription and translation

      ZNF177

      Transcriptional regulator

      Alu/LINE-1c/ERV

      > Human

      Exonization

      Novel isoform

      Various

      Active

      Landry et al., 2001 [161]

      Production of salivary amylase

      AMY1s

      Starch digestion

      ERV

      Old World primate

      Regulatory

      Major promoter

      Salivary gland

      Active

      Ting et al., 1992 [99]

       

      BAAT

      Bile metabolism

      ERV

      > Human

      Regulatory

      Major promoter

      Liver

      Active

      van de Lagemaat et al., 2003 [73]

       

      CETP

      Cholesterol metabolism

      Alu

      > Human

      Regulatory

      Negative regulation

      Liver

      Active

      Le Goff et al., 2003 [162]

      Absence of FMO1 in adult liver/altered drug metabolism?

      FMO1

      Xenobiotic metabolism

      LINE-1

      > Human

      Regulatory

      Negative regulation in liver

      Kidney

      Active

      Shephard et al., 2007 [163]

       

      RNF19A

      Ubiquitin ligase

      LTRd

      > Human

      Regulatory

      Alternative promoter

      Various

      Active

      Huh et al., 2008 [157]

       

      APOC1

      Lipid metabolism

      ERV

      Ape

      Regulatory

      Alternative promoter

      Various

      Active

      Medstrand et al., 2001 [134]

       

      KRT18

      Epithelial keratin

      Alu

      > Human

      Regulatory

      Retinoic acid responsiveness

      Various

      Active

      Vansant and Reynolds, 1995 [77]

       

      PTH

      Parathyroid hormone

      Alu

      > Old World primate

      Regulatory

      Negative calcium responsiveness

      Parathyroid gland

      Active

      McHaffie and Ralston, 1995 [164]

       

      PRKACG

      cAMP signalling/regulation of metabolism

      Unknown

      > Old World primate

      Retrotransposition

      Novel gene

      Various

      Active

      Reinton et al., 1998 [165]

       

      NBR2

      Unknown

      Alu

      Old World primate

      Duplication

      Novel gene

      Various

      Passive

      Jin et al., 2004 [166]

       

      LRRC37A

      Unknown

      Alu

      Old World primate

      Duplication

      Novel genes

      Various

      Passive

      Jin et al., 2004 [166]

       

      ARF2

      GTPase/vesicle trafficking

      Alu

      Great ape

      Inversion

      Novel fusion gene

      Various

      Passive

      Jin et al., 2004 [166]

      Altered arterial wall function?

      ELN

      Elastin

      Alu

      > Old World primate/human

      Deletion

      Exon losses

      Various

      Passive

      Szabo et al., 1999 [167]

      Low body mass?

      ASIP

      Energy metabolism/pigmentation

      Alu

      Lesser ape (gibbon)

      Deletion

      Gene loss

      Various

      Passive

      Nakayama and Ishida, 2006 [101]

      a > = Maximum known distribution.

      bERV = endogenous retrovirus

      cLINE = long interspersed nuclear element

      dLTR = long terminal repeat

      L1 and the primate-specific Alu predominate in simians [21, 40, 41], and thus strongly contribute to TE-Thrust in this lineage (Figure 1A). The autonomous L1 is almost universal in mammals, whereas the non-autonomous Alu, like most SINEs, is conspicuously lineage-specific, having been synthesized de novo, extremely unusually, from a 7SL RNA-encoding gene. The confinement of Alu to a single mammalian order is typical of younger SINEs, whereas ancient SINEs, or exapted remnants of them, may be detectable across multiple vertebrate classes [43]. Alu possesses additional unusual characteristics: extreme abundance (1.1 million copies, occurring every 3 kb on average in the human genome), frequent location in gene-rich regions, and a lack of evolutionary divergence [21, 44]. Their relatively high homology is most easily explained as being the result of functional selection helping to prevent mutational drift. Thus, Alus have been hypothesized to serve biological functions in their own right, leading to their selection and maintenance in the primate genome [22]. For example, A-to-I RNA editing, which has a very high prevalence in the human genome, mainly occurs within Alu elements [45], which would seem to provide primates with a genetic sophistication beyond that of other mammals. Alus may therefore not represent a peculiar, evolutionary neutral invasion, but rather positively selected functional elements that are resistant to mutational degradation [46]. This has significance for TE-Thrust, as it would greatly prolong the usefulness of Alus as facilitators of evolution within primate lineages.

      Other human retro-TEs include the fossil tRNA mammalian-wide intespersed repeat (MIR) SINE, which amplified approximately 130 Mya [21, 47] and the much younger SVA, a non-autonomous composite element partly derived from ERV and Alu sequences, which is specific to the great apes and humans [48]. Like Alus, SVAs are mobilised by L1-encoded enzymes and, similar to Alu, a typical full-length SVA is GC-rich, and thus constitutes a potential mobile CpG island. Importantly, ERVs are genome builders/modifiers of exogenous origin [49]. Invasion of ERVs seems to be particularly associated with a key mammalian innovation, the placenta (Table 4). The endogenisation of retroviruses and the horizontal transfer of DNA-TEs into germlines clearly show that the Weismann Barrier is permeable, contrary to traditional theory.

      The DNA-TEs, which comprise just 3% of the human genome, are extremely diverse, but are now completely inactive [21, 50]. Although some have been exapted within the simian lineage as functional coding sequences (Table 3; Table 4; Table 5; Table 6), DNA-TEs, it seems, cannot now be a significant factor for TE-Thrust in primates, unless there are new infiltrations.

      TE-Thrust influences evolutionary trajectories

      A key proposal of our TE-Thrust hypothesis is that TEs can promote the origin of new lineages and drive lineage divergence through the engineering of specific traits. Ancestral TEs shared across very many lineages can, by chance, lead to the delayed generation of traits in one lineage but not in another. For example, more than 100 copies of the ancient amniote-distributed AmnSINE1 are conserved as non-coding elements specifically among mammals [51]. However, as they often show a narrow lineage specificity, we hypothesize that younger SINEs (with their partner LINEs) may have a large influence upon the trajectory and the outcomes of the evolution within clades, as is apparent with the Alu/L1 pair in primates (Figure 1A). Probably not all SINEs are equal in this ability; it seems that some SINEs are more readily mobilised than others, and when mobilised, some SINEs are more effective than others at facilitating evolution by TE-Thrust. The extremely abundant primate Alu dimer seems to illustrate this. Whereas the overwhelming majority of SINEs are derived from tRNAs, Alus may have proliferated so successfully because they are derived from the 7SL RNA gene [52], which is part of the signal recognition particle (SRP) that localises to ribosomes. Alu RNAs can therefore bind proteins on the SRP and thus be retained on the ribosome, in position to be retrotransposed by newly synthesized proteins encoded by their partner L1 LINEs [53].

      Among the primates, the simians have undergone the greatest evolutionary transitions and radiation. Of the approximately 367 extant primate species, 85% are simians, with the remainder being prosimians, which diverged about 63 Mya. Significantly, large amplifications of L1, and thus of Alus and other sequences confined to simians, offer a plausible explanation for the lack of innovation in the trajectory of evolution in the prosimian lineages, compared with the innovation in the simian lineages. Since their divergence from the basal primates, the simians have experienced repeated periods of intense L1 activity that occurred from about 40 Mya to about 12 Mya [54]. The highly active simian L1s were responsible for the very large amplification of younger Alus and of many gene retrocopies [55]. Possibly, differential activity of the L1/Alu pair may have driven the trajectory and divergence of the simians, compared with the prosimians. The greater endogenization of some retroviruses in simians compared with prosimians [56] may also have played a part. These events may also explain the larger genome size of the simians compared with prosimians [57].

      A significant feature of Alus is their dimeric structure, involving a fusion of two slightly dissimilar arms [58]. This added length and complexity seems to increase their effectiveness as a reservoir of evolutionarily useful DNA sequence or as an inducer of ectopic recombination. It may therefore be no coincidence that simian genomes are well endowed with dimeric Alus. Viable SINEs in the less fecund and less evolutionary innovative prosimians are heterogeneous, and include the conventional dimeric Alu, Alu-like monomers, Alu/tRNA dimers and tRNA SINEs [59]. This distinctly contrasts with simian SINEs; in simians, viable SINEs are almost entirely dimeric Alus. Thus, both qualitatively and quantitatively, the Alu dimer seems to represent a key example of the power of a SINE to strongly influence evolutionary trajectory.

      Although these coincident events cannot, by themselves, be a clear indication of cause and effect, distinct Alu subfamilies (AluJ, AluS, AluY) correlate with the divergence of simian lineages [38, 39]. Whereas the AluJ subfamily was active about 65 Mya when the separation and divergence between the simians and the prosimians occurred, the AluS subfamily was active beginning at about 45 Mya, when the Old World monkey proliferation occurred, followed by a surge in AluY activity and expansion beginning about 30 Mya, contemporaneous with the split between apes and Old World monkeys [38, 39]. Thus, periodic expansions of Alu subfamilies in particular seem to correspond temporally with major divergence points in primate evolution. More recent Alu activity may be a factor in the divergence of the human and chimpanzee lineages, with Alus having been three times more active in humans than in chimpanzees [40, 60]. Moreover, at least two new Alu subfamilies (AluYa5 and AluYb8) have amplified specifically within the human genome since the human-chimpanzee split [40, 60, 61].

