Analysis staff completes long-anticipated genome sequencing of Y chromosome

Twenty years in the past, when researchers from the Human Genome Venture introduced that they’d accomplished the first-ever sequence of a complete set of human DNA, the invention was heralded as similar to “splitting the atom or going to the moon.” The announcement endlessly remodeled the fields of genomics, biology, and drugs, permitting researchers to research extra advanced questions and search extra difficult solutions associated to the human physique and the right way to deal with illness.

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

A very accomplished sequence was printed final 12 months by the Telomere-to-Telomere (T2T) consortium, a global scientific collaboration that includes the work of geneticist Rachel O’Neill, director of UConn’s Institute for Methods 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 had been nonetheless groundbreaking, however since roughly half of the human inhabitants has XY chromosomes moderately than XX, researchers knew that their work wasn’t carried out.

“There are plenty 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 range throughout 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 staff of Adam Phillippy on the Nationwide Institutes of Well being supplied the meeting work for the chromosome and pioneered the work.

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

The work benefited from the development of sequencing expertise, which has come a great distance for the reason that Human Genome Venture’s first sequencing try accomplished in 2003. Lengthy-read sequencing expertise, O’Neill explains, is essential for efficiently decoding sections of DNA which can be extremely repetitive.

With out the long-read tech, O’Neill says, “it was like making an attempt to place a e-book collectively when all you may have is a pile of phrases.” The brand new expertise, in distinction, “provides you entire 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 had been additionally within the strategy of Y chromosome meeting. JAX professor Charles Lee and affiliate analysis scientist Pille Hallast had been heading up a staff that analyzed and sequenced 43 completely different Y chromosomes from distinct people, with almost half coming from African descent (vital 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 expertise 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 an extra 42 protein-coding genes that had not beforehand been studied and added an extra 30 million base pairs to the present 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 issues and ailments,” notes the JAX launch.

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