How much "junk DNA" is hidden in your body? Their mission is mysterious

In life, everyone is familiar with what garbage is; however, in the journey of exploring the human genetics, researchers are divided on which DNA is garbage and whether there is junk DNA.

"One thing is certain, 'junk DNA' is definitely not junk." Professor Gu Chaojiang of the Institute of Biomedical Sciences of Wuhan University of Science and Technology said that there is a stage of cognition and judgment in the study of human genes. "Knowing what you know and knowing what you don't know is wisdom." The same is true for scientific exploration. For a long time, research results on "junk DNA" have emerged in an endless stream, with both corroboration and deviation from each other, gradually unraveling the mystery of "junk DNA" genes.

Image source: Visual China

Understanding and technology of “junk DNA” keep pace

The name "junk DNA" is directly translated from the English "Junk DNA". The concept was originally proposed by Japanese geneticist Ohno Inui to describe the DNA sequences in the genome that cannot encode proteins.

Gu Chaojiang introduced that according to early definitions, the number of genes responsible for protein encoding in human genes is only 40,000, accounting for only 2% of the genome, and the other 98% are classified as "junk DNA."

With the progress of scientific research, "junk DNA" now refers to fragments in the genome sequence that have no coding function and neither generate RNA nor protein, including various types of "non-coding DNA". They are widely present in the human genome in the form of repetitive sequences, and are structurally divided into interspersed repetitive sequences, tandem repetitive sequences and fragmentary repetitive sequences. According to the number of repetitions, they can be divided into moderate repetitive sequences and highly repetitive sequences.

As early as 2003, the ENCODE (Encyclopedia of DNA Elements) project was launched, attracting more than 400 scientists from around the world to participate. Based on the human genome map drawn by the Human Genome Project, the project studies the functional information of each gene and establishes a biological functional gene catalog. The project's research results show that 80% of the regions in the human genome have certain biochemical functions.

Dan Grauer, a professor of biology and biochemistry at the University of Houston, published a paper in the latest issue of the journal Genome Biology and Evolution, saying that using a new model to count the functional genes in the human genome, it was found that functional genes accounted for only 25% at most, and the other genes were so-called "junk DNA", that is, useless or even harmful DNA.

Gu Chaojiang believes that this study will not only "overturn" the conclusion of ENCODE, but will also guide scientific researchers to refocus on human genome research.

As cognition and technology advance, where does “junk DNA” come from?

Studies have shown that some "junk DNA" originates from viruses and can regulate the human immune system. Researchers have found that in this process, a type of "junk DNA" called "transposable elements" plays an important role.

Transposable elements are fragments of DNA that can move around in the genome and appear to be relics of pathogens such as viruses or bacteria that have evolved over millions of years to become integrated into the human genome.

Gu Chaojiang introduced that the tandem repeat sequences, which account for 10% of the human genome, are mainly distributed in non-coding regions, with a few located in coding regions. Tandem repeat sequences in coding regions are related to function, while tandem repeat sequences in non-coding regions are mostly distributed in spacer DNA or introns. The repeat unit can be as short as 2bp or as long as tens of base pairs, with the number of repetitions ranging from a few times to hundreds of times. The different number of repetitions of the repeat sequence is the basis for the formation of DNA length polymorphism.

At the same time, there are also studies showing that "junk DNA" is preferentially inherited to offspring due to asymmetric distribution of chromosomes. In 2017, a paper published in Science showed that the source of "junk DNA" is due to asymmetric distribution of chromosomes. The study showed that the centromeres of two sister chromosomes compete with each other for inheritance during female meiosis, and the centromere repeat sequence is the most abundant non-coding DNA in the human genome. "Strong" centromeres with more repeat copies and more kinetochore proteins are preferentially inherited to offspring.

Functional identification has only just begun

The large number of repeated DNA sequences in "junk DNA" can form special DNA high-level structures and regulate the activity of nearby genes. Some special proteins (transcription factors) that control the on and off of genes can specifically recognize non-coding "junk DNA" near genes and participate in gene inhibition and activation by interacting with them.

Gu Chaojiang said that these "junk DNA" can be regarded as the "molecular" switches of genes.

Recently, American scientists analyzed 330 exons derived from the Alu (highly repetitive sequence) genome in 11 human tissues and identified many exons with interesting expression and functional characteristics. Alu is a primate-specific retrotransposon, and the production of exons through it may help to form the unique characteristics of primates.

There is also evidence that "junk DNA" can function by synthesizing regulatory RNA. They can be transcribed into small RNA molecules, which can control protein expression, such as RNA-mediated gene silencing, which is called RNA interference. They can also activate or inhibit gene expression, assisting very complex physiological phenomena such as cell division and differentiation.

Gu Chaojiang said that if this method is used in medicine, it can silence cancer genes, which is of great significance. Other studies have shown that "junk DNA" may change the way genes are assembled.