      Passive TE-Thrust mediated by the Alu/L1 pair has also been evident as a force contributing to lineage divergence in the primates. Ectopic recombinations between Alus, in particular, are a frequent cause of lineage-specific deletion, duplication or rearrangement. Comparisons between the human and chimpanzee genomes have revealed the extent to which they have passively exerted their effects in the relatively recent evolutionary history of primates. An examination of human-specific Alu recombination-mediated deletion (ARMD) identified 492 ARMD events responsible for the loss of about 400 kb of sequence in the human genome [62]. Likewise, Han et al.[63] reported 663 chimpanzee-specific ARMD events, deleting about 771 kb of genomic sequence, including exonic sequences in six genes. Both studies suggested that ARMD events may have contributed to the genomic and phenotypic diversity between chimpanzees and humans. L1-mediated recombination also seems to be a factor in primate evolution, with Han et al.[64] reporting 50 L1-mediated deletion events in the human and chimpanzee genomes. The observed high enrichment of TEs such as Alu at low-copy-repeat junctions indicates that TEs have been an important factor in the generation of segmental duplications that are uniquely abundant in primate genomes [39]. Such genomic duplications provide a major avenue for genetic innovation by allowing the functional specialization of coding or regulatory sequences. Karyotypic changes are thought to be an important factor in speciation [65]. Major differences between the human and chimpanzee genomes include nine pericentric inversions, and these have also been linked to TE-mediated recombination events [66]. It thus seems that both the active and passive effects of Alu and L1 have greatly facilitated and influenced the trajectory of simian evolution by TE-Thrust. Transfer RNA-type SINEs, with suitable partner LINEs, probably perform this role in other lineages.

      TE-Thrust affects evolutionary trajectory by engineering lineage-specific traits

      TEs can act to generate genetic novelties and thus specific phenotypic traits in numerous ways. Besides passively promoting exon, gene or segmental duplications (or deletions) by unequal recombination, or by disruption of genes via insertion, TEs can actively contribute to gene structure or regulation via exaptation. On multiple occasions, TEs have been domesticated to provide the raw material for entire genes or novel gene fusions [11]. More frequently, TEs have contributed partially to individual genes through exonization after acquisition of splice sites [67, 68]. Independent exons generated by TEs are often alternatively spliced, and thereby result in novel expressed isoforms that increase the size of the transcriptome [69]. The generation of novel gene sequences during evolution seems to be heavily outweighed by genetic or epigenetic changes in the transcriptional regulation of pre-existing genes [34, 70]. Consistent with this, much evidence indicates that a major way in which TEs have acted to functionally modify primate genomes is by actively inserting novel regulatory elements adjacent to genes, thus silencing or enhancing expression levels or changing expression patterns, often in a tissue-specific manner [7173]. Moreover, because they are highly repetitious and scattered, TEs have the capacity to affect gene expression on a genome-wide scale by acting as distributors of regulatory sequences or CpG islands in a modular form [74]. Many functional binding sites of developmentally important transcription factors have been found to reside on Alu repeats [75]. These include oestrogen receptor-dependent enhancer elements [76] and retinoic acid response elements, which seem to have been seeded next to retinoic acid target genes throughout the primate genome by the AluS subfamily [77]. As a consequence, TEs are able to contribute significantly to the species-specific rewiring of mammalian transcriptional regulatory networks during pre-implantation embryonic development [78]. Similarly, primate-specific ERVs have been implicated in shaping the human p53 transcriptional network [79] and rewiring the core regulatory network of human embryonic stem cells [80].

      Certain classes of retro-TEs can actively generate genetic novelty using their retrotranspositional mechanism to partially or fully duplicate existing cellular genes. Duplication is a crucial aspect of evolution, which has been particularly important in vertebrates, and constitutes the primary means by which organisms evolve new genes [81]. LINEs and SVAs have a propensity to transduce host DNA due to their weak transcriptional termination sites, so that 3' flanking regions are often included in their transcripts. This can lead to gene duplication, exon shuffling or regulatory-element seeding, depending on the nature of the sequence involved [37, 82, 83]. Duplication of genes can also occur via the retrotransposition of mRNA transcripts by LINEs. Such genes are termed retrocopies, which, after subsequent useful mutation, can sometimes evolve into retrogenes, with a new, related function. There are reportedly over one thousand transcribed retrogenes in the human genome [84], with about one new retrogene per million years having emerged in the human lineage during the past 63 Myr [26]. Some primate retrogenes seem to have evolved highly beneficial functions, such as GLUD2[37].

      Specific evidence for TE-Thrust: examples of traits engineered by TEs in the higher primates

      TEs seem to have heavily influenced the trajectories of primate evolution and contributed to primate characteristics, as the simians in particular have undergone major evolutionary advancements in cognitive ability and physiology (especially reproductive physiology). The advancement and radiation of the simians seems to be due, in part and all else being equal, to exceptionally powerful TE-Thrust, owing to its especially effective Alu dimer, partnered by very active novel L1 families, supplemented by ERVs and LTRs. These have engineered major changes in the genomes of the lineage(s) leading to the simian radiations and major transitions. We identified more than 100 documented instances in which TEs affected individual genes and thus were apparently implicated at a molecular level in the origin of higher primate-specific traits (Table 3; Table 4; Table 5; Table 6). The Alu SINE dominated, being responsible for nearly half of these cases, with ERVs/sLTRs being responsible for a third, followed by L1-LINEs at 15% (Figure 1A). Just 2% were due to the young SVAs, and 1% each to ancient MIR SINEs and DNA-TEs. More than half the observed changes wrought by TEs were regulatory (Figure 1B). As discussed below, TEs seem to have influenced four main aspects of the primate phenotype: brain and sensory function, reproductive physiology, immune defence, and metabolic/other (Figure 1C and Table 3; Table 4; Table 5; Table 6). Notably, ERVs, which are often highly transcribed in the germline and placenta [85], were strongly associated with reproductive traits, whereas Alus influenced these four aspects almost equally (Figure 2).
      http://static-content.springer.com/image/art%3A10.1186%2F1759-8753-2-8/MediaObjects/13100_2011_Article_33_Fig2_HTML.jpg
      Figure 2

      Comparison of aspects of primate phenotype affected by (A) Alu elements and (B) LTR/ERVs. Based on the published data shown in Tables 3 to 6.

      Brain and sensory function

      The large brain, advanced cognition and enhanced colour vision of higher primates are distinct from those of other mammals. The molecular basis of these characteristics remains to be fully defined, but from evidence already available, TEs (particularly Alus) seem to have contributed substantially via the origination of novel genes and gene isoforms, or via altered gene transcription (Table 3). Most of the neuronal genes affected by TEs are restricted to the apes, and they seem to have roles in synaptic function and plasticity, and hence learning and memory. These genes include multiple neurotransmitter receptor genes and glutamate dehydrogenase 2 (GLUD2), a retrocopy of GLUD1 that has acquired crucial point mutations. GLUD2 encodes glutamate dehydrogenase, an enzyme that seems to have increased the cognitive powers of the apes through the enhancement of neurotransmitter recycling [37]. The cell cycle-related kinase (CCRK) gene represents a good example of how the epigenetic modification of TEs can be mechanistically linked to the transcriptional regulation of nearby genes [86]. In simians, this gene possesses regulatory CpGs contained within a repressor Alu element, and these CpGs are more methylated in the cerebral cortex of human compared with chimpanzee. Concordantly, CCRK is expressed at higher levels in the human brain [86]. TEs may also affect the brain at a somatic level, because embryonic neural progenitor cells have been found to be permissive to L1 activity in humans [87]. This potentially provides a mechanism for increasing neural diversity and individuality. As our human lineage benefits from a diversity of additional individual talents, as well as shared talents, this phenomenon, if confirmed, could increase the 'fitness' of the human lineage, and is entirely consistent with the concept of differential survival of lineages, as stated in our TE-Thrust hypothesis.

      The trichromatic vision of Old World monkeys and apes immensely enhanced their ability to find fruits and other foods, and probably aided them in group identity. This trait evidently had its origin in an Alu-mediated gene-duplication event that occurred about 40 Mya, and subsequently resulted in two separate cone photoreceptor (opsin) genes [36], the tandem OPN1LW and OPN1MW, which are sensitive to long- and medium-wave light respectively. Other mammals possess only dichromatic vision.

