Alu Repeats and Human Disease

doi:10.1006/mgme.1999.2864

Molecular Genetics and Metabolism

Volume 67, Issue 3, July 1999, Pages 183-193

https://doi.org/10.1006/mgme.1999.2864 Get rights and content

Abstract

Alu elements have amplified in primate genomes through a RNA-dependent mechanism, termed retroposition, and have reached a copy number in excess of 500,000 copies per human genome. These elements have been proposed to have a number of functions in the human genome, and have certainly had a major impact on genomic architecture. Alu elements continue to amplify at a rate of about one insertion every 200 new births. We have found 16 examples of diseases caused by the insertion of Alu elements, suggesting that they may contribute to about 0.1% of human genetic disorders by this mechanism. The large number of Alu elements within primate genomes also provides abundant opportunities for unequal homologous recombination events. These events often occur intrachromosomally, resulting in deletion or duplication of exons in a gene, but they also can occur interchromosomally, causing more complex chromosomal abnormalities. We have found 33 cases of germ-line genetic diseases and 16 cases of cancer caused by unequal homologous recombination between Alu repeats. We estimate that this mode of mutagenesis accounts for another 0.3% of human genetic diseases. Between these different mechanisms, Alu elements have not only contributed a great deal to the evolution of the genome but also continue to contribute to a significant portion of human genetic diseases.

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Alu elements are retrotransposons with ubiquitous presence in the human genome that have contributed to human genomic diversity and health. These approximately 300-bp sequences can cause or mediate disease by disrupting coding/splicing regions in the germline, by insertional mutagenesis in somatic cells, and in promoting formation of copy-number variants. Alu elements may also disrupt epigenetic regulation by affecting non-coding regulatory regions. There are increasing reports of apparently sporadic and inherited genetic disorders caused by Alu-related gene disruption, but Marfan syndrome resulting from Alu element insertion has not been previously described. We report a family with classic features of Marfan syndrome whose previous FBN1 genetic testing was inconclusive. Using contemporary next-generation sequencing and bioinformatics analysis, a pathogenic/disruptive Alu insertion occurring in the coding region of the FBN1 gene was identified (c.6564_6565insAlu; p. Glu2189fs) and was confirmed and specified further with Sanger sequencing. This identified the molecular basis of disease in the family that was missed using previous genetic testing technologies and highlights a novel pathogenic mechanism for Marfan syndrome. This case adds to the growing literature of Mendelian diseases caused by Alu retrotransposition, and it also shows the growing capability of genomic technologies for detecting atypical mutation events.
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¹: To whom correspondence should be addressed at Tulane Cancer Center, SL-66, Tulane University Medical Center, 1430 Tulane Ave., New Orleans, LA 70112. Fax: (504) 588-5516. E-mail: [email protected].

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MinireviewAlu Repeats and Human Disease

Abstract

Genomics

J Mol Biol

Cell

Cell

J Biol Chem

Trends Microbiol

J Biol Chem

Cell

Genomics

Trends Genet

Gene

Am J Hum Genet

J Biol Chem

J Mol Biol

Curr Opin Genet Dev

Cell

Cell

Genomics

J Biol Chem

Lancet

J Biol Chem

J Mol Biol

Genomics

Cell

J Biol Chem

Am J Hum Genet

Retroposons defined

Nature

Structure and variability of recently inserted Alu family members

Nucleic Acids Res

Evolution of the master Alu gene(s)

J Mol Evol

SINE master genes and population biology

A fundamental division in the Alu family of repeated sequences

Proc Natl Acad Sci USA

A transpositionally and transcriptionally competent Alu subfamily

Mol Cell Biol

The Alu family developed through successive waves of fixation closely connected with primate lineage history

J Mol Evol

Clustering and sub-family relationships of the Alu family in the human genome

Mol Biol Evol

Existence of at least three distinct Alu subfamilies

J Mol Evol

Master genes in mammalian repetitive DNA amplification

Trends Genet

Transcription and processing of the rodent ID repeat family in germline and somatic cells

Nucleic Acids Res

LINEs and Alus—The polyA connection

Nature Genet

The impact of L1 retrotransposons on the human genome

Nature Genet

Reverse transcriptase encoded by a human transposable element

Science

Sequence patterns indicate an enzymatic involvement in integration of mammalian retroposons

Proc Natl Acad Sci USA

Ubiquitous, interspersed repeated sequences in mammalian genomes

Proc Natl Acad Sci USA

Standardized nomenclature for Alu repeats

J Mol Evol

Potential Alu function: Regulation of the activity of double-stranded RNA-activated kinase PKR

Mol Cell Biol

Does SINE evolution preclude alu function

Nucleic Acids Res

Capture of retrotransposon DNA at the sites of chromosomal double-strand breaks

Nature

The consensus sequence of a major Alu subfamily contains a functional retinoic acid response element

Proc Natl Acad Sci USA

DNA sequence insertion and evolutionary variation in gene regulation

Proc Natl Acad Sci USA

Minireview
Alu Repeats and Human Disease