A DNA Mystery

Exploring the shadowy role of foreign cells in our bodies—and other genetic puzzles. 

The Incredible Expanding Adventures of the X Chromosome

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In the early 1980s I met and began an unofficial training with Anna Freud—Sigmund Freud's youngest daughter, and his only child to follow him into psychoanalysis. I was a young social scientist who had been carrying out a self-analysis for some years.

Anna Freud's couch was a daybed on which I lay, with her seated in a chair at its head. On one or two occasions I couldn't help but think that the voice I heard coming from her chair was in fact that of her father, speaking to me from beyond the grave.

I can even recall her exact words in one case. I had been free-associating about my attempt to analyze myself when Anna Freud remarked, "In your self-analysis you sank a deep but narrow shaft into your unconscious. Here we clear the whole area, layer by layer." This produced a spine-tingling reaction in me, and I surprised Miss Freud (as I called her) by stating that her remark reminded me of her father, because he was particularly fond of archaeological metaphors in his published writings. Most people would simply attribute her statement to the influence of her father's writing on her own choice of words. Thirty years ago, I would probably have said the same. But today, having spent decades researching the links between genetics and psychology, I can offer a different hypothesis, one that goes to the core of all we now know about the inheritance and expression of genes in the brain.

The Royal X

Everyone inherits 23 chromosomes from each parent, 46 in all, making 23 matched pairs—with one exception. One pair comprises the chromosomes that determine sex. Female mammals get an X chromosome from each parent, but males receive an X from their mother and a Y sex chromosome from their father.

The X chromosome a woman inherits from her mother is, like any other chromosome, a random mix of genes from both of her mother's Xs, and so does not correspond as a whole with either of her mother's X chromosomes. By contrast, the X a woman inherits from her father is his one and only X chromosome, complete and undiluted. This means that a father is twice as closely related to his daughter via his X chromosome genes as is her mother. To put it another way: Any X gene in a mother has a 50/50 chance of being inherited by her daughter, but every X gene in a father is certain to be passed on to a daughter.

These laws of genetic transmission have major implications for family lineages. When it comes to grandparents, women are always most closely X-related to their paternal grandmother and less related to their paternal grandfather. Consider how this plays out in the current British royal family: The late Diana, Princess of Wales, will be more closely related to any daughter born to William and Kate than will Kate's parents, thanks to William's passing on his single X from her. Kate's mother's X genes passed on to a granddaughter, by contrast, will be diluted by those of Kate's father in the X this girl would receive from Kate, meaning that the X-relatedness of the Middletons to any granddaughter would be half that of Princess Diana. Prince Charles, however, would be the least related of all four grandparents to Prince William's daughters because he confers no sex chromosome genes on them.

Of course, if William and Kate produce a son, the situation is reversed, and now Prince Charles is most closely related to his grandson, via his Y chromosome. Princess Diana will have no sex-chromosome relatedness to William and Kate's sons because the X she bequeathed William will not be passed on to the grandsons.

Calculations of X-relatedness may seem abstract, but they have probably played a huge role in European history, thanks to the fact that Queen Victoria passed on hemophilia, an X-chromosome disorder that was in the past fatal to males. Victoria and her female descendants were protected by a second, unaffected X, but princes in several European royal houses—not least the Romanovs—were affected, with disastrous consequences for successions based on male primogeniture.

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The X in Sex

Not only are X chromosomes bequeathed and inherited differently, depending on whether you are male or female, they also have different patterns of expression in the body. For example, in 1875, Darwin described a disorder that appeared in each generation of one family's male members, affecting some but sparing others: "...small and weak incisor teeth ... very little hair on the body ... excessive dryness of the skin .... Though the daughters in the ... family were never affected, they transmit the tendency to their sons; and no case has occurred of a son transmitting it to his sons."

Today we know this to be anhidrotic ectodermal dysplasia (AED), a disorder involving sweat glands, among other things, that affects males and females differently. Because AED is carried on an X chromosome, affected males have no sweat glands whatsoever. They express their one and only X in all their cells. Affected females with the AED gene on only one X have different patterns of expression because areas of their body randomly express one or the other of their two X chromosomes. It is perfectly possible for an affected woman to have one armpit that sweats and one that doesn't.

