Why the human genome was never completely deciphered – 09/03/2023 – Science

The Human Genome Project is considered one of the most important scientific achievements in history. It was launched in 1990 by an international consortium of scientists, at a cost of US$ 3 billion (about R$ 15.6 billion, in current values).

His goal was to determine the sequence of the 3.2 billion base pairs (or letters) that make up human DNA: all of your hereditary information and instructions for building and maintaining your cells, tissues, and organs.

In the year 2000, with great publicity, came the announcement that the first draft of the human genome had been completed.

“Today’s announcement represents more than a historic triumph of science and reason… With this new and profound knowledge, humanity is on the verge of obtaining immense new healing power”, declared the then president of the United States , Bill Clinton.

The project held a lot of promise. It would reveal, for example, the function of genes, especially those related to diseases, which would bring personalized medicine, with treatments based on our genetic composition.

The genome also promised to reveal information about our evolutionary origins, so we would know exactly where we came from and how we differed from other primates.

But the study presented in 2000 was not complete. It wasn’t just an unrevised first draft. It also included huge regions where the DNA sequence didn’t even appear.

The project continued. In 2003 came another announcement, this time with less fanfare, that the human genome had been completed. But about 8% of the information was still missing.

These gaps included the most difficult-to-sequence fragments, in which DNA letters are repeated more than once. And, with the technology available at the time, reading it was impossible.

Thus, the human genome was officially complete, but it remained for 20 years without being fully deciphered. Until, in 2021, a scientific consortium called Telometer-to-Telometer (Telomere to Telomere, T2T) announced that it had managed to read the entire genome.

But was it true?

Yes, but… Although they reached places previously inaccessible (specifically, those 8% that could not be read), the reality is that there are parts of the human genome that remain beyond the reach of geneticists.

Advances in technology have made it possible to read the complete human genome, without gaps and with a minimum of errors. But this reference human genome is a “composite”, for which DNA extracted from several individuals was used.

That is, it is not the genome of a real person who has lived among us.

The difficulties

Why is deciphering the human genome such a difficult job?

“The main limitation was that the technologies that allow us to decipher the DNA sequence use short fragments that are read on a machine and then need to be recomposed, as if they were pieces of a complicated puzzle”, explains the professor of genomics Manuel Corpas of the School of Life Sciences at the University of Westminster in London.

“If, in the puzzle, you find a region where the color and shape of the pieces don’t change (it’s repetitive), it’s hard to place them in the correct order unambiguously without having a frame of reference,” he explains. to BBC News Mundo, the BBC’s Spanish-language service.

Indeed, sequencing a genome is like cutting a book into text fragments and trying to reconstruct the book by putting all the fragments back together. Text snippets that contain repeated, common words and phrases are much harder to piece together than snippets that are unique and different.

With the human genome, it is necessary to assemble millions of parts that describe the diversity of an individual. Large fragments of these pieces are full of repeats and these are the hardest regions to read in the human genome.

But that was until 2021, when new sequencing techniques were able to capture these repeats.

“It’s as if we had a cartographic map from the 18th century, describing the world’s geography”, explains Corpas.

“First, the shapes of the coastline of nearby continents were verified and the empty spaces were being filled in as our ability to define ambiguous regions was refined”, he adds.

The important breakthrough achieved in 2021 by T2T, which was made official in 2022 by several studies published in the journal Science, was the ability to accurately read much longer DNA fragments, after discovering how to map its most mysterious repetitive regions and forgotten.

The T2T consortium was created in 2018 by Adam Phillippy, from the National Human Genome Research Institute in Maryland, in the United States, and Karen Miga, a geneticist at the University of California at Santa Cruz, in the United States.

T2T was not a billion-dollar project, but its achievement — being able to read an entire human genome — was considered a milestone.

In order to sequence the genome, the scientists used a kind of “shortcut”.

Normal human cells are diploid, which means they have two copies of each type of chromosome. The father and mother each provide the pair with one chromosome.

But the cells used by the T2T team for their sequencing contained only one set of chromosomes inherited from the father. This made it easier to reconstruct the precise sequence, but it also meant that the T2T genome cannot reveal how DNA varies within the same person.

That is, even with the enormous advance of T2T, the sequenced genome is a single version of a genome that does not represent a human being who has actually lived. It is not “the” human genome.

But this sequenced genome will now lay the groundwork for further genomic research.

With the ability to read the entire human genome, scientists now hope to be able to sequence the genomes of people from diverse populations around the world to form a true picture of our species’ genetic diversity.

That is, the real success will be being able to read several genomes that allow observing how their regions vary within a person, from one person to another, from one population to another or from one species to another.

“There are many variants or differences in each organism, around five million in each human being”, says Corpas. “The vast majority of variants have no effect, but a small percentage do.”

“Understanding the effect caused by these variants and how they condition the functioning of the organism is one of the main frontiers of knowledge of the genome, but not the only one”, explains the professor. “Clearing what the predisposition to rare or common diseases is, therefore, is one of the main objectives to be achieved.”

“Another important objective is to understand how many of the variants that determine the appearance of cancer evolve within the organism to produce tumors”, adds Corpas.

human pangenome

A new effort in this area is being undertaken by scientists from the so-called Human Pangenome Reference Consortium.

In conjunction with T2T, the Pangenome Consortium hopes to sequence the genomes of about 450 people from around the world in order to gain a better understanding of how DNA varies within a person and from one person to another.

One of the main objectives of this knowledge will be to identify the variants that contribute to a person’s disease risk and to have personalized medicine in the future.

“Being able to develop cancer therapies that are personalized for each patient is a very active area, as well as pharmacogenomics, that is, the influence of genetics on our ideal dose or even on adverse drug reactions”, according to Manuel Corpas.

The professor also explains that efforts are being made to alter our genetic code with techniques such as CRISPR. Its aim is to “edit” genes to eliminate and correct disease-causing flaws.

But Corpas points out that this “is just the tip of the iceberg”. The medicine of the future will be based on genomics and how genetic information is inherited and modified from one generation to the next.

the successes

Most of the promises made in 1990, when the Human Genome Project was launched, have already been achieved. Today, we know much more about the functions of many genes and their role in diseases ranging from breast cancer to schizophrenia.

But in practice, genomic medicine has not been able to get very far, as most diseases have been found to be affected by hundreds of genes.

There are very few inherited diseases that are caused by a single faulty gene. And genetic tests to detect people at risk of contracting rare diseases are adopted, for the most part, only for people considered to be at higher risk.

But genetics has managed to alter our understanding of human evolution. We now know, for example, that our ancestors intermingled with other hominids, such as Neanderthals.

The question that arises is whether, with new initiatives such as the Human Pangenome project, will we finally be able to complete the human genome?

The answer is no. And the reason is that there is no single human genome. Each person’s DNA is different and the differences are considerable.

“We all have a unique genome, which conditions our response to pathogens, illnesses, medications, etc.”, explains Manuel Corpas.

“There will come a time when the reference genome will be that of each person, a single genome for each individual, to detect and predict diseases before symptoms appear”, continues the professor.

“In the meantime, there is already a lot that can be done with the common variations that we find in populations of individuals, in different proportions. These variations help us to understand why Asians are less tolerant of alcohol or lactose and why Europeans are more sensitive to skin cancer.”

Therefore, we will really only be able to understand the genome when we have a record of how it varies from one person to another and between different populations.

That is, as long as there are human beings, there will be new genomes. And we will never finish reading the human genome.