Research Article Open Access
Transposable elements: a comparative study in the introns and UTRs of the homologous mitochondrial solute carrier genes of Human, Mouse and Zebrafish
Antonia Cianciulli, Rosa Calvello and Maria Antonietta Panaro*
Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, via Orabona, 4, I-70126 Bari, Italy
*Corresponding authors address: Maria Antonietta Panaro, Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, via Orabona, 4, I-70126 Bari, Italy; E-mail: mariaantonietta.panaro@uniba.it
Received: March 20, 2017; Accepted: April 7, 2017; Published: April 25, 2017
Citation: Panaro.M, Antonia Cianciulli, et.al. (2017) Transposable elements: a comparative study in the introns and UTRs of the homologous mitochondrial solute carrier genes of Human, Mouse and Zebrafish. Int J Struct Comput Biol 1(1):1-24.
Abstract
We studied the localization of transposable elements (TEs) in the 5’ and 3’ flanking regions and in the introns of Mouse, Human and Zebrafish mitochondrial solute carrier genes. The canonical transcripts of these highly homologous genes exhibit superimposable patterns of exon-intron alternation in the three species. In introns, two sections approximately corresponding to the first and last 20 nucleotides are relatively, but not completely, depleted of TEs. The distributions of the distances of the TEs which are the closer to the start and stop codons are right-skewed, with lower values for short distances, a peak at 750 nt in Mouse and Human and 450 nt in Zebrafish, followed by an exponential decay. Taken together these results suggest that the exon/ intron structuring of the mitochondrial solute carrier genes has been under strict evolutionary control from fish to mammals and variants with potentially dangerous inserts (such as LTR elements) nearing the regulatory sequences have been selected against, whilst the extant TEs do not exert any significant action not even at relatively short distances.

Keywords: Mitochondrial solute carrier genes; Transposable elements; UTRs; Introns; Human; Mouse; Zebrafish.
Introduction
Transposable elements (Transposons, TEs) are mobile segments of genetic material which may be found in DNA noncoding sections, either intergenic or intragenic (introns). TEs are widespread in the genomes of all Vertebrates representing a very variable, yet always significant, percentage of the genome [1]. TEs account for about 32% of the genome in Mouse, 45% in Human and 55 % in Zebrafish [1,2,3]. Their biological success is owed to their ability to reproduce several copies of themselves, which may settle in the same and other genes. When TEs settle in germline cells they are thenceforth transmitted to the offspring in a Mendelian manner. TEs are heterogeneous as regards their origin and mode of propagation. The DNA transposons are derived from segments of endogenous retroviruses (ERVs) or pseudogenes or other DNAs of different origin and may move directly to new genomic loci without being reverse-transcribed. On the contrary, the retrotransposons, which are DNAs derived from ancient RNA precursors, need to be transcribed into RNA before being retrotranscribed into DNA and inserted into another site of the host genome. However, the retrotransposons of the SINE (Short Interspersed Elements) class are unable to retrotranspose autonomously and are thought to borrow the enzymatic machinery required for their amplification (reverse transcriptase and endonuclease) from their “partner” autonomous retrotransposon LINE (Long Interspersed Element) L1 [4,5].

TEs at many locations are possibly biologically inactive, but in specific instances they have been shown to play important roles in gene regulation or have been implicated in various diseases.

When settling at specific sites, TEs could interfere with the gene regulatory sequences residing in the noncoding DNA of the 5’ and 3’ flanking regions and the introns of individual genes [6,7,8,9]. Amongst the different players controlling gene expression, TEs are thought to interfere especially with some microRNAs (miRNAs) and some transcription factors. miRNAs are short (about 22 nt) endogenous RNAs [10,11]. Which regulate gene expression mainly by binding specific sequences at both UTRs or AUGs upstream of the start codon (uAUGs in the 5’UTRs)[12,13]. Furthermore, the Primate SINE Alu elements are possible microRNA targets [14,15,16]. In addition, thanks to their numerous binding sites both Alus and the Rodent SINE B1 elements could regulate the gene expression by directly binding some transcription factors [1,3,17,18].

In other instances the gene protein product may be modified by TE insertions through the activation of alternative promoters and non-canonical start codons and/or the activation of alternative splice sites [18,20,21,22,23]. It has been demonstrated that some of the protein products generated by these alternative transcripts have been adapted to serve some essential physiological function, but in most cases the splice variants generated by TE inserts result in short-lived protein products [20,24,25].

TEs may also have had a significant impact on genome evolution, including the formation of new genes by some form of “reshuffling” of genetic material or the exonization of some TE sections [3,19,26].

Finally, TE insertions in somatic cells have been implicated in various diseases, including cancer, [3,19].when they interfere with critical sequences in the 5’- and 3’-untranslated regions of mRNAs [28,29,30].

The TE distribution in the genome of extant organisms is determined by both the original insertion site preferences and the succeeding natural selection. Actually TEs are not evenly distributed in the non-coding DNA of Mouse and Human; for instance, Alu and B1 are more represented in the upstream and intronic regions of genes of specific functional classes, but highly expressed genes or loci that might require subtle regulation of transcript levels or precise activation timing tend to be TEdepleted, possibly as a result of a purifying selection [30,31,32].

A few wide scale investigations have been dedicated to the study of the general TE distribution in Mouse and Human genes. A preferential location/persistence of some TE types has been demonstrated, e.g., of Alus in GC-rich isochores [30,33,34]. Zhang et al. have addressed the issue of the likely harmful effects of intronic TE insertions in Mouse and Human [35].

In the present investigation we address the specific issue of TE distribution in the introns and the UTRs of the mitochondrial solute carrier (SLC25) genes of Zebrafish, Mouse and Human. In this very homogeneous family of genes the exon conservation is approximately 70% throughout vertebrates, while the intronic Mouse/Human conservation averages 15% and the Zebrafish/Mouse or Zebrafish/Human conservation is extremely low (at most 0.2%)[36,37]. Despite such divergence, the relative positions of exons and introns have often been kept unaltered during vertebrate evolution,so that the introns of the three species may be considered as strictly homologous.
Methods
Sequences of all available homologous Mouse, Human and Zebrafish SLC25 genes (A1 to A54; 52 Mouse genes, 53 Human genes and 44 Zebrafish genes) were retrieved from NCBI GenBank (http://www.ncbi.nlm.nih.gov/homologene/; http:// www.ncbi.nlm.nih.gov/); the transcript variants with superimposable exon-intron arrangements in the three species were preferentially selected for the present analysis. All TEs of the different classes in the 5’- and 3’-flanking regions (each 10,000 nt long) and in the introns of Mouse, Human and Zebrafish genes were identified using the CENSOR tool (http://www.girinst.org/ censor , accepting TEs with a score 400 or higher. The significance of the pairwise alignments between the relevant gene sequences and the corresponding TE sequences was further checked with the NCBI BLAST tool [http://blast.ncbi.nlm.nih.gov/Blast.cgi] with settings: “Nucleotide Blast”, “Align Two or More Sequences” and “Somewhat similar sequences (blastn)”; only alignments with Expect equal to or lower than 9e-6 were considered [38,39].

In particular, at the flanking regions we recorded at 5’ the distance (LAG, measured in nucleotides) between the last upstream significant TE insert and the Start codon [5’UTR-LAG] and at 3’ the distance between the Stop codon and the first downstream TE insert [3’UTR-LAG]. In each intron we recorded the number of nucleotides intervening between the last nucleotide of the preceding exon and the first nucleotide of the TE (if any) [INTRON-5’-LAG] and the number of nucleotides intervening between the last nucleotide of the TE (if any) and the first nucleotide of the following exon [INTRON-3’-LAG]. In the case of introns, only LAGs 0 to 100 were considered.

Whenever possible we studied the positions of the proximal promoters or silencers relative to the last TE in the 5’ flanking region and of the polyA signal relative to the first TE in the 3’ flanking region. Only a small number of experimentally validated promoters could be retrieved from published reports or the EPD Eukaryotic Promoter Database [http://epd.vital-it.ch/]. The positions of the polyA signal were derived from PubMed Nucleotide (http://www.ncbi.nlm.nih.gov/pubmed)[40].

Statistical analyses were made according to the standard methods for comparisons of percentages [41].
Results
General
All introns began with the canonical dinucleotide GT and ended with the canonical dinucleotide AG, except the first intron of SLC25A42 which began with GC in Mouse and Human. However, the initial and terminal hexanucleotides of the introns were highly polymorphic, exhibiting 75 and 102 different configurations, respectively, in our material.

Although about 65 % of the Mouse and Human introns carried at least one TE insert, only 12% circa of Mouse and Human introns exhibited an insert which was 100 nt or less distant from the end of the preceding exon or the beginning of the following exon. In Zebrafish about 80% of the introns carried TE inserts and 29% of the introns exhibited inserts which were less than 100 nt distant from the end of the preceding exon or the beginning of the following exon (including 7% of introns which carried nearing TEs at both ends).

The TEs were usually shorter than 400 nt, but could vary in length from 70 nt up to 600 nt in some ERV-derived TEs.

