Science: Some hard-to-decipher genomic regions carry genes that make us unique

Genome scientists at UW Medicine were among the major contributors to the first complete, gap-free sequence of the human genome published this week by the National Human Genome Research Institute

The lab of Evan Eichler, a professor of genomic sciences at the University of Washington in Seattle, is part of the lead paper, "The Complete Human Genome," published April 1 in the journal Science.

Eichler's team and collaborators from other institutions also published a companion paper that provides the first comprehensive account of large, highly identical repeating regions (called segmented duplications) and their variation in the human genome

These regions of the human genome are critical for understanding human evolution and genetic diversity and resistance or susceptibility to many diseases

However, due to its complexity, segmented duplication is one of the last regions of the human genome assembly to be fully sequenced

The desire to address these regions is part of what drives advances in sequencing technologies, such as the ability to read long stretches of DNA

The research team, led by Eichler's lab, report their findings and analysis in a paper published this week in the journal Science, titled "Segmented duplication in the complete human genome.

"In 2001, when I was a kid, I saw a magazine cover about the complete human genome," recalls Walger

Several interesting findings have emerged in recent studies that sequenced these regions

In addition to the medical research implications of completing the assembly, it also helps answer: What is contained in our genome that makes us unique? Some genetic gaps in the original genome are now considered critical, helping to Made the human brain bigger than other great apes

Echler's lab has also generated long-read combinations from other nonhuman primate genomes and compared them to the new gap-free human genome combination

These human-specific segment duplications are a reservoir of new genes that drive the formation of more neurons in the developing brain and increase synaptic connectivity in the frontal cortex

In the TBC1D3 gene family, a family of genes associated with expansion of the human prefrontal cortex, analysis by Xavi Guitart, a graduate student in Eichler's lab, shows that periodic and independent expansion occurs during primate evolution.

"Different people carry completely different complements and arrangements of the TBC1D3 gene family," the researchers explain in their paper, which is unexpected for a gene thought to be so important for brain function
.
The scientists also discovered diversity in the complex structure of the LPA gene, part of the variation in the lipoprotein gene that constitutes the most important genetic risk factor for cardiovascular disease caused by abnormal lipid levels in the blood
.

The researchers also looked at SMN, a motor neuron gene, whose mutations are associated with certain neuromuscular diseases
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Having a better sequence to address regions of spinal muscular atrophy -- one of the most difficult regions to complete 5 -- may be a practical advantage on chromosomes in treating disease risk decisions and the SMN2 gene duplication target is one of the most effective gene therapies
.

Based on these and other findings, the scientists note that the new reference genome "reveals unprecedented levels of human genetic variation in genes critical for neurodevelopment and human disease
.
"

In addition to being a source of new knowledge about human biology, the recently completed human genome may also answer some fundamental questions about cell biology
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For example, this combination will help to better understand the differences in centromeres that exist on each human chromosome
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Problems with centromeres can cause difficulties during cell division
.

Studying the sequence of centromeres can find the root cause of errors in cell division and the distribution of genetic material between cells
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This includes cancer as well as abnormalities that affect prenatal development, such as Down syndrome or Robertsonian translocations
.

Glennis A.
Logsdon, a postdoctoral fellow in genomics sciences at the UW School of Medicine, made several discoveries in centromere sequencing
.

"We had to develop new ways to target these regions," she explained
.
"To span these regions, we took advantage of new technologies that had emerged, such as ultra-long sequencing
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We also worked hard to polish the genome sequence to ensure it was highly accurate
.
"

Eichler comments on the training and experience gained by early career human genome researchers in the T2T project
.

"I think it's a privilege to be able to help train the next generation of scientists," he said
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"It's fun to watch them start as students, work on a big project, and then take it to the next level
.
"

Eichler was involved in the original Human Genome Project back in 2001
.
He is fascinated by regions of the genome that are complex from a highly repetitive perspective but can also encode genes
.

When the Human Genome Sequence Project came to an end, many regions were not yet complete
.

Eichler added that he has had a strong desire to complete these works ever since
.

"I always come back to this, in order to fully understand genetic variation, we need a complete reference
.
Otherwise, we lose part of the puzzle
.
For some people, solving 95 percent of the puzzle is enough
.
But I think it's very important for me to get the last 5% because I believe that what we don't know about disease or evolution, in the 5% of the genome that we didn't sequence in the first place, there is too much What a disproportionate representation
.
"

This is not the end, he said
.
"Although people will say, 'Okay, we're done with a genome
.
' We've done a genome
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Over the next few years, there will be hundreds or thousands of genomes
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I think there will be a shift in how we think about human differences, and more complex genetic variation is not only important for how we are human, but also for how we are different
.
"

article title

Segmental duplications and their variation in a complete human genome