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Researchers led by Arizona State University assistant professor Melissa Wilson Sayres have shown that swapping of genes between the sex chromosomes X and Y may be more common than believed, blurring rigid interpretations of sexual identity. Sex could be decoupled from the chromosomes, or at least a sum of many factors.

A strict recombination boundary that suppresses a swapping of genes between these sex chromosomes has been an assumption for long. The team showed two regions at the tip of the chromosomes which recombine.

"Studying our sex chromosomes has consequences for human health and for trying to understand our history," said Melissa Wilson Sayres, an assistant professor in the School of Life Sciences and member of the Biodesign Institute's Center for Evolution and Medicine. "To me, understanding the evolution of the X and Y is so important because we need to understand that there are all of these variations in the genetics of sex determination."

Much of human diversity results from the shuffling of an estimated 25,000 genes between 23 pairs of chromosomes of a male and female in a process called recombination. This occurs routinely everywhere except on the sex chromosomes, where shuffling information is limited to two small regions located at the tips of the X and Y chromosome, called pseudoautosomal regions (PAR1 and PAR2) studied by the team.

"The pseudoautosomal region, this tiny region that still recombines, is extremely understudied, typically filtered out of all analyses," said Wilson Sayres.

Also exposed to be indulging in the prohibited mingling was a rogue island of the X chromosome, called the X-transposed region, or XTR, which was duplicated from the X to the Y million years ago in the last common ancestor of all humans.

About 200 million years ago when mammals began to appear, the X and Y were indistinguishable, but slowly grew apart. What was to become the Y underwent genetic 'inversions' that made it harder to recombine. In addition to the PAR regions, XTR duplicated from the X to the Y in humans after the human-chimp split about 6 million years ago carrying away two genes.

Finally today the male Y has ended up having lost nearly 90 percent of the genes on the ancestral sex chromosomes and the ability to exchange information with the X.

An "unlucky" break was also involved in a key male reproductive switch, a testis determination (the SRY protein that makes up for maleness) region, being located near to the boundary. "The big implication is that because of the way our Y chromosome is structured, SRY is immediately next to the boundary, and because the boundary is fuzzy, we can get SRY hopping over to an X chromosome."

When this happens it can result in an increase in sex-linked disorders, such as males carrying XX chromosomes instead of XY, known as de la Chapelle syndrome leading to infertility and breast development in males. Understanding the differences between the sex chromosomes helps understand traits involved in some sex-biased diseases like color-blindness and hemophilia.
Turner syndrome (females with only one X), affecting one in 2,500 individuals, and Klinefelter's syndrome, found in one in a 1,000 individuals are some other sex-related disorders. Wilson Sayres notes that the condition is not that rare once we change our mind-set about male and female.

The fuzzy boundary is another reason why we need to be careful in defining someone by their chromosomes, says Sayres. Many people will not be aware of their chromosome complement.

In their study of complete DNA sequence information from the X chromosomes of 26 unrelated females, the ASU team show that the genetic diversity in the region, called PAR1, is far greater than the other regions of the X. The diversity is elevated across the PAR1 region, instead of an abrupt cutoff as previously expected. Beyond the PAR1, the diversity instead of a cliff like drop is gradual indicating many X-linked disorders.

Recombination suppression between X and Y is still evolving in humans. There are 24 additional genes located within PAR1 and countless others near the PAR1 boundary, important for bone growth, melatonin production, and links to psychiatric disorders, including bipolar affective disorder.

The study was published in the early online edition of the journal Genetics.

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