In the Supplementary Material section are listed, for the different species, the TEs found in the 100 upstream and downstream nucleotides of the introns and the UTR TEs which are the more closer to the Start and Stop codons (Suppl-Tables 1-12).
Suppl-Table 1: 5’ end of Mouse Introns. Distances of the first TE from the intron 5’ end (INTRON-5’-LAGs)

Carrier

Intron

Distance (nt)

TE name

TE class

Direction

Position

slc25a3

5

34

B1_Mur2

NonLTR/SINE/SINE1

c

TM5

slc25a12

5

48

HAL1

NonLTR/L1

c

upstream of TM1

9

73

B3

NonLTR/SINE/SINE2

d

upstream of TM1

slc25a16

2

16

MTC

ERV/ERV3

c

between TM1 and TM2

8

56

B2_Mm1a

NonLTR/SINE/SINE2

c

between TM5 and TM6

slc25a20

7

64

ID_B1

NonLTR/SINE/SINE2

c

between TM5 and TM6

slc25a24

4

61

RMER5

ERV/ERV1

c

upstream of TM1

7

55

MLT1F1

ERV/ERV3

c

between TM3 and TM4

slc25a26

5

92

B2_Rat3

NonLTR/SINE/SINE2

d

TM4

slc25a27

6

61

B3A

NonLTR/SINE/SINE2

c

nd

slc25a31

3

64

B1_Rn

NonLTR/SINE/SINE1

c

between TM3 and TM4

slc25a36

5

20

B1F

NonLTR/SINE/SINE1

c

between TM3 and TM4

slc25a38

2

91

PB1D10

NonLTR/SINE/SINE1

c

between TM1 and TM2

slc25a39

3

99

B1_Mus1

NonLTR/SINE/SINE1

d

between TM1 and TM2

slc25a40

3

83

Lx_3end

NonLTR/L1

c

between TM1 and TM2

slc25a41

1

55

B1_Mus2

NonLTR/SINE/SINE1

d

upstream of TM1

5

97

B1_Mus1

NonLTR/SINE/SINE1

c

between TM4 and TM5

slc25a42

1

24

URR1

DNA/hAT

c

upstream of TM1

2

50

B1F

NonLTR/SINE/SINE1

c

between TM1 and TM2

slc25a46

6

16

LX5

NonLTR/L1

c

TM3

Slc25a50

7

58

B3

NonLTR/SINE/SINE2

c

nd

11

39

B4A

NonLTR/SINE/SINE2

c

nd
Suppl-Table 2: 5’ end of Human Introns. Distances of the first TE from the intron 5’ end (INTRON-5’-LAGs)

Carrier

Intron

Distance (nt)

TE name

TE class

Direction

Position

SLC25A3

4

89

AluYd2

NonLTR/SINE/SINE1

c

between TM3 and TM4

SLC25A6

2

9

MLT1B

ERV/ERV3

c

TM4

SLC25A12

3

68

AluJ_Mim

NonLTR/SINE/SINE1

d

upstream of TM1

12

69

Alu2_TS

NonLTR/SINE/SINE1

d

TM2

SLC25A13

5

33

AluYb3a2

NonLTR/SINE/SINE1

d

upstream of TM1

SLC25A14

5

5

MIRb

NonLTR/SINE/SINE2

d

between TM3 and TM4

SLC25A15

1

3

GOLEM_A

DNA/Mariner

d

TM1

2

53

Alu2_TS

NonLTR/SINE/SINE1

d

between TM2 and TM3

5

55

AluYb3a1

NonLTR/SINE/SINE1

d

downstream of TM6

SLC25A16

2

80

LTR10C

ERV/ERV1

d

between TM1 and TM2

4

84

MER4CL34

ERV/ERV1

d

between TM2 and TM3

SLC25A17

2

78

AluSq2

NonLTR/SINE/SINE1

c

between TM1 and TM2

5

84

L1-2_Cja

NonLTR/L1

c

between TM3 and TM4

SLC25A20

3

73

AluSx1

NonLTR/SINE/SINE1

d

between TM2 and TM3

4

94

AluJo

NonLTR/SINE/SINE1

d

between TM3 and TM4

SLC25A21

6

78

AluSp

NonLTR/SINE/SINE1

c

between TM3 and TM4

7

52

MIRb

NonLTR/SINE/SINE2

c

between TM4 and TM5

SLC25A24

7

39

MLT1F1

ERV/ERV3

c

between TM3 and TM4

9

100

MER106B

DNA/hAT

c

between TM5 and TM6

SLC25A38

6

56

MER5B

DNA/hAT

d

between TM5 and TM6

SLC25A39

2

61

AluSx

NonLTR/SINE/SINE1

d

between TM1 and TM2

SLC25A40

1

70

MER11A

ERV/ERV2

c

TM1

SLC25A46

5

48

L1PA16

NonLTR/L1

c

TM2

SLC25A50

9

75

AluSx

NonLTR/SINE/SINE1

d

between TM2 and TM3
Suppl-Table 3: 5’ end of Zebrafish Introns. Distances of the first TE from the intron 5’ end (INTRON-5’-LAGs)

Carrier

Intron

Distance (nt)

TE name

TE class

Direction

slc25a1

3

72

I-3_DR

NonLTR/Nimb

d

slc25a11

6

54

HE1_DR1

NonLTR/SINE/SINE2

d

7

35

TC1DR3

DNA

c

slc25a12

8

54

DNA-1-5_DR

DNA

d

9

38

IS3EU-4_DR

DNA/IS3EU

d

11

36

hAT-N88_DR

DNA/hAT

c

14

85

hAT-N66B_DR

DNA/hAT

c

15

13

ANGEL

DNA/Kolobok

c

17

60

EnSpm-14_HM

DNA/EnSpm/CACTA

d

slc25a16

6

42

DNA11TA1_DR

DNA

c

slc25a18

4

45

I-3_DR

NonLTR/Nimb

d

slc25a19

3

46

TDR2

DNA/Mariner

c

5

39

Rex1-40_DRe

NonLTR/Rex1

d

slc25a21

2

30

ANGEL

DNA/Kolobok

c

3

41

Mariner-N7_DR

DNA/Mariner

d

slc25a23

6

90

Kolobok-N10B_DR

DNA/Kolobok

c

slc25a24

7

62

TDR7

DNA

d

8

67

HATN10_DR

DNA/hAT

c

slc25a25

3

67

Transib-6_HM

DNA/Transib

d

slc25a26

2

16

Tc1-6_AFC

DNA/Mariner

c

slc25a27

5

33

DNAX-16_DR

DNA

d

slc25a29

3

21

Helitron-N2_DR

DNA/Helitron

d

slc25a32

1

61

L2-1B_DR

NonLTR/L2

c

2

41

Helitron-N3_DR

DNA/Helitron

d

3

32

DNA-6-N2_DR

DNA

c

6

70

hAT-N129_DR

DNA/hAT

c

slc25a33

2

82

Kolobok-N3_DR

DNA/Kolobok

d

slc25a38

3

18

DNAX-16_DR

DNA

d

4

41

Gypsy-223_DR-LTR

LTR/Gypsy

d

6

91

TDR2

DNA/Mariner

d

slc25a40

2

57

ANGEL

DNA/Kolobok

c

6

17

DNAX-1B_DR

DNA

d

7

40

ANGEL

DNA/Kolobok

c

9

11

TDR12

DNA/Mariner

d

slc25a42

1

23

HE1_DR1

NonLTR/SINE/SINE2

c

4

65

Kolobok-1N2_DR

DNA/Kolobok

c

5

17

CR1-24_DR

NonLTR/CR1

d

6

10

Harbinger-2_DR

DNA/Harbinger

d

slc25a43

3

93

TDR3

DNA/hAT

c

slc25a44

1

69

SINE2-1B_DR

NonLTR/SINE/SINE2

d

slc25a45

1

42

DNA-N15_DR

DNA

d

2

27

TC1DR3

DNA

c

5

76

Kolobok-N1_DR

DNA/Kolobok

c

slc25a46

4

49

L2-2_DRe

NonLTR/L2

d

slc25a47

4

17

Zator-N1_DR

DNA/Zator

d
Suppl-Table 4: 3’ end of Mouse Introns. Distances of the last TE end from the intron 3’ end (INTRON-3’-LAGs)

Carrier

Intron

Distance (nt)

