Article 1 Your DNA, Decoded
Ten years ago, it cost billions of dollars to map a single human genome. Today, it’s about $20,000 and likely to get even cheaper. If the average consumer can afford to have her own genetic map drawn up, what will it mean for medicine and how we approach our health care?
In early 2008, Henry Louis Gates Jr. stepped off his flight at LaGuardia Airport and began the process of having an elaborate set of blueprints drawn up: the map of himself, his entire human genome.
The Harvard professor of African American studies had at the time just hosted PBS’ successful miniseries, African American Lives 1 & 2. The miniseries, which Gates jokingly calls “Roots in a Test Tube,” traced the genealogical and genetic heritage of prominent figures and celebrities such as Oprah Winfrey, Morgan Freeman, Tina Turner and Chris Rock.
Also on Gates’ flight were officials from the Cambridge, Massachusetts-based genetics company Knome, who told Gates they were interested in working with him on other projects involving DNA testing. Already prompted by the mini-series’ fans to do a show about all Americans, Gates told the Knome representatives that this time he wanted to make a PBS series based on testing the full DNA (or “genome”) of some of his guests.
Every living thing on Earth is built from instruction manuals—an organism’s genes—found inside its cells. The complete set of instruction manuals is called a genome. For humans, the complete set is 6 billion characters long. We all inherit half of our body’s instruction manual (3 billion characters) from our mother and half from our father. When these strands bond together, the connections create units of information called “base-pairs.” Base-pairs can take on one of four values, signified by the names of the molecules from which they’re made: A, C, G or T.
Sequencing a person’s genome means discovering the value of all 3 billion DNA base-pairs—every A, C, G and T—in your body’s instruction manual. It’s the full host of biological blueprints that encodes uniquely who you are.
In 2003, only one human genome had been sequenced in the world, and it cost 50 cents per character. Today, just seven years later, the price has dropped to an astonishing 1/300,000 of a dollar per character. Within two to four years, because of rapidly advancing technology and economies of scale, the price is expected to fall by another factor of 10 or more—bringing the total cost of a full genome down to about $2,000.
The era of affordable genomes hasn’t yet arrived, but it isn’t far off—and mapping personal genomes at the price point of a laptop computer will change the face of medicine and, in a sense, the world.
For his 2009 series Faces of America, Gates traced the genealogical and genetic heritage of guests such as Eva Longoria Parker, Yo-Yo Ma, Meryl Streep, Stephen Colbert, Dr. Mehmet Oz and figure skater Kristi Yamaguchi. And, although Gates wanted to do full genomes of two of his guests, his scientific advisers recommended instead sequencing the genomes of both Gates and his father, 97-year-old Henry Louis Gates Sr. (Scientists hadn’t yet sequenced any African American’s genomes, nor had they sequenced a father-son pair.)
In fact, perhaps the most heart-wrenching moment in Faces of America comes when the program’s genetic experts subtract Gates Sr.’s 3 billion DNA base-pairs from Gates Jr.’s genome. And there, in bold blue and yellow lines, lies the stark genetic outline of the younger Gates’ mother, who died in 1987. “I put my father in this series,” Gates says. “And the big shock is, I got my mother back.” What Gates discovered about his mother was largely symbolic. He, like everyone, carries the blueprint of each of his parents inside his every cell for every moment of his life.
However, Gates also learned a boatload of information about his own life and health. A person’s genome carries crucial information about individual weaknesses to disease, susceptibility to various cancers, the effectiveness and ineffectiveness of various drugs and, ominously, some of a person’s more likely ultimate causes of death.
Human Genome Project
In 2000, President Bill Clinton announced that the government had created the first draft of the entire human genome. Ten years later, scientists still haven’t been able to apply the $3 billion Human Genome Project to curing some of our deadly, elusive diseases.
In May, genomic researcher J. Craig Venter announced that he and his colleagues had created the first synthetic cell. Using chemicals, they recreated the genetic code of a species of bacterium and then transplanted the manufactured genome into a closely related bacterium. Then the synthetic DNA took over.
