Inner piece: The final secrets of the human genome

But wait a minute. Hadn’t we mapped the human genome already? Yes and no.

The first draft of the human genome was released in 2001. It was a path-breaking first step. But the full blueprint of what constituted a human being was far was complete. By 2003, a team of international scientists announced they had sequenced 92% of it – enough to fire up research into inherited traits, and predispositions to certain diseases.

The rest of the eight percent took us 20 years to decipher. More than 100 scientists from around the world collaborated on Slack, adding 400 million letters to the previously sequenced DNA and correcting several errors . It means that we now have the most gapless version of our genome. Scientists call it CHM13 and it’s opening new doors in medicine, health and our understanding of what it means to be human.

HOW IT STARTED

The Telomere to Telomere (T2T) consortium, a team of scientists at the National Human Genome Research Institute (NHGRI), the University of California, Santa Cruz, and the University of Washington, Seattle, who worked with scientists around the world, merely built on established but eventually abandoned research.

The first draft, announced with much fanfare in 2001, was the result of a race between the public-funded Human Genome Project and a private company named Celera Genomics. It was only as complete as the technology of the time allowed. Celera moved on to other projects. But scientists on the Human Genome Project soldiered on to fill in the gaps, releasing the revised 92% draft in 2003.

What remained were the most difficult regions to sequence, with repeating letters that were simply impossible to read at the time. “The issue was not that the part that we had wasn’t right. It was, by and large, very, very right and it has done enormous good for medicine,” said David Haussler, scientific director, UC Santa Cruz Genomics Institute, University of California, who led the team that put together the first human genome sequence. “But it was the hidden parts of it that we had no access to that was the real challenge.”

Since then, researchers have developed better laboratory tools, computational methods and strategic approaches. Adam Phillipy, who co-founded the T2T project, is responsible for overseeing the technical infrastructure for the project. He is the head of the Genome Informatics Section at NHGRI. Two new technologies, PacBio HiFi and Oxford Nanopore, helped too, allowing scientists to read longer stretches of the genome in one go, making the haziest parts of the inside of the human cell a little clearer.

The other breakthrough is simply how the work got done. Karen Miga, assistant professor of biomolecular engineering at the University of California, Santa Cruz, who co-lead the T2T consortium opened up the project to collaborators around the world. “She said everybody could join. A lot of software is built that way, it’s open source,” said Haussler. “This concept was not popular earlier and certainly not in biology, in 1990 and 2000.”

THE SLOW MARCH

The missing bits were sequences that looked very similar to one another. Researchers could not read the entire genome in one go previously. It was too long for the tech to allow it. So they cut it up into chunks a few hundred bases long, read those, then reconstructed them using a computer. With repetitive segments, the computer had no way to figure out how it all fit together.

Miga likens the process to completing a jig-saw puzzle, in which the “complex and difficult regions would represent a blue sky”. New tech views the puzzle not as 10,000 small pieces like computers previously did but 100 large ones. The consortium found 79 new genes hidden among the repeats too. “What we are celebrating is the right technology, the right team of scientists, and the right time,” she said.

ZOOMING IN

The missing sequences provide new details about genetic variations. Doctors and geneticists hope it will help us understand how errors occur in cell division, tell us more about cancers, birth defects, and other human health outcomes, and how our great ape-ancestors developed in Africa.

As with any new data, putting it together is only part of the challenge. The tougher part is understanding what it all means. “We are only beginning a very long journey of understanding ourselves,” said Haussler. And while it’s a complete blueprint, it’s still been built from bits and pieces from a small sample of humans. “CHM13 does not capture the full diversity of human genetic variation,” said Miga. More inclusive and varied samples will be completed in the coming years.

CLOSER HOME

Sridhar Sivasubbu, senior principal scientist at the Council of Scientific and Industrial Research – Institute of Genomics and Integrative Biology (CSIR-IGIB) is waiting and watching. According to him, the milestone does not translate into great healthcare predictions at the moment. “It is not talking about RNA ,or ribonucleic acid, which is a larger component than the DNA in our genome,” he said. “Eventually people will start mapping them, at a greater resolution.”

Meanwhile, India, with its rich genetic diversity, is already building a genome bank of its own, to help understand diseases better. “Because the genome remains largely constant throughout our entire lives, once you map a person’s genome, they can refer to it through their life while making medical decisions,” said Sivasubbu. “It opens a door into predictive and precision medicine.”

Since 2009, Sivasubbu and Vinod Scaria (a clinician turned computational biologist at CSIR) have been studying and mapping genomes of Indian people. They mapped genomes of centenarians and then of certain rare diseases. In 2019, they realised that both the fields of studies represented two extremes of humanity: Long and short lifespans. It prompted them to also create a baseline – a collection of self-declared healthy Indians, whose genes could be used to compare the two extremes.

They’ve since mapped 1,008 Indians, across 55 ethnic groups under the IndiGen project. The database is invaluable to anyone studying how genetic variations occur within communities. For instance, the Arya Vaisya Chettiyar community of Tamil Nadu is fatally allergic to certain anaesthetics. We don’t know why. Perhaps the answer lies in genes.

Another program anchored by Sivasubba and Scaria is the GUaRDIAN Programme (Genomics for Understanding Rare Disease International Alliance Network.) The consortium works through a network of 200 clinicians and 80 hospitals which alert them to patients who present with ailments no one has a name for. The programme helps the scientists use gene mapping to identify the mutation that caused the problem and where it occurs in the genome.

Sivasubba’s team also tests the patient’s extended family to determine if they carry the mutation. “These carriers can then make an informed decision when they marry or decide to have children,” he said. “So they can stop or eradicate the disease in one generation.”

Ten years ago, in Tirunelveli, Tamil Nadu, one community was beset with epilepsy cases in every generation. Local doctors contacted GUaRDIAN. IGIB spent two years collecting blood samples and sequencing the community’s genome. In 2018, the disease was identified as adult-onset myoclonic epilepsy, a rare genetic disorder caused by a mutation of Chromosome 8. Tirunelveli Medical College has since treated more than 700 cases, becoming the world’s largest centre to treat the condition.