      Reproductive physiology

      Compared with other mammals, simian reproduction is characterized by relatively long gestation periods and by the existence of a hemochorial-type placenta that has evolved additional refinements to ensure efficient fetal nourishment. Available data suggests that TE-Thrust has contributed much of the uniqueness of the higher primate placenta, which seems to be more invasive than that of other mammals, and releases a large number of factors that modify maternal metabolism during pregnancy. These characteristics appear to be due to the generation of novel placenta genes and to various TEs having been exapted as regulatory elements to expand or enhance the expression of pre-existing mammalian genes in the primate placenta (Table 4). The growth hormone (GH) gene locus is particularly notable for having undergone rapid evolution in the higher primates compared with most other mammals. A crucial aspect of this evolutionary advance was a burst of gene-duplication events in which Alu-mediated recombination is implicated as a driving force [88]. The simians thus possess between five and eight GH gene copies, and these show functional specialization, being expressed in the placenta, in which they are thought to influence fetal access to maternal resources during pregnancy [88, 89]. Longer gestation periods in simians were accompanied by adaptations to ensure an adequate oxygen supply. One key event was an L1-mediated duplication of the HBG globin gene in the lineage leading to the higher primates, which generated HBG1 and HBG2[90]. HBG2 subsequently acquired expression specifically in the simian fetus, in which it ensures the high oxygen affinity of fetal blood for more efficient oxygen transfer across the placenta. Old World primates additionally express HBG1 in the fetus, owing to an independent LINE insertion at the beta globin locus [91]. Thus, the important process of placental gas exchange has been extensively improved by TEs in simians, in contrast to that of many mammals, including prosimians, in which fetal and adult haemoglobins are the same.

      Two prominent examples of functionally exapted genes whose sequences are entirely TE-derived are syncytin-1 (ERVWE1) and syncytin-2 (ERVWE2). Both of these primate-specific genes are derived from ERV envelope (env) genes [92, 93]. The syncytins play a crucial role in simian placental morphogenesis by mediating the development of the fetomaternal interface, which has a fundamental role in allowing the adequate exchange of nutrients and other factors between the maternal bloodstream and the fetus. In a remarkable example of convergent evolution, which attests to the importance of this innovation, two ERV env genes, syncytin-A and syncytin-B, independently emerged in the rodent lineage about 20 Mya [94], as did syncytin-Ory1 within the lagomorphs 12-30 Mya, and these exhibit functional characteristics analogous to the primate syncytin genes [95]. This example, as well as many others (Table 3; Table 4; Table 5; Table 6) suggests the possibility that TE-Thrust may be an important factor in convergent evolution, a phenomenon that can be difficult to explain by traditional theories.

      Immune defence

      Immune-related genes were probably crucial to the primate lineage by affording protection from potentially lethal infectious diseases. TEs have been reported to contribute to higher primate-restricted transcripts, or to the expression of a wide variety of immunologically relevant genes (Table 5). One example is the insertion of an AluY element into intron 1 of the fucosyltransferase (FUT)1 gene in an ancestor of humans and apes. This enabled erythrocytic expression of FUT1, and thus the ABO blood antigens [96], an adaptation linked to the selective pressure by malarial infection [97]. A particularly good example of a primate-specific adaptation that can be accounted for by a TE is the regulation of the cathelicidin antimicrobial peptide (CAMP) gene by the vitamin D pathway. Only simians possess a functional vitamin D response element in the promoter of this gene, which is derived from the insertion of an AluSx element. This genetic alteration enhances the innate immune response of simians to infection, and potentially counteracts the anti-inflammatory properties of vitamin D [98].

      Metabolic/other

      TEs seem to underlie a variety of other primate adaptations, particularly those associated with metabolism (Table 6). A striking example, related to dietary change, was the switching of the expression of certain α-amylase genes (AMY1A, AMY1B and AMY1C) from the pancreas to the salivary glands of Old World primates. This event, which was caused by the genomic insertion of an ERV acting as a tissue-specific promoter [99], facilitated the utilization of a higher starch diet in some Old World primates. This included the human lineage, in which consumption of starch became increasingly important, as evidenced by the average human having about three times more AMY1 gene copies than chimpanzees [100]. Another example was the loss of a 100 kb genomic region in the gibbons, due to homologous recombination between AluSx sites [101], resulting in gibbons lacking the ASIP gene involved in the regulation of energy metabolism and pigmentation, which may help to account for their distinctive low body mass, so beneficial for these highly active arboreal primates.

      TE-Thrust and divergence of the human lineage

      Human and chimpanzee genomes exhibit discernable differences in terms of TE repertoire, TE activity and TE-mediated recombination events [21, 40, 54, 6064]. Thus, although nucleotide substitutions to crucial genes are important [31], TE-Thrust is likely to have made a significant contribution to the relatively recent divergence of the human lineage [102, 103]. In support of this, at least eight of the examples listed (Table 3; Table 4; Table 5; Table 6) are unique to humans. A notable example of a human-specific TE-mediated genomic mutation was the disruption of the CMAH gene, which is involved in the synthesis of a common sialic acid (Neu5Gc), by an AluY element over 2 Mya [104]. This may have conferred on human ancestors a survival advantage by decreasing infectious risk from microbial pathogens known to prefer Neu5Gc as a receptor.

      Conclusions

      A role for TEs in evolution has long been recognized by many, yet its importance has probably been underestimated. Using primates as exemplar lineages, we have assessed specific evidence, and conclude that it points strongly to an instrumental role for TEs, via TE-Thrust, in engineering the divergence of the simian lineage from other mammalian lineages. TEs, particularly Alu SINEs, have essentially acted as a huge primate-restricted stockpile of potential exons and regulatory regions, and thereby have provided the raw material for these evolutionary transitions. TEs, including Alu SINEs, L1 LINEs, ERVs and LTRs have, through active TE-Thrust, contributed directly to the primate transcriptome, and even more significantly by providing regulatory elements to alter gene expression patterns. Via passive TE-Thrust, homologous Alu and L1 elements scattered throughout the simian genome have led to both genomic gain, in the form of segmental and gene duplications, and genomic loss, by promoting unequal recombination events. Collectively, these events seem to have heavily influenced the trajectories of primate evolution and contributed to characteristic primate traits, as the simian clades especially have undergone major evolutionary advancements in cognitive ability and physiology. Although as yet incompletely documented, the evidence presented here supports the hypothesis that TE-Thrust may be a pushing force for numerous advantageous features of higher primates. These very beneficial features apparently include enhanced brain function, superior fetal nourishment, valuable trichromatic colour vision, improved metabolism, and resistance to infectious-disease agents. Such large evolutionary benefits to various primate clades, brought about by various TE repertories, powerfully demonstrate that if TEs are 'junk' DNA then there is indeed much treasure in the junkyard, and that the TE-Thrust hypothesis could become an important part of some future paradigm shift in evolutionary theory.

      Abbreviations

      ARMD: 

      Alu recombination-mediated deletion

      DNA-TE: 

      DNA transposon

      ERV: 

      endogenous retrovirus

      L1: 

      LINE-1

      LINE: 

      long interspersed nuclear element

      LTR: 

      long terminal repeat

      MIR: 

      mammalian-wide interspersed repeat

      Mya: 

      million years ago

      Myr: 

      million years

      retro-TE: 

      retrotransposable element

      RT: 

      reverse transcriptase

      SINE: 

      short interspersed nuclear element

      SVA: 

      SINE-VNTR-Alu

      TE: 

      transposable element.

      Declarations

      Acknowledgements

      We are grateful to Professor Jen McComb of Murdoch University for critical assessment of the manuscript.

      Authors’ Affiliations

      (1)
      Faculty of Science and Engineering, School of Biological Sciences and Biotechnology, Murdoch University
      (2)
      Faculty of Health Sciences, School of Veterinary and Biomedical Sciences, Murdoch University

