The Human Genome Is Finally Fully Sequenced

As part of the Human Genome Project, the first human genome was mapped in 2001, although scientists were aware that the map was neither precise nor comprehensive. Scientists have now developed the most fully sequenced human genome to date, fixing errors and gaps in the earlier draft.

As of now, the sequence represents the fullest reference genome known for any animal. The results of six recently published genome characterizing publications in Science could help us understand human evolution better and may also point to new avenues for treating a variety of ailments.

An improved human genome

"Adam Phillippy, head of genome informatics at the National Human Genome Research Institute (NHGRI) of the National Institutes of Health and senior author of one of the new papers, states that the Human Genome Project relied on DNA obtained through blood draws; that was the technology at the time." The methods used at the time resulted in mistakes and flaws that have lasted for years. It's good to close those gaps and fix those errors immediately.

As another senior author of the same research and a professor of computer science and biology at Johns Hopkins University, Michael Schatz explains, "We always knew there were parts missing, but I don't think any of us appreciated how extensive they were, or how interesting."

The project is the outcome of the Telomere to Telomere cooperation, which is funded by the National Institutes of Health and includes computational biologists and geneticists from several international institutes. The team concentrated on completing the 8% of the human genome that was left as a genetic void from the initial draft sequencing. Geneticists have been working to gradually add those missing parts ever since. A chromosome's worth of additional sequences have been found in the most recent round of research, which translates to 200 million more base pairs (the letters that make up the genome) and 1,956 new genes.

Professor of genomic sciences at the University of Washington and another senior author of one of the publications, Evan Eichler, adds, "We have declared victory a few times over the last two decades since the Human Genome Project [in 2001]." The focus of the material that has been remapped, according to Eichler, who was also engaged in the mapping of the original sequence, is different. The Human Genome Project's first objective was to arrange and orient every base pair, however it was not possible to accomplish that since the technology wasn't developed enough. As a result, we completed the portions that we could.

The new results' promise

The previously unreachable parts of the newly sequenced regions include the centromeres, the tightly wound central regions of chromosomes that maintain the organization of the long double strands of DNA as the strands unwind gradually to copy themselves and split into two cells during a single cell division. In addition to being essential for healthy human development, these areas are involved in brain growth and neurodegenerative illnesses. The fact that all eukaryotes—plants, animals, humans, trees, flowers, and higher organisms—have centromeres has long been considered one of biology's great mysteries. It plays a very basic role in the replication of DNA, the organization of chromosomes, and cell division. However, Schatz notes that despite the fact that its role has existed for billions of years, it has been a big contradiction to investigate since we lacked a centromere sequence to examine. "We do it at last now."

Long lengths of DNA with repeating sequences were also sequenced by scientists; at first, genetic specialists rejected these sequences as "junk DNA" and believed they were akin to copying mistakes. However, several human disorders may be related to these repetitive patterns. According to Eichler, "a sequence isn't necessarily garbage just because it repeats itself." He draws attention to the fact that these repetitive areas contain important genes: genes that control the machinery that makes proteins, genes that control the division and even splitting of a cell's DNA into its two daughter cells, and genes unique to humans that may set us apart from our closest evolutionary relatives, the primates. For instance, researchers discovered in one of the publications that monkeys differ from humans in the quantity of copies of these repetitive areas and the locations of these copies inside the genome.

According to Eichler, "these are some of the most significant processes that are necessary for life and for what makes us human." It is obvious that you cannot survive if these genes are eliminated. To me, that is not garbage.

