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."
