On March 23rd, 1997, the Buffalo evening news ran an ad for volunteers to participate in
a very large international research effort.
You may know it as the Human Genome Project.
The goal of this 13-year and almost three billion-dollar scientific endeavor was to
read out the blueprint of the human species — that is, the DNA making up the human genome.
Researchers started with DNA samples from multiple anonymous volunteers.
The largest amount came from someone who responded to the Buffalo evening news ad.
The end result was the generation of the first-ever sequence of the human genome in 2003.
Scientists call this the human genome reference sequence.
By acting as a baseline to compare other genomes to, the draft human sequence has been pivotal
for advancing our understanding of human evolution, how diseases are caused, and how the environment
and heredity work together in defining our biology.
But the human genome sequence generated wasn’t quite complete.
While the sequence reflected about 95% of the human genome, 5% was unknown - regions
called “gaps”.
Since 2003, researchers have been methodically filling in those gaps, and today, there are
only around 100 left, down from 150,000!
But why are there still gaps in the human genome reference sequence?
One major reason is technology.
The machines that read DNA cannot read all 3 billion letters in the human genome at once.
When they try to read too much DNA in one go, they tend to make more mistakes – like
trying to understand one really really long sentence at once.
The remaining 100 gaps mostly contain long stretches of DNA sequences repeated over and
over again.
These regions have turned out to be exceptionally difficult to sequence.
Back in the 90s and 2000s, older DNA-sequencing technologies couldn’t determine if such
sequences were repeated 10, 20 or 50 times.
But researchers did not give up.
They knew there was a possibility that such repeated DNA regions could contain genomic
information relevant to human health and disease.
But generating a truly complete human genome sequence is only part of the challenge.
Even after the human genome reference sequence is made gapless, you can’t represent all
of humanity with just one reference.
But why?
Why isn’t one human genome sequence enough?
While the genome sequence among all humans is 99.9% identical, that other 0.1% accounts
for all of the genomic differences in the human species.
And populations from different ancestries have genomic variations that may be specific
to each group.
Which is why one human genome reference sequence won’t reflect all these different genomic
variations.
Researchers need a range of reference sequences that encompass the genomic differences in
any ancestrally diverse population.
Put together, they would showcase all human genomic diversity.
Unfortunately, up till now, most data about genomic variants that may be involved in different
diseases have been gathered from people of European ancestry.
But that’s just one ancestral group!
This means we may be making some medical decisions for other ancestral groups based on incompatible
data.
But scientific efforts are underway to eliminate this historical bias.
One such effort is the Human Genome Reference Program, funded by the National Human Genome
Research Institute.
Over the next couple of years, at least 350 high quality, gapless human genome sequences
will be generated from ancestrally diverse people.
Remember those gaps in the genome?
Another group of international scientists called the Telomere-to-Telomere Consortium,
are working to fill them in and generate totally complete sequences with improved technologies.
Using these 350 complete genomes, The Human Genome Reference Program will then combine
the data and create a unified genomic representation of the human species, calling it a “pan-genome”.
Will this be enough to serve as a single reference for all human genomics research in the future?
Perhaps not, but so long as these people are thoughtfully chosen, this effort will go a
long way towards that goal.
Slowly but surely, we are moving closer to one of the fundamental aims of the Human Genome
Project - a complete and accurate representation of the genomic blueprint of the human species.