The genetic counselors Gates hired for Faces of America told him he carried an innate resistance to certain forms of malaria and that caffeine breaks down quickly in his digestive system. So coffee has less effect on him than it does on most people. “For years I hadn’t drunk [coffee] after noontime, being afraid it’d keep me awake,” he says. But emboldened by his genome results, Gates tried drinking a cup of joe one night before bed. “I went right to sleep,” he says.
Other than a variant of sickle cell anemia that makes him more susceptible to a stroke at high altitudes, Gates also learned that no unexpected ticking time bombs awaited him. Thanks to the lack of grave surprises in his DNA, Gates joined a project by his colleague George Church of Harvard Medical School that posts a patient’s entire genome on the Internet (at http://snp.med.harvard.edu) for scientists—and anyone else—to study.
The need for publicly accessible genomes to compare and study became evident in Faces of America. An initial analysis of a single character in one of Gates’ genes suggested he also had an exceptionally good ability to digest dairy products. But Gates is lactose intolerant. “I’m the one with the stomach for 59 years,” he said. “I know I can’t drink milk.”
It was only on a closer examination of Gates’ genome—enabled by more detailed analysis of his own genes and comparisons to other peoples’ genes—that Knome researchers discovered the source of Gates’ difficulty with dairy products. His particular DNA blueprint, they discovered, also makes it hard for him to process a dairy digestive by-product, called galactose. This is why he can drink plenty of coffee, but not with milk.
One of the first full families—mother, father and children—to sequence their genomes was the West family of Cupertino, California. John West, the father, is a former executive of one of the leading genome sequencing companies in the world—Illumina of San Diego. West, his wife, Judy, and children, Anne and Paul, had blood samples drawn late last year and in January received an iMac that contained all 24 billion A’s, C’s, T’s and G’s which represented the whole West family genome.
Although the family is keeping the kids’ genomic results private, 17-year-old Anne has given a public presentation about inheriting a genetic defect from her father that in 2004 resulted in a trip to the emergency room for him. Raced to the hospital with a blood clot in his lung, John West endured a painful and frightening few days staring at his own mortality.
But now he and his daughter know the likely cause of his hospitalization. They also know the diet to follow and medications to take to drastically reduce the chances of anything like this happening to either of them in the future. West says his Illumina genome fortunately revealed no bombshells other than the known “misspelling” in a gene of his called “Factor 5.” Such genetic errors, resulting from single-character transcription mistakes soon after a child is conceived in the womb, are sprinkled throughout everyone’s genome. Most DNA mutations are harmless. But just one well-positioned mistake—imagine a car repair manual containing the typo “plug the fuel line” instead of “plumb the fuel line”—can wreak havoc.
Many will remember Dolly, a Finn Dorset ewe that in 1996 became the first mammal to be successfully cloned from an adult cell. She was cloned at the Roslin Institute in Scotland and lived there until her death in 2003. Before that, however, a tadpole was the first vertebrate to be cloned, in 1952. Since Dolly’s death, many animals have been cloned, including a camel and a water buffalo.
Genetics in Pop Culture
Spitting isn’t au courant at New York Fashion Week, but that’s what notables such as Rupert Murdoch and Ivanka Trump were doing in 2008 at 23 and Me’s genetic testing spit party, hosted by founders Anne Wojcicki (wife of Google co-founder Sergey Brin) and Linda Avey.
Mapping Your Past
The Genographic Project, driven by National Geographic Explorer-in-Residence Dr. Spencer Wells, is “seeking to chart new knowledge about the migratory history of the human species.” If you wish to participate, a $99.95 kit is available to test your DNA and determine your ancestry along your maternal or paternal line.
Ancestry on TV
Two shows on television this spring, Faces of America and Who Do You Think You Are, featured prominent people who went looking for their lineage. NBC’s Who Do You Think used old-fashioned, document-based genealogy, while PBS’ Faces paired genealogy with genetic testing.
