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Intelligence and the X-chromosome Lancet 1996: 347: 1814-5

Gillian Turner Hunter Genetics, PO Box 84, Waratah, Newcastle, NSW 2298, Australia (Prof Gillian Turner FRCPC)

T-shirts that read: "Xq28-Thanks for the genes, Mom!" were produced in the homosexual community in San Francisco when linkage studies first suggested that the gay gene might be at that location. A T-shirt with a wider application might be one that gives thanks to mothers from their children for her X chromosomes for their major contribution to their intelligence. Intelligence has been defined "as the ability to deal adaptively with the changing environment, to benefit from past experience, to proceed in goal-directed fashion, to pursue productive avenues of problem solving, and to perceive common properties in otherwise separate domains of experience"., The inheritance of intelligence is reported to be multifactorial, with continuing controversy over the importance of the nature-nurture components. Several studies of monozygotic twins reared apart show a correlation in adult intelligence quotient (IQ) values of about 0-7 "indicating that about 70% of the observed variation in IQ....... can be attributed to genetic variation".2 The distribution of IQ scores measuring some aspect of intelligence is bell-shaped, with both sexes having the same mean scores but with wider variability in the male. There are significant differences in scoring between the sexes, with male individuals having better mathematical and musical abilities, and female better verbal abilities. Lehrke" was the first to suggest that the genes for coding intellectual function might be on the X chromosome.

He based his argument on the known excess of males with mental handicap, the different distributions of IQ in male and female individuals, and from a personal study of ten families in which non- specific mental retardation was segregating in an X-linked pattern. This suggestion was regarded as so unorthodox that Lehrke's first published paper was followed by two invited commentaries,51 both of which were highly critical but offered no evidence to refute his conclusions . TIn 1992 with Partington,11 restated Lehrke's hypothesis, suggesting that there was now molecular evidence to support his proposal. Morton 9 gently replied, stating that on theoretical grounds the evidence presented was not strong enough. The epidemiological and molecular evidence has continued to grow such that there is need for reappraisal. At the time of the Lehrke controversy our group was studying the epidemiology of mental handicap in New South Wales. We documented the expected excess of males with moderate handicap as 32%. We also found many more families with two affected sons than two affected daughters, which was supportive evidence that genes on the X chromosome were contributing substantially to the male excess. Herbst and Miller" recorded the same male and brother pair excess in British Colombia, their data including the mildly handicapped. They suggested that there might be nine to 17 single genes on X that were involved with mental handicap. Since then at least 154 entities have been described with mental retardation and X-linked inheritance.11 In some of these, the intellectual handicap is clearly a secondary feature, and one would not suspect that these genes were directly concerned with intelligence. For example, we can reasonably suppose that in X-linked hydrocephalus the mental retardation is secondary to the structural abnormality of the brain and that in the Lesch- Nyhan syndrome it is secondary to the inborn error of purine metabolism. However, there is an increasing number of other conditions in which loss of intelligence (mental retardation or intellectual handicap) is equally clearly the primary or only event. In primary or non-specific X-linked mental retardation (XLMR) affected males have no phenotypical, neurological, or biochemical features in common apart from mental retardation. The prevalence of XLMR is three times that of the fragile X syndrome (2-5 per 10,000 11) in the moderately handicapped and may be even more common in the mildly handicapped. There are now 32 extended pedigrees in which linkage studies have localised the genes to areas on the X chromosome. In many the limits of the locations overlap, but eight discrete localisations have emerged, which define the lowest limit of the number of genes involved. They extend over the short and long arm of the X chromosome. 14 Tne genes themselves are not sequenced and their individual functions are unknown.

Morton's counterargument was that there were a calculated 325 recessively inherited genes associated with mental retardation. Therefore by calculating total DNA content of all the chromosomes the contribution of the X chromosome should be 17 genes. Theoretically there may be 308 genes on the autosomes that contribute to mental retardation. Indeed there are many recessive or dominantly inherited conditions that are associated with mental retardation but no families listed in the McKusick catalogue in which the single and only feature is mental handicap. The total number of genes on X relating to mental handicap is now at least 154 plus these eight locations for XLMR, which greatly exceeds the theoretical 17 suggested from Morton's calculations. The conclusion seems inescapable that the genes now localised in families with XLMR indicate mutations in genes coding for aspects of intelligence. These genes are distributed along the whole length of the X chromosome and, presumably, code for various anatomical or functional parts of the neural substratum of intelligence. The female is a mosaic of two X chromosomes, one of which is methylated and inactivated randomly early in embryogenesis.

Figure: Abridged pedigree of the Wedgwood, Darwin, Galton family tree 15.

