Ever try to put together a puzzle of a black cat in a graveyard at midnight? That’s what it was like for researchers trying to fully sequence the Y chromosome.
While chromosomes all contain sections of very repetitive DNA, well over half of the Y chromosome is like that.
“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,” said Justin Zook, research leader at the National Institute of Standards and Technology (NIST).
Still, two decades after the Human Genome Project produced the first draft human genome sequence, researchers at NIST and many other organizations have—for the first time—mapped out the Y chromosome in its entirety. The advance improves DNA sequencing accuracy for the male reproductive chromosome, which could help identify certain genetic disorders and potentially uncover the genetic roots of others.
Last year, a team from the Telomere-to-Telomere (T2T) consortium, which is made up of experts from dozens of organizations, 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 arduous Y chromosome.
Even so, T2T did not need to start from scratch for their latest endeavor. NIST’s Genome in a Bottle (GIAB) consortium—led by Zook—had already accumulated the largest collection of Y chromosome data prior to the new study. Thus, that data served as a jumping-off point for the new study’s authors, who focused their analysis on GIAB’s best-understood Y chromosome.
More than 62 million letters of genetic code later, the researchers spelled out the GIAB Y chromosome front to back—with the help of a machine learning analysis tool and other advanced programs.
The scientists then tested their 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, now represents the world’s first complete genome for the half of the population with a Y chromosome.
The study results, published Wednesday in Nature, could be useful in identifying and diagnosing the few known conditions related to genes in the Y chromosome. More than that, the sequencing data could also help identify certain genetic disorders and 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.”