When President Bill Clinton announced the completion of the human genome sequence on the White House podium 20 years ago, he called this breakthrough “the most important and wonderful map in human history.” The scientific achievement is comparable to the lunar landing.
It is hoped that obtaining this sequence will change our understanding of human diseases within 20 years, leading to better treatment, detection and prevention. The famous journal article that shared our genetic components with the world published in February 2001 is known as the “Book of Life”
But for the next two decades, this order remained unmoved. The potential of our newly discovered genetic self-knowledge has not yet been realized. Instead, a new field of genetic research has emerged: new questions for a new group of researchers to answer.
Today, the gap between our genes and the transformation that guides genetic activity is becoming a powerful determinant of our appearance and how we get sick-perhaps 90% of what makes us different from each other. Using the knowledge provided by the human genome sequence to understand this “genetic dark matter” will help us further explore the genetic secrets of species.
The process of cracking the human genetic code took 13 years and cost US$2.7 billion (£1.9 billion). Hundreds of scientists stared at the more than 3 billion base pairs of proteins in our DNA. Once the map is drawn, our genetic data can help projects such as cancer dependency maps and genome-wide association studies to better understand the diseases that plague humans.
But some results were disappointing. As early as 2000, as people gradually realized that the genome sequence was imminent, the genomics community began to bet excitedly on how many genes the human genome would contain. Some bets are as high as 300,000, while others are as low as 40,000. For context, the onion genome contains 60,000 genes.
Read more: Interpreter: What is a gene?
Frustratingly, it turns out that our genome contains roughly the same number of genes as mice or fruit flies (approximately 21,000), three times fewer than onions. Few people would argue that humans are three times more complex than onions. Instead, this finding suggests that the number of genes in our genome has nothing to do with our complexity or differences from other species, as previously assumed.
Entering the human genome sequence also raised many important ethical issues to the scientific community. Prime Minister Tony Blair emphasized when he warned him in 2000: “The power of this discovery comes with the responsibility to use it wisely.”
Ethicists pay special attention to the issue of “genetic discrimination”, such as whether our genes can be used against us as evidence in court or as a basis for exclusion: a new type of distorted hierarchy determined by our biology.
Legislation against genetic discrimination addresses some of these issues, such as the 2008 “U.S. Genetic Information Non-Discrimination Act.” Issues such as those surrounding the so-called “design babies” are still being tested today.
Read more: Should we edit the genome of human embryos?Geneticists and social scientists discuss
In 2018, a Chinese scientist used a method called CRISPR to gene-edit human embryos, which can excise and replace target DNA fragments with other parts. Subsequently, the scientist involved was sentenced to jail, which shows that people have little interest in human genetic experiments.
On the other hand, denying willing patients to receive gene therapy may one day be considered unethical—just as some countries choose to legalize euthanasia for moral reasons. There are still questions about how humans handle their genetic data.
Because human gene editing is still highly controversial, researchers turned to find out which genes might be related to human diseases. However, when scientists investigated which genes are related to human diseases, they were surprised to find them. After comparing huge human DNA samples to find out whether certain genes cause certain diseases, they found that many unexpected parts of the genome are related to the development of human diseases.
The genome consists of two parts: coding genome and non-coding genome. The coding genome only accounts for 1.7% of our DNA, but is responsible for coding the proteins that make up the essential proteins of life. Genes are defined by their ability to encode proteins: therefore, 1.7% of our genome is made up of genes.
The non-coding genome, which accounts for 98.3% of our DNA, does not code for proteins. This little-known part of the genome was once regarded as “junk DNA” and was previously considered useless. It does not contain protein producing genes, so it can be considered that the non-coding genome has nothing to do with life.
Confusingly, scientists discovered that non-coding genomes are actually responsible for most of the information that affects the development of human diseases. These findings have clearly shown that the non-coding genome is actually much more important than previously thought.
Within this non-coding part of the genome, the researchers then discovered short regions of DNA called enhancers: genetic switches that turn genes on and off in different tissues at different times. They found that the enhancers needed during embryo formation have changed little during evolution, indicating that they are an important part of genetic information.
These studies motivated one of us, Arasdal, to explore the possible role of enhancers in behaviors such as alcohol intake, anxiety, and fat intake. By comparing the genomes of mice, birds, and humans, we identified an enhancer that has not changed much in 350 million years-which shows its importance in the survival of the species.
When we used CRISPR genome editing to delete the enhancer from the mouse genome, these mice ate less fat, drank less alcohol, and showed reduced anxiety. Although these all sound like positive changes, these enhancers are likely to have evolved in an extremely poor environment full of predators and threats. At the time, eating high-calorie foods, such as fat and fermented fruits, and being alert to carnivores were vital to survival. However, in modern society, these same behaviors may now lead to obesity, alcoholism and chronic anxiety.
Interestingly, subsequent genetic analysis of the main population showed that changes in the same human enhancer were also related to differences in alcohol intake and mood. These studies show that enhancers are not only important for normal physiology and health, but that changing them may lead to changes in behavior, which can have a significant impact on human health.
With these new research approaches, we seem to be at a crossroads in genetic biology. The importance of gene enhancers in health and disease is disturbing because we are relatively unable to recognize and understand them.
Therefore, in order to take full advantage of human genome sequencing two decades ago, it is clear that current research must exceed 1.7% of the protein-coding genome. When exploring the field of unknown genes (such as the field represented by enhancers), biology can well position the next wave of healthcare breakthroughs.