The male with his single X chromosome is, therefore, likely to be more affected by either advantageous genes on the X chromosome or by deleterious mutational events, which may explain the difference in distribution of IQ between the sexes. The variation in patterns of ability between the sexes could result from greater diversity in the female, she being mosaic reflecting the functioning of genes on both her X chromosomes. A second approach to identifying genes for intelligence would be through linkage studies in families in which high intelligence is segregating. The classic family is that of Charles Darwin (figure). His grandfather was the founder of Wedgwood Pottery and his cousin, Galton, was a prolific writer and the founder of the Eugenic movement. The pedigree shown in the figure was said, at the beginning of the century, to indicate that genius is a Y- linked dominant, but it could equally well be explained by X linkage. Charles Darwin received Joshua Wedgwood's X chromosome and therefore his intelligence through his mother (II-3), and Erasmus Darwin's brilliance having reappeared in Francis Galton via his mother (II-7), rather than his father. Mary Howard (I-3), was also related to the Galtons. If the genes coding for intelligence have evolved on the X chromosome this has evolutional advantage. The X or Y system is the mechanism in mammals of sex determination. The X is conserved throughout mammalian evolution.16 The more intelligent male would be the better provider and may father more children, allowing for rapid propagation of any advantageous change. In day-to-day practical evolutionary terms for our new millennium the male needs to remember that his primitive urges in mate selection are coded in his genome, and that they target current ideals of sexual attractiveness and youth. His frontal cortex should interpose reminding him that his sons' intelligence, if that is important to him, is solely dependent on his partner, and that is mirrored in both her parents. The female has more freedom of choice-, she may be driven to mate by her partners physique but the brightness of her children lies mainly within her. His daughters are helped by the paternal contribution but it is her potential mother-in-law, not her father-in-law, who needs checking out.

Based on the Oration to Human Genetics Society of Australasia, Brisbane, September, 1995.


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  13. Turner G, Webb T, Wake S, Robinson H. The prevalence of the Fragile X syndrome. Am,J Med Genet (in press).
  14. Gedeon A, Donnelly A, Keer B, Tumer G, Mullev J. How many genes for non-specific mental retardation are there? Am J Med Genet (in press).
  15. Resta R. Genetic drift whispered hints. Am J Med Genet 1995; 59: 131-33.
  16. Ohno S. Sex chromosomes and sex linkage genes. Berlin: Springer Veriag, 1967.

X-linked retardation picks on the Girls New Scientist 30 Aug 97

A SURPRISING role reversal in the male-afflicted world of genetic disease has been uncovered by scientists in the US. They say that a rare form of mental retardation is clearly linked to a faulty gene on the X chromosome but, strangely, the disease only affects women. Until now, diseases caused by faulty genes on the X chromosome, such as haemophilia, have been found almost exclusively in men. This is because men have one X and one Y chromosome in each cell, whereas women have two X chromosomes. If a man's X chromosome carries the haemophilia mutation then, unlike a woman, he lacks a second, normal gene on the other chromosome to compensate. But now Stephen Ryan and his colleagues at the University of Pennsylvania in Pittsburgh say they have found a rare example of role reversal in X-linked defects. The team studied an extended family in the Midwest of the US in which many female members suffer an inherited form of epileptic fits and mental retardation, which the researchers call EFMR. The condition is clearly X-linked, the researchers say in the latest issue of Nature Genetics (vol 17, p 92). Men always pass on their sole X chromosome to their daughters. In the study, if the men had the mutant gene their daughters always developed the illness. Ryan admits that his discovery is hard to explain. He speculates that the faulty EFMR gene might have a normal counterpart on the Y chromosome which compensates for the mutation and protects men from the disease. In women, however, the presence of an EFMR mutation on one X chromosome may somehow shut down the normal EFMR gene on the other X chromosome.

"There's certainly a precedent for this," Ryan told New Scientist. "We know there is a type of messenger RNA molecule called XIST that causes one of the X chromosomes to be inactivated in female cells." He thinks that if the X chromosome containing the normal copy of the EFMR gene is switched off for long enough, mental illness might result. Tissue studies of affected individuals suggest that the EFMR gene codes for a protein involved in nerve cell migration in the developing fetus. In an accompanying article in Nature Genetics, geneticist David Page of the Massachusetts Institute of Technology describes this theory as "intriguing". But there are problems, he says. Principally, the region of the X chromosome where EFMR lies is a long way from the area where the majority of genes common to X and Y chromosomes tend to be. However, the Pennsylvania team says the unmapped region where the EFMR gene lies is close to, possibly within, a block of 4000 base pairs that is common to both X and Y chromosomes. They are currently trying to identify the exact position of the gene. Page says the pattern of illness in this small population could be a rare example of relatively recent genetic changes that evolved to help protect men from X-linked diseases. The fact that the 4000 base-pair clump of DNA on the Y chromosome is absent from the great apes suggests that it duplicated itself and crossed over from the X to the Y chromosome less than 3 million years ago, when hominids diverged from the ancestors of gorillas and chimpanzees. Michael Day