Sex disorders linked to Y chromosome’s instability

When researchers first reported the sequence of the human Y chromosome, they referred to it as a “literal hall of mirrors.” That is, the male sex chromosome, and in particular the genes essential for sperm production, are encoded in long stretches of mirror-image sequence. That unique pattern provides the lone Y chromosome with pairs of genes within its own structure that can back each other up, helping to maintain its integrity.

Now, a new report in the September 4th issue of the journal Cell, a Cell Press publication, details exactly how Y chromosomes overwrite or swap those genes. It also reveals a considerable downside to these massive palindromes: They can lead to a remarkable array of sex disorders, from sperm failure to sex reversal to Turner syndrome. (“Palindrome” refers to sequence that reads the same in either direction).

Genes often get swapped within one of the Y chromosome’s arms, from one half of a palindrome to the other. The new report shows that errors in that recombination process turn the whole chromosome into one big mirror-image structure, a so-called isodicentric Y. And those isodicentric Y chromosomes can lead to a kind of “roulette game” with regard to developmental outcome, says David Page, a Howard Hughes Medical Institute Investigator and Director of the Whitehead Institute.

“Basically, a fertilized egg can contain a modified Y chromosome that is itself a palindrome,” Page says. “That modified or isodicentric Y chromosome is so unpredictably stable or unstable that individuals who develop from such a fertilized egg range from a man with no sperm who is otherwise healthy to someone raised as a boy who is later found to have an ovary on one side to a girl or woman with Turner syndrome. These wildly different outcomes result from the very same starting point.”

The key to an isodicentric Y chromosome’s instability is its two centromeres, Page explained. Centromeres are critical for the proper segregation of chromosomes into two daughter cells at each cell division.

“If there are two centromeres, the apparatus for partitioning chromosomes becomes very confused,” Page said. “A chromosome can get tugged in two directions at once.” As a result, the chromosome has a tendency to get broken or lost each time cells divide. During the development of an embryo, cells divide extensively to form the ten trillion specialized cells that make up our bodies.

This means that different parts of an individual can wind up keeping or losing the isodicentric Y in essentially random fashion. If the cells that form the gonads in the developing embryo keep the Y, they will be anatomic males, he explained. If they lose it, they become anatomic females.

Intriguingly, the chances of sex reversal in those who inherit a modified, isodicentric Y chromosome is greater in those with more of the male-specific genes and a larger Y chromosome to start. That’s because the instability of the chromosome grows with the distance between the two centromeres, a principle first discovered 20 years ago in yeast that Page’s group found holds up in human development.

How commonly do these isodicentric Y chromosomes arise in the first place? Page says it is hard to say, but he suspects it is among the more common genetic causes of spermatogenic failure and male infertility.

This kind of Y chromosome instability may also be a major cause of Turner syndrome, he suggests, a relatively common chromosomal abnormality that affects one in every 2,500 girls. Girls with Turner syndrome are typically “XO,” meaning they lack one of the sex chromosomes, and most had assumed it was the second X — not a Y — that had gone missing.

There were some clues that might not be the case, Page says. For one, unlike other chromosomal abnormalities, the incidence of Turner syndrome does not increase with the mother’s age. In fact, the existing X chromosome comes from mom 75 percent of the time; it is dad’s contribution that is usually lacking. They now propose that, in many cases, the missing paternal sex chromosome was not an X at all, but an unstable isodicentric Y.

In total, their study details 51 patients with an isodicentric Y chromosome, 18 of which are anatomically female, and Page thinks it offers just a first glimpse into the clinical consequences of the chromosome’s palindromic structure.”I suspect this is the tip of the iceberg,” he says.

The researchers include Julian Lange, Howard Hughes Medical Institute, Whitehead Institute, and Massachusetts Institute of Technology, Cambridge, MA; Helen Skaletsky, Howard Hughes Medical Institute, Whitehead Institute, and Massachusetts Institute of Technology, Cambridge, MA; Saskia K.M. van Daalen, University of Amsterdam, the Netherlands; Stephanie L. Embry, Duke University, Durham, NC; Cindy M. Korver, University of Amsterdam, the Netherlands; Laura G. Brown, Howard Hughes Medical Institute, Whitehead Institute, and Massachusetts Institute of Technology, Cambridge, MA; Robert D. Oates, Boston University Medical Center, Boston, MA; Sherman Silber, Infertility Center of St. Louis, St. Luke’s Hospital, St. Louis, MO; Sjoerd Repping, University of Amsterdam, the Netherlands; and David C. Page, Howard Hughes Medical Institute, Whitehead Institute, and Massachusetts Institute of Technology, Cambridge, MA.

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