X chromosome expression can explain not only differences between males and females but also differences between identical female twins. Such twins may routinely differ more than their male counterparts, because in each woman, one of their two X chromosomes is normally silenced. Identical twins result when the cells of the fertilized egg have divided only a few times and the egg then splits into two individuals. The pattern of differential X expression in cells is set at this stage. In females, an X chromosome gene called Xist effectively tosses a coin and decides which of the two X chromosomes will be expressed and which silenced in any particular cell.

Differential X chromosome gene expression explains why one of a pair of living Americans is a successful athlete yet her identical twin sister suffers from Duchenne muscular dystrophy (DMD), an X-linked genetic disease that predominantly affects males and leaves sufferers unable to walk. In this case only one twin was unfortunate enough to inherit the cell lineages that expressed the DMD gene from one parental X chromosome, while the other twin inherited those expressed from the other parent's unaffected X.

A predisposition to sex-linked disorders is just one of the ways female identical twins differ more than males. A recent study found that compared with male twins, female identical twins vary more on measures of social behavior and verbal ability. This is also due to differential expression of genes on their two X chromosomes in contrast to male twins' single, truly identical X. In the past, such differences between identical twins would have been attributed to nongenetic or environmental factors, but now we know that these dissimilarities are in fact the result of gene expression. Where X chromosome genes are concerned, what once seemed to be nurture now turns out to be nature.

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The X Factor in IQ

Another important factor in sex chromosome expression is the huge dissimilarity between the information carried on the X and Y chromosomes. The Y has a mere 100 or so genes, and there is no evidence that any of them are linked to cognition. This contrasts sharply with the 1,200-odd genes on the X chromosome. There is mounting evidence that at least 150 of these genes are linked to intelligence, and there is definite evidence that verbal IQ is X-linked. It suggests that a mother's contribution to intelligence may be more significant than a father's—especially if the child is male, because a male's one and only X chromosome always comes from his mother. And in females, the X chromosome derived from the father is in fact bequeathed directly from the father's mother, simply setting the maternal X-effect back one generation, so to speak.

The fact that males have only a single X, uniquely derived from the mother, has further implications for variations in intelligence. Look at it this way: If you are the son of a highly intelligent mother and if there is indeed a major X chromosome contribution to IQ, you will express your one and only maternal X chromosome without dilution by the second X chromosome that a female would inherit. The effects cut both ways: If you are a male with a damaged IQ-linked gene on your X, you are going to suffer its effects much more obviously than a female, who can express the equivalent, undamaged gene from her second X chromosome. This in itself likely explains why there are more males than females with very high and very low IQs: males' single X chromosome increases variance in IQ, simply because there is not a second, compensatory X chromosome.

The inheritance of intelligence is not limited to the influence of sex-linked genes. Non-sex-chromosome genes can also vary in their pattern of expression depending on which parent they come from (so-called genomic imprinting). One such gene on chromosome 6 (IGF2R) has been found to correlate with high IQ in some studies. The mouse version of this gene is expressed only from the maternal chromosome, and to that extent such genes resemble X chromosome ones in their maternal bias. Although it remains highly controversial to what extent the same is true of the human version of this gene, several syndromes that feature mental retardation are associated with imprinted genes on others of the 22 non-sex chromosomes.

X Expression in Autism

Autism spectrum disorder is yet another phenomenon that can be clarified through the prism of X chromosome inheritance and expression. Researchers have recently begun to suspect that autism is X-linked, in part because more males than females are affected by ASD, particularly at the high-functioning end of the spectrum—Asperger's syndrome—where males outnumber females by at least 10 to 1. Asperger's syndrome impairs prosocial behavior, peer relations, and verbal ability (among other deficits)—the very same traits that vary between identical female as opposed to identical male twins, and all of which are thought to have some linkage to the X chromosome. Because males have only a single X, they could be much more vulnerable to such X-linked deficits than are females, who normally have a second X chromosome to compensate and dilute the effect.

Indeed, women afflicted with autism spectrum disorders may be among the minority of females who disproportionately express one parent's X. Women on the autism spectrum are probably among the 35 percent of women who have a greater than 70:30 skew in their pattern of X expression in favor of one rather than the other parent's X. Indeed, 7 percent of women have more than a 90:10 skew. Such a hugely one-sided expression of one X would closely resemble the single X chromosome found in males. And if X expression peculiarities affect critical genes implicated in autism in the case of these women, Asperger's would result, just as it does in males. Furthermore, the fact that only a small minority of females have such highly skewed X expression could explain why so many more males than females are affected. Most females have more equitable patterns of X expression and are therefore protected by their second X.

