Editorial Comment

The Other Side of the Coin: A Hypothesis Concerningthe Importance of Genes for High Intelligence andEvolution of the X Chromosome

Herbert A. Lubs1,2*1University of Miami, Miami, Florida2Department of Medical Genetics, University Hospital of Tromsoe, Tromsoe, Norway

The observation that there are more males than fe-males at the lower end of the IQ distribution has beenconfirmed many times and is generally accepted. Be-cause the mean IQ of males and females is the same,there should be a concomitant increase in the numberof males at the higher end of the IQ distribution. This,in fact, has been observed and reported many times inthe literature over the last 50 years. In 1945, FraserRoberts reviewed data from two relatively unbiasedstudies of IQs in British children, both showing greatervariability in males but no difference in mean IQ. Us-ing the smaller, more conservative variance (13%), hepresented tables showing the relative number of boys/100 girls in the extreme percentiles. For both the clev-erest and dullest 1%, there were 144 boys per 100 girls.For the cleverest or dullest 0.1%, there were 186 boysper 100 girls.

Although conveniently ignored for most of the last 50years, the published evidence of greater male variabil-ity in intelligence and related tests at both ends of thespectrum is very strong, as shown by a recent review[Hedges and Nowell, 1995] of a series of related tests.They performed secondary analyses of six data sets col-lected over 20 years on large, national samples of U.S.children. Among the 32 tests for reading comprehen-sion, vocabulary, mathematics, perceptual speed, sci-ence, social studies, nonverbal reasoning, associativememory, and spatial ability, the variance was greaterin males in 30. However, in no test were males morevariable in both the high and low end of the distribu-tion, and the direction usually followed a small (10%)but significant difference in means. When there was ahigher mean in males, there were more males in theupper percentiles and vice versa. Males were better atmathematics, science, and spatial ability and worse atperceptual speed, associative memory, and readingcomprehension, but clearly were more variable. Theseresults are very similar to those reported by Wechslerin 1958 in a chapter on sex differences in intelligence.Among the 11 subtests, males were better in four, fe-

males were better in two, and there was little differ-ence in five. Therefore, the similar means in males andfemales are, in part, a result of the selection of tests inwhich males do better in some and females do better inothers. It could be done differently and, indeed, Wexler,in the same chapter, also sorted the tests to show pro-files of maleness and femaleness. However, it neverbecame popular. He did not comment on the small ex-cesses in male variances, but these were largely in thedirection of being greater in males. The conclusionsremain the same. Males are better at some things,worse at others, but more variable.

These results, which indicate that the overall male orfemale distribution is shifted upwards or downwardsfor a particular cognitive function, are much more eas-ily explained by testosterone (or estrogen) effects onmales in general, rather than the effects of rare geneticvariations that would affect only a few. However, thepossibility remains that variation in some specificabilities could result from a series of relatively commonalleles affecting performance. Even a three-allele sys-tem, when smoothed by environmental, developmental,and testing variations, could result in an apparentlynormal distribution. It is possible to detect such allelesand test this idea, as discussed below.

The X chromosome was interjected into this argu-ment by Lehrke in his Ph.D. thesis [1975]. His thesisthat there were genes on the X chromosome that influ-enced intelligence was greeted very skeptically by in-vestigators rebutting this idea largely on the basis oflack of evidence. Only a few poorly described familieswith X-linked mental retardation (XLMR) were knownthen. The fragile X, which had been reported in 1969,was ignored in these debates probably because its sig-nificance was not yet clear. Times change quickly, andthe latest review of X-linked mental retardation syn-dromes found 121 disorders and 58 families with non-specific XLMR with localized genes [Lubs et al., 1998],an increase of 34 localizations in 2 years [Lubs et al.,1996]. There is no longer any doubt that there aremany genes on the X chromosome that affect brain de-velopment and intelligence at least at the lower end ofthe distribution.

Are there more genes on the X chromosome affectingintelligence? This possibility was raised by Partingtonand Turner [1991] and again in by Turner in 1996. Thisis a seductive possibility, based on the findings dis-

Contract grant sponsor: NICHD; Contract grant number: R01HD26202-07.

