Last year, scientists unveiled the most complete sequence of the human genome ever, but it was missing one small piece: the Y chromosome.
Now, the smallest member of the human chromosome family has been fully sequenced, completing a mystery that took three decades to unravel.
The result is a comprehensive human reference genome, which may now contain secrets about male fertility.
“Now that we have this 100% complete sequencing of the Y chromosome, we can identify and explore the many genetic variations that can affect human traits and diseases in a way that we haven’t been able to do before.” He says Dylan Taylor, a geneticist at Johns Hopkins University and one of the study’s authors.
The Y chromosome has so many repeat sequences – including a few long homologues – that it has been largely “unreadable” so far.
Led by genomics scientist Arang Rai of the US National Institute of Human Genome Research, the aptly named Telomere-to-Telomere Consortium used advanced sequencing techniques and newly developed bioinformatics algorithms to stitch together long stretches of DNA, finally mapping the entire Y chromosome.
“We knew we had an incomplete picture yet.” He says Johns Hopkins University computational biologist Rajeev McCoy said in what could be considered a slight understatement, given that the previous draft of the Y chromosome was missing more than half of its bases.
These gaps, many of which extend to genes related to sperm production, have led to all kinds of incorrect assumptions being made in other studies. Some previously unknown human Y sequences were, for example, I thought wrong To be traces of contaminated bacterial DNA of the samples.
“But now we can see the entire genome from end to end for the first time,” McCoy said He says.
The team filled in more than 30 million “letters” in the DNA sequence to fully assemble the Y chromosome: all 62,460,029 base pairs. They also corrected multiple errors in previously sequenced sections and discovered 41 new protein-coding genes.
“The big surprise was how organized the repeats were,” says Adam Phillippe, a computer scientist at the US National Human Genome Research Institute.
“Almost half of a chromosome is made up of alternating blocks of two specific repeating sequences known as satellite DNA. It forms a beautiful, quilt-like pattern.”
In a second study led by geneticist Bill Hallast of the University of Washington, the researchers went one step further, using reference sequences to assemble human Y chromosomes from 43 male individuals, half of whom are of African ancestry.
Together, the clusters span 183,000 years of human evolution and reveal some surprising variations in the Y chromosome.
For example, the Y chromosomes were of vastly different sizes, ranging from 45.2 million to 84.9 million base pairs in length.
There were also striking structural differences: the exact sequence of genes was preserved (so they still encode the correct proteins) but sometimes larger pieces of DNA were inverted, orientated in the opposite direction along the Y chromosome.
“When you find a difference that you haven’t seen before, the hope is always that those genomic variants are going to be important for understanding human health,” says Felipe.
Recently, genes located on the Y chromosome It was complicated In aggressive forms of common cancers in men, while the loss of the Y chromosome was found to be the cause of cancer Bladder cancer growth. But we don’t know what else we missed.
A new era of personalized medicine will come if sequencing technologies continue to advance, allowing whole genomes – not just selected parts – to be sequenced inexpensively.
But genome sequencing can happen Exacerbating disparities in health care If historical grievances and lack of diversity in research studies are not resolved.
“Eventually, when the complete, accurate, and gap-free assembly of diploid human genomes becomes routine, we expect that ‘reference genomes’ will become known simply as ‘genomes.'” we conclude.
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