Deanna Church, a vice president at Inscripta, a genome engineering company, who wrote a commentary accompanying the scientific articles, says that the process of figuring out what these repeated sections mean, if anything, and how the sequences of previously unsequenced regions like the centromeres will translate to new therapies or better understanding of human disease, is just getting started. It's not the same as deciphering a human genome; among those whose genomes have been sequenced and are suspected of having genetic illnesses, she points out that around half may be linked to particular genetic alterations. This implies that a great deal of the function of the human genome is still unknown.

upcoming studies

There's still space for development. The new sequence is derived from nearly half of a human, or from half of the genetic material typically present in an individual's DNA. A mother's and a father's pair of chromosomes make up each individual. With slightly different gene versions present in each of the DNA strands, we basically have two genomes. It is not an easy process to assemble the two genomes, and such difficulties hindered and ultimately caused the missing portions of the first Human Genome Project. The scientists might encounter areas where they failed to match because they were actually working with the paternal chromosome if they tried to match up certain sections thinking they were working with the maternal chromosome, for example, because the sequencing technology at the time could not easily separate the maternal and paternal copies of DNA. As Phillippy puts it, "it's like having two puzzles in one box." "You need to determine the differences and rebuild both."

The researchers exploited a fertilization defect for this unique pattern, resulting in an embryo with solely paternal chromosomes. The resultant growth was excised, and in the early 2000s it was maintained in the laboratory as a viable cell line with aberrant chromosomal makeup. As a result, the scientists had a simpler time assembling the genome since they were effectively tackling a single genetic problem.

In the end, though, scientists will require a more comprehensive human genome that includes the whole sequences of the paternal and maternal chromosomes. That will happen shortly. To separate the maternal DNA from the paternal sequences and effectively construct two genomes independently, Phillippy and colleagues are working with trios of DNA samples from volunteers and their moms and dads. By year's end, the researchers hope to have finished the so-called diploid human genome sequencing.

Winston Timp, a co-author of one of the publications and an associate professor of biomedical engineering at Johns Hopkins, notes that "the new genome assembly is paying dividends because it provides a more accurate map to understand what data we had from before meant" already. This involves discovering novel variations that might, for example, differentiate healthy individuals from ill individuals and variants that could increase a person's chance of contracting specific diseases.

Another co-author and associate professor of biology at Johns Hopkins, Rajiv McCoy, states, "We've discovered millions of genetic variants that were previously unknown across samples of thousands of individuals whose genomes have already been sequenced." "Finding new genetic variations that were previously uncharacterized will be a major focus of work now; we will have to wait until future work to learn more about their associations with disease."

Scientists probably won't be rushing to replace the outdated human genome, even with its more complete form, despite its flaws and holes. This is due to the fact that decades of research on human genetics have left the older version significantly more annotated than the new one; it's like the difference between a brand-new book from the bookshop and your favorite copy of a book you've had for years, complete with handwritten notes and margin highlights. According to Eichler, "a genome is only as good as its annotation." "Decades' worth of data have been accumulated by all clinical and research facilities using the outdated, incomplete genome. For any given lab, it would be horrifying to have to repeat all of that work. He thinks a lot of laboratories will progressively move to using the new genome, testing it out on smaller datasets first to see how much richer and more complete the data they get from the updated genome is. The new human genome is accessible to all scientists via a public database, just like the previous one. He states, "At this time, both genomes will be maintained, so there won't be a replacement."

In the upcoming years, scientists want to build more complete genomes utilizing both father and maternal DNA. This will aid in the identification of optimal targets for novel therapeutics as well as the advancement of knowledge on human development and evolution. The more genomes they have, the more potentially significant patterns may become apparent, which may lead to fresh insights into human illness and novel therapeutic approaches. The ultimate objective is for every individual to have their entire genome sequenced and included in their medical file. This will enable medical professionals to compare each patient's sequence to a reference sequence and identify any changes that may be linked to certain disorders.

As a senior author of one of the studies and an associate professor of biomolecular engineering at the University of California, Santa Cruz, Karen Miga states, "This is presenting the world with a whole additional chromosome that we have never seen before." "There are new sequences, new landscapes, and the possibility and promise of new discoveries."

There's a tangible buzz in the medical and genetic communities. During a briefing, Eichler remarked, "Hallelujah, we finally finished one human genome, but the best is yet to come." "This should not be viewed as the end, but rather as the start of a revolution in clinical medicine and genomic research."