TE name

TE class

Direction

Position

slc25a12

2

25

B3A

NonLTR/SINE/SINE2

c

upstream of TM1

6

41

B1_Mus1

NonLTR/SINE/SINE1

d

upstream of TM1

slc25a14

4

39

B2_Rat4

NonLTR/SINE/SINE2

c

between TM2 and TM3

slc25a16

3

29

B3

NonLTR/SINE/SINE2

c

between TM2 and TM3

7

90

ID_B1

NonLTR/SINE/SINE2

c

between TM4 and TM5

slc25a17

1

93

B3

NonLTR/SINE/SINE2

d

TM1

slc25a19

4

68

B3A

NonLTR/SINE/SINE2

c

between TM4 and TM5

slc25a20

3

83

B1_Mus1

NonLTR/SINE/SINE1

c

between TM2 and TM3

4

64

B4

NonLTR/SINE/SINE2

c

between TM3 and TM4

slc25a23

2

68

RSINE2A

NonLTR/SINE/SINE2

d

upstream of TM1

slc25a27

4

95

RMER4B_LTR

ERV/ERV2

d

nd

slc25a30

1

48

B4

NonLTR/SINE/SINE2

c

TM1

7

33

MTB

ERV/ERV3

c

between TM5 and TM6

slc25a32

5

49

B1_Mus1

NonLTR/SINE/SINE1

d

between TM4 and TM5

slc25a36

6

49

B1_Rn

NonLTR/SINE/SINE1

d

between TM5 and TM6

slc25a40

8

66

ORR1C2_LTR

ERV/ERV3

d

between TM5 and TM6

slc25a41

2

54

ZP3AR

Simple/Sat

d

between TM1 and TM2

slc25a43

4

44

B3A

NonLTR/SINE/SINE2

d

TM6

slc25a46

7

34

B3

NonLTR/SINE/SINE2

d

between TM3 and TM4

Carrier

Intron

Distance (nt)

TE name

TE class

Direction

Position

slc25a12

2

25

B3A

NonLTR/SINE/SINE2

c

upstream of TM1

6

41

B1_Mus1

NonLTR/SINE/SINE1

d

upstream of TM1

slc25a14

4

39

B2_Rat4

NonLTR/SINE/SINE2

c

between TM2 and TM3

slc25a16

3

29

B3

NonLTR/SINE/SINE2

c

between TM2 and TM3

7

90

ID_B1

NonLTR/SINE/SINE2

c

between TM4 and TM5

slc25a17

1

93

B3

NonLTR/SINE/SINE2

d

TM1

slc25a19

4

68

B3A

NonLTR/SINE/SINE2

c

between TM4 and TM5

slc25a20

3

83

B1_Mus1

NonLTR/SINE/SINE1

c

between TM2 and TM3

4

64

B4

NonLTR/SINE/SINE2

c

between TM3 and TM4

slc25a23

2

68

RSINE2A

NonLTR/SINE/SINE2

d

upstream of TM1

slc25a27

4

95

RMER4B_LTR

ERV/ERV2

d

nd

slc25a30

1

48

B4

NonLTR/SINE/SINE2

c

TM1

7

33

MTB

ERV/ERV3

c

between TM5 and TM6

slc25a32

5

49

B1_Mus1

NonLTR/SINE/SINE1

d

between TM4 and TM5

slc25a36

6

49

B1_Rn

NonLTR/SINE/SINE1

d

between TM5 and TM6

slc25a40

8

66

ORR1C2_LTR

ERV/ERV3

d

between TM5 and TM6

slc25a41

2

54

ZP3AR

Simple/Sat

d

between TM1 and TM2

slc25a43

4

44

B3A

NonLTR/SINE/SINE2

d

TM6

slc25a46

7

34

B3

NonLTR/SINE/SINE2

d

between TM3 and TM4
Suppl-Table 5: 3’ end of Human Introns. Distances of the last TE end from the intron 3’ end (INTRON-3’-LAGs)

Carrier

Intron

Distance (nt)

TE name

TE class

Direction

Position

SLC25A7

2

93

AluSx

NonLTR/SINE/SINE1

d

between TM2 and TM3

5

42

AluJr

NonLTR/SINE/SINE1

d

TM6

SLC25A12

3

27

L1MC5

NonLTR/L1

c

upstream of TM1

SLC25A14

3

93

L1MC1_EC

NonLTR/L1

c

between TM1 and TM2

SLC25A15

2

94

AluJr

NonLTR/SINE/SINE1

c

between TM2 and TM3

SLC25A16

8

73

AluSx

NonLTR/SINE/SINE1

d

between TM5 and TM6

SLC25A17

1

65

AluJr

NonLTR/SINE/SINE1

d

TM1

2

56

AluS

Interspersed_Repeat

d

between TM1 and TM2

SLC25A20

5

27

AluJ

Interspersed_Repeat

c

TM4

SLC25A24

3

80

Charlie25

DNA/hAT

d

upstream of TM1

6

35

MLT1A0

ERV/ERV3

c

between TM2 and TM3

SLC25A27

7

96

AluY

NonLTR/SINE/SINE1

c

between TM5 and TM6

SLC25A30

7

72

AluY

NonLTR/SINE/SINE1

c

between TM5 and TM6

SLC25A33

1

94

AluYb3a1

NonLTR/SINE/SINE1

c

TM1

6

85

AluSz

NonLTR/SINE/SINE1

c

between TM5 and TM6

SLC25A38

3

53

LTR16C

ERV/ERV3

d

TM2

SLC25A39

2

71

AluSx

NonLTR/SINE/SINE1

d

between TM1 and TM2

SLC25A50

4

40

AluS

Interspersed_Repeat

d

nd

6

39

AluSq2

NonLTR/SINE/SINE1

c

nd
Suppl-Table 6: 3’ end of Zebrafish Introns. Distances of the last TE end from the intron 3’ end (INTRON-3’-LAGs).

Carrier

Intron

Distance (nt)

TE name

TE class

Direction

slc25a3

1

94

EnSpm-N21_DR

DNA/EnSpm/CACTA

c

slc25a8

5

39

hAT-27N1_DR

DNA/hAT

c

slc25a9

1

89

SINE2-3_DR

NonLTR/SINE/SINE2

d

slc25a11

1

75

hAT-N86_DR

DNA/hAT

d

2

48

Gypsy41-LTR_DR

LTR/Gypsy

c

5

37

LOOPERN4B_DR

DNA/Kolobok

c

7

75

TDR24

DNA

d

slc25a12

5

19

Mariner-N8_EL

DNA/Mariner

d

11

93

hAT-N88_DR

DNA/hAT

c

14

53

hAT-N66B_DR

DNA/hAT

c

15

68

Kolobok-N3_DR

DNA/Kolobok

c

17

85

Harbinger-N11_DR

DNA/Harbinger

d

slc25a16

4

48

Rex1-38_DRe

NonLTR/Rex1

c

6

32

DNA11TA1_DR

DNA

c

slc25a18

2

92

TDR7

DNA

d

7

42

hAT-N48B_DR

DNA/hAT

c

slc25a19

4

59

hAT-N157_DR

DNA/hAT

d

slc25a21

8

72

ANGEL

DNA/Kolobok

c

9

26

Kolobok-N10B_DR

DNA/Kolobok

d

slc25a22

2

37

Kolobok-N5_DR

DNA/Kolobok

d

slc25a23

2

82

Mariner-7_DR

DNA/Mariner

c

8

59

SINE2-4_DR

NonLTR/SINE/SINE2

d

slc25a25

6

65

SINE3-1

NonLTR/SINE/SINE3

c

slc25a27

5

46

EnSpm-N4_DR

DNA/EnSpm/CACTA

d

slc25a29

3

72

DNAX-1_DR

DNA

c

slc25a32

5

53

Kolobok-N5_DR

DNA/Kolobok

c

slc25a36

3

42

HATN12B_DR

DNA/hAT

d

slc25a37

1

84

Kolobok-N1_DR

DNA/Kolobok

c

3

60

HATN6_DR

DNA/hAT

c

slc25a38

1

85

TDR25

DNA

c

3

72

HATN4_DR

DNA/hAT

c

4

27

L2-2_DRe

NonLTR/L2

d

6

45

CryptonV-N5_DR

DNA/Crypton/CryptonV

d

slc25a39

10

90

EnSpm1_SB

DNA/EnSpm/CACTA

c

slc25a42

4

15

Kolobok-1N2_DR

DNA/Kolobok

c

6

22

Helitron-N3_DR

DNA/Helitron

c

slc25a44

2

70

hAT-N48_DR

DNA/hAT

c

slc25a45

1

3

Polinton-1_DR

DNA/Polinton

c

2

52

TC1DR3

DNA

c

3

9

hAT5-N2_DR

DNA/hAT

d

5

65

DNA-8-3_DR

DNA

d

slc25a46

3

90

DNA13TA1_DR

DNA

d

4

88

TDR17B

DNA

d

slc25a47

1

71

HE2_DR

NonLTR/SINE/SINE2

d

slc25a50

12

51

hAT-27N1_DR

DNA/hAT

d
Suppl-Table 7: Mouse 5’UTR. Distances from the start codon to the end of the immediately upstream TE (5’UTR-LAGs).

