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# X and Y, A Wild Pair

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Science  01 Aug 2003:
Vol. 301, Issue 5633, pp. 599-600
DOI: 10.1126/science.1086520

The X in Sex How the X Chromosome Controls Our Lives

by David Bainbridge

Harvard University Press, Cambridge, MA, 2003. 215 pp. $22.95, £15.50. ISBN 0-674-01028-0. Y The Descent of Men by Steve Jones Houghton Mifflin, New York, 2003. 272 pp.$25. ISBN 0-618-13930-3. Little, Brown, London, 2002. 288 pp. £14.99. ISBN 0-316-85615-0.

Occasionally one comes across a book (or two) that engage us immediately in the delicious process of scientific inquiry and understanding. Recent books by David Bainbridge, The X in Sex: How the X Chromosome Controls Our Lives, and Steve Jones, Y: The Descent of Men, are such a pair. Both add fresh perspectives to old issues surrounding human sexual development and, more important, bring clarity and insight to lingering questions. Readers will acquire new respect for the intricacies and vagaries of both the X chromosome and the much smaller Y.

Bainbridge, an anatomist at the University of Cambridge, starts his account with a retrospective on the early history of research on the sex chromosomes. This story begins in Leipzig in 1890, when Hermann Henking detected a lonely chromosome that entered only half the sperm of the insect Pyrrhocoris. He called it “X,” a name that has endured to this day. How exactly this unusual structure contributed to sexual development stayed unresolved until 1905 when Nettie Stevens, at Bryn Mawr College, identified the Y chromosome in her studies of another insect, the mealworm Tenebrio. She correctly deduced the chromosomal basis of sex, namely that being male or female depended upon the presence or absence of the Y. (Strangely, Jones's account of the Y chromosome includes only a very brief mention of Stevens's landmark work.)

The success of Bainbridge's book stems from his clear and interesting descriptions of complex concepts and from his deft enhancement of well-known material with rich scientific nuggets. To the author's credit, he delivers his messages with scientific acumen and good humor. In the chapter “The Duke of Kent's Testicles,” he describes a “cosmic ray” passing through one of the Duke's sperm-producing cells that “neatly punched a hole in the cell's X chromosome.” We are told that “[t]his unusual convergence of monarchy, supernova, and testicle set the scene for the royal genetics for the next century.” Of course, there is no evidence that there actually was a cosmic ray, but it serves as a metaphor for rare and random cellular events with crucial reproductive consequences—in this case the X-linked recessive disorder hemophilia. In fascinating fashion, Bainbridge shows how transmission of that damaged chromosome, within and across royal families and generations, significantly affected the political landscapes of Great Britain, Russia, and Spain.

Some of the questions that Bainbridge answers are rarely addressed sufficiently in other accounts. For example, it is generally believed that women who carry a detrimental recessive allele on one X chromosome are phenotypically indistinguishable from homozygous normals, but this is not always the case. The blood of women who have one defective copy of the gene coding factor VIII (a protein that detects damaged blood vessel walls) clots more slowly than normal; women with one damaged dystrophin gene show elevated creatine kinase levels, a sign of muscle impairment. It is commonly assumed that the X and Y never exchange chromosomal segments, but this is also false. Exchanges occur in a very small area, one that does not include the SRY (sex-determining region of the y) gene. And, contrary to accepted belief, many Turner Syndrome (XO) females show ovarian activity and produce eggs that appear to be normal; it is only after puberty that these eggs disappear. Adult XO women who desire children currently adopt them, but Bainbridge raises the novel possibility that their eggs could be harvested at a young age and preserved for future use.

In another section, Bainbridge discusses how the X chromosome's behavior has resolved a key issue in the controversy over cancer development: does cancer result from uncontrolled replication of a single cell or from replicating tissue patches with common triggers? He explains that cancerous cells in women contain the same inactivated X chromosome, which demonstrates their derivation from a common cell. And a question often asked by my students—do mothers transmit their X-inactivation patterns to their daughters?—receives a satisfactory response: Some female cells, the eggs, are dedicated to X-reactivation, so each new generation is given a “fresh start.”