Talk about one-of-a-kind art. DNA 11 takes a sample of your DNA and reproduces it in color on a canvas you can hang on your wall. You can even mingle your DNA with your spouse’s, for a truly unique anniversary gift. It’s genetics as home décor.
After years on the road with Black Sabbath and a 40-year “bender,” how has Ozzy Osbourne survived? That’s what DNA research company Knome is going to try to find out by sequencing the 61-year-old’s entire genetic code. The company is reportedly interested in Osbourne because of his “extreme medical history.”
Although genetic testing is still in its infancy, West says there is one way to enjoy access to every genetic test in the world—and every one yet to come. “There are hundreds of genetic tests. And if you were to take every single one of them separately, it’d cost you a fortune and you’d have to pay attention to all these individual pieces,” he says. “The advantage of having your genome sequenced is you’re doing all possible genetic tests all in one shot.”
There are hundreds of genetic tests. And if you were to take every single one of them separately, it’d cost you a fortune and you’d have to pay attention to all these individual pieces. The advantage of having your genome sequenced is you’re doing all possible genetic tests, all in one shot.
Mike Spear, communications director for Genome Alberta, a genetics funding organization in Calgary, Canada, has had small snippets of his genome tested by genetic-test companies deCODE and 23andMe. He learned, for one, that he’s at high risk for early onset Alzheimer’s disease. And he already knew that longevity runs in his family—a grandmother lived to be 101 and his father is still in the work-force at age 85.
“So I’m going to live long, but the last 30 years will be in a corner,” he says. He also says, though, that most genetic test results just weigh the dice a little, so it’s important not to get too carried away.
Spear learned, for instance, that he has twice the risk of baldness compared to the average man. “Your genome is what you are, but there are so many factors involved,” he says. “So I’m at higher risk for baldness, but … I have a full head of hair, and I’m 56. I’m at very low ‘risk’ for asthma, but I have always been an asthmatic.”
Spear says anyone who already tends toward hypochondria or excessive worrying might want to think twice about personal genome sequencing or genetic testing—especially since the marketplace is still so new and people are still only beginning to learn how to interpret the results. “When you get these tests done, you sign a lot of pieces of paper that say you know what you’re walking into,” he says. “They even at one point in your waivers say, in caps, ‘You may find out things you don’t want to know.’”
Knome founder George Church of Harvard Medical School says the U.S. Genetic Information Nondiscrimination Act of 2008 prevents insurance companies from upping their premiums or dropping consumers who discover bad things from genetic testing. However, he adds, the act “doesn’t stop consumers from gaming the system.” If a patient finds out her genome gives her a clean bill of health, she might cut back on insurance coverage—reducing the pool of money insurance companies use to pay for expensive care for sick subscribers. Or if a patient learns he’s at a high risk for something such as Lou Gehrig’s disease, he may preemptively sign up for all the medical coverage money can buy. Such scenarios ultimately aren’t fair to insurance companies, Church says. He suggests that the insurance industry now needs to team up with geneticists to brainstorm ways to work within GINA while still discouraging abuses of the system.
Genetics in Criminology
While it’s common practice now, DNA evidence wasn’t used to convict or exonerate criminal suspects until 1986, when Richard Buckland was exonerated despite having confessed to rape and murder near Leicestershire, England. A year later, the first person was convicted in America on the basis of DNA evidence. According to the Innocence Project, more than 250 people in the U.S. have been exonerated through postconviction DNA testing since 1989.
Victor McElheny, author of the new book Drawing the Map of Life: Inside the Human Genome Project (Basic Books), says some cancer patients today are already having parts of their genome—and sometimes a tumor’s genome—sequenced. “When you do cancer chemotherapy, you’re operating pretty much by guess and by God,” he says. “An awful lot of cancer drugs only help maybe one-third of the people who get them. … You’d like to know what the person’s own genetic predispositions are, so you can start picking the right drug the first time.”
Cancer treatments are the first in a line of predicted “personalized medicine” breakthroughs, in which a person’s genetic information helps doctors tailor the treatment to the patient’s specific body chemistry. One big problem, however, is that well-trained doctors in genetics are still a rare breed today. And patients, more and more, will need good genetic advice.