Carrier

Distance (nt)

TE name

TE class

Direction

slc25a1

3125

B1_Mus1

NonLTR/SINE/SINE1

d

slc25a2

596

PB1D9

NonLTR/SINE/SINE1

c

slc25a3

1405

B3A

NonLTR/SINE/SINE2

c

slc25a4

2029

Lx7_3end

NonLTR/L1

d

slc25a5

1415

MTD

ERV/ERV3

d

slc25a7

1558

B1_Mur4

NonLTR/SINE/SINE1

c

slc25a8

4462

RLTR14

ERV/ERV1

c

slc25a9

617

B1

NonLTR/SINE/SINE1

d

slc25a10

2966

B1

NonLTR/SINE/SINE1

c

slc25a11

1549

B3

NonLTR/SINE/SINE2

d

slc25a12

754

ID_B1

NonLTR/SINE/SINE2

c

slc25a13

1355

MLT1A1

ERV/ERV3

c

slc25a14

784

LX5c

NonLTR/L1

c

slc25a15

1512

LX9

NonLTR/L1

c

slc25a16

351

B1F1

NonLTR/SINE/SINE1

c

slc25a17

506

B3A

NonLTR/SINE/SINE2

c

slc25a18

400

B2_Mm1a

NonLTR/SINE/SINE2

c

slc25a19

185

B1_Rn

NonLTR/SINE/SINE1

c

slc25a20

1076

B3

NonLTR/SINE/SINE2

c

slc25a21

158

B1F

NonLTR/SINE/SINE1

c

slc25a22

2242

B1_Rn

NonLTR/SINE/SINE1

d

slc25a23

4119

B1_Mus1

NonLTR/SINE/SINE1

d

slc25a24

1422

ORR1F_Str

ERV/ERV2

c

slc25a25

6901

B1_Mus2

NonLTR/SINE/SINE1

c

slc25a26

714

RSINE1

NonLTR/SINE/SINE2

c

slc25a27

1516

RSINE1

NonLTR/SINE/SINE2

c

slc25a28

2642

B1_Rn

NonLTR/SINE/SINE1

c

slc25a29

3625

B2

NonLTR/SINE/SINE2

c

slc25a30

103

ORR1C2_LTR

ERV/ERV3

d

slc25a31

1176

LX8

NonLTR/L1

d

slc25a32

755

B1_Mus1

NonLTR/SINE/SINE1

c

slc25a33

0

BEL-636_AA-I

LTR/BEL

d

slc25a34

497

B1_Mur1

NonLTR/SINE/SINE1

d

slc25a35

2205

B1_Mur4

NonLTR/SINE/SINE1

d

slc25a36

1676

B1_Mus1

NonLTR/SINE/SINE1

c

slc25a37

1417

B1F

NonLTR/SINE/SINE1

c

slc25a38

335

B1_Mus1

NonLTR/SINE/SINE1

c

slc25a39

2210

B1_Mm

NonLTR/SINE/SINE1

c

slc25a40

937

B1_Mur2

NonLTR/SINE/SINE1

c

slc25a41

267

ID_B1

NonLTR/SINE/SINE2

d

slc25a42

1290

B1_Mur2

NonLTR/SINE/SINE1

c

slc25a43

1251

RSINE2A

NonLTR/SINE/SINE2

c

slc25a44

1137

B1_Mus2

NonLTR/SINE/SINE1

c

slc25a45

1552

L1MA1

NonLTR/L1

c

slc25a46

1977

B1_Mm

NonLTR/SINE/SINE1

c

slc25a47

1646

B1_Mus1

NonLTR/SINE/SINE1

d

slc25a48

504

BGLII_LTR

ERV/ERV2

d

slc25a49

1641

ORR1A0

ERV/ERV3

c

slc25a50

606

B1_Mur1

NonLTR/SINE/SINE1

c

slc25a51

706

B2_Rat1

NonLTR/SINE/SINE2

d

slc25a53

3300

B1_Rn

NonLTR/SINE/SINE1

c

slc25a54

786

B1_Rn

NonLTR/SINE/SINE1

c
Suppl-Table 8: Human 5’UTR. Distances from the start codon to the end of the immediately upstream TE (5’UTR-LAGs)

Carrier

Distance (nt)

TE name

TE class

Direction

SLC25A1

6650

AluY

NonLTR/SINE/SINE1

c

SLC25A2

364

AluJ

Interspersed_Repeat

c

SLC25A3

1242

AluSx

NonLTR/SINE/SINE1

d

SLC25A4

1832

AluSx

NonLTR/SINE/SINE1

c

SLC25A5

620

MER96B

DNA/hAT

c

SLC25A6

1435

AluSp

NonLTR/SINE/SINE1

d

SLC25A7

2689

MLT1H1

ERV/ERV3

c

SLC25A8

886

AluSx

NonLTR/SINE/SINE1

c

SLC25A9

395

AluJr

NonLTR/SINE/SINE1

d

SLC25A10

599

AluS

Interspersed_Repeat

c

SLC25A11

1541

MIRb

NonLTR/SINE/SINE2

c

SLC25A12

1014

AluSx1

NonLTR/SINE/SINE1

d

SLC25A13

1192

THE1C

ERV/ERV3

d

SLC25A14

894

AluSz

NonLTR/SINE/SINE1

c

SLC25A15

769

MER5A1

DNA/hAT

d

SLC25A16

357

AluSz

NonLTR/SINE/SINE1

c

SLC25A17

1120

AluSz

NonLTR/SINE/SINE1

c

SLC25A18

558

AluSx1

NonLTR/SINE/SINE1

c

SLC25A19

82

L2

NonLTR/CR1

c

SLC25A20

310

L2

NonLTR/CR1

d

SLC25A21

705

MER5A

DNA/hAT

c

SLC25A22

3681

AluSz

NonLTR/SINE/SINE1

c

SLC25A23

1299

AluSq

NonLTR/SINE/SINE1

d

SLC25A24

1553

AluS

Interspersed_Repeat

d

SLC25A25

2908

AluSq

NonLTR/SINE/SINE1

c

SLC25A26

1196

MIR

NonLTR/SINE/SINE2

c

SLC25A27

1600

L1ME4A

NonLTR/L1

d

SLC25A28

1702

AluJb

NonLTR/SINE/SINE1

c

SLC25A29

222

EnSpm-2_PGr

DNA/EnSpm/CACTA

c

SLC25A30

414

AluJo

NonLTR/SINE/SINE1

c

SLC25A31

769

MER5B

DNA/hAT

c

SLC25A32

1932

Charlie7_Aves

DNA/hAT

c

SLC25A33

111

MuDR-9_SBi

DNA/MuDR

d

SLC25A34

652

MIRb

NonLTR/SINE/SINE2

c

SLC25A35

1126

AluY

NonLTR/SINE/SINE1

d

SLC25A36

586

L1ME3F_3end

NonLTR/L1

c

SLC25A37

1444

L1ME4A

NonLTR/L1

c

SLC25A38

702

CHARLIE5

DNA/hAT

c

SLC25A39

93

AluSc

NonLTR/SINE/SINE1

d

SLC25A40

445

AluY

NonLTR/SINE/SINE1

c

SLC25A41

260

AluY

NonLTR/SINE/SINE1

d

SLC25A42

505

AluSx1

NonLTR/SINE/SINE1

d

SLC25A43

648

MIRb

NonLTR/SINE/SINE2

c

SLC25A44

1097

Alu2_TS

NonLTR/SINE/SINE1

c

SLC25A45

669

L2

NonLTR/CR1

c

SLC25A46

1104

L1MA3

NonLTR/L1

d

SLC25A47

812

MIRc

NonLTR/SINE/SINE2

d

SLC25A48

8043

MIRb

NonLTR/SINE/SINE2

c

SLC25A49

2322

AluSq

NonLTR/SINE/SINE1

c

SLC25A50

640

AluSg

NonLTR/SINE/SINE1

d

SLC25A51

228

CHARLIE1

DNA/hAT

c

SLC25A52

641

AluJr

NonLTR/SINE/SINE1

c

SLC25A53

696

MER20

DNA/hAT

d
Suppl-Table 9: Zebrafish 5’UTR. Distances from the start codon to the end of the immediately upstream TE (5’UTR-LAGs)

Carrier

Distance (nt)

