What was once the final
frontier of the human genome — the Y chromosome — has been mapped out in its
entirety.
Led by the National Human Genome
Research Institute (NHGRI), a team of researchers at the National Institute of
Standards and Technology (NIST) and many other organizations used advanced
sequencing technologies to read out the full DNA sequence of the Y chromosome —
a region of the genome that typically drives male reproductive
development. The results of a study published in Nature demonstrate that this advance improves DNA
sequencing accuracy for the chromosome, which could help identify certain
genetic disorders and potentially uncover the genetic roots of others.
DNA sequencing isn’t as simple as
reading genetic material from a genome’s beginning to its end. DNA gets chopped
up when it is extracted from cells, plus even the best sequencing equipment can
only handle relatively small bits of DNA at a time. So, researchers and
clinicians rely on special software to piece together fragments of sequenced
code in the correct order like a puzzle.
A reference genome is a separate,
already pieced-together genome that serves as a guide, similar to the pictures
on the front of puzzle boxes. And because 99.9% of our species’ genetic code is
shared, any human genome would closely match a reference.
Last year, a team from the
Telomere-to-Telomere (T2T) consortium, which is made up of experts from dozens
of organizations such as NIST, generated the most
complete reference genome at
the time by using new sequencing technologies to crack previously
indecipherable regions of the genome. But cells used in that work did not
contain the most puzzling of all, the Y chromosome.
“Chromosomes all contain sections of
very repetitive DNA, but well over half of the Y chromosome is like that,” said
study co-author Justin Zook, who leads NIST’s Genome in a Bottle
(GIAB) consortium. “If you
use the puzzle analogy, a lot of the Y chromosome looks like the backgrounds
often do, where all the pieces look really similar.”
With this new endeavor, T2T was not
starting at zero as the GIAB had already gotten the ball rolling.
The GIAB’s mission is to produce test
materials, or benchmarks, that can be used to evaluate sequencing technologies
or methods. The materials themselves are highly accurate readouts of specific
genes that can act as an answer key for checking the results of a particular
sequencing method.
NIST has rigorously analyzed several
individual human genomes to create their benchmarks. While GIAB has not yet
produced a benchmark for the Y chromosome specifically, the consortium has
studied one genome extensively, accumulating the largest collection of Y
chromosome data prior to the new study.
That data served as a jumping-off point
for the new study’s authors, who focused their analysis on the best understood
GIAB Y chromosome. They examined the sample with a combination of cutting-edge
technologies — namely high fidelity and nanopore sequencing — that make the DNA
fragment puzzle pieces larger and thus easier to assemble.
A machine-learning analysis tool and
gamut of other advanced programs helped the team identify and assemble the
pieces of the chromosome. More than 62 million letters of genetic code later,
the authors had spelled out the GIAB Y chromosome front to back.
The researchers pitted their complete Y
chromosome sequence, named T2T-Y, against the most widely used reference
genome’s Y chromosome parts, which are riddled with stretches of absent code.
Using them both as guides for sequencing a diverse group of over 1,200 separate
genomes, they found that T2T-Y drastically improved the outcomes.
T2T-Y, in combination with the group’s
previous reference genome, T2T-CHM13, represents the world’s first complete
genome for the half of the population with a Y chromosome.
The newest addition could be useful in
identifying and diagnosing the few known conditions related to genes in the Y
chromosome. But what’s more is the new reference’s potential to shed light on
new genes and their function.
“There are certainly aspects of
fertility and some genetic disorders that are connected to genes in the Y
chromosome,” Zook said. “But because it’s been so hard to analyze up to this
point, we may not even know yet just how important the Y chromosome is.”
At NIST, Zook and his fellow GIAB
researchers have developed a new benchmark based on the X and Y chromosomes
assembled by T2T to help translate the potential impact of the new reference
material into reality.
Source: https://www.nist.gov/news-events/news/2023/08/researchers-fully-sequence-y-chromosome-first-time
Journal
article: https://www.nature.com/articles/s41586-023-06457-y
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