It's been 20 years since scientists put together the first draft of the human genome, the 3 billion tightly coiled genetic letters of DNA inside most of our cells.
Today, scientists are still struggling to figure it out.
But a series of studies published Thursday in
Science
has shed a bright light on the dark recesses of the human genome by comparing it to those of 239 other mammals, including narwhals, cheetahs and screeching hairy armadillos.
Base pair sequences on a computer screen.
Photo David Parker/Science Source
By tracing this genomic evolution over the past 100 million years, the so-called
Zoonomia Project
has revealed millions of stretches of human DNA that have changed little since our shrew-like ancestors scampered in the shadow of the dinosaurs.
According to the project, it is very likely that these ancient genetic elements play essential roles in our bodies today, and that their mutations expose us to various diseases.
The strength of the project lies in the enormous amount of data analysed:
not just genomes, but experiments with thousands of
DNA fragments and information from
medical studies, says Alexander Palazzo, a geneticist at the University of Toronto who was not involved in the work.
"This is how you have to do it."
Mammalian genomes also allowed the Zoonomia team to locate fragments of human DNA with radical mutations that set them apart from other mammals.
Some of these genetic adaptations may have played an important role in the
evolution
of our large, complex brains.
The researchers have only scratched the surface of the potential revelations from their database.
Other researchers say it will serve as a treasure map to guide future exploration of the human genome.
"The crucible of evolution is all-seeing," says Jay Shendure, a geneticist at the University of Washington who was not involved in the project.
Scientists have long known that only a small fraction of our DNA contains so-called protein-coding genes, which make crucial proteins like digestive enzymes in our stomachs, collagen in our skin, and hemoglobin in our blood.
Light micrograph of human DNA strands of various lengths precipitated in alcohol from a suspension of lysed (bursted) blood cells.
Photo Philippe Plailly/Science Source
The 20,000 protein-coding genes make up
only 1.5%
of our genome.
The remaining 98.5% is much more mysterious.
Scientists have discovered that bits of that inscrutable DNA help determine which proteins are produced at which places and at which times.
Other bits of DNA act like switches, turning on nearby genes.
Others can amplify the production of those genes.
And others act as switches.
Through painstaking experiments, scientists have discovered thousands of these switches embedded in long stretches of DNA that seem to do nothing for us—what some biologists call "junk DNA."
Our genome contains thousands of
broken copies
of genes that no longer work, for example, and remnants of viruses that invaded the genomes of our distant ancestors.
But it's not yet possible for scientists to directly look at the human genome and identify all the switches.
"We don't understand the language that makes these things work," says Steven Reilly, a geneticist at Yale School of Medicine and one of more than 100 members of the Zoonomia team
.
When the project began more than a decade ago, the researchers recognized that evolution could help them crack this language.
They reasoned that switches that lasted for millions of years were
probably essential
for our survival.
In each generation, mutations randomly affect the DNA of all species.
If they affect a part of the DNA that is not essential, they do not cause any damage and can be passed on to future generations.
In contrast, mutations that destroy an essential switch are unlikely to be passed on.
Instead, they can kill a mammal, for example by turning off genes essential for organ development.
"You won't have a kidney," says Kerstin Lindblad-Toh, a geneticist at the Broad Institute and Uppsala University who started the Zoonomia Project.
Lindblad-Toh and her colleagues determined that they would need to compare more than 200 mammalian genomes to trace these mutations over the past 100 million years.
They collaborated with wildlife biologists to obtain tissues from species spread throughout the mammalian evolutionary tree.
calculations
The scientists calculated the sequence of genetic letters - known as bases - in each genome and compared them to the sequences of other species to determine how mutations arose in different branches of mammals as they evolved from a common ancestor.
"It took a lot of computational work," says Katherine Pollard, a data scientist at Gladstone Institutes who helped create the Zoonomia database.
The researchers found that a relatively small number of bases in the human genome - 330 million, or about 10.7% - underwent few mutations in any branch of the mammalian tree, a sign that they were essential
for the survival
of all these species. including ours.
Our genes make up a small part of that 10.7%.
The rest lies outside of our genes and probably includes elements that turn genes on and off.
According to the researchers, mutations in these little-modified parts of the genome were harmful for millions of years and remain so today.
Mutations associated with genetic diseases often alter bases that the researchers say have evolved little in the last 100 million years.
Nicky Whiffin, a geneticist at
Oxford University
who was not involved in the project, said clinical geneticists had difficulty finding disease-causing mutations outside of protein-coding genes.
According to Whiffin, the Zoonomia Project could guide geneticists to unexplored regions of the genome with relevance to health.
"That could greatly reduce the number of variants that are tested," he said.
The DNA that governs our essential biology has changed very little in the last 100 million years.
But of course we are not identical to kangaroo rats or blue whales.
The Zoonomia Project is enabling researchers to identify the mutations in the human genome that contribute to making us unique.
Pollard focuses on thousands of stretches of DNA that have not changed in that period of time, except in our own species.
Interestingly, many of these rapidly evolving pieces of DNA are active in the developing human brain.
Based on the new data, Pollard and his colleagues now believe they understand how our species broke with 100 million years of tradition.
In many cases, the first step was a mutation that accidentally created an extra copy of a long stretch of DNA.
By elongating our DNA, this mutation changed the way it folded.
As it folded back, a genetic switch controlling a nearby gene was removed from contact with it.
Instead, he contacted a new one.
Over time, the switch acquired mutations that allowed it to control its new neighbor.
Pollard's research suggests that some of these changes helped human brain cells grow longer in infancy, a crucial step in the evolution of our big, powerful brains.
Yale's Reilly has discovered other mutations that might also have helped our species build
a more powerful brain
: those that accidentally snip off bits of DNA.
Search
Reilly and his colleagues analyzed Zoonomia's genomes looking for DNA that would have survived in various species, but been deleted in humans.
They found 10,000 of these deletions.
Most were from a few bases, but some had profound effects on our species.
One of the most striking deletions altered a switch in the human genome.
It lies near a gene called LOXL2, which is active in the developing brain.
Our ancestors only lost one base of DNA from the switch.
That tiny change turned the off switch into an on switch.
Reilly and his researchers conducted experiments to see how the human version of LOXL2 behaved in neurons compared to the standard mammalian version.
Their experiments suggest that LOXL2 remains active in children longer than in young apes.
LOXL2 is known to keep neurons in a state where they can continue to grow and sprout branches.
Therefore, if it remains active for a longer time in childhood, our brain could grow more than that of apes.
"It changes our idea of how evolution can work," Reilly says.
"Breaking things in the genome can lead to new functions."
The Zoonomia Project team plans to add more mammalian genomes to their comparative database.
Zhiping Weng, a computational biologist at UMass Chan School of Medicine in Worcester, is especially interested in studying another 250 primate species.
His own Zoonomics research suggests that virus-like bits of DNA multiplied in the genomes of our monkey ancestors, inserting new copies of themselves and rewiring our on and off switches in the process.
Comparing more primate genomes will allow Weng to get a better idea of how those changes may have rewired our genome.
"I'm still very obsessed with being human," she says.
c.2023 The New York Times Company
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