Matthew Bower, a genetic counselor at the University of Minnesota Medical Center in Minneapolis, says his field is entering an age of data overload. A’s, C’s, G’s and T’s can crowd out useful medical knowledge and counseling as much as it can help bring it on. “There are not enough genetics professionals to be managing everyone’s genome out there,” he says. And without good counseling, he says, people can still make bad decisions.
For instance, Bower says he recently spoke to two journalists who had small parts of their genome sequenced and learned that they didn’t have one particular gene mutation that increases the risk of breast cancer. “They said, At least I don’t have to worry about breast cancer,’” Bower recalls. But breast cancer is caused by both environmental and genetic factors. And its genetic causes alone, he says, could come from dozens or hundreds of possible mutations in a person’s genome.
“People tend to perceive genetic information as black-and-white, all-or-nothing,” he says. “So if they don’t have the Parkinson’s marker, then they’re not going to get Parkinson’s. That’s false. Or if they have the Parkinson’s marker, then they’re going to get Parkinson’s. That’s also false.”
The likelihood for confusion as the personal genome marketplace heats up has recently inspired the federal government to act. In June, the U.S. Food and Drug Administration informed the top consumer genetic-sequencing companies in the country—such as Knome and Illumina—that the agency could soon be regulating the personal genome and consumer genetics marketplace.
Regulation, says Church, could entwine companies in red tape and slow the market down. On the other hand, he adds, it may not hurt much. The FDA’s intervention could actually help the fledgling genome industry: “Reading about this in the news and seeing the FDA seal of approval,” he says, might also lead consumers to want to try out consumer genetic testing.
Grant Campany, senior director of the Archon X-Prize for Genomics, says the FDA’s move itself constitutes a kind of endorsement. “The industry is going through a natural state of evolution,” he says. “It’s in everybody’s best interest that there’s a certain standard or benchmark—what quality really means.” FDA regulation of the marketplace also means that the June 2010 price tag for complete genome sequencing from the top two companies—Knome ($39,500, which includes genetic counseling) and Illumina ($19,500)—may soon be subject to change.
Campany particularly has his eyes on the future of the marketplace, as he’s supervising the privately funded $10 million “X-Prize,” which will be awarded to the first company that can sequence 100 genomes in 10 days or less at no more than $10,000 per genome.
Biotech journalist David Ewing Duncan says it’s still early, but at least a subset of the world is fascinated at the prospect of being the first generation in human history to read their own blueprint. In 2009, he published Experimental Man, a book that traces his sometimes enlightening, sometimes-confounding experiences subjecting himself to genetic tests from companies such as 23andMe and deCODE. (Duncan hasn’t yet had his whole genome sequenced, however.)
His conclusion, in short, is that a lot of genetic and genomic tests are scattershot: A little bit of information here, a little bit there and a lot of confusion elsewhere. Yet the field is progressing at great speed, too. It’s not just looking at individual DNA base-pairs, but also making sense of larger patterns within the genome—discovering, for instance, that one DNA base-pair may suggest that a person is good at digesting milk, but a larger grouping suggests he’s actually, on balance, lactose intolerant.
“We’re a lot closer than I’d have thought. But it’s like a thousand points of light that need to be connected,” he says. “We took apart the human body. Now we have to put it back together.”
Article 2 The Incredible Expanding Adventures of the X Chromosome
Genes housed on the powerhouse x chromosome shed new light on the human mind, including why identical female twins differ more than their male counterparts, why there are more male geniuses and male autists, and why you may have mom to thank for your brains.
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.
Prince Charles would be the least related grandparent to any daughters of prince William and Kate because he confers no sex chromosome to girls.
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.
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.
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.
If you are the son of a highly intelligent mother and there is indeed a major X chromosome contribution to IQ, you’re in luck.
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.
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 intelligenc.
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.
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 pro-social 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 disorder 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.
Female identical twins differ more than their male counterparts, because in each woman one of their two X chromosomes is normally silenced.
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.