Fully sequencing the Y chromosome was once considered an impossible task. The chromosome that makes biological males is chock-full of repetitive and inverted stretches of DNA, making it challenging to put stretches of deciphered DNA back together in the right order. Now, using state-of-the-art techniques, researchers report today in a pair of papers in Nature that they have succeeded in sequencing not just one Y chromosome, but dozens from men from around the world. In doing so, they have completed the final step in the long-awaited goal of completely sequencing the human genome.
The first paper details how the repetitive regions are arranged and identifies dozens of new genes; the second reveals that this arrangement, as well as the number of genes, varies dramatically from man to man. The accomplishment “represents an impressive finale, thus marking the beginning of a whole new era in human genetics,” says Toomas Kivisild, a geneticist at KU Leuven who was not involved with the effort. “These two studies are starting to reveal the scale of interindividual variation.”
Adds Jenny Graves, an evolutionary geneticist at La Trobe University: “The Y really is as weird, and as interesting, as we thought.”
Scientists believe the Y and X chromosomes were once identical. Over time, the part of the Y that contains genes shrank to one-sixth the size of that region in the X, and today it bears half as many genes as its larger counterpart. Some researchers have argued that this degeneration could gradually continue, possibly leading to the loss of the Y chromosome altogether, as has happened in some lineages of animals.
Despite its small size, the Y chromosome was hard to sequence. The first tries at sequencing the human genome didn’t even attempt the Y, in part because it was considered an unimportant “graveyard” for genes destined to disappear. Moreover, its repetitive regions made it “the most troublesome chromosome in our genome,” says Agnar Helgason, a biological anthropologist at deCODE Genetics who was not involved with the new work. Eventually, one group did sequence part of the Y and learned it was quite dynamic, shuffling genes around by having multiple copies in mirror image stretches of DNA. By structuring itself in this way, the chromosome manages to keep its few genes in good order.
In March, Adam Phillippy, a bioinformatician at the National Human Genome Research Institute, and the Telomere-to-Telomere consortium described the complete sequencing of the human genome except for the Y chromosome. At that time, the consortium tweeted that it had the Y sequence in hand. Now, the team has analyzed and detailed the complex arrangement of 62 million bases from the Y chromosome, adding 30 million that were previously missing after earlier partial sequencing attempts. “It’s a bit like high-definition TV—we could see the picture before, and these studies bring it into supersharp focus,” says Mark Jobling, a geneticist at the University of Leicester who was not involved with the work.
In a second paper accompanying Phillippy’s, Charles Lee, a geneticist and director of the Jackson Laboratory for Genomic Medicine, and colleagues sequenced 43 Y chromosomes from men belonging to 21 distinct populations across the world, previously identified as part of the 1000 Genomes Project that sampled genetic variation among humans.
Ys vary significantly, they discovered. “I was surprised to see the extent of copy number variation for certain genes on the Y chromosome,” Lee says. For example, one man’s Y chromosome had 23 copies of a gene called TSPY, which is thought to be involved in the formation of sperm, whereas another had 39 copies. The study also found variation in the size and makeup of the massive repetitive region of this chromosome. This so-called heterochromatic block stretches from between 17.6 million to 37.2 million bases long in different men; it’s the largest such block in the human genome. And it seems the repetition in this segment isn’t totally random, as some had thought, but instead features distinct patterns of repetitive pieces of DNA.
That level of organization and conservation of DNA suggests the Y chromosome isn’t degenerating into obsolescence, Jobling says. This “paper confirms that gene content of the Y chromosome is essentially conserved,” he says. “The idea that the Y is still degenerating and destined to disappear is really scotched by this.”
So far, it’s unclear whether all this variation affects men’s fertility or other traits. But knowing it exists is “laying the foundation for subsequent research,” Helgason says. For example, researchers could now do large-scale studies to see how differences in the Y chromosome correlate with health problems, such as certain types of cancers like bladder cancer in which the Y has been implicated. The Y “is still going to be very tricky to study, but at least we know where the tricky parts are,” he says.