TE name

TE class

Direction

slc25a1

575

Ginger1-10_HM

DNA/Ginger1

d

slc25a3

455

GYCUME1_LTR

LTR/Gypsy

d

slc25a4

2793

HATN4_DR

DNA/hAT

d

slc25a5

1868

L2-5_DRe

NonLTR/L2

d

slc25a6

382

ANGEL

DNA/Kolobok

c

slc25a8

175

ANGEL

DNA/Kolobok

d

slc25a9

413

DNA-X-8_DR

DNA

d

slc25a11

215

Tx1-36_DR

NonLTR/Tx1

c

slc25a12

139

Tx1-17_DR

NonLTR/Tx1

c

slc25a13

307

DNA-N15_DR

DNA

c

slc25a14

1037

DNA-5-8B_DR

DNA

c

slc25a15

373

HE1_DR1

NonLTR/SINE/SINE2

d

slc25a16

936

Kolobok-N7_DR

DNA/Kolobok

d

slc25a17

2089

EnSpm-N4_DR

DNA/EnSpm/CACTA

d

slc25a18

727

TDR7

DNA

c

slc25a19

443

Ginger1-N1_DR

DNA/Ginger1

c

slc25a20

268

MuDR-N1_DR

DNA/MuDR

c

slc25a21

1070

HATN10_DR

DNA/hAT

c

slc25a22

981

DNA-CCGG-1_DR

DNA

c

slc25a23

1469

EnSpm-N6_DR

DNA/EnSpm/CACTA

d

slc25a24

2165

TDR14

DNA

d

slc25a25

879

ANGEL

DNA/Kolobok

c

slc25a26

185

Tx1-23_DR

NonLTR/Tx1

c

slc25a27

575

Kolobok-2_DR

DNA/Kolobok

d

slc25a28

575

DNA-8-13_DR

DNA

d

slc25a29

442

EnSpm-N13_DR

DNA/EnSpm/CACTA

c

slc25a32

700

DNA-8-28_DR

DNA

c

slc25a33

500

Tx1-5_DR

NonLTR/Tx1

c

slc25a35

410

L2-5_DRe

NonLTR/L2

d

slc25a36

703

DNA-6-N4_DR

DNA

d

slc25a37

1211

L1-72_DR

NonLTR/L1

d

slc25a38

617

EnSpm-N6_DR

DNA/EnSpm/CACTA

c

slc25a39

584

DNA8-7_DR

DNA/hAT

d

slc25a40

1405

SINE2-4_DR

NonLTR/SINE/SINE2

c

slc25a42

112

HATN10_DR

DNA/hAT

c

slc25a43

417

DNAX-16_DR

DNA

d

slc25a44

315

EnSpm-N13_DR

DNA/EnSpm/CACTA

d

slc25a45

542

hAT-N137_DR

DNA/hAT

c

slc25a46

1944

hAT-N25_DR

DNA/hAT

d

slc25a47

774

ANGEL

DNA/Kolobok

d

slc25a48

2284

DNA2-10_DR

DNA

d

slc25a50

335

SINE2-5_DR

NonLTR/SINE/SINE2

d

slc25a51

341

ANGEL

DNA/Kolobok

c

slc25a52

354

ANGEL

DNA/Kolobok

d
Suppl-Table 10: Mouse 3’UTR. Distances from the stop codon to the first downstream TE (3’UTR-LAGs)

Carrier

Distance (nt)

TE name

TE class

Direction

slc25a1

5566

ID_B1

NonLTR/SINE/SINE2

d

slc25a2

619

L1MdTf_II

NonLTR/L1

c

slc25a3

1325

B1_Mus1

NonLTR/SINE/SINE1

d

slc25a4

1381

B3

NonLTR/SINE/SINE2

d

slc25a5

1394

B2_Mm2

NonLTR/SINE/SINE2

c

slc25a7

1332

RMER17A

ERV/ERV2

c

slc25a8

855

B1F

NonLTR/SINE/SINE1

c

slc25a9

1324

ORR1D2_LTR

ERV/ERV3

d

slc25a10

2821

RSINE2

NonLTR/SINE/SINE2

d

slc25a11

624

B1_Mus1

NonLTR/SINE/SINE1

d

slc25a12

2152

B1F

NonLTR/SINE/SINE1

c

slc25a13

1165

B2_Rat4

NonLTR/SINE/SINE2

c

slc25a14

457

B2_Rat2

NonLTR/SINE/SINE2

c

slc25a15

2059

ORR1C2_LTR

ERV/ERV3

d

slc25a16

229

B1F2

NonLTR/SINE/SINE1

c

slc25a17

757

ORR1D1_LTR

ERV/ERV

d

slc25a18

717

B3A

NonLTR/SINE/SINE2

c

slc25a19

1277

MTC

ERV/ERV3

c

slc25a20

1508

RSINE1

NonLTR/SINE/SINE2

d

slc25a21

2103

B1_Mus1

NonLTR/SINE/SINE1

d

slc25a22

5628

B1_Mm

NonLTR/SINE/SINE1

d

slc25a23

2160

Gypsy-14B_ATr-LTR

LTR/Gypsy

d

slc25a24

1197

B1_Rn

NonLTR/SINE/SINE1

d

slc25a25

2395

B2_Mm2

NonLTR/SINE/SINE2

d

slc25a26

3011

RSINE2A

NonLTR/SINE/SINE2

d

slc25a27

2494

B3

NonLTR/SINE/SINE2

c

slc25a28

2711

PB1D7

NonLTR/SINE/SINE1

c

slc25a29

1971

RSINE1

NonLTR/SINE/SINE2

c

slc25a30

1726

B1_Rn

NonLTR/SINE/SINE1

c

slc25a31

1762

LX8

NonLTR/L1

c

slc25a32

1297

MER99

DNA

d

slc25a33

559

PB1D10

NonLTR/SINE/SINE1

c

slc25a34

859

ID_B1

NonLTR/SINE/SINE2

d

slc25a35

2922

B1_Mus2

NonLTR/SINE/SINE1

c

slc25a36

4294

RLTR11A2

ERV/ERV2

d

slc25a37

3883

B3

NonLTR/SINE/SINE2

d

slc25a38

790

B2_Rat4

NonLTR/SINE/SINE2

d

slc25a39

326

PB1D7

NonLTR/SINE/SINE1

d

slc25a40

982

RSINE1

NonLTR/SINE/SINE2

c

slc25a41

4240

B1_Mus1

NonLTR/SINE/SINE1

d

slc25a42

1253

B1_Mus1

NonLTR/SINE/SINE1

c

slc25a43

225

B2_Mm1a

NonLTR/SINE/SINE2

d

slc25a44

1418

ID_B1

NonLTR/SINE/SINE2

c

slc25a45

950

B3

NonLTR/SINE/SINE2

d

slc25a46

2374

IAPEY3_LTR

ERV/ERV2

d

slc25a47

2037

B1_Mur1

NonLTR/SINE/SINE1

c

slc25a48

2092

B1_Mus1

NonLTR/SINE/SINE1

c

slc25a49

899

MLTR25A

ERV/ERV2

d

slc25a50

1212

Charlie16a

DNA/hAT

c

slc25a51

1342

PB1D10

NonLTR/SINE/SINE1

c

slc25a53

1743

LTRIS_Mm

ERV/ERV1

d

slc25a54

1090

L1MB3

NonLTR/L1

d
Suppl-Table 11: Human 3’UTR. Distances from the stop codon to the first downstream TE (3’UTR-LAGs)

Carrier

Distance (nt)

