The many roles of repetitive DNA; The many roles of repetitive DNA—a cartoon explainer

...But a journey into our cells, that zooms in closely enough to take a look at our DNA, reveals the importance of repetition.

DNA contains the instructions needed to build and maintain our bodies. While our genetic code is made of only four building blocks, called nucleotides—the molecules adenine (A), cytosine (C), thymine (T) and guanine (G)—these building blocks can be arranged into many variations. Repeating sequences of these letters, or repetitive DNA, are everywhere. In fact, two thirds of the human genome is made of repetitive elements.

Repetitive DNA is defined as a specific sequence of nucleotides that is repeated, sometimes many times, within our genetic material. The repeated sequence in question can be short, with a pattern consisting of only a few nucleotides, or long—more than 50 nucleotides. It can be repeated a handful of times, or hundreds of times, and can show up all in the same area of the genome, or be scattered throughout.

Satellite DNA is known for being composed of very short sequences that repeat many, many times. Ten percent of our genome is made of satellite DNA, but this type of repetitive DNA doesn't contain any genes—a fact that has led some researchers to label satellite DNA as "junk." (But "junk DNA" is a misnomer, more on that later!)

Another simple way to classify repetitive DNA is looking at whether repeating sequences occur next to each other, or if they're scattered in between other sequences. Repeating sequences that are next to each other are labeled as tandem repeats. A well-known example of a tandem repeat is found in telomeres, structures at the ends of chromosomes. Telomeres are primarily made of the repeating sequence “TTAGGG.” These repeats fold into one another, creating a special structure that helps protect the ends of our chromosomes from fraying.

Repetitive DNA that is scattered throughout the genome is labeled as interspersed repeats. Most of these interspersed repeats can be classified as transposable elements—sequences that move from one part of the genome to another, earning themselves the nickname “jumping genes.” A whopping 45% of the human genome is made of transposable elements. Some transposable elements are transcribed into RNA, then reverse-transcribed back into DNA and reinserted in the genome. These are called retrotransposons.

Repetitive DNA is a normal part of the genome, but in some contexts it can pose a threat to health.

Researchers at Whitehead Institute study cases in which repetitive DNA contributes to disease.

Researchers in Whitehead Institute Member Ankur Jain's lab recently identified a key mechanism that links repetitive DNA in the gene associated with Huntington's disease to dysfunction in the cell, which may contribute to symptoms associated with the disease. They discovered that repeat-containing RNA aggregates form not only in the cell nucleus, but in the cytoplasm. Aggregates in the cytoplasm grow in size over time, pressing up against and deforming the cell's nucleus.

In the case of Fragile X syndrome, the sequence "CGG" is repeated too many times in the FMR1 gene, located on the X chromosome. With too many CGG repeats, the FMR1 gene is silenced, interfering with how connections between neurons develop. In Whitehead Institute Member Rudolf Jaenisch's lab, researchers study how a CRISPR/Cas9 gene editing may be able to restore function in neurons affected by Fragile X syndrome. Scientists hope that one day this research will contribute to therapies used to treat the syndrome.

Repetitive DNA is not always bad. Ribosomes, which are essential cellular machines that translate RNA into proteins, are generated from ribosomal DNA, which is interspersed throughout the genome. Highly repetitive sequences like ribosomal DNA tend to shrink in size as cells continue to divide. To preserve the ability to reproduce over generations, germline stem cells must maintain a high number of ribosomal DNA sequences while dividing.

Using a fruit fly model, researchers in Whitehead Institute Member Yukiko Yamashita's lab showed that a specific retrotransposon, a repetitive sequence that jumps from one part of the genome to the next via RNA transcription and reversed transcription, helps maintain a high number of ribosomal DNA sequences in germline stem cells. As retrotransposons reinsert themselves into the genome, they create breaks in the DNA sequence that must be repaired. A dividing cell has two copies of each chromosome, and the retrotransposon cuts open both copies of the chromosome containing ribosomal DNA. When the cell goes to mend these breaks, it will insert some copies of ribosomal DNA from one chromosome into the other, ensuring that one of the dividing cells has enough ribosomal DNA to carry on.

In the case of some repeating elements, their function remains rather mysterious to researchers. For many years, some scientists wrote off satellite DNA as "junk."

Over time, research from the Yamashita lab has revealed that repeating elements are not just junk. Instead, this so-called "junk" satellite DNA works like the binding of a book—it keeps chromosomes organized and contained within the cells' nucleus. In experiments that removed a protein that binds to specific satellite DNA sequences, researchers observed cells that had chromosomes separated within multiple nuclei, a state that is generally incompatible with life. 

What is important to note is that even between closely related species, satellite DNA is highly variable. It’s as if each species has a different method of bookbinding. The result? Close genetic relatives who are nonetheless different species.

Repetitive DNA is at the same time ubiquitous and misunderstood. It accounts for vast swaths of the human genome, yet has been written off as "genomic junk." Researchers, including those at Whitehead Institute, will continue to discover ways in which repetitive DNA can contribute to diseases in some contexts, and serve an essential purpose in others. 

Written by Madeleine Turner