      References

      1. McClintock B: Controlling elements and the gene. Cold Spring Harb Symp Quant Biol. 1956, 21: 197-216.PubMedView Article
      2. Georgiev GP: Mobile genetic elements in animal cells and their biological significance. Eur J Biochem. 1984, 145: 203-220. 10.1111/j.1432-1033.1984.tb08541.x.PubMedView Article
      3. Brosius J: Retroposons - seeds of evolution. Science. 1991, 251: 753-10.1126/science.1990437.PubMedView Article
      4. Fedoroff NV: Transposable elements as a molecular evolutionary force. Ann NY Acad Sci. 1999, 870: 251-264. 10.1111/j.1749-6632.1999.tb08886.x.PubMedView Article
      5. Kidwell MG, Lisch DR: Perspective: transposable elements, parasitic DNA, and genome evolution. Evolution. 2001, 55: 1-24.PubMedView Article
      6. Bowen NJ, Jordan IK: Transposable elements and the evolution of eukaryotic complexity. Curr Issues Mol Biol. 2002, 4: 65-76.PubMed
      7. Deininger PL, Moran JV, Batzer MA, Kazazian HH: Mobile elements and mammalian genome evolution. Curr Opin Genet Dev. 2003, 13: 651-658. 10.1016/j.gde.2003.10.013.PubMedView Article
      8. Kazazian HH: Mobile elements: drivers of genome evolution. Science. 2004, 303: 1626-1632. 10.1126/science.1089670.PubMedView Article
      9. Wessler SR: Eukaryotic transposable elements: teaching old genomes new tricks. The Implicit Genome. Edited by: Caporale LH. 2006, New York: Oxford University Press, 138-165.
      10. Biémont C, Vieira C: Genetics: junk DNA as an evolutionary force. Nature. 2006, 443: 521-524. 10.1038/443521a.PubMedView Article
      11. Volff JN: Turning junk into gold: domestication of transposable elements and the creation of new genes in eukaryotes. Bioessays. 2006, 28: 913-922. 10.1002/bies.20452.PubMedView Article
      12. Feschotte C, Pritham EJ: DNA transposons and the evolution of eukaryotic genomes. Annu Rev Genet. 2007, 41: 331-368. 10.1146/annurev.genet.40.110405.090448.PubMed CentralPubMedView Article
      13. Muotri AR, Marchetto MC, Coufal NG, Gagen FH: The necessary junk: new functions for transposable elements. Hum Mol Genet. 2007, 16: R159-R167. 10.1093/hmg/ddm196.PubMedView Article
      14. Böhne A, Brunet F, Galiana-Arnoux D, Schultheis C, Volff JN: Transposable elements as drivers of genomic and biological diversity in vertebrates. Chromosome Res. 2008, 16: 203-215. 10.1007/s10577-007-1202-6.PubMedView Article
      15. Oliver KR, Greene WK: Transposable elements: powerful facilitators of evolution. BioEssays. 2009, 31: 703-714. 10.1002/bies.200800219.PubMedView Article
      16. Matzke MA, Mette MF, Aufsatz W, Jakowitsch J, Matzke AJ: Host defenses to parasitic sequences and the evolution of epigenetic control mechanisms. Genetica. 1999, 107: 271-287. 10.1023/A:1003921710672.PubMedView Article
      17. Schulz WA, Steinhoff C, Florl AR: Methylation of endogenous human retroelements in health and disease. Curr Top Microbiol Immunol. 2006, 310: 211-250. 10.1007/3-540-31181-5_11.PubMed
      18. Dupressoir A, Heidmann T: Germ line-specific expression of intracisternal A-particle retrotransposons in transgenic mice. Mol Cell Biol. 1996, 16: 4495-4503.PubMed CentralPubMedView Article
      19. Brouha B, Meischl C, Ostertag E, de Boer M, Zhang Y, Neijens H, Roos D, Kazazian HH: Evidence consistent with human L1 retrotransposition in maternal meiosis I. Am J Hum Genet. 2002, 71: 327-336. 10.1086/341722.PubMed CentralPubMedView Article
      20. van den Hurk JA, Meij IC, Seleme MC, Kano H, Nikopoulos K, Hoefsloot LH, Sistermans EA, de Wijs IJ, Mukhopadhyay A, Plomp AS, de Jong PT, Kazazian HH, Cremers FP: L1 retrotransposition can occur early in human embryonic development. Hum Mol Genet. 2007, 16: 1587-1592. 10.1093/hmg/ddm108.PubMedView Article
      21. Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Devon K, Dewar K, Doyle M, FitzHugh W, Funke R, Gage D, Harris K, Heaford A, Howland J, Kann L, Lehoczky J, LeVine R, McEwan P, McKernan K, Meldrim J, Mesirov JP, Miranda C, Morris W, Naylor J, Raymond C, Rosetti M, Santos R, Sheridan A, Sougnez C, et al: Initial sequencing and analysis of the human genome. Nature. 2001, 409: 860-921. 10.1038/35057062.PubMedView Article
      22. Walters RD, Kugel JF, Goodrich JA: InvAluable junk: the cellular impact and function of Alu and B2 RNAs. IUBMB Life. 2009, 61: 831-837. 10.1002/iub.227.PubMed CentralPubMedView Article
      23. Haring E, Hagemann S, Pinsker W: Ancient and recent horizontal invasions of Drosophilids by P elements. J Mol Evol. 2000, 51: 577-586.PubMedView Article
      24. Gerasimova TI, Matjunina LV, Mizrokhi LJ, Georgiev GP: Successive transposition explosions in Drosophila melanogaster and reverse transpositions of mobile dispersed genetic elements. EMBO J. 1985, 4: 3773-3779.PubMed CentralPubMed
      25. Kim TM, Hong SJ, Rhyu MG: Periodic explosive expansion of human retroelements associated with the evolution of the hominoid primate. J Korean Med Sci. 2004, 19: 177-185. 10.3346/jkms.2004.19.2.177.PubMed CentralPubMedView Article
      26. Marques AC, Dupanloup I, Vinckenbosch N, Reymond A, Kaessmann H: Emergence of young human genes after a burst of retroposition in primates. PLoS Biol. 2005, 3: e357-10.1371/journal.pbio.0030357.PubMed CentralPubMedView Article
      27. Ray DA, Feschotte C, Pagan HJ, Smith JD, Pritham EJ, Arensburger P, Atkinson PW, Craig NL: Multiple waves of recent DNA transposon activity in the bat, Myotis lucifugus. Genome Res. 2008, 18: 717-728. 10.1101/gr.071886.107.PubMed CentralPubMedView Article
      28. Zeh DW, Zeh JA, Ishida Y: Transposable elements and an epigenetic basis for punctuated equilibria. BioEssays. 2009, 31: 715-726. 10.1002/bies.200900026.PubMedView Article
      29. Gould SJ: The Structure of Evolutionary Theory. 2002, Cambridge: The Belknap Press of Harvard University Press
      30. Ridley M: Evolution. 2004, Oxford: Blackwell Science
      31. Pollard KS, Salama SR, Lambert N, Lambot MA, Coppens S, Pedersen JS, Katzman S, King B, Onodera C, Siepel A, Kern AD, Dehay C, Igel H, Ares M, Vanderhaeghen P, Haussler D: An RNA gene expressed during cortical development evolved rapidly in humans. Nature. 2006, 443: 167-172. 10.1038/nature05113.PubMedView Article
      32. Kashi Y, King DG: Simple sequence repeats as advantageous mutators in evolution. Trends Genet. 2006, 22: 253-259. 10.1016/j.tig.2006.03.005.PubMedView Article
      33. Margulis L, Chapman MJ: Endosymbioses: cyclical and permanent in evolution. Trends Microbiol. 1998, 6: 342-346. 10.1016/S0966-842X(98)01325-0.PubMedView Article
      34. Monk M: Epigenetic programming of differential gene expression in development and evolution. Dev Genet. 1995, 17: 188-197. 10.1002/dvg.1020170303.PubMedView Article
      35. McLysaght A, Hokamp K, Wolfe KH: Extensive genomic duplication during early chordate evolution. Nat Genet. 2002, 31: 200-204. 10.1038/ng884.PubMedView Article
      36. Dulai KS, von Dornum M, Mollon JD, Hunt DM: The evolution of trichromatic color vision by opsin gene duplication in New World and Old World primates. Genome Res. 1999, 9: 629-638.PubMed
      37. Burki F, Kaessmann H: Birth and adaptive evolution of a hominoid gene that supports high neurotransmitter flux. Nat Genet. 2004, 36: 1061-1063. 10.1038/ng1431.PubMedView Article
      38. Batzer MA, Deininger PL: Alu repeats and human genomic diversity. Nat Rev Genet. 2002, 3: 370-379. 10.1038/nrg798.PubMedView Article
      39. Bailey JA, Liu G, Eichler EE: An Alu transposition model for the origin and expansion of human segmental duplications. Am J Hum Genet. 2003, 73: 823-834. 10.1086/378594.PubMed CentralPubMedView Article