TE name

TE class

Direction

SLC25A1

8119

MER81

DNA/hAT

c

SLC25A2

462

AluSx1

NonLTR/SINE/SINE1

c

SLC25A3

642

AluSp

NonLTR/SINE/SINE1

c

SLC25A4

725

AluSz6

NonLTR/SINE/SINE1

d

SLC25A5

730

AluSc

NonLTR/SINE/SINE1

c

SLC25A6

747

MLT1A0

ERV/ERV3

c

SLC25A7

1147

LTR16C

ERV/ERV3

d

SLC25A8

963

AluSz6

NonLTR/SINE/SINE1

c

SLC25A9

1610

AluJr

NonLTR/SINE/SINE1

d

SLC25A10

1151

ALU

NonLTR/SINE/SINE1

c

SLC25A11

2125

AluJb

NonLTR/SINE/SINE1

c

SLC25A12

1670

L1ME4A

NonLTR/L1

c

SLC25A13

3498

AluSp

NonLTR/SINE/SINE1

c

SLC25A14

1111

L1MC1

NonLTR/L1

c

SLC25A15

508

AluSz

NonLTR/SINE/SINE1

c

SLC25A16

579

PB1

NonLTR/SINE/SINE1

d

SLC25A17

2496

MIRc

NonLTR/SINE/SINE2

c

SLC25A18

1312

AluY

NonLTR/SINE/SINE1

d

SLC25A19

3572

AluJb

NonLTR/SINE/SINE1

d

SLC25A20

1526

Alu2_TS

NonLTR/SINE/SINE1

d

SLC25A21

2227

MER126_Crp

DNA

d

SLC25A22

6060

Alu2_TS

NonLTR/SINE/SINE1

d

SLC25A23

2129

AluSz

NonLTR/SINE/SINE1

c

SLC25A24

3075

THE1B

ERV/ERV3

d

SLC25A25

2203

L2

NonLTR/CR1

d

SLC25A26

7663

AluSz6

NonLTR/SINE/SINE1

c

SLC25A27

1861

MIR3

NonLTR/SINE/SINE2

c

SLC25A28

731

MIRc

NonLTR/SINE/SINE2

c

SLC25A29

2427

AluSz

NonLTR/SINE/SINE1

c

SLC25A30

3188

AluSq

NonLTR/SINE/SINE1

d

SLC25A31

900

CR1_Mam

NonLTR/CR1

d

SLC25A32

505

AluY

NonLTR/SINE/SINE1

c

SLC25A33

441

AluS

Interspersed_Repeat

d

SLC25A34

316

MIRb

NonLTR/SINE/SINE2

c

SLC25A35

1178

AluJb

NonLTR/SINE/SINE1

c

SLC25A36

4268

Alu2_TS

NonLTR/SINE/SINE1

c

SLC25A37

2332

AluSz

NonLTR/SINE/SINE1

d

SLC25A38

863

L1ME1

NonLTR/L1

c

SLC25A39

601

AluSc

NonLTR/SINE/SINE1

d

SLC25A40

2386

L1PA13

NonLTR/L1

d

SLC25A41

1763

BEL-636_AA-I

LTR/BEL

c

SLC25A42

2802

AluJo

NonLTR/SINE/SINE1

d

SLC25A43

471

AluJo

NonLTR/SINE/SINE1

c

SLC25A44

3035

AluJ

Interspersed_Repeat

c

SLC25A45

314

AluY

NonLTR/SINE/SINE1

c

SLC25A46

3422

L1MB4_5

NonLTR/L1

d

SLC25A47

2166

AluY

NonLTR/SINE/SINE1

c

SLC25A48

498

MamGypLTR2c

LTR/Gyps

c

SLC25A49

2362

L1MB8

NonLTR/L1

d

SLC25A50

1361

Charlie16a

DNA/hAT

c

SLC25A51

324

AluSg

NonLTR/SINE/SINE1

c

SLC25A52

2447

AluSz

NonLTR/SINE/SINE1

d

SLC25A53

1181

AluSq

NonLTR/SINE/SINE1

c
Suppl-Table 12: Zebrafish 3’UTR. Distances from the stop codon to the first downstream TE (3’UTR-LAGs)

Carrier

Distance (nt)

TE name

TE class

Direction

slc25a1

854

hAT-N22_DR

DNA/hAT

d

slc25a3

395

DNA-5-8_DR

DNA

d

slc25a4

982

Helitron-N2_DR

DNA/Helitron

c

slc25a5

409

CryptonV-N5_DR

DNA/Crypton/CryptonV

c

slc25a6

386

EnSpm-N4_DR

DNA/EnSpm/CACTA

c

slc25a8

616

TC1DR3

DNA

d

slc25a9

243

hAT-N145_DR

DNA/hAT

d

slc25a11

30

TDR16

DNA

c

slc25a12

885

DNAX-1_DR

DNA

d

slc25a13

1614

DNA-X-5_DR

DNA

d

slc25a14

725

Kolobok-N10_DR

DNA/Kolobok

c

slc25a15

821

TDR2

DNA/Mariner

d

slc25a16

949

hAT-N141_DR

DNA/hAT

c

slc25a17

332

DNA15TA1_DR

DNA

c

slc25a18

1395

SINE3-1a

NonLTR/SINE/SINE3

c

slc25a19

957

TC1DR3B

DNA/Mariner

c

slc25a20

403

TDR24

DNA

d

slc25a21

3805

TDR7

DNA

c

slc25a22

844

TDR23

DNA

d

slc25a23

417

hAT-N137_DR

DNA/hAT

c

slc25a24

824

ANGEL

DNA/Kolobok

c

slc25a25

194

Mariner-N5_HSal

DNA/Mariner

d

slc25a26

460

TDR13

DNA

c

slc25a27

657

Mariner-N38_DR

DNA/Mariner

d

slc25a28

289

hAT-N134_DR

DNA/hAT

d

slc25a29

103

DNAX-1C_DR

DNA

c

slc25a32

502

Mariner-N38_DR

DNA/Mariner

d

slc25a33

979

EXPANDER1_DR

NonLTR/RTE

d

slc25a35

220

P-30_HM

DNA/P

d

slc25a36

1741

Kolobok-N10B_DR

DNA/Kolobok

c

slc25a37

692

TDR3C

DNA

c

slc25a38

955

hAT-N161_DR

DNA/hAT

c

slc25a39

1018

ASAT_CY

Simple/Sat/SAT

c

slc25a40

762

DNA11TA1_DR

DNA

d

slc25a42

221

hAT-N22_DR

DNA/hAT

c

slc25a43

3940

CryptonV-N5_DR

DNA/Crypton/CryptonV

c

slc25a44

720

SINE3-1a

NonLTR/SINE/SINE3

c

slc25a45

89

DNAX-1_DR

DNA

d

slc25a46

834

CryptonV-N5_DR

DNA/Crypton/CryptonV

c

slc25a47

34

TDR17B

DNA

d

slc25a48

536

Daphne-27_DRe

NonLTR/Daphne

c

slc25a50

1106

SINE3-1

NonLTR/SINE/SINE3

d

slc25a51

121

EnSpm-N21_DR

DNA/EnSpm/CACTA

c

slc25a52

230

Mariner-N7_DR

DNA/Mariner

d
For each TE the type, class and direction are reported. For intronic TEs, the number of the hosting intron and the distance from its upstream or downstream end are indicated and in Mouse and Human is also reported the position of the intron concerned with reference to the six transmembrane (TM) coding segments. For UTR TEs, the distance in nucleotides from the Start or Stop codon is reported.
The nature of TEs
In the text Table 1 are reported the per cent incidences of the different classes (and subclasses) of TEs at the different locations (intronic 5’ and 3’ ends, UTR 5’ and 3’) in the different species.

LTR Retrotransposons, Non-LTR Retrotransposons and DNA transposons were found in all three species, but Endogenous Retrovirus-derived TEs were not found in Zebrafish, although represented in Mouse and Human. In our material, the other main difference between Mammals and Zebrafish is that in Mammals Non-LTR Retrotransposons are highly prevalent on DNA transposons (78-81% vs. 2-11%), while in Zebrafish the majority of TEs are DNA transposons (81%) and the Non-LTR Retrotransposon are 17% only.

The SINE1 subclass of Non-LTR Retrotransposons, typically represented in Mammals by the widespread primate Alu and the rodent B1 [both derived from the 7SL RNA], is not represented in Zebrafish. The SINE3 subclass of Non-LTR Retrotransposons [derived from the 5S rRNA] is represented in Zebrafish but not in Mammals. On the contrary, the SINE2 subclass (derived from tRNA) is represented in all species [5,42,43].

DNA transposons are present in all three species, but TEs of the subclass Kolobok were not found in Mammals and those of the subclasses EnSpm/CACTA and Mariner were absent in the Human, while expressed in Mouse.

In Mammals the overall frequency of SINE1 is about twice of that of SINE2, but, at all locations, the incidence of SINE1 is higher in Human than in Mouse (on average, 60% vs. 36%; p< 0.01), while the incidence of SINE2 is significantly higher in Mouse as compared to Human (on average, 37% vs. 7%; p< 0.01).

TE type composition may vary significantly between the two UTRs in the same species. In Mouse the SINE1 subclass is significantly more represented at 5’ than at 3’ (51.9% vs 34.6%; p< 0.01), whereas the SINE2 subclass is significantly more represented at 3’ than at 5’ (36.5% vs. 23.1%; p< 0.01). In Human, no significant 5’/3’ differences were detected. In Zebrafish the DNA transposon Mariner is represented at the 3’ UTR, but not at UTR 5’ (p< 0.05).

The incidence differences in TE direction (whether direct or complement) are not statistically significant, except for the SINE1 subclass in Mouse 5’ flanking region, in which the antisense direction prevails (74%).

We also compared the frequency of the different TE classes in the proximity of the coding regions with the estimated general frequency in the corresponding genomes, as reported by Chalopin et al. (2015; for Mouse, Human and Zebrafish) and Howe et al. (2013; for Zebrafish) (Table 2). In all the three species at intronic and UTR sites nearing coding sequences the overall percentage of Non-LTR Retrotransposons is higher and that of LTR Retrotransposons + Endogenous Retroviruses is lower, as compared to the average global TE distribution in the corresponding genome.
Exon-next TE distances at the 5’ end of the introns [INTRON- 5’-LAGs]
In this section the results will be treated cumulatively for Mouse, Human and Zebrafish since, despite the differences in TE types, no remarkable difference was observed between these species as regards the statistical distribution of the TE distances from the intron 5’ ends. The individual INTRON-5’-LAGs are listed in the Suppl-Tables 1-3. The cumulative frequency distribution of TE LAGs 0-100 at the 5’ end of introns is shown in Figure: 1, both as a column bar graph and as a line graph of the central moving average of five consecutive data.
Figure 1: Distribution of INTRON-5’-LAGs 0 to 100. Number of introns (Mouse + Human + Zebrafish) = 91. INTRON-5’-LAG is the distance (in nucleotides) between the TE first nucleotide and the last nucleotide of the preceding exon. Column bar graph: actual data. Line graph: central moving average of five consecutive data (values for Lags 0 and 1 and 99 and 100 are not-valid).
The average TE frequency per Lag in Lags 0 to 20 is 0.67 ± 0.13 and in Lags 21 to 100 is 0.96 ± 0.03. Thus, the TE frequency is significantly (p< 0.01) lower in a segment approximately 20-nt long at the 5’ end of the intron than at longer distances from the preceding exon.

TE-next Exon distances at the 3’ end of the introns [INTRON- 3’-LAGs]

As for the INTRON-5’-LAGs, the INTRON-3’-LAGs are treated cumulatively for Mouse, Human and Zebrafish.

