Why the human genome was never completed

Before the end of 2023, you should be able to read something remarkable. It will be the story of a single individual, who they are and where they come from – and it will offer hints about what their future holds. It probably won’t be the most entertaining read on first glance, and it will be very, very long. But it will be a seminal moment – the publication online of the entire genome of a human being, end to end with no gaps.

At this point you may feel that you have heard this before. Surely the human genome was published decades ago? Isn’t that all done?

It was, in fact, never finished. The first draft of the human genome was released in 2001, before a consortium of international scientists of the Human Genome Project announced that they had “completed” the job with a finished sequence in 2003. Assembled from chunks of various people’s DNA, this became the “reference” sequence against which all other human DNA could be compared.

It was certainly the best that could be done at the time, but had major gaps and errors. Later releases improved on it, but many of the problems persisted. Only in the last few years has technology advanced to the point that it is possible to read the entire human genome, without gaps and with minimal errors. But these have all been composites, using DNA drawn from multiple individuals. This year, for the first time, the entire genome of a single human being – a man named Leon Peshkin – is due to be released.

This complete, single human genome will be a monumental technical achievement. Only 70 years have passed since the doublehelix structure of DNA was first revealed, thanks in part to a grainy black and white image taken by Rosalind Franklin, transforming our understanding of how genetic information is stored. Today we have the capability to read the entire genetic ‘textbook’ that makes a person unique.

But the geneticists involved say it is also a beginning, not an end. They now want to sequence the genomes of people from around the world, to build up a true picture of our species’ genetic diversity. They want to understand what the previously unsequenced sections of DNA are doing. And they want to roll out end-to-end genome sequencing in clinics, to help doctors diagnose and treat us when we get sick.

In short, the human genome will never be complete. We will never be done reading it.

The first human genome

The original Human Genome

Project (HGP) was one of the biggest scientific projects ever attempted, costing about $3bn (£2.5bn) . Launched in 1990, its aim was to read all the DNA the average human carries in their cells. The first draft sequence was published just over a decade later, in 2001. Simultaneously, another version of the genome was published by Celera Genomics.

Leon Peshkin, a biologist at Harvard Medical School, will be the first person to have this whole genome sequenced without gaps

(Credit: Virginia Savova)

Leon Peshkin, a biologist at Harvard Medical School, will be the first person to have this whole genome sequenced without gaps

(Credit: Virginia Savova)

WHAT IS A GENOME?

The genome is often compared to a kind of book, written in the alphabet of DNA rather than English. The DNA alphabet only has four letters: A, C, G and T. They each represent different molecules called bases that are strung along the length of the DNA molecule. When read correctly, a particular sequence of these letters forms a gene.

The job of translating this information falls to the molecular machinery inside our cells. Some genes provide the information needed to make an enormous variety of different proteins that perform assorted functions important to life, while other sections of DNA have regulatory functions. What the Human Genome Project team figured out was the exact order of the bases along the DNA, something like CGATTTCCGAAAA – and so on for over three billion letters.

The human genome promised many things. We would discover what the genes were doing, especially those involved in diseases. This would enable a future of personalised medicine, in which we all received treatments shaped around our genetic makeups. The genome also promised insights into our evolutionary origins: exactly how are we different from our closest living relatives, chimpanzees and bonobos?

Some of this has happened, some of it hasn’t. We certainly know a lot more about the functions of many genes and their roles in diseases ranging from breast cancer to schizophrenia. However, in practice it has turned out that most diseases are affected by hundreds of genes, so genomic medicine hasn’t got very far. Few inherited diseases are caused by a single faulty gene, and the use of genetic screening to detect those at risk of rare conditions is largely only used for those considered at the highest risk.

In contrast, genetics has reshaped our understanding of human evolution, for instance revealing that our ancestors interbred with other hominins like Neanderthals.

Meanwhile, lurking in the background has been the awkward fact that the human genome was never actually finished. While geneticists have been cleaning it up ever since the first draft was published, most recently in February 2022, some parts of the genome remained out of reach. Repeats, repeats and more repeats

The problem is that some DNA is extremely repetitive. Certain stretches of the genome repeat the same sequences over and over, sometimes for thousands of bases.

DNA sequencing has made it possible to conduct genetic diagnosis of inherited, although often rare, diseases (Credit: Dickson Lee/Getty Images)

The repetitive DNA often turns up in the same bits of the genome. Our DNA isn’t stored in one long continuous rope, but is instead split into smaller chunks called chromosomes. These are X-shaped (apart from one Y-shaped chromosome carried by men) and there are 23 pairs of them in humans. Each has repetitive DNA at the tips of its four arms – the telomeres – and at the central cross, the centromere. Both are important.

Eight per cent was missing from the officially finished version in 2003 – Adam Phillippy

The telomeres are thought to act as protective caps, and damage to them has been linked to ageing. Meanwhile, the centromeres are crucial to the process of cell division that underlies growth and reproduction, and which goes wrong in cancer. Reshuffling of the DNA in the centromeres has been implicated in the development of some cancers.

However, the Human Genome Project could not sequence the repetitive DNA, and didn’t try. Their method was not up to the challenge. They did not read the entire genome in one go, but instead cut it up into small chunks a few hundred bases long, read those, then stitched them back together with a computer. This would not work for repetitive sections, because the computer had no way to figure out what order the segments fitted together. It would be like trying to do a jigsaw that was all cloudless blue sky.

“Eight per cent was missing from the officially finished version in 2003,” says Adam Phillippy, head of genome informatics at the National Human Genome Research Institute in Bethesda, Maryland.

And so our repetitive DNA sat, almost entirely unread, for 20 years. Then in 2021 Phillippy and his colleagues announced they had read it all.

Source; BBC

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