There are places where this wonderful book could have been improved. In an otherwise excellent discussion of monozygotic female twins who have discordant X-inactivation patterns and, consequently, discordant X-linked traits, Bainbridge fails to mention the links between timing of zygotic splitting and similarity in X-inactivation (1). Elsewhere, he overlooks research on associations among maternal personality, testosterone, and sex of infant—work that challenges the assumption that the male parent is the sole determiner of infant sex (2). He also omits any discussion of the exciting, albeit controversial, twin research that suggests a relation between acquired skewing of X-inactivation in peripheral blood cells and sex differences in aging (3). One other concern is that the absence of footnotes makes it difficult to identify the original sources of the findings discussed in the text. However, the glossary and the list of chapter references and suggestions for further reading are helpful additions. On balance, The X in Sex provides a remarkable read for anyone eager to learn more about the intriguing X chromosome.

For discussion of the other mammalian sex chromosome, Steve Jones's book enters the scientific scene at exactly the right time. It was recently reported that the survival of the Y chromosome depends on a process that allows recombination within the chromosome (4). The tiny chromosome includes eight long palindrome regions, each of which comprises two highly symmetrical DNA sequences separated by a unique spacer. Dips and tricks by the chromosomes' two arms allow the exchange and reshuffling of genes. The further discovery that the Y chromosome contains 78 active genes undermines previous conceptions that it is a mere repository of genetic junk. That this work is not cited by Jones is understandable, because it only appeared after the publication of his book. But the study suggests that his dismal view of the Y chromosome as “the most decayed, redundant, and parasitic of the lot” might require some revision.

Y is rich with stirring facts that inform and entertain, delivered with equal doses of perspicacity and entertainment. Jones, a professor of genetics at University College, London, successfully develops his central themes, in particular that being male is far more complex than has been realized and that “man, and not woman, is the second sex.” (However, his choice of value-laden terms, “first” and “second sex,” may pique some readers, as might a reference to crime as “a hobby of half the population.”) He argues his thesis with reference to a compelling array of facts, anecdotes, and speculations. We learn, for example, that genes older than the SRY gene (a trigger of testicular development in mammals) “rule the world of maleness.” One in several thousand children is born with a mix of testicles and ovaries, and most such children are XX. Jones poses the puzzle of how embryonic humans who lack a Y can grow a testis, usually on the right side. He finds the answer in the developmental asymmetry of hermaphrodites, which is caused by early accelerated growth of the embryo's right half, growth triggered by these more ancient genes. Jones also challenges the notion that older mothers, not fathers, are mostly responsible for producing children with genetic defects. He notes that many sperm fail to mature or are abnormal in some way. Furthermore, DNA in each sperm undergo multiple replication cycles, which leads to more errors in male than female gametes. In fact, for some conditions (for example, the common form of dwarfism) children of older fathers are at twenty times the risk as children of younger fathers.

In a particularly strong chapter, “James James's Skull,” Jones provides many striking examples of how the Y chromosome can be used to track family lineages, population migrations, and genetic mutations. The details of these cases support his conclusion that “genes say more than anything in the records.”

On occasion, the vast collection of facts Jones presents in Y reads more like a laundry list than the coherent compendium of scientific examples he intended. We learn that men and hamsters produce the same number of sperm; that because of a support bone in the penis, weasels more easily enjoy extended sexual contact than humans; and that males anticipating sex experience hair growth. Such information is fascinating, but the sheer number of items detracts somewhat from the bigger, more important picture the author tries to develop. Had he used a smaller number of well-chosen examples to support his thesis, his arguments would have been more effective.

It is unfortunate that Jones did not give more consideration to research on opposite-sex twins that explores the effects of prenatal hormones and behavior. Animal models that show masculinization of female mice and rats situated between male fetuses in utero have prompted a series of studies attempting to uncover human parallels. The findings have been suggestive, but—with a few exceptions, such as the reduced frequency of otoacoustic emissions (low level sounds produced in the cochlea) in females with male co-twins (5)—inconclusive, due to confounding of biological and psychosocial factors (6). Nor does Jones discuss the informative case of male monozygotic twin infants, one of whom suffered penile ablation due to a surgical accident. Despite intense social pressure supplemented by hormonal treatments, efforts to rear the child as a girl proved unsuccessful, and the child reclaimed his male status during his teenage years (7). This tragic case uniquely illustrates the effects of the SRY gene and its sequelae in male sexual development and identity. Lastly, like its fraternal tome, Y lacks footnotes to the text material and instead offers only a chapter-by-chapter list of reference sources at the back of the book.

These concerns aside, I found that Y clearly informs and excites the scientific imagination. Jones ends optimistically by noting that males' choices over what to do about their current circumstances are unrelated to their biology, which leaves social remedies as their best option.

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