The individual INTRON-3’-LAGs are listed in the Suppl- Tables 4-6. The cumulative frequency distribution of TE LAGs 0-100 is shown in Figure: 2, both as a column bar graph and as a line graph of the central moving average of five consecutive data.
Figure 2: Distribution of INTRON-3’-LAGs 0 to 100. Number of introns (Mouse + Human + Zebrafish) = 83. INTRON-3’-LAG is the distance (in nucleotides) between the TE last nucleotide and the first nucleotide of the succeeding exon. Column bar graph: actual data. Line graph: central moving average of five consecutive data (values for Lags 0 and 1 and 99 and 100 are not-valid).
The average TE frequency per Lag is 0.19 ± 0.11 in Lags 0 to 20 and 0.99 ± 0.02 in Lags 21 to 100. Thus, the TE frequency is significantly (p< 0.01) lower in a segment approximately 20-nt long at the 3’ end of the intron than at longer distances from the next exon.

As shown previously, the TE frequency is significantly lower at both the 20-nucleotide ends of the introns, but a comparison between the relative frequencies at the upstream end (0.67 ± 0.13) and the downstream end (0.19 ± 0.11) demonstrates that the TE frequency is significantly (p< 0.01) more reduced at the 3’ than at the 5’.

On the whole, in Mouse and Human introns with TE inserts in the proximity of their ends were apparently randomly distributed in the different sections of the genes, i.e., upstream of TM 1, within all the six TM-coding segments and the intervening segments, and downstream of TM 6 (Suppl-Tables 1 and 2 and 4 and 5).
TEs at the 5’ flanking region [5’UTR-LAGs] in Mouse and Human (the relative position of regulatory 5’ sequences)
The individual 5’UTR-LAGs are listed in the Suppl- Tables 7 and 8. The distances recorded were widely variable in the different genes, but the overall cumulative (Mouse + Human) distribution was unimodal and distinctly right-skewed with Excel asymmetry index = 2.66 (Figure: 3). The distribution peaked at 750 nt and the average was 1350 nt. However, 10% of distances were less than 300 nt and in one exceptional case (Mouse slc25a33) a BEL-636_AA-I (LTR/BEL class) TE immediately preceded the start codon.
Figure 3: Distribution of 5’UTR-LAGs. Cumulative distribution of all SLC25 Mouse and Human genes. 5’UTR-LAGs are the distances (in nucleotides) between the start codon and the end of the immediately upstream TE.
There is little currently known about experimentally validated proximal promoter sites. In human SLC25As members 1 4 (EPD database), 5 (EPD database)in which the 5’UTR-LAG interval is 620 nt or more long, the proximal promoter site was found to be located within this region. In addition, the 5’UTR-LAG regions of SLC25A1 and SLC25A3 also comprised a silencer sequence [27,32,44,45,46,47]. In SLC25A20, in which the 5’UTRLAG interval is 310 nt long, the promoter is likely to reside at the very upstream limit of the LAG region [48,49]. In SLC25A19, in which the 5’UTR-LAG region is only 82 nt long, the basal promoter is reported to reside about 2,500 nt upstream the LAG region [50].
TEs at the 3’ flanking region [3’UTR-LAGs] in Mouse and Human (the relative position of polyA signals)
The individual 3’UTR-LAGs are listed in the Suppl-Tables 10 and 11. Like at the 5’, the distances recorded were widely variable. The overall cumulative (Mouse + Human) distribution was unimodal and markedly right-skewed with Excel asymmetry index = 1.97 (Figure: 4). The distribution peak was at 750 nt and the average was 1850 nt, but 2% of distances were less than 300 nt.

The Mouse/Human UTR-LAGs (5’ + 3’) in corresponding genes are positively correlated (r = 0.45; p< 0.01). Data on the polyA signal position were available for some genes only. In 10 Mouse genes (slc25a members 3, 5, 8, 10, 21, 23, 29, 31, 32, and 37) and 22 Human genes (SLC25A members 1, 3, 4, 5, 6, 8, 9, 10, 12, 13, 14, 18, 19, 22, 24, 25, 29, 36, 38, 42, 47, and 49) the polyA signal was located in the TE-free area following the stop codon. In one Mouse gene (slc25a16) and four Human genes (SLC25A members 15, 16, 32, and 43) the polyA signal was located downstream of the first significant TE insert.

The position of the polyA signal is very variable, but, in Human, it regularly fell in the TE-free region in all genes in which this region was at least 640 nt long.

In the special case of the Mouse slc25a15 gene the polyA signal (ATTAAA) was entirely provided by the first TE, an ORR1C2_LTR insert derived from the ERV3 murine endogenous retrovirus.
Figure 4: Distribution of 3’UTR-LAGs. Cumulative distribution of all SLC25 Mouse and Human genes. 3’UTR-LAGs are the distances (in nucleotides) from the stop codon to the beginning of the first downstream TE.
Modeling the TE distributions at the 5’ and 3’ flanking regions in Mouse and Human
We attempted a general modeling of the spatial distribution of the most proximal TEs at the 5’ and 3’ flanking regions. If the TEs did insert in the flanking regions at purely random sites, the frequency distribution of the minimum TE distances would be expected to decay exponentially from shorter distances to longer distances, as shown in Figure: 5 by the dot-and-line graph of the function y = 30.5 e-0.233 (LAG/300) (where 30.5 is a scaling factor). In Figure:5 the gray columns represent the actual combined distribution of the 5’ and 3’UTR-LAGs. In this simulation, the theoretical frequencies match the actual values for the UTRLAGs 750 and higher, while at lower LAGs the actual frequency is reduced by comparison to the theoretical frequency by 77 % at LAG 150 and 32 % at LAG 450. Thus, the spatial distribution of TEs at UTRs seem to be essentially random at a certain distance from the start and stop codons, whereas the TE settlement seems to be the more “inhibited” the more a specific UTR section is close to the coding regions.
Figure 5: Dots and exponential interpolating line: the theoretical frequency distribution of genes according to the 5’UTR-LAGs or 3’UTR-LAGs in the hypothesis of TEs inserting at purely random sites. Column graph: the combined actual distributions of the Mouse and Human 5’ and 3’UTR-LAGs.
TEs at 5’ and 3’ flanking regions [5’UTR-LAGs and 3’UTR-LAGs] in Zebrafish and modelin
The individual 5’UTR-LAGs and 3’UTR-LAGs are listed in the Suppl-Tables 9 and 12, respectively. The frequency distributions are very similar at 5’ and 3’ and they will be treated cumulatively. The resulting distribution was unimodal and right-skewed as in Mouse and Human, but peaked at 450 nt and the average was about 800 nt; the Excel asymmetry index (1.66) was also lower than in the corresponding Mouse and Human distributions (Figure: 6).

The actual distribution may be modeled as previously explained (Figure:6; dots and exponential interpolating line, plotting the function y = 70.0 e-0.493 (LAG/300), where 70.0 is a scaling factor). The theoretical frequencies match the actual values for the UTR-LAGs 450 and higher, while at LAG 150 the actual frequency is reduced in comparison to the theoretical frequency by about 65 %. While the Mouse/Human UTR-LAGs in corresponding genes are positively correlated, the Mouse/Zebrafish and Human/ Zebrafish UTR-LAGs are not significantly correlated.
Figure 6: Column graph: cumulative distribution of the 5’UTR-LAGs and 3’UTR-LAGs in Zebrafish genes. Dots and exponential interpolating line: the theoretical frequency distribution of genes according to the UTR-LAGs in the hypothesis of TEs inserting at purely random sites.
Discussion
TE type and direction
In Human and Mouse, LTR elements have been reported to be underrepresented in the proximity to genes and in the introns, as compared to the intergenic regions [35,51]. This may be due to a negative selection at these sites, since the LTRs can impact the genome in many ways, being extremely recombinogenic and carrying transcriptional regulatory signals very similar to those in genes [52,53]. Indeed, there is evidence of transcriptional disruption of some Mouse genes by LTR element insertions [35]. We have found that, like in mammals, also in Zebrafish LTR elements are underrepresented in the proximity of coding sections (Results: The nature of TEs and Table 2).

At some sites the direction (sense/antisense) of TEs may exhibit significant biases. At the intron 3’ end, SINEs have been reported to be strongly antisense-biased in Mouse, but not in Human [35]. We were unable to confirm this finding, but we found that the SINE1 TEs at the 5’ UTR of Mouse genes are oriented with a significant antisense bias (Results: The nature of TEs). Selection against sense-oriented elements is likely due to the greater chance that such elements will disrupt gene transcript processing [51]. In Zebrafish, according to a previous report and our own data, no direction bias in the different TE classes could be detected. Obviously, this issue deserves to be further investigated [2].

