Research team completes long-anticipated genome sequencing of Y chromosome

Twenty years in the past, when researchers from the Human Genome Mission announced that they’d accomplished the first-ever sequence of a complete set of human DNA, the invention was heralded as akin to “splitting the atom or going to the moon.” The announcement without end reworked the fields of genomics, biology, and drugs, permitting researchers to analyze extra complicated questions and search extra difficult solutions associated to the human physique and tips on how to deal with illness.

However the researchers had not, actually, accomplished a full human genome sequence. Their landmark findings have been outlined as “extremely correct” and “extremely contiguous,” with “the one remaining gaps equivalent to areas whose sequence can’t be reliably resolved with present know-how.”

A really accomplished sequence was published last year by the Telomere-to-Telomere (T2T) consortium, a world scientific collaboration that includes the work of geneticist Rachel O’Neill, director of UConn’s Institute for Techniques Genomics (ISG) and Board of Trustees Distinguished Professor within the Division of Molecular and Cell Biology, and her lab.

The T2T consortium sequenced your entire human genome from a cell with XX chromosomes. The findings have been nonetheless groundbreaking, however since roughly half of the human inhabitants has XY chromosomes somewhat than XX, researchers knew that their work wasn’t achieved.

“There are a number of medical outcomes linked to the Y chromosome,” notes O’Neill.

In two new papers, printed August 23, 2023, within the journal Nature, O’Neill and her collaborators supply an in-depth evaluation of the Y chromosome for the primary time, augmenting the findings of the T2T consortium.

The primary paper, a publication of the T2T consortium, is the primary full Y chromosome meeting from a person (T2T-Y), The second, a collaboration with The Jackson Laboratory for Genomic Drugs (JAX), presents the Y chromosome sequences from 43 unrelated people, offering a basis for future inquiry into how genetic variety inside the Y chromosome impacts well being outcomes.

O’Neill’s lab labored with a number of different key investigators and labs to perform this monumental feat. Particularly, she notes, the lab crew of Adam Phillippy on the Nationwide Institutes of Well being supplied the meeting work for the chromosome and pioneered the work.

“We did the entire repeat annotations,” she says, “which have been fairly intensive, as a result of greater than 50% of that chromosome is repetitive.”

The work benefited from the development of sequencing know-how, which has come a great distance for the reason that Human Genome Mission’s first sequencing try accomplished in 2003. Lengthy-read sequencing know-how, O’Neill explains, is vital for efficiently deciphering sections of DNA which might be extremely repetitive.

With out the long-read tech, O’Neill says, “it was like attempting to place a ebook collectively when all you have got is a pile of phrases.” The brand new know-how, in distinction, “offers you complete sentences, paragraphs, pages.”

As the primary paper, led by Arang Rhie of Phillippy’s group, was coming into the publication course of in Nature, O’Neill was contacted by researchers at JAX, who have been additionally within the technique of Y chromosome meeting. JAX professor Charles Lee and affiliate analysis scientist Pille Hallast have been heading up a crew that analyzed and sequenced 43 completely different Y chromosomes from distinct people, with almost half coming from African descent (important as a result of the T2T-Y chromosome sequence had been achieved utilizing DNA from a person of European descent).

As soon as once more, O’Neill’s lab assisted with the repeat annotations, utilizing long-read know-how to find out the precise quantity and order of repeating sections on the chromosome. Repeating sections of DNA—which can differ in quantity or sequence between people—account for many of human genetic variation.

The T2T-Y chromosome sequence recognized a further 42 protein-coding genes that had not beforehand been studied and added a further 30 million base pairs to the prevailing reference human genome, whereas the JAX sequencing work contributed 43 new distinctive Y chromosome sequences.

“Taken collectively, these two papers present intriguing insights into human Y chromosomes, reveal the extremely variable nature of Y chromosomes throughout people, and supply an necessary basis for future research on how they could be contributing to sure problems and illnesses,” notes the JAX launch.

They characterize a monumental advance within the area of genomics and one other thrilling publication for the lab of O’Neill, who continues to pioneer work exploring the consequences of repetitive components within the human genome.