Ten years ago this month, in what was heralded as the opening to a new era in human biology and medicine, two rival teams of scientists published their first official reports of the sequencing of the human genome.
"Humanity has been given a great gift," announced one of the two journals, Science, to publish the drafts.
A genome is made of DNA molecules, which in turn are composed of a four-letter code. The genome, the full blueprint for a human being, has 3.2 billion letters in it, and two copies are contained in the nucleus of every cell in our bodies. These reports were, essentially, drafts of instructions to build a human being. A decade later, we asked experts what we've learned since. This is by no means an exhaustive list.
We must rethink who we are
"We have not just primate evolution, not just mammalian, but almost back to the very beginning of life on Earth leaving a kind of archaeological footprint in our DNA sequence," said Ronald Cole-Turner, professor of theology and ethics at the Pittsburg Theological Seminary. "It suggests how deeply interwoven we are with the history of life on Earth."
Since the human genome was sequenced, we know more about our own history, and the lines between us and other species have blurred, Cole-Turner said. A comparison with the Neanderthal genome revealed that Neanderthals likely mated with our ancestors, since between 1 percent and 4 percent of some modern humans' DNA came from Neanderthals. Even the genome from the first amphibian to be sequenced, the African clawed frog, showed surprising similarities to the human genome.
Humans share capacities, such as for tool-making and culture with other animals, but even so, tiny differences in DNA have allowed humans to develop art, culture and, not least of all, the technical prowess to probe these sorts of questions, Cole-Turner said.
"We are less clearly defined than we once thought, less set apart from the rest of life, but uniquely able to probe the data and ponder the questions," he wrote in Thursday's issue of the journal Science, as part of a series of short articles marking the anniversary. "And, being humans, we let our discomfort give way to wonder. Who are we, and where will we go next?"
The era of genomic medicine isn't here yet
The sequencing of the human genome brought with it the promise of a revolution in medicine, giving us each the potential access to our own blueprint.
There are cases where this has already happened, Francis Collins, the current head of the National Institutes of Health and head of one of the rival teams, recounts in the same issue of Science.
For instance, an analysis of the genome of a 6-year-old Wisconsin boy suffering from inflammatory bowel disease led his medical team to find a mutation linked with a severe blood disorder that can be cured through a bone marrow transplant, which was performed successfully.
"The once-hypothetical medical benefits of individual genome sequencing are beginning to be realized in the clinic," Collins wrote.
Craig Venter, the scientist who headed the competing, privately funded team, paints a less rosy picture.
"We have a very long way to go before having your genome sequenced leads to really helpful, useful information except in rare, one-off cases," Venter said.
The time and expense required to sequence an individual genome has dropped dramatically. The government team spent about $3 billion from 1990 to 2003 sequencing the genome and performing related research, while Venter put the cost of the sequencing work for his team, Celera Genomics, at $100 million. That cost has now dropped to about $10,000 for a single genome.
"I've been disappointed in how few actual scientific advances there have (been) in the last decade in the field of genomics, other than the technology," Venter told LiveScience. While a genome sequenced today does yield more information than it would have 10 years ago, it is still not to a point where it could be used as a diagnostic tool.
Not only does accuracy and quality need to improve, but our ability to interpret the information in a genome sequence has far to go, he said.
"Everybody talks about 30 percent increased risk of breast cancer; well, what does that mean? That means you have a lot of genes and other traits protecting you from getting breast cancer," Venter said. "But why isn't it 100 percent? Why not zero?"
We need to reach a basic understanding of not only the risk genes for certain diseases, but also the protective ones, he added.
'Big science' can win
The human genome project came with a hefty price tag, and going in, scientists didn't know what questions they would be answering. This "not knowing" generated some opposition, said Richard Gibbs, director of the Baylor College of Medicine Human Genome Sequencing Center.
"The opposition to the genome projects was really based on excessive use of resources to generate answers to questions that weren't asked," Gibbs told LiveScience.
But research made possible by the genome projects has eroded opposition to this type of science, which can generate data to answer questions that can't be anticipated in advance, Gibbs said. "It's become OK to do a very big experiment."
The initial results of the sequencing immediately sparked such questions. For example, how can an organism as complex as a human function with 20,000 to 25,000 genes, not many more than the lowly roundworm? Before the results of the sequences were announced 10 years ago, it was widely believed that humans had about 100,000 genes. (In 2001, researchers estimated humans had more than 30,000; however, that estimate has since been questioned.)
We have our own dark matter
Under the classical dogma of DNA, the sequences that matter are ones that code for proteins – the building blocks of cells. These sequences, called genes, make up roughly 2 percent of the code we carry in our cells. The rest of the DNA was considered junk.
"Now that we have the sequence for the whole genome, including the 98 percent (considered junk), we find that at least half of it is functional. It is even difficult nowadays to say what a gene is," said Robert Plomin, a research professor at the Institute of Psychiatry at King's College London.
So, hidden among this "junk" DNA is the mysterious dark matter of our genomes. Rather than directly coding for proteins, it can play a role regulating the expression of the genes that do. In fact, RNA (a molecule similar to DNA) generated by this "dark matter" may have a regulatory effect on the other 2 percent, he said.
"We know that for sure, what we are also discovering is (the dark matter) has lots of other effects, too," he said.
Some genes matter more, some less, than thought
When it comes to influencing disease, genes can be divided into two categories. A single gene could have a profound influence over whether its carrier suffers from an illness such as sickle cell anemia or cystic fibrosis. However, it turns out that this situation underlies only a small minority of diseases. In most cases, genes exert only a limited influence, and only a small portion of the variation within a population can be attributed to them. This is also the case for complex, heritable traits, like behavior, according to Plomin.
"Now we have tools to identify the genes but so far it's been very difficult to find all of the genes responsible for heritability; in fact, we have only found relatively few," he said. "The general assumption is the effects are much smaller than we thought, so it makes it much harder to find these genes."
For instance, a change in the so-called FTO gene has been linked to obesity, but this "fat gene" has been found to be responsible for only 1 percent of the variation in Body Mass Index (a calculation used to measure body fatness) within the population, Plomin said. Meanwhile, inherited mutations in two tumor-suppressing genes have been associated with 5 to 10 percent of breast cancer among white women in the United States.
Scientists knew the picture would be complicated before the genome was sequenced 10 years ago, Gibb said.
"It's not chaos. It is tractable. We can understand all the nuts and bolts of a living system; there are just so many moving parts it's just hard to describe," he said.
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You can follow LiveScience writer Wynne Parry on Twitter @Wynne_Parry.