In the first intron of Mouse and Human SLC25A42 the initial GT is changed into GC (Results: General). This is a relatively rare event occurring in less than 1% of cases [54]. In Zebrafish the corresponding intron starts by GT, indicating that the mutation occurred relatively late in the Mouse and Human common ancestor.
Intronic TEs and the control of splicing
TEs appear to be randomly distributed in the different intronic sections of the genes. Lack of preference for specific introns is also indicated by the observation that the number of TEbearing introns shared by the different species is lower than the expectance based on random coincidences (calculated from the percentages of introns bearing significant TEs, Results: General): Mouse and Human (Suppl-Tables 1 and 4 and 2 and 5) 4 vs. expected 4.8; Mouse and Zebrafish (Suppl-Tables 1 and 4 and 3 and 6) 6 vs. 8.8; Human and Zebrafish (Suppl-Tables 2 and 5 and 3 and 6) 3 vs. 8.5.

It had been already reported that in Mouse and Human the frequency of TEs is in general lower at both intron ends, especially so at the 3’ end [35]. In these species most of TEs are non-LTR Retrotransposons and DNA transposons are poorly represented (Table 2). Our present results confirm this finding for the family of mitochondrial carrier genes of Mouse and Human and add novel data on the homologous introns of Zebrafish, a species distantly related to mammals and in which the vast majority of TEs belongs to the class of DNA transposons (Table 2). Despite such differences, the Zebrafish pattern of distribution of the TE inserts paralleled the mammalian distribution. In all, in our material, the TE frequency was 0.67 per unit distance (nt) in the initial 0-20 nucleotides of the intron 5’ end and 0.96 in the more downstream 21-100 nucleotides (Results: Exon-next TE distances at the 5’ end of the introns [INTRON-5’-LAGs]). At the intronic 3’ end the corresponding figures were 0.19 and 0.99 (Results: TE/nextexon distances at the 3’ end of the introns [INTRON-3’-LAGs]). Statistical analysis demonstrates that at both 20-nt intron ends the TE density is reduced as compared to the adjoining sections and, in addition, the density is significantly lower at the 3’ 20-nt end than at the corresponding 5’ end.

The pre-mRNA splicing of introns is a very complex and not fully understood process in which there is thought to be an interplay among several components. The effector machine is the spliceosome, a massive ribonucleoprotein complex which responds to an ensemble of signals which likely originate from both the intron concerned and the flanking exons harboring specific splicing enhancer and silencer motifs. The seemingly more robust signals originate from the nucleotide sequences at the 5’ and 3’ ends of each intron, the so called 5′ and 3’ splice site (5′ss and 3’ss, or splice donor and acceptor site, respectively)[55].

Based on sequence conservation in homologous genes it has been estimated that the effective 5’ss signal stretches for a maximum of 5 or 6 nt beyond the initial GT, i.e., from +1 to +7 or +8 [56,58]. However, the nucleotide composition of this segment is very variable: in a study on the first six nucleotides in 216 couples of orthologous Mouse/Human cytokine receptor gene introns we found 51 different configurations and 75 different configurations in the present study [59].

The arrangement at the 3’ end of introns is more complicated. A “branch site” (a very short sequence including an adenine nucleotide) is localized at a variable distance (averaging 33–34 nt in Mammals); from the terminal AG. Further downstream there is a short polypyrimidine tract (rich in Ts and Cs) followed by a few variable nucleotides up to the AG end. The more evident T positive bias seems to extend in Vertebrates approximately from -5 to -20 with a peak at -10 [58,60]. On the whole, the typical sequence span of the 3’ss signal has been estimated to stretch approximately from -16 down to the AG end [56]. The nucleotide composition at 3’ end is even more variable than at the 5’ end: in our study on the last six nucleotides in 216 couples of orthologous Mouse/Human cytokine receptor gene introns we found as many as 94 different configurations and 102 different configurations in the present study [61].

TE elements and host genes co-evolved and selection was responsible for balancing the tension between retrotransposon proliferation and host survival so that the actual TE distribution may depend largely upon a secondary purging selection [35,62,63]. The relative TE depletion at the intron ends observed in Mouse, Human and Zebrafish likely results from a negative selection of genes harboring TEs which could overlap the 5’ or 3’ss. The evolutionary control would be more stringent at the 3’ where the splicing signal involves a longer series of nucleotides.

However, in some instances the TEs were likely to fell partly into the 5’ splicing signal regions. In Human SLC25A14 (Suppl-Table 2) the INTRON-5’-LAG following the fifth exon is 5 and the initial hexanucleotide is GTAAGA. In Human SLC25A15 (Suppl-Table 2) the INTRON-5’-LAG following the first exon is 3 and the initial hexanucleotides is GTACAG. Both hexanucleotides are often found at the 5’ end of other introns. Thus, due to the high degeneracy of the short 5’ss, the leftmost part of a TE could happen to integrate a genuine splicing signal.

At 3’, in the Zebrafish slc25a42 the INTRON-3’-LAG upstream of the fifth exon is 15 and in slc25a45 the INTRON-3’-LAG upstream of the second exon is only 3 (Suppl-Table 6). The terminal segments of the corresponding TEs are not sufficiently rich in Ts and Cs to integrate a polypyrimidine tract (details not shown). On the contrary, in Zebrafish slc25a45, where the INTRON-3’-LAG upstream of the forth exon is 9 (Suppl-Table 6), the terminal segments of the corresponding TE is TCTTCTCT.

The comparative analysis demonstrates that the genetically fixed Zebrafish/Mouse/Human scheme of exon/intron alternation keeps unaltered even when a TE settles near (< 100 nt) the splicing sites. It is thus concluded that the extant TEs do not exert any short-range disturbing activity on the splicing process. The extant TEs which are at a very short distance from the intron ends in certain cases may be even integrated in the splicing signal, while in the other cases there seem to be a relatively wide tolerance.
TEs in 5’ and 3’ flanking UTRs
The issues of TE differences between the 5’ and 3’ UTRs and of TE distances from the start and stop of the translation have not been specifically addressed so far.

Minding that our results make reference only to the TEs more nearing the coding region, it may be of interest that some TEs (SINE1 and SINE2 in Mouse and Mariner in Zebrafish) are asymmetrically represented in the two UTRs (Results: The nature of TEs).

Should TEs in the proximity of start or stop codons randomly located, the distribution of the minimum TE distances would have a maximum next to these codons, then declining exponentially. However, the actual distribution of the minimum distances exhibits relatively low frequencies near start and stop codons, then rises to a maximum (at about 750 nt in Mouse and Human and 450 nt in Zebrafish) to decline progressively thereafter. Superimposition of a suitable exponentially-decaying distribution shows that at the shortest distances the actual frequency is much lower than the theoretical frequency, but for higher distances the gap decreases and eventually the two distributions become similar. Therefore, it appears that the theoretical stochastic distribution is modified by a deterministic component which acts abating the short distances, viz., preventing TEs to settle too close to starts and stops of the translation region, this inhibition being the stronger the closer to the translation region, then vanishing at longer distances.

We were unable to correlate the extent of these upstream and downstream “relative inhibition regions” with the position of the regulatory sequences which may be present upstream and downstream of the translation region. Information on the proximal promoter sites is too scanty to allow general conclusions. In Mouse and Human genes for which the polyA signal position was available this sequence fell in the TE-free region in all genes in which this region was at least 640 nt long, but in other instances the polyA signal was located downstream of the first significant TE insert.

In summary, at both UTRs the net balance between insertion site preferences and selection tends to determine in mammals and Zebrafish a TE-free area of very varying extent, from a few tens up to a few thousands of nucleotides. On average, the TE-free area is narrower in Zebrafish than in mammals (Suppl-Tables 7-12). In addition, it is remarkable that the TE-free area at the UTRs is much wider than the TE-underrepresentation area at the intron ends. The present results shed no clear light on the relationships between these TE-free areas and the position of the regulating sequences hosted in the UTRs. Possibly the recorded more proximal TEs do not interfere with the regulatory sequences and the positioning of TEs and these sequences are independently regulated, as suggested by the TE/polyA signal relative positioning. But the hypothesis that TEs may in some way modulate the main regulatory signals cannot be ruled out. Obviously, all these poorly understood issues need further investigation.

As already noticed, a strong deterministic component regulates the exon/intron alternation in the mitochondrial solute carrier genes of vertebrates; furthermore, in these genes the lengths of the individual homologous Mouse/Human introns are strongly positively correlated [61]. The present results show that the Mouse/Human UTR-LAGs in corresponding genes are positively correlated, while the Mouse/Zebrafish and Human/Zebrafish UTR-LAGs are not correlated. These results illustrate the existence of a residual common deterministic component regulating the structure of Mouse and Human introns; such component, likely inherited from the common ancestor, had persisted despite the extensive intron re-editing and the incorporation of different TE species after the rodent/primate divergence, about 100 million years ago.

We conclude that, unlike some large intronic retroviral insertions which have been found to affect the expression of coding sequences even at a certain distance the extant TE inserts present in mitochondrial solute carrier genes, despite the differences in location and type in different species, do not alter the structural exon/intron plane of the individual genes, which has been kept conserved from fish to mammals along about 400-450 million years [64,65,66]. Such strict evolutionary control is possibly to be put in relation to the essential role of these genes in cell activity and survival.
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