      40. Mikkelsen TS, Hillier LW, Eichler EE, Zody MC, Jaffe DB, Yang SP, Enard W, Hellmann I, Lindblad-Toh K, Altheide TK, Archidiacono N, Bork P, Butler J, Chang JL, Cheng Z, Chinwalla AT, de Jong P, Delehaunty KD, Fronick CC, Fulton LL, Gilad Y, Glusman G, Gnerre S, Graves TA, Hayakawa T, Hayden KE, Huang XQ, Ji HK, Kent WJ, King MC, et al: Initial sequence of the chimpanzee genome and comparison with the human genome. Nature. 2005, 437: 69-87. 10.1038/nature04072.View Article
      41. Gibbs RA, Rogers J, Katze MG, Bumgarner R, Weinstock GM, Mardis ER, Remington KA, Strausberg RL, Venter JC, Wilson RK, Batzer MA, Bustamante CD, Eichler EE, Hahn MW, Hardison RC, Makova KD, Miller W, Milosavljevic A, Palermo RE, Siepel A, Sikela JM, Attaway T, Bell S, Bernard KE, Buhay CJ, Chandrabose MN, Dao M, Davis C, Delehaunty KD, Ding Y, et al: Evolutionary and biomedical insights from the rhesus macaque genome. Science. 2007, 316: 222-234.PubMedView Article
      42. Mills RE, Bennett EA, Iskow RC, Devine SE: Which transposable elements are active in the human genome?. Trends Genet. 2007, 23: 183-191. 10.1016/j.tig.2007.02.006.PubMedView Article
      43. Gilbert N, Labuda D: CORE-SINEs: Eukaryotic short interspersed retroposing elements with common sequence motifs. Proc Natl Acad Sci USA. 1999, 96: 2869-2874. 10.1073/pnas.96.6.2869.PubMed CentralPubMedView Article
      44. Labuda D, Striker G: Sequence conservation in Alu evolution. Nucleic Acids Res. 1989, 17: 2477-2491. 10.1093/nar/17.7.2477.PubMed CentralPubMedView Article
      45. Levanon EY, Eisenberg E, Yelin R, Nemzer S, Hallegger M, Shemesh R, Fligelman ZY, Shoshan A, Pollock SR, Sztybel D, Olshansky M, Rechavi G, Jantsch MF: Systematic identification of abundant A-to-I editing sites in the human transcriptome. Nat Biotechnol. 2004, 22: 1001-1005. 10.1038/nbt996.PubMedView Article
      46. Mattick JS, Mehler MF: RNA editing, DNA recoding and the evolution of human cognition. Trends Neurosci. 2008, 31: 227-233. 10.1016/j.tins.2008.02.003.PubMedView Article
      47. Krull M, Petrusma M, Makalowski W, Brosius J, Schmitz J: Functional persistence of exonized mammalian-wide interspersed repeat elements (MIRs). Genome Res. 2007, 17: 1139-1145. 10.1101/gr.6320607.PubMed CentralPubMedView Article
      48. Ostertag EM, Goodier JL, Zhang Y, Kazazian HH: SVA elements are nonautonomous retrotransposons that cause disease in humans. Am J Hum Genet. 2003, 73: 1444-1451. 10.1086/380207.PubMed CentralPubMedView Article
      49. Mayer J, Meese E: Human endogenous retroviruses in the primate lineage and their influence on host genomes. Cytogenet Genome Res. 2005, 110: 448-456. 10.1159/000084977.PubMedView Article
      50. Pace JK, Feschotte C: The evolutionary history of human DNA transposons: evidence for intense activity in the primate lineage. Genome Res. 2007, 17: 422-432. 10.1101/gr.5826307.PubMed CentralPubMedView Article
      51. Nishihara H, Smit AF, Okada N: Functional non-coding sequences derived from SINEs in the mammalian genome. Genome Res. 2006, 16: 864-874. 10.1101/gr.5255506.PubMed CentralPubMedView Article
      52. Ullu E, Tschudi C: Alu sequences are processed 7SL RNA genes. Nature. 1984, 312: 171-172. 10.1038/312171a0.PubMedView Article
      53. Dewannieux M, Esnault C, Heidmann T: LINE-mediated retrotransposition of marked Alu sequences. Nat Genet. 2003, 35: 41-48. 10.1038/ng1223.PubMedView Article
      54. Khan H, Smit A, Boissinot S: Molecular evolution and tempo of amplification of human LINE-1 retrotransposons since the origin of primates. Genome Res. 2006, 16: 78-87.PubMed CentralPubMedView Article
      55. Ohshima K, Hattori M, Yada T, Gojobori T, Sakaki Y, Okada N: Whole-genome screening indicates a possible burst of formation of processed pseudogenes and Alu repeats by particular L1 subfamilies in ancestral primates. Genome Biol. 2003, 4: R74-10.1186/gb-2003-4-11-r74.PubMed CentralPubMedView Article
      56. Bénit L, Lallemand JB, Casella JF, Philippe H, Heidmann T: ERV-L elements: a family of endogenous retrovirus-like elements active throughout the evolution of mammals. J Virol. 1999, 73: 3301-3308.PubMed CentralPubMed
      57. Liu G, Zhao S, Bailey JA, Sahinalp SC, Alkan C, Tuzun E, Green ED, Eichler EE: Analysis of primate genomic variation reveals a repeat-driven expansion of the human genome. Genome Res. 2003, 13: 358-368. 10.1101/gr.923303.PubMed CentralPubMedView Article
      58. Quentin Y: Fusion of a free left Alu monomer and a free right Alu monomer at the origin of the Alu family in the primate genomes. Nucleic Acids Res. 1992, 20: 487-493. 10.1093/nar/20.3.487.PubMed CentralPubMedView Article
      59. Schmid CW: Does SINE evolution preclude Alu function?. Nucleic Acids Res. 1998, 26: 4541-4550. 10.1093/nar/26.20.4541.PubMed CentralPubMedView Article
      60. Mills RE, Bennett EA, Iskow RC, Luttig CT, Tsui C, Pittard WS, Devine SE: Recently mobilized transposons in the human and chimpanzee genomes. Am J Hum Genet. 2006, 78: 671-679. 10.1086/501028.PubMed CentralPubMedView Article
      61. Hedges DJ, Callinan PA, Cordaux R, Xing J, Barnes E, Batzer MA: Differential Alu mobilization and polymorphism among the human and chimpanzee lineages. Genome Res. 2004, 14: 1068-1075. 10.1101/gr.2530404.PubMed CentralPubMedView Article
      62. Sen SK, Han K, Wang J, Lee J, Wang H, Callinan PA, Dyer M, Cordaux R, Liang P, Batzer MA: Human genomic deletions mediated by recombination between Alu elements. Am J Hum Genet. 2006, 79: 41-53. 10.1086/504600.PubMed CentralPubMedView Article
      63. Han K, Lee J, Meyer TJ, Wang J, Sen SK, Srikanta D, Liang P, Batzer MA: Alu recombination-mediated structural deletions in the chimpanzee genome. PLoS Genet. 2007, 3: 1939-1949.PubMedView Article
      64. Han K, Sen SK, Wang J, Callinan PA, Lee J, Cordaux R, Liang P, Batzer MA: Genomic rearrangements by LINE-1 insertion-mediated deletion in the human and chimpanzee lineages. Nucleic Acids Res. 2005, 33: 4040-4052. 10.1093/nar/gki718.PubMed CentralPubMedView Article
      65. Rieseberg LH: Chromosomal rearrangements and speciation. Trends Ecol Evol. 2001, 16: 351-358. 10.1016/S0169-5347(01)02187-5.PubMedView Article
      66. Kehrer-Sawatzki H, Sandig C, Chuzhanova N, Goidts V, Szamalek JM, Tänzer S, Müller S, Platzer M, Cooper DN, Hameister H: Breakpoint analysis of the pericentric inversion distinguishing human chromosome 4 from the homologous chromosome in the chimpanzee (Pan troglodytes). Hum Mutat. 2005, 25: 45-55. 10.1002/humu.20116.PubMedView Article
      67. Sela N, Mersch B, Hotz-Wagenblatt A, Ast G: Characteristics of transposable element exonization within human and mouse. PLoS One. 2010, 5: e10907-10.1371/journal.pone.0010907.PubMed CentralPubMedView Article
      68. Shen S, Lin L, Cai JJ, Jiang P, Kenkel EJ, Stroik MR, Sato S, Davidson BL, Xing Y: Widespread establishment and regulatory impact of Alu exons in human genes. Proc Natl Acad Sci USA.
      69. Sorek R, Ast G, Graur D: Alu-containing exons are alternatively spliced. Genome Res. 2002, 12: 1060-1067. 10.1101/gr.229302.PubMed CentralPubMedView Article
      70. Carroll SB: Evolution at two levels: on genes and form. PLoS Biol. 2005, 3: e245-10.1371/journal.pbio.0030245.PubMed CentralPubMedView Article
      71. Nigumann P, Redik K, Mätlik K, Speek M: Many human genes are transcribed from the antisense promoter of L1 retrotransposon. Genomics. 2002, 79: 628-634. 10.1006/geno.2002.6758.PubMedView Article
      72. Jordan IK, Rogozin IB, Glazko GV, Koonin EV: Origin of a substantial fraction of human regulatory sequences from transposable elements. Trends Genet. 2003, 19: 68-10.1016/S0168-9525(02)00006-9.PubMedView Article
      73. van de Lagemaat LN, Landry JR, Mager DL, Medstrand P: Transposable elements in mammals promote regulatory variation and diversification of genes with specialized functions. Trends Genet. 2003, 19: 530-536. 10.1016/j.tig.2003.08.004.PubMedView Article
