Transposable elements in human genetic disease

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Transposable elements are abundant in the human genome, and great strides have been made in pinpointing variations in these repetitive sequences using whole-genome sequencing. Now, the focus is shifting to understanding their expression and regulation, and the functional consequences of their insertion and retention in the genome over time. Whereas transposable element insertions have been known to cause human genetic disease since the 1980s, the scope of their contributions to heritable phenotypes is now starting to be uncovered. Here, we review the many ways human retrotransposons contribute to genome function, their dysregulation in diseases including cancer and how they affect genetic disease.

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Fig. 1: Transposable elements.
Fig. 2: Long interspersed element 1 expression.
Fig. 3: Mechanisms by which disease-causing transposable element insertions disrupt normal gene function.
Fig. 4: Transposable elements can cause disease by introducing regulatory sequences or through large regional effects.


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The authors thank many members of the transposable element research community for engaging conversations that have shaped their ideas, and they apologize to these colleagues for unreferenced work. The authors thank M. Gorbounov for technical assistance with L1 ORF1p staining.

Author information

The authors contributed equally to all aspects of the article.

Correspondence to Kathleen H. Burns.

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Competing interests

K.H.B. and the Johns Hopkins University School of Medicine have licenced antibodies for L1 ORF1p to EMD Millipore. L.M.P. declares no competing interests.

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Nature Reviews Genetics thanks G. Faulkner, I. K. Jordan and D. Mager for their contribution to the peer review of this work.

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Online Mendelian Inheritance in Man:


Transposable elements

(TEs). DNA sequences that have the ability to move (transpose) to new locations in the genome.


DNA sequences that proliferate in the genome using an RNA intermediate and a ‘copy-and-paste’ retrotransposition mechanism.

Complex diseases

Common diseases caused by interactions of genetics, behaviour and the environment.

Long interspersed element 1

(LINE-1 or L1). An autonomous (protein-coding) retrotransposon; currently, Homo sapiens-specific L1 (L1Hs) are active.

Target primed reverse transcription

(TPRT). The form of retrotransposition used by non-long terminal repeat elements; in humans, this requires L1 ORF2p-encoded endonuclease and reverse transcriptase activities.


A short interspersed element derived from 7SL RNA, a non-autonomous retrotransposon that relies on L1-encoded ORF2p.


A composite retrotransposon made of short interspersed element, variable number tandem repeat and Alu sequences; also uses L1 protein to transpose.

Processed pseudogenes

cDNA copy of a gene transcript inserted into the genome.

Endogenous retroviruses

(ERVs). Autonomous (protein-coding) retrotransposons recently active in humans; also known as LTR elements for their long terminal repeats.

Polymorphic TEs

Also known as retrotransposon insertion polymorphisms or polymorphic mobile element insertions. A transposable element (TE) insertion that is a structural variant in a population, present or absence at a locus.

Minor allele frequency

For biallelic loci, the allele frequency for the second most common allele, as opposed to the major allele frequency; the two sum to 1 (p + q = 1).

Synthetic lethalities

Cell deaths in response to a combination of two attributes, most often genetic lesions, when either one of which would be well tolerated.

A-to-I editing

Conversion of adenosine (A) to inosine (I) in double-stranded RNA by adenosine deaminase acting on RNA 1 (ADAR1); relaxes strand annealing. Unedited hybrids in contact with cytoplasmic double-stranded RNA sensors can prompt interferon responses.


Incorporation of a new exon into a processed transcript; in this review, the incorporation of some transposable element sequences into a spliced mRNA.

Endonuclease-independent retrotransposition

A process whereby a retrotransposon inserts at a pre-existing DNA break.


An interval of DNA wherein a set of alleles is inherited as a group because of linkage disequilibrium.

Linkage disequilibrium

The non-random association of alleles on the same DNA strand.

Expression quantitative trait loci

(eQTLs). Sequence variants that are associated with alterations in mRNA levels.

Splicing quantitative trait loci

Sequence variants that are associated with alterations in mRNA splicing.


Chromosomal shattering. A large number of rearrangements occurring in a single event over limited genomic regions.

GWAS trait-associated SNP

A single-nucleotide polymorphism (SNP) identified by a genome-wide association study (GWAS) as being associated with a disease or phenotypic trait.

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