Previously, researchers at the University of North Carolina in the United States discovered that small fragments of genetic sequences in some "junk DNA" tell genes how to splice, or enhance or inhibit the splicing process, thereby changing the way genes are assembled.

More importantly, "junk DNA" affects human life in many aspects, including immune system diseases, tumor occurrence, nervous system diseases, development and even appearance.

Scientists from the Max Planck Institute in Germany, the University of Oxford in the UK and other institutions have discovered that after chemotherapy, hematopoietic stem cells in the bone marrow will use "junk DNA" to transcribe RNA molecules to enhance activation, produce fresh cells and promote blood regeneration.

The researchers also found that as the number of people undergoing personal genome sequencing increases rapidly, when interpreting mutations in their genomes, especially mutations in non-coding regions, they recently found nearly 100 potential "triggers" for breast and prostate cancer in the "junk DNA" region, indicating that "junk DNA" can be a potential source of cancer. Other researchers said that they have proven in Hodgkin's lymphoma under what circumstances "junk DNA" can remain active, thereby accelerating tumor growth.

Contrary to the above view, researchers from the University of Bath and the University of Cambridge found that "junk DNA" located between genes can be transcribed into non-coding RNA, and this process can block the cell from becoming cancerous.

In addition, American researchers have developed a new bioinformatics method to identify and determine de novo tandem repeat mutations (referred to as de novo TR mutations) from sequencing data, and to perform genome-wide characterization of de novo TR mutations in probands with ASD (autism spectrum disorder) and unaffected siblings. It was found that a large number of de novo TR mutations were present in the whole genome of ASD probands, which were more enriched in the regulatory regions of the fetal brain and were expected to be more harmful in evolution.

More mysteries to be solved

Recently, a research report published in the international journal Neuron stated that the retrotransposon LINE-1, which is considered to be "junk DNA", was found to be present at high levels in the brains of schizophrenia patients and can modify the expression of genes related to schizophrenia. Therefore, researchers speculate that it may be the main cause of schizophrenia.

At the same time, this part of "junk DNA" was placed under the genetic factors that cause schizophrenia for study. Using whole genome analysis, the researchers found that in schizophrenia patients, LINE-1 can be inserted into genes related to synaptic function, destroying their normal functions. Therefore, they believe that this "junk DNA" may be the culprit that causes schizophrenia.

Gu Chaojiang introduced that foreign research teams have found that during development, microRNA (miRNA) transcribed from "junk DNA" plays an important role in the distribution of cells and germ layers. Researchers at the Sydney Centennial Institute in Sydney used the next generation of gene sequencing technology and complex computer analysis technology to reveal how specific white blood cells use non-coding DNA to regulate the activity of a series of genes that control shape and function.

Interestingly, researchers at the Lawrence Berkeley National Laboratory in the United States have found that there are some sequences in "junk DNA" that can affect the function of facial genes like switches or amplifiers. The size of eyes, the height of noses, and the shape of heads may all be closely related to these sequences called "enhancers."

A single leaf can tell the coming of autumn, and the fog can be seen through the clouds. What other questions need to be answered regarding "junk DNA"?

Gu Chaojiang said that with the advent of the post-genomic era, the interpretation of "junk DNA" has benefited from the advancement of sequencing technology. The second and third generation sequencing technologies have greatly improved the sequencing throughput, and can sequence hundreds of thousands to millions of DNA molecules at a time, making it convenient to perform deep sequencing of the genome and transcriptome of a species, providing technical support for the interpretation of "junk DNA".

At present, as more and more functional "junk DNA" is recognized and identified, the actual "junk DNA" will become less and less.

Gu Chaojiang believes that in the future, we should continue to deeply analyze the functions of large amounts of repetitive sequences ("junk DNA") in the following ten directions, namely, regulation of DNA replication, transcription regulation, marking sites for programmed rearrangement of genetic material, affecting the normal folding and maintenance of chromosomes, controlling the interaction between chromosomes and the nuclear membrane, controlling RNA processing, editing and splicing, modulating translation, regulating embryonic development, DNA repair and helping to fight disease.

Gu Chaojiang said that not long ago, Christopher Gruner of the University of Montpellier in France, Christopher Grievelding of the University of Giessen in Germany and others published a paper in the journal Genome Biology and Evolution, saying that the era of "junk DNA" has ended. At the same time, with the continuous development of life sciences, people have gradually realized that "junk DNA" is no longer junk.

"With the updating of technology and the deepening of research, more and more functional sequences will be generated in 'junk DNA'," Gu Chaojiang said firmly.

◎ Science and Technology Daily reporter Wu Chunxin and correspondent Cheng Yu

Source: Science and Technology Daily

Editor: Zhang Qiqi

Review: Julie

Final review: Liu Haiying