      74. Feschotte C: Transposable elements and the evolution of regulatory networks. Nat Rev Genet. 2008, 9: 397-405. 10.1038/nrg2337.PubMed CentralPubMedView Article
      75. Polak P, Domany E: Alu elements contain many binding sites for transcription factors and may play a role in regulation of developmental processes. BMC Genomics. 2006, 7: 133-10.1186/1471-2164-7-133.PubMed CentralPubMedView Article
      76. Norris J, Fan D, Aleman C, Marks JR, Futreal PA, Wiseman RW, Iglehart JD, Deininger PL, McDonnell DP: Identification of a new subclass of Alu DNA repeats which can function as estrogen receptor-dependent transcriptional enhancers. J Biol Chem. 1995, 270: 22777-22782. 10.1074/jbc.270.39.22777.PubMedView Article
      77. Vansant G, Reynolds WF: The consensus sequence of a major Alu subfamily contains a functional retinoic acid response element. Proc Natl Acad Sci USA. 1995, 92: 8229-8233. 10.1073/pnas.92.18.8229.PubMed CentralPubMedView Article
      78. Xie D, Chen CC, Ptaszek LM, Xiao S, Cao X, Fang F, Ng HH, Lewin HA, Cowan C, Zhong S: Rewirable gene regulatory networks in the preimplantation embryonic development of three mammalian species. Genome Res. 2010, 20: 804-815. 10.1101/gr.100594.109.PubMed CentralPubMedView Article
      79. Wang T, Zeng J, Lowe CB, Sellers RG, Salama SR, Yang M, Burgess SM, Brachmann RK, Haussler D: Species-specific endogenous retroviruses shape the transcriptional network of the human tumor suppressor protein p53. Proc Natl Acad Sci USA. 2007, 104: 18613-18618. 10.1073/pnas.0703637104.PubMed CentralPubMedView Article
      80. Kunarso G, Chia NY, Jeyakani J, Hwang C, Lu X, Chan YS, Ng HH, Bourque G: Transposable elements have rewired the core regulatory network of human embryonic stem cells. Nat Genet. 2010, 42: 631-634. 10.1038/ng.600.PubMedView Article
      81. Ohno S: Evolution by Gene Duplication. 1970, New York: Springer-VerlagView Article
      82. Moran JV, DeBerardinis RJ, Kazazian HH: Exon shuffling by L1 retrotransposition. Science. 1999, 283: 1530-1534. 10.1126/science.283.5407.1530.PubMedView Article
      83. Goodier JL, Ostertag EM, Kazazian HH: Transduction of 3'-flanking sequences is common in L1 retrotransposition. Hum Mol Genet. 2000, 9: 653-657. 10.1093/hmg/9.4.653.PubMedView Article
      84. Vinckenbosch N, Dupanloup I, Kaessmann H: Evolutionary fate of retroposed gene copies in the human genome. Proc Natl Acad Sci USA. 2006, 103: 3220-3225. 10.1073/pnas.0511307103.PubMed CentralPubMedView Article
      85. Prudhomme S, Bonnaud B, Mallet F: Endogenous retroviruses and animal reproduction. Cytogenet Genome Res. 2005, 110: 353-364. 10.1159/000084967.PubMedView Article
      86. Farcas R, Schneider E, Frauenknecht K, Kondova I, Bontrop R, Bohl J, Navarro B, Metzler M, Zischler H, Zechner U, Daser A, Haaf T: Differences in DNA methylation patterns and expression of the CCRK gene in human and nonhuman primate cortices. Mol Biol Evol. 2009, 26: 1379-1389. 10.1093/molbev/msp046.PubMedView Article
      87. Coufal NG, Garcia-Perez JL, Peng GE, Yeo GW, Mu Y, Lovci MT, Morell M, O'Shea KS, Moran JV, Gage FH: L1 retrotransposition in human neural progenitor cells. Nature. 2009, 460: 1127-1131. 10.1038/nature08248.PubMed CentralPubMedView Article
      88. De Mendoza A, Escobedo DE, Dávila IM, Saldaña H: Expansion and divergence of the GH locus between spider monkey and chimpanzee. Gene. 2004, 336: 185-193. 10.1016/j.gene.2004.03.034.View Article
      89. Lacroix MC, Guibourdenche J, Frendo JL, Muller F, Evain-Brion D: Human placental growth hormone-a review. Placenta. 2002, 23: S87-94.PubMedView Article
      90. Fitch DH, Bailey WJ, Tagle DA, Goodman M, Sieu L, Slightom JL: Duplication of the gamma-globin gene mediated by L1 long interspersed repetitive elements in an early ancestor of simian primates. Proc Natl Acad Sci USA. 1991, 88: 7396-7400. 10.1073/pnas.88.16.7396.PubMed CentralPubMedView Article
      91. Johnson RM, Prychitko T, Gumucio D, Wildman DE, Uddin M, Goodman M: Phylogenetic comparisons suggest that distance from the locus control region guides developmental expression of primate beta-type globin genes. Proc Natl Acad Sci USA. 2006, 103: 3186-3191. 10.1073/pnas.0511347103.PubMed CentralPubMedView Article
      92. Mi S, Lee X, Li X, Veldman GM, Finnerty H, Racie L, LaVallie E, Tang XY, Edouard P, Howes S, Keith JC, McCoy JM: Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. Nature. 2000, 403: 785-789. 10.1038/35001608.PubMedView Article
      93. Blaise S, de Parseval N, Bénit L, Heidmann T: Genomewide screening for fusogenic human endogenous retrovirus envelopes identifies syncytin 2, a gene conserved on primate evolution. Proc Natl Acad Sci USA. 2003, 100: 13013-13018. 10.1073/pnas.2132646100.PubMed CentralPubMedView Article
      94. Dupressoir A, Marceau G, Vernochet C, Bénit L, Kanellopoulos C, Sapin V, Heidmann T: Syncytin-A and syncytin-B, two fusogenic placenta-specific murine envelope genes of retroviral origin conserved in Muridae. Proc Natl Acad Sci USA. 2005, 102: 725-730. 10.1073/pnas.0406509102.PubMed CentralPubMedView Article
      95. Heidmann O, Vernochet C, Dupressoir A, Heidmann T: Identification of an endogenous retroviral envelope gene with fusogenic activity and placenta-specific expression in the rabbit: a new "syncytin" in a third order of mammals. Retrovirology. 2009, 6: 107-10.1186/1742-4690-6-107.PubMed CentralPubMedView Article
      96. Apoil PA, Roubinet F, Despiau S, Mollicone R, Oriol R, Blancher A: Evolution of alpha 2-fucosyltransferase genes in primates: relation between an intronic Alu-Y element and red cell expression of ABH antigens. Mol Biol Evol. 2000, 17: 337-351.PubMedView Article
      97. Cserti CM, Dzik WH: The ABO blood group system and Plasmodium falciparum malaria. Blood. 2007, 110: 2250-2258. 10.1182/blood-2007-03-077602.PubMedView Article
      98. Gombart AF, Saito T, Koeffler HP: Exaptation of an ancient Alu short interspersed element provides a highly conserved vitamin D-mediated innate immune response in humans and primates. BMC Genomics. 2009, 10: 321-10.1186/1471-2164-10-321.PubMed CentralPubMedView Article
      99. Ting CN, Rosenberg MP, Snow CM, Samuelson LC, Meisler MH: Endogenous retroviral sequences are required for tissue-specific expression of a human salivary amylase gene. Genes Dev. 1992, 6: 1457-1465. 10.1101/gad.6.8.1457.PubMedView Article
      100. Perry GH, Dominy NJ, Claw KG, Lee AS, Fiegler H, Redon R, Werner J, Villanea FA, Mountain JL, Misra R, Carter NP, Lee C, Stone AC: Diet and the evolution of human amylase gene copy number variation. Nat Genet. 2007, 39: 1256-1260. 10.1038/ng2123.PubMed CentralPubMedView Article
      101. Nakayama K, Ishida T: Alu-mediated 100-kb deletion in the primate genome: the loss of the agouti signaling protein gene in the lesser apes. Genome Res. 2006, 16: 485-490. 10.1101/gr.4763906.PubMed CentralPubMedView Article
      102. Cordaux R, Batzer MA: The impact of retrotransposons on human genome evolution. Nat Rev Genet. 2009, 10: 691-703. 10.1038/nrg2640.PubMed CentralPubMedView Article
      103. Britten RJ: Transposable element insertions have strongly affected human evolution. Proc Natl Acad Sci USA. 2010, 107: 19945-19948. 10.1073/pnas.1014330107.PubMed CentralPubMedView Article
      104. Hayakawa T, Satta Y, Gagneux P, Varki A, Takahata N: Alu-mediated inactivation of the human CMP- N-acetylneuraminic acid hydroxylase gene. Proc Natl Acad Sci USA. 2001, 98: 11399-11404. 10.1073/pnas.191268198.PubMed CentralPubMedView Article
      105. Parrott AM, Mathews MB: snaR genes: recent descendants of Alu involved in the evolution of chorionic gonadotropins. Cold Spring Harb Symp Quant Biol. 2009, 74: 363-373. 10.1101/sqb.2009.74.038.PubMedView Article
