"The female geneticist points out that living without a Y chromosome is not a problem (46, XX = normal female; 45,X = Turner Syndrome), whereas living without an X chromosome is impossible, given that 45,Y is lethal. In reply, the male geneticist argues that though one can have multiple X chromosomes, one single (tiny) Y chromosome is powerful enough to determine male sex (e.g. 47, XXY = Klinefelter Syndrome)."

This is just a joke about the role of human sex chromosomes. However, in the past this joke reminded scientists that the molecular basis for this phenomenon had not been elucidated. Things have changed this month. In a June issue of Nature, Page´s group at the Massachusetts Institute of Technology published the entire genetic sequence of the human Y chromosome.¹

Wasn´t the genetic sequencing of the entire human genome already completed earlier? Why not the entire Y chromosome? The male specific region of the Y chromosome (MSY) is a mosaic of complex and interrelated sequences that made this one of the most problematic regions of the human genome to be successfully sequenced and assembled. However, now the human Y chromosome is the first to be sequenced in any detail, which represents "... a celebratory tale of a successful sequencing journey ..."

The male-defining chromosome was previously thought of as a wasteland where genes go to die. However, these reports of the demise of the Y chromosome and an impending extinction of men may have been exaggerated. The Y's full genome sequence reveals that we have underestimated its powers of self-preservation. Instead of doubling up to protect its genetic cargo like other chromosomes, an international consortium has found that the lone Y safeguards its genes by having sex with itself.

But what conclusions can be drawn from this new information; what are the implications for the future? First, the Y chromosome was always of special interest for basic researchers. Crossing-over is a process of pairing and exchanging of genetic material between the chromatids of synapsed homologues during meiosis. This reflects a most important mechanism to repair mutations and to preserve genes during evolution. Since the Y chromosome has no pairing partner, it was assumed that Y chromosome-specific genes slowly disappear over time. The Y chromosome sequence published by Page´s team reveals that the Y chromosome has a mechanism to correct itself. Portions of genes lie in complex repetitive regions of the Y chromosome that are mirror images of each other. This unique structure enables the genes to pair and repair each other. The underlying molecular mechanism is called gene conversion. Gene conversion is related to crossing-over and has formerly been speculated to be involved in somatic hypermutation to introduce single-base changes in the re-arranged variable regions, resulting in the production of immunoglobulin molecules with dramatically increased affinity for antigen. The Y chromosome sequencing solves the issue of repair and preservation of genes on this sex chromosome, and provides evidence that gene conversion in general may be more common than previously suspected.

Furthermore, it now can be concluded that the Y chromosome harbors more genes than always assumed in the past. Evidence is provided that about 78 genes (instead of earlier calculations of about 40 genes) are located on the Y chromosome. Although it's widely known that one cause of male infertility can be deletions of specific genetic regions on the Y chromosome, the molecular role of the corresponding genes has not been elucidated. There is no doubt that research on male infertility of genetic origin will be facilitated now the sequence has been published.

While men and women may be quite different, their sex chromosomes have some remarkable similarities. Between 10% and 15% of the genetic material on the Y chromosome comes from the X chromosome, the new study shows. These regions are 99% identical to their original sequence. The meaning of the similarity isn't clear. The higher number of genes on the Y chromosome also raises the possibility that other important differences between males and females might be due to genes on the Y chromosome, which women do not have. For example, the known differences between males and females in susceptibility to certain diseases might be co-regulated through such genes. A lot of work will be initiated by these new data.

And, last but not least, a revival of old questions can be predicted. What's the contribution of genes for gender differences, and what's the contribution of environment or upbringing? What are the regulators of sexual identity? Are there genetic determinants for the style of one's behavior, for sexual orientation, or for the deep-seated inner feeling one has that she/he is female or male? Is there any genetic determination, no genetic determination, or is it multifactorial? At the moment it remains an open question whether the identification and characterization of one of these new male-specific genes on the Y chromosome will provide an answer to any or all these questions.

The new findings and their questions add to the report and recommendations from the Committee on Understanding the Biology of Sex and Gender Differences (Wizemann & Pardue, 2001). Among other very important recommendations to promote research on sex at the cellular level, the committee recommended that research be conducted to:

• determine the functions and effects of X-chromosome- and Y-chromosome-linked genes in somatic cells as well as germ-line cells;
• determine how genetic sex differences influence other levels of biological organization (cell, organ, organ system, organism), including susceptibility to disease;
• develop systems that can identify and distinguish between the effects of genes and the effects of hormones.

Furthermore, to monitor sex differences and similarities for all human diseases that affect both sexes, investigators should:

• consider sex as a biological variable in all biomedical and health-relates research,
• design studies that will:
    * control for exposure, susceptibility, metabolism, physiology (cycles), and immune response variables;
    * consider how ethical concerns (e.g., risk of fetal injury) constrain study designs and affect outcomes;
    * detect sex differences across the life span.

Understanding the sex differences at all levels makes it possible to design health care more effectively for individuals, both males and females! As we've already said, a lot of work will be initiated by this new publication.