Alu element

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An Alu element is a short stretch of

The study of Alu elements has also been important in elucidating human population genetics and the evolution of primates, including the evolution of humans.

Alu family

The Alu family is a family of repetitive elements in

B1 elements in rats and mice are similar to Alus in that they also evolved from 7SL RNA, but they only have one left monomer arm. 95% percent of human Alus are also found in chimpanzees, and 50% of B elements in mice are also found in rats. These elements are mostly found in introns and upstream regulatory elements of genes.[12]

The ancestral form of Alu and B1 is the fossil Alu monomer (FAM). Free-floating forms of the left and right arms exist, termed free left Alu monomers (FLAMs) and free right Alu monomers (FRAMs) respectively.^[13] A notable FLAM in primates is the BC200 lncRNA.

Sequence features

The recognition sequence of the Alu I endonuclease is 5' ag/ct 3'; that is, the enzyme cuts the DNA segment between the guanine and cytosine residues (in lowercase above).^[16]

Alu elements

Alu elements are responsible for regulation of tissue-specific genes. They are also involved in the transcription of nearby genes and can sometimes change the way a gene is expressed.^[17]

Alu elements are retrotransposons and look like DNA copies made from RNA polymerase III-encoded RNAs. Alu elements do not encode for protein products. They are replicated as any other DNA sequence, but depend on LINE retrotransposons for generation of new elements.^[18]

Alu element replication and mobilization begins by interactions with signal recognition particles (SRPs), which aid newly translated proteins to reach their final destinations.^[19] Alu RNA forms a specific RNA:protein complex with a protein heterodimer consisting of SRP9 and SRP14.^[19] SRP9/14 facilitates Alu's attachment to ribosomes that capture nascent L1 proteins. Thus, an Alu element can take control of the L1 protein's reverse transcriptase, ensuring that the Alu's RNA sequence gets copied into the genome rather than the L1's mRNA.^[10]

Alu elements in primates form a fossil record that is relatively easy to decipher because Alu element insertion events have a characteristic signature that is both easy to read and faithfully recorded in the genome from generation to generation. The study of Alu Y elements (the more recently evolved) thus reveals details of ancestry because individuals will most likely only share a particular Alu element insertion if they have a common ancestor. This is because insertion of an Alu element occurs only 100 - 200 times per million years, and no known mechanism of deletion of one has been found. Therefore, individuals with an element likely descended from an ancestor with one—and vice versa, for those without. In genetics, the presence or lack thereof of a recently inserted Alu element may be a good property to consider when studying human evolution.^[20]

Most human Alu element insertions can be found in the corresponding positions in the genomes of other primates, but about 7,000 Alu insertions are unique to humans.^[21]

Impact in humans

Alu elements have been proposed to affect

However, the variation generated can be used in studies of the movement and ancestry of human populations,[26] and the mutagenic effect of Alu^[27] and retrotransposons in general^[28] has played a major role in the evolution of the human genome. There are also a number of cases where Alu insertions or deletions are associated with specific effects in humans:

Associations with human disease

Alu insertions are sometimes disruptive and can result in inherited disorders. However, most Alu variation acts as markers that segregate with the disease so the presence of a particular Alu allele does not mean that the carrier will definitely get the disease. The first report of Alu-mediated recombination causing a prevalent inherited predisposition to cancer was a 1995 report about hereditary nonpolyposis colorectal cancer.^[29] In the human genome, the most recently active have been the 22 AluY and 6 AluS Transposon Element subfamilies due to their inherited activity to cause various cancers. Thus due to their major heritable damage it is important to understand the causes that affect their transpositional activity.^[30]

The following human diseases have been linked with Alu insertions:^[26][31]

• Alport syndrome
• Breast cancer
• chorioretinal degeneration
• Diabetes mellitus type II
• Ewing's sarcoma
• Familial hypercholesterolemia
• Hemophilia
• Leigh syndrome
• mucopolysaccharidosis VII
• Neurofibromatosis
• Macular degeneration^[32]

And the following diseases have been associated with

• Alzheimer's disease
• Lung cancer
• Gastric cancer

The following disease have been associated with repeat expansion of AAGGG pentamere in Alu element :

• RFC1 mutation responsible of CANVAS (Cerebellar Ataxia, Neuropathy & Vestibular Areflexia Syndrome) ^[34]

Associated human mutations

• The ACE gene, encoding angiotensin-converting enzyme, has 2 common variants, one with an Alu insertion (ACE-I) and one with the Alu deleted (ACE-D). This variation has been linked to changes in sporting ability: the presence of the Alu element is associated with better performance in endurance-oriented events (e.g. triathlons), whereas its absence is associated with strength- and power-oriented performance.^[35]
• The opsin gene duplication which resulted in the re-gaining of trichromacy in Old World primates (including humans) is flanked by an Alu element,^[36] implicating the role of Alu in the evolution of three colour vision.

References