The peculiarities of X chromosome gene expression might even explain the often-remarked variability of the symptoms in Asperger's. Classically heritable single-gene disorders like anhidrotic ectodermal dysplasia or Duchenne muscular dystrophy usually have strikingly consistent symptoms because only one gene is affected, often in the same way. But if variable expression of several X-linked genes is the norm in Asperger's syndrome, the outcome in each case might be surprisingly different, and the combined effects highly variable—just as researchers find.

X Marks the Spot in the Brain

What light might this shed on Anna Freud's eerie use of metaphors favored by her father? In her case, the woman who became a psychoanalyst just like her father might have been among the minority of women who disproportionately express one parent's set of X-linked genes in the brain. We saw earlier that anhidrotic ectodermal dysplasia affects only some areas of a woman's skin, depending on where the affected X is expressed. Both the skin and the brain develop from the same layer in the ball of cells (or blastocyst) from which the embryo first forms. We also saw that in females this can result in some cells expressing one parent's X and some expressing the other's, and if this can happen to the skin, then it could also occur in the brain: Some parts might express the father's X and some parts the mother's. Indeed, there is persuasive evidence that this occurs in mice, and circumstantial evidence that it also does in humans.

Given the possibility of an extreme skew in the pattern of X expression, such as likely occurs in women with Asperger's syndrome, we can envisage a situation in which critical parts of a woman's brain are built entirely by one parent's genes. And if that parent is the father, then the same genes that constructed his brain would be expressed in his daughter's brain. Theoretically, a woman could be an X chromosome clone of her father in that each and every X gene he has would be inherited and expressed by her, perhaps in exactly the same regions of the brain. This could result in a daughter's mind being very like her father's—and surprisingly dissimilar to her mother's.

Freud emphasized the importance of the relationship between mothers and sons, but in my experience it pales in comparison to that between many fathers and daughters, who often seem to have a close emotional bond that intensifies with time.

Sigmund Freud's own relationship with his daughter Anna certainly seems a case in point, as I was able to observe firsthand—at least in the daughter at the end of her life. At the time, I felt I was hearing the voice of Freud speaking from beyond the grave. But of course only a person's DNA can survive his or her death, and even then it has to be packaged in a living descendant. So today I am more inclined to think that the words I heard may indeed have been those of Sigmund Freud, but expressed from his daughter's paternal X chromosome.

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The Case Against "Genius" Sperm Banks

If intelligence is X-linked to the degree that some researchers speculate, there are important implications for our views of the heritability of talent—and even genius. The Repository for Germinal Choice was a California sperm bank that operated in the 1980s and 1990s and claimed that its donors reflected a range of Nobel laureates. (In fact the only confirmed Nobel Prize-winning donor was William Shockley, and most donors are now known not to have been laureates at all.) But beyond the actual composition of the sperm bank, there is a fundamental problem with an enterprise founded on the belief that Nobel Prize-winning talent might be heritable from the father, given the likely role of the X chromosome in intelligence.

In the case of a "genius" sperm bank, only half the sperm donated would on average be carrying the Nobel laureate's X chromosome, and any child resulting from such a fertilization would be female, and so would have a second X from the mother to dilute its effect. In the beginning, mothers receiving Nobel laureates' sperm from the Repository for Germinal Choice had to be members of Mensa, and so would have had high IQs to pass on to their offspring of either sex via their X chromosomes. Indeed, this in itself might explain any apparent heritability of Nobel laureate "genius" via the Repository.

The other half of the preserved sperm would have a Y chromosome instead of an X. These sperm assuredly would produce sons, but there is no evidence that the Y is implicated in intelligence. On the contrary, the sole X of sons conceived this way would increase their vulnerability to intellectual impairment in the way that it does for all males, and would also mean that any "genius" seen in them most likely came from their single, undiluted maternal X.

Finally, there is the environmental factor in IQ. Clearly this too would be wholly attributable to the mothers in the case of a sperm bank, because the father provides only his genes.

Ironically then, mothers with children of "genius" sperm-bank fathers were probably laboring under something of a delusion. Any intellectual talent in their children was most likely predominantly attributable to them, both via their X chromosome genes and the home environment they provided. However, the single mothers who nowadays constitute the major clientele for sperm banks may not be too displeased to realize that, where heritability of intelligence is concerned, Mother Nature is something of a feminist.