      106. Watson JB, Sutcliffe JG: Primate brain-specific cytoplasmic transcript of the Alu repeat family. Mol Cell Biol. 1987, 7: 3324-3327.PubMed CentralPubMedView Article
      107. Li CY, Zhang Y, Wang Z, Zhang Y, Cao C, Zhang PW, Lu SJ, Li XM, Yu Q, Zheng X, Du Q, Uhl GR, Liu QR, Wei L: A human-specific de novo protein-coding gene associated with human brain functions. PLoS Comput Biol. 2010, 6: e1000734-10.1371/journal.pcbi.1000734.PubMed CentralPubMedView Article
      108. Cordaux R, Udit S, Batzer MA, Feschotte C: Birth of a chimeric primate gene by capture of the transposase gene from a mobile element. Proc Natl Acad Sci USA. 2006, 103: 8101-8106. 10.1073/pnas.0601161103.PubMed CentralPubMedView Article
      109. Mola G, Vela E, Fernández-Figueras MT, Isamat M, Muñoz-Mármol AM: Exonization of Alu-generated splice variants in the survivin gene of human and non-human primates. J Mol Biol. 2007, 366: 1055-1063. 10.1016/j.jmb.2006.11.089.PubMedView Article
      110. Lai F, Chen CX, Carter KC, Nishikura K: Editing of glutamate receptor B subunit ion channel RNAs by four alternatively spliced DRADA2 double-stranded RNA adenosine deaminases. Mol Cell Biol. 1997, 17: 2413-2424.PubMed CentralPubMedView Article
      111. Rodriguez IR, Mazuruk K, Schoen TJ, Chader GJ: Structural analysis of the human hydroxyindole-O-methyltransferase gene. Presence of two distinct promoters. J Biol Chem. 1994, 269: 31969-31977.PubMed
      112. Fornasari D, Battaglioli E, Flora A, Terzano S, Clementi F: Structural and functional characterization of the human alpha3 nicotinic subunit gene promoter. Mol Pharmacol. 1997, 51: 250-261.PubMed
      113. Ebihara M, Ohba H, Ohno SI, Yoshikawa T: Genomic organization and promoter analysis of the human nicotinic acetylcholine receptor alpha6 subunit (CHNRA6) gene: Alu and other elements direct transcriptional repression. Gene. 2002, 298: 101-108. 10.1016/S0378-1119(02)00925-3.PubMedView Article
      114. Romanish MT, Nakamura H, Lai CB, Wang Y, Mager DL: A novel protein isoform of the multicopy human NAIP gene derives from intragenic Alu SINE promoters. PLoS One. 2009, 4: e5761-10.1371/journal.pone.0005761.PubMed CentralPubMedView Article
      115. Kjeldbjerg AL, Villesen P, Aagaard L, Pedersen FS: Gene conversion and purifying selection of a placenta-specific ERV-V envelope gene during simian evolution. BMC Evol Biol. 2008, 8: 266-10.1186/1471-2148-8-266.PubMed CentralPubMedView Article
      116. Larsson E, Andersson AC, Nilsson BO: Expression of an endogenous retrovirus (ERV3 HERV-R) in human reproductive and embryonic tissues - evidence for a function for envelope gene products. Ups J Med Sci. 1994, 99: 113-120. 10.3109/03009739409179354.PubMedView Article
      117. Hsu DW, Lin MJ, Lee TL, Wen SC, Chen X, Shen CK: Two major forms of DNA (cytosine-5) methyltransferase in human somatic tissues. Proc Natl Acad Sci USA. 1999, 96: 9751-9756. 10.1073/pnas.96.17.9751.PubMed CentralPubMedView Article
      118. Damert A, Löwer J, Löwer R: Leptin receptor isoform 219.1: an example of protein evolution by LINE-1-mediated human-specific retrotransposition of a coding SVA element. Mol Biol Evol. 2004, 21: 647-651. 10.1093/molbev/msh056.PubMedView Article
      119. Piriyapongsa J, Polavarapu N, Borodovsky M, McDonald J: Exonization of the LTR transposable elements in human genome. BMC Genomics. 2007, 8: 291-10.1186/1471-2164-8-291.PubMed CentralPubMedView Article
      120. Huh JW, Kim TH, Yi JM, Park ES, Kim WY, Sin HS, Kim DS, Min DS, Kim SS, Kim CB, Hyun BH, Kang SK, Jung JS, Lee WH, Takenaka O, Kim HS: Molecular evolution of the periphilin gene in relation to human endogenous retrovirus m element. J Mol Evol. 2006, 62: 730-737. 10.1007/s00239-005-0109-0.PubMedView Article
      121. Komiyama H, Aoki A, Tanaka S, Maekawa H, Kato Y, Wada R, Maekawa T, Tamura M, Shiroishi T: Alu-derived cis-element regulates tumorigenesis-dependent gastric expression of GASDERMIN B (GSDMB). Genes Genet Syst. 2010, 85: 75-83. 10.1266/ggs.85.75.PubMedView Article
      122. Cohen CJ, Lock WM, Mager DL: Endogenous retroviral LTRs as promoters for human genes: a critical assessment. Gene. 2009, 448: 105-114. 10.1016/j.gene.2009.06.020.PubMedView Article
      123. Bièche I, Laurent A, Laurendeau I, Duret L, Giovangrandi Y, Frendo JL, Olivi M, Fausser JL, Evain-Brion D, Vidaud M: Placenta-specific INSL4 expression is mediated by a human endogenous retrovirus element. Biol Reprod. 2003, 68: 1422-1429.PubMedView Article
      124. Dunn CA, Romanish MT, Gutierrez LE, van de Lagemaat LN, Mager DL: Transcription of two human genes from a bidirectional endogenous retrovirus promoter. Gene. 2006, 366: 335-342. 10.1016/j.gene.2005.09.003.PubMedView Article
      125. Scofield MA, Xiong W, Haas MJ, Zeng Y, Cox GS: Sequence analysis of the human glycoprotein hormone alpha-subunit gene 5'-flanking DNA and identification of a potential regulatory element as an Alu repetitive sequence. Biochim Biophys Acta. 2000, 1493: 302-318.PubMedView Article
      126. Wu J, Grindlay GJ, Bushel P, Mendelsohn L, Allan M: Negative regulation of the human epsilon-globin gene by transcriptional interference: role of an Alu repetitive element. Mol Cell Biol. 1990, 10: 1209-1216.PubMed CentralPubMedView Article
      127. Trujillo MA, Sakagashira M, Eberhardt NL: The human growth hormone gene contains a silencer embedded within an Alu repeat in the 3'-flanking region. Mol Endocrinol. 2006, 20: 2559-2575. 10.1210/me.2006-0147.PubMedView Article
      128. Hewitt SM, Fraizer GC, Saunders GF: Transcriptional silencer of the Wilms' tumor gene WT1 contains an Alu repeat. J Biol Chem. 1995, 270: 17908-17912. 10.1074/jbc.270.30.17908.PubMedView Article
      129. Bi S, Gavrilova O, Gong DW, Mason MM, Reitman M: Identification of a placental enhancer for the human leptin gene. J Biol Chem. 1997, 272: 30583-30588. 10.1074/jbc.272.48.30583.PubMedView Article
      130. Wheelan SJ, Aizawa Y, Han JS, Boeke JD: Gene-breaking: a new paradigm for human retrotransposon-mediated gene evolution. Genome Res. 2005, 15: 1073-1078. 10.1101/gr.3688905.PubMed CentralPubMedView Article
      131. Huh JW, Kim YH, Lee SR, Kim H, Kim DS, Kim HS, Kang HS, Chang KT: Gain of new exons and promoters by lineage-specific transposable elements-integration and conservation event on CHRM3 gene. Mol Cells. 2009, 28: 111-117. 10.1007/s10059-009-0106-z.PubMedView Article
      132. Mätlik K, Redik K, Speek M: L1 antisense promoter drives tissue-specific transcription of human genes. J Biomed Biotechnol. 2006, 2006: 71753-PubMed CentralPubMedView Article
      133. Romanish MT, Lock WM, van de Lagemaat LN, Dunn CA, Mager DL: Repeated recruitment of LTR retrotransposons as promoters by the anti-apoptotic locus NAIP during mammalian evolution. PLoS Genet. 2007, 3: e10-10.1371/journal.pgen.0030010.PubMed CentralPubMedView Article
      134. Medstrand P, Landry JR, Mager DL: Long terminal repeats are used as alternative promoters for the endothelin B receptor and apolipoprotein C-I genes in humans. J Biol Chem. 2001, 276: 1896-1903. 10.1074/jbc.M006557200.PubMedView Article
      135. Schulte AM, Lai S, Kurtz A, Czubayko F, Riegel AT, Wellstein A: Human trophoblast and choriocarcinoma expression of the growth factor pleiotrophin attributable to germ-line insertion of an endogenous retrovirus. Proc Natl Acad Sci USA. 1996, 93: 14759-14764. 10.1073/pnas.93.25.14759.PubMed CentralPubMedView Article
      136. Landry JR, Rouhi A, Medstrand P, Mager DL: The Opitz syndrome gene Mid1 is transcribed from a human endogenous retroviral promoter. Mol Biol Evol. 2002, 19: 1934-1942.PubMedView Article
      137. Huh JW, Ha HS, Kim DS, Kim HS: Placenta-restricted expression of LTR-derived NOS3. Placenta. 2008, 29: 602-608. 10.1016/j.placenta.2008.04.002.PubMedView Article
