Researchers Fully Sequence the Y Chromosome for the First Time (2024)

Researchers Fully Sequence the Y Chromosome for the First Time (1)

What was once the final frontier of the human genome — the Y chromosome — has just 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.

Paper: Arang Rhie et al. The complete sequence of a human Y chromosome. Nature. Published online Aug. 23, 2023. DOI:10.1038/s41586-023-06457-y

Bioscience, Genomics, Health, Clinical diagnostics and Precision medicine

Researchers Fully Sequence the Y Chromosome for the First Time (2024)


Did researchers fully sequence the Y chromosome for the first time? ›

Scientists have fully sequenced the Y chromosome for the first time, uncovering information that could have implications for the study of male infertility and other health problems. Neanderthals differ in DNA from what scientists call "modern humans" by less than 1%.

Who sequenced the Y chromosome? ›

“People were guessing at it, but no one could prove that this was happening until now.” UC Santa Cruz assistant professor of biomolecular engineering Karen Miga is a co-leader of the T2T consortium, an international group of scientists who achieved the first complete Y chromsome sequence.

Why is the Y chromosome so hard to sequence? ›

It is difficult to fully sequence because it contains some regions that are highly repetitive and very densely packed. The Y chromosome is one of the smallest in the human genome, and it contributes less than 1% of a man's nuclear DNA.

When did the Y chromosome first appear? ›

For example, the human X and Y chromosomes originated about 200-300 million years ago in eutherian mammals1,2 after the split of monotremes, and sex chromosomes evolved independently in birds, snakes, and multiple times in other reptiles, amphibians and fish; they also formed repeatedly in many invertebrate taxa and ...

When was the first human chromosome completely sequenced? ›

It was declared complete on April 14, 2003, and included about 92% of the genome. Level "complete genome" was achieved in May 2021, with a remaining only 0.3% bases covered by potential issues.

Is the Y chromosome fully mapped? ›

An international team of researchers has successfully completed the sequencing of the Y chromosome. Understanding the male sex chromosome also revealed 41 additional protein-coding genes. The find could create additional avenues of research into disease risk.

Who passed the Y chromosome? ›

Females always pass an X chromosome onto their offspring. If the father passes on an X chromosome, the baby will be genetically female, and if the father passes on a Y chromosome, the baby will be genetically male.

Is the Y chromosome only from the father? ›

The y-chromosome is inherited more or less unchanged from father to son to grandson, indefinitely. Chromosomes contain the DNA that determines our inherited characteristics, and the y-chromosome is one of the 46-chromosomes in the nucleus of each of the cells of all human males.

Which was the last chromosome to be completely sequenced? ›

Amongst them, chromosome 1 is the largest chromosome and has the most number of genes, that is, 2968 genes. It was the last human chromosome to be sequenced completely in the Human Genome Project in 2006.

Is the Y chromosome really disappearing? ›

But research suggests that the Y chromosome has been rapidly degenerating over the course of our evolution. In fact, the gene may one day disappear altogether.

Can a male have no Y chromosome? ›

An individual with an X chromosome that carries the SRY gene will develop as a male despite not having a Y chromosome, but will not be able to produce sperm to father biological children.

Why is the Y chromosome weird? ›

Like all human DNA, the human Y chromosome sequence is spelled out in A,T,C, and G base pairs, but the Y chromosome is unique in that it is full of palindromes — sequences of letters that are the same backward and forward, like kayak or racecar.

How do scientists think the Y chromosome evolved? ›

Evolutionary forces on the Y chromosome

The first step in the evolution of Y chromosomes is likely to be the acquisition of a male-determining gene on one member of a pair of autosomes that will ultimately become the sex chromosomes (for example, a male-determining gene forming a proto-Y chromosome).

Is xx male or female? ›

Females usually have two X chromosomes (46,XX), and males usually have one X chromosome and one Y chromosome (46,XY). The SRY gene, normally located on the Y chromosome, provides instructions for making the sex-determining region Y protein.

Can the Y chromosome repair itself? ›

The Y chromosome has shrunk over time because, unlike every other chromosome in the human body, it has no partner. This means it cannot easily be repaired when harmful mutations occur. Typically, people have 23 pairs of chromosomes including two that govern sex, which areX and Y in males, or two Xs in females.

Is the Y chromosome genetic puzzle finally complete? ›

The human Y chromosome, responsible for determining male sex, finally has gotten an end-to-end examination. Researchers sequenced the chromosome, which contains many genes involved in sperm production and fertility, from a male of European descent.

Who mapped chromosome first? ›

Linkage or genetic or chromosome map is a linear graphical representation of the sequence and relative distances of the various genes present in a chromosome. The first chromosome maps were prepared by Sturtevant in 1911 for two chromosomes and in 1913 for all the four chromosomes of Drosophila.

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