*Correspondence to: H. A. Lubs, M.D., P.O. Box 016820, Miami,FL 33101. E-mail: hlubs@peds.med.miami.edu

Received 22 August 1997; Accepted 7 December 1998

American Journal of Medical Genetics 85:206–208 (1999)

© 1999 Wiley-Liss, Inc.

cussed in the previous paragraph. Despite the increas-ing number of pertinent X-linked genes, the rebuttalsto Turner’s initial proposal [Morton et al., 1992] remaincorrect. The counts of XLMR disorders are very biasedobservations because of the greater ease in recognizingX-linked mental retardation than autosomal recessiveretardation, particularly nonspecific retardation. Thisidea remains an attention getter not a factually basedanswer. The data are insufficient to accept or refute theidea, and extrapolations from OMIM [1995] comparingbrain related localizations are not appropriate. Turneralso raised the possibility in 1996 that genes for(higher) intelligence might also be on the X chromo-some and might have played a major role in the evolu-tion of the Homosapiens’ brain and intelligence. Again,the argument was thought to have no basis in fact[Morton et al., 1992] because there was no evidence ofallelic variation resulting in higher intelligence.

Why rework these issues now? The techniques anddata are in hand, or soon will be, to answer these ques-tions, and they are important and vital questions. Thegeneral idea that genes affecting brain developmentand function may have been retained on the X chromo-some through mammalian evolution could be studiedby comparing the number of X-linked EST’s expressedin brain tissue relative to all (or specific) autosomalEST’s in several species. The first and most criticalanswer to these questions will follow from the HumanGenome Project. We have only to ask the questionproperly when the job is done or even nearly done. Thehuman X chromosome is scheduled for complete se-quencing in less than 2 years. If there is no concentra-tion of brain-expressed sequences in X chromosomeEST’s, the question is answered. If there is, then manyintriguing questions can be asked and discussed withrespect to mammalian evolution.

Alleles of X-linked genes resulting in high intelli-gence or high function of specific intellectual processesmay exist. Because any allele of such an X chromosomegene that undergoes lyonization would have a greatereffect on intelligence in males, it would likely have sig-nificant survival and possibly reproductive value inmales. Because the effect(s) would be transmitted in anX-linked fashion, part of this hypothesis could be testedby studying the transmission of high IQ scores or, bet-ter, high subtest scores by segregation and linkageanalysis. Selection of pedigrees for study that werelarge and have several appropriate males with ex-tremely high scores on subtests known to have higherscores and to be more variant in males would seem areasonable approach.

The problem is simply that they have not been lookedfor. The mindset of cognitive and behavior scientists isdifferent from that of clinical geneticists, who scour theworld for a family with XLMR or an XLMR syndrome.Many of the known 121 XLMR disorders consist of areport of a single family, but each is neverthelesshighly informative. Behavior scientists need to adoptthis approach and work with the clinical geneticists.One could think of testing the better students in agraduate school of architecture for their aptitude inspatial visualization (something males excel at), ob-taining family histories on those with outstanding

scores, and asking for their family participation in test-ing for spatial aptitude and a linkage analysis using25-30 X markers just as is done by the clinical geneti-cists for XLMR. If such alleles exist, a clever and per-sistent group of investigators would likely identifythem. Such a study should be designed by a person whothinks like a clinical investigator and who searches forextremes. Any gene on the X chromosome or a numberof genes affecting intelligence positively would be acandidate for study.

Testing could also be approached on a population ba-sis if an appropriate gene with sufficient qualitative orquantitative molecular variation was known and avail-able for testing. The triplet repeat diseases come tomind, but in this case one would test the opposite hy-pothesis that fewer repeats might result in higher in-telligence or related intellectual function. The samplewould have to be carefully planned and constructed sothat sufficient numbers of individuals with a low num-ber of repeats were included. The usual randomly se-lected sample would not likely be productive becausethere would be only a few individuals with a low num-ber of repeats. The FMR1 gene is one reasonable “can-didate gene” for such an effect, particularly in view ofits long evolutionary history, its quantitative effect onFMR1 protein, and the recent studies by Brazelton etal. [1997]. These have demonstrated the important rolethat FMR1 protein plays in both the fine developmentof the central nervous system at the synapse and den-drite level and its probable equally critical role in syn-aptic function. The one reported study, which ad-dressed the relationship of repeat number and IQ inmales [Daniels, 1994], did not find a relationship be-tween high IQ and low repeat number, but the numberof males with a low repeat number among the 32 maleswith high IQ was not specified and could not have beenlarge.

The sexual dimorphisms in specific cognitive func-tions may have been important in our evolution andmay have been selected for. Because of these dimor-phisms, the species may have had a greater variety ofabilities and, therefore, been more adaptable and morecompetent for survival. Whatever their etiology, thesedimorphisms, in themselves, may have been critical inour rapid evolution, and it is possible that the X chro-mosome has also played a significant role in evolutionthrough this mechanism.

ACKNOWLEDGMENT

Research supported by the National Institute ofChild Health and Human Development (NICHD)Grant R01 HD26202-07.

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