      138. Sin HS, Huh JW, Kim DS, Kang DW, Min DS, Kim TH, Ha HS, Kim HH, Lee SY, Kim HS: Transcriptional control of the HERV-H LTR element of the GSDML gene in human tissues and cancer cells. Arch Virol. 2006, 151: 1985-1994. 10.1007/s00705-006-0764-5.PubMedView Article
      139. Xing J, Wang H, Belancio VP, Cordaux R, Deininger PL, Batzer MA: Emergence of primate genes by retrotransposon-mediated sequence transduction. Proc Natl Acad Sci USA. 2006, 103: 17608-17613. 10.1073/pnas.0603224103.PubMed CentralPubMedView Article
      140. Lee Y, Ise T, Ha D, Saint Fleur A, Hahn Y, Liu XF, Nagata S, Lee B, Bera TK, Pastan I: Evolution and expression of chimeric POTE-actin genes in the human genome. Proc Natl Acad Sci USA. 2006, 103: 17885-17890. 10.1073/pnas.0608344103.PubMed CentralPubMedView Article
      141. Babushok DV, Ohshima K, Ostertag EM, Chen X, Wang Y, Mandal PK, Okada N, Abrams CS, Kazazian HH: A novel testis ubiquitin-binding protein gene arose by exon shuffling in hominoids. Genome Res. 2007, 17: 1129-1138. 10.1101/gr.6252107.PubMed CentralPubMedView Article
      142. Lahn BT, Page DC: Retroposition of autosomal mRNA yielded testis-specific gene family on human Y chromosome. Nat Genet. 1999, 21: 429-433. 10.1038/7771.PubMedView Article
      143. Betrán E, Long M: Expansion of genome coding regions by acquisition of new genes. Genetica. 2002, 115: 65-80. 10.1023/A:1016024131097.PubMedView Article
      144. Zhang R, Wang YQ, Su B: Molecular evolution of a primate-specific microRNA family. Mol Biol Evol. 2008, 25: 1493-1502. 10.1093/molbev/msn094.PubMedView Article
      145. Than NG, Romero R, Goodman M, Weckle A, Xing J, Dong Z, Xu Y, Tarquini F, Szilagyi A, Gal P, Hou Z, Tarca AL, Kim CJ, Kim JS, Haidarian S, Uddin M, Bohn H, Benirschke K, Santolaya-Forgas J, Grossman LI, Erez O, Hassan SS, Zavodszky P, Papp Z, Wildman DE: A primate subfamily of galectins expressed at the maternal-fetal interface that promote immune cell death. Proc Natl Acad Sci USA. 2009, 106: 9731-9736. 10.1073/pnas.0903568106.PubMed CentralPubMedView Article
      146. Caras IW, Davitz MA, Rhee L, Weddell G, Martin DW, Nussenzweig V: Cloning of decay-accelerating factor suggests novel use of splicing to generate two proteins. Nature. 1987, 325: 545-549. 10.1038/325545a0.PubMedView Article
      147. Singer SS, Männel DN, Hehlgans T, Brosius J, Schmitz J: From "junk" to gene: curriculum vitae of a primate receptor isoform gene. J Mol Biol. 2004, 341: 883-886. 10.1016/j.jmb.2004.06.070.PubMedView Article
      148. Bekpen C, Marques-Bonet T, Alkan C, Antonacci F, Leogrande MB, Ventura M, Kidd JM, Siswara P, Howard JC, Eichler EE: Death and resurrection of the human IRGM gene. PLoS Genet. 2009, 5: e1000403-10.1371/journal.pgen.1000403.PubMed CentralPubMedView Article
      149. Thomson SJ, Goh FG, Banks H, Krausgruber T, Kotenko SV, Foxwell BM, Udalova IA: The role of transposable elements in the regulation of IFN-lambda1 gene expression. Proc Natl Acad Sci USA. 2009, 106: 11564-11569. 10.1073/pnas.0904477106.PubMed CentralPubMedView Article
      150. Brini AT, Lee GM, Kinet JP: Involvement of Alu sequences in the cell-specific regulation of transcription of the gamma chain of Fc and T cell receptors. J Biol Chem. 1993, 268: 1355-1361.PubMed
      151. Hambor JE, Mennone J, Coon ME, Hanke JH, Kavathas P: Identification and characterization of an Alu-containing, T-cell-specific enhancer located in the last intron of the human CD8 alpha gene. Mol Cell Biol. 1993, 13: 7056-7070.PubMed CentralPubMedView Article
      152. Dunn CA, Medstrand P, Mager DL: An endogenous retroviral long terminal repeat is the dominant promoter for human beta 1,3-galactosyltransferase 5 in the colon. Proc Natl Acad Sci USA. 2003, 100: 12841-12846. 10.1073/pnas.2134464100.PubMed CentralPubMedView Article
      153. Gerlo S, Davis JR, Mager DL, Kooijman R: Prolactin in man: a tale of two promoters. Bioessays. 2006, 28: 1051-1055. 10.1002/bies.20468.PubMed CentralPubMedView Article
      154. Piedrafita FJ, Molander RB, Vansant G, Orlova EA, Pfahl M, Reynolds WF: An Alu element in the myeloperoxidase promoter contains a composite SP1-thyroid hormone-retinoic acid response element. J Biol Chem. 1996, 271: 14412-14420. 10.1074/jbc.271.24.14412.PubMedView Article
      155. Ackerman H, Udalova I, Hull J, Kwiatkowski D: Evolution of a polymorphic regulatory element in interferon-gamma through transposition and mutation. Mol Biol Evol. 2002, 19: 884-890.PubMedView Article
      156. Hess JF, Fox M, Schmid C, Shen CK: Molecular evolution of the human adult alpha-globin-like gene region: insertion and deletion of Alu family repeats and non-Alu DNA sequences. Proc Natl Acad Sci USA. 1983, 80: 5970-5974. 10.1073/pnas.80.19.5970.PubMed CentralPubMedView Article
      157. Huh JW, Kim DS, Ha HS, Lee JR, Kim YJ, Ahn K, Lee SR, Chang KT, Kim HS: Cooperative exonization of MaLR and AluJo elements contributed an alternative promoter and novel splice variants of RNF19. Gene. 2008, 424: 63-70. 10.1016/j.gene.2008.07.030.PubMedView Article
      158. Wu M, Li L, Sun Z: Transposable element fragments in protein-coding regions and their contributions to human functional proteins. Gene. 2007, 401: 165-171. 10.1016/j.gene.2007.07.012.PubMedView Article
      159. Yi P, Zhang W, Zhai Z, Miao L, Wang Y, Wu M: Bcl-rambo beta, a special splicing variant with an insertion of an Alu-like cassette, promotes etoposide- and Taxol-induced cell death. FEBS Lett. 2003, 534: 61-68. 10.1016/S0014-5793(02)03778-X.PubMedView Article
      160. Lee JR, Huh JW, Kim DS, Ha HS, Ahn K, Kim YJ, Chang KT, Kim HS: Lineage specific evolutionary events on SFTPB gene: Alu recombination-mediated deletion (ARMD), exonization, and alternative splicing events. Gene. 2009, 435: 29-35. 10.1016/j.gene.2009.01.008.PubMedView Article
      161. Landry JR, Medstrand P, Mager DL: Repetitive elements in the 5' untranslated region of a human zinc-finger gene modulate transcription and translation efficiency. Genomics. 2001, 76: 110-116. 10.1006/geno.2001.6604.PubMedView Article
      162. Le Goff W, Guerin M, Chapman MJ, Thillet J: A CYP7A promoter binding factor site and Alu repeat in the distal promoter region are implicated in regulation of human CETP gene expression. J Lipid Res. 2003, 44: 902-910. 10.1194/jlr.M200423-JLR200.PubMedView Article
      163. Shephard EA, Chandan P, Stevanovic-Walker M, Edwards M, Phillips IR: Alternative promoters and repetitive DNA elements define the species-dependent tissue-specific expression of the FMO1 genes of human and mouse. Biochem J. 2007, 406: 491-499. 10.1042/BJ20070523.PubMed CentralPubMedView Article
      164. McHaffie GS, Ralston SH: Origin of a negative calcium response element in an ALU-repeat: implications for regulation of gene expression by extracellular calcium. Bone. 1995, 17: 11-14. 10.1016/8756-3282(95)00131-V.PubMedView Article
      165. Reinton N, Haugen TB, Orstavik S, Skålhegg BS, Hansson V, Jahnsen T, Taskén K: The gene encoding the C gamma catalytic subunit of cAMP-dependent protein kinase is a transcribed retroposon. Genomics. 1998, 49: 290-297. 10.1006/geno.1998.5240.PubMedView Article
      166. Jin H, Selfe J, Whitehouse C, Morris JR, Solomon E, Roberts RG: Structural evolution of the BRCA1 genomic region in primates. Genomics. 2004, 84: 1071-1082. 10.1016/j.ygeno.2004.08.019.PubMedView Article
      167. Szabó Z, Levi-Minzi SA, Christiano AM, Struminger C, Stoneking M, Batzer MA, Boyd CD: Sequential loss of two neighboring exons of the tropoelastin gene during primate evolution. J Mol Evol. 1999, 49: 664-671. 10.1007/PL00006587.PubMedView Article

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