Sex Chromosome Aneuploidies
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Hover over keys for definitions:Sex chromosome aneuploidies (individuals with abnormal numbers of sex chromosomes) are found not infrequently in the general population and have characteristic deficits of cognitive ability: Individuals with an extra X chromosome (XXY or Klinefelter's syndrome, and XXX syndrome) have delays in the acquisition of language, as also do individuals with XYY syndrome. Individuals who lack an X chromosome (X0 or Turner's syndrome) have deficits in spatial ability. These syndromes thus reflect deviations from the normal sex difference - females have an advantage in verbal ability and males for spatial ability - and yield a clue to its genetic basis.
The facts suggest that there is a genetic determinant of the sexual dimorphism located in a region of XY homology.
The Protocadherin11XY gene pair that was established at the chimpanzee-hominid separation is a candidate to explain a sex difference and possible differences between Homo sapiens and other mammalian species.
Aneuploidies of the sex chromosomes are present in the general population with a frequency of approximately 1 in a 1000 for each syndrome. Often these individuals are unaware of their condition; this may come to light in routine cytogenetic surveys in infancy, or through infertility clinics. Individuals with an extra chromosome (XXY, XXX or XYY) are tall, and individuals who lack an X chromosome (Turner's syndrome) are short, and have other features such as webbed neck and ovarian failure. It has been known for more than 30 years that individuals with Turner's syndrome have particular difficulties with spatial ability. More recently it has been recognised that each of the syndromes with an extra chromosome, whether this is an X or Y, have delays in acquiring language. These relatively specific deficits provide a clue to the nature of the human sex difference in cognition, females having an advantage in verbal ability and males in spatial capacity. Since the aneuploidy deficits are the same in XXY who are male, and XXX individuals who are female, these must be genetic and not hormonal in origin.
The acquisition of words and the ability to represent the outside world in a spatial format are aspects of cognition that arguably are human specific. They are also abilities which most clearly differentiate the sexes. Although with considerable overlap females have an advantage in the acquisition of words and males in tasks involving spatial ability.
As far as is known aneuploidies of the sex chromosome occur in all human populations, probably with the same frequency. If true this suggests that the phenomenon reflects a baseline ' mutation rate ' associated with the mechanism of meiosis.
Given that the X chromosome carries over one thousand genes it is surprising that individuals with such anomalies survive and may reproduce. The reason appears to be that most genes on one X chromosome are subject to ' X inactivation ' in females, that is to say genes are expressed from only one of the two X chromosomes. This can be understood as ' dosage compensation ' between males and females that ensures that genes on the X are expressed to approximately the same extent in either sex. The rule is that one X remains active, and extra X's are inactivated. Why then does the absence or presence of an extra X have any effect? The explanation appears to be that the small class of genes that is present on both X and Y chromosomes is protected from inactivation on the inactive X in females. Again this can be seen as a compensatory mechanism ensuring equivalence of gene dosage in males (XY) and females (XX). But when the number of sex chromosomes is increased above two or decreased to one it is the genes that are present on both the X and the Y that are abnormally expressed. Thus the phenomena of sex chromosome aneuploidy point to the selective involvement of X-Y homologous genes: the features of Klinefelter's and Turner's syndrome etc are attributable to this small class. For example the changes in stature are almost certainly due to the expression of three doses of a growth factor gene located within the pseudo-autosomal (exchange) region in Klinefelter's syndrome and one dose in Turner's syndrome. Where then are the genes responsible for the cognitive deficits? 6 million years ago a 3.5 Mb block on the X chromosome long arm was duplicated onto the Y chromosome short arm. From its timing this must have occurred in Australopithecus and is a candidate for the event that initiated the hominin lineage. Within this block is located the Protocadherin 11 XY gene pair that codes for two closely related cell-surface adhesion molecules expressed in the brain. The two genes have become differentiated in the course of hominid evolution with 16 amino acid substitutions in the Y sequence and five in the X sequence. These therefore are candidates to account for the human sexual dimorphism in cognitive ability and perhaps speciation of the hominin lineage.
In the Descent of Man Darwin expressed the opinion that the mechanism of sexual selection which he had differentiated from the process of natural selection was somehow involved in the origins of Homo sapiens, but he did not specify how. It is generally accepted that sexual dimorphisms are species-specific, that is to say that differences between the sexes separate quite closely related species. Some authors (e.g. Kaneshiro, Carson) hold that sexual selection and speciation are closely related and that speciation is initiated by a change in one sex that is selected by the other. Other workers (e.g. Rice) have pointed out that sexual dimorphisms could well be associated with sex linked genes. There is also a strong case that speciation events are related to the sex chromosomes, particularly the X.
Relatively little is known about the frequency or even the occurrence of sex chromosome aneuploidies in other mammalian species. It may be assumed that the phenomenon reflects an aberration in meiosis, and there is therefore reason to suspect that aneuploidies occur with a similar frequency in other species. What the phenotype is, and whether it is associated with a survival disadvantage, in other species is little-known.
References
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The influence of sex chromosome aneuploidy on brain asymmetry., , Am J Med Genet B Neuropsychiatr Genet, 01/2009, Volume 150B, Issue 1, p.74-85, (2009)
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Accelerated evolution of Protocadherin11X/Y: a candidate gene-pair for cerebral asymmetry and language., , Am J Med Genet B Neuropsychiatr Genet, 09/2006, Volume 141B, Issue 6, p.623-33, (2006)
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The case for an X-Y homologous determinant of cerebral asymmetry, , Cytogenet Cell Genet., Volume 67, Issue 4, p.393-394, (1994)
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Sexual selection, Machiavellian intelligence, and the origins of psychosis., , Lancet, 1993 Sep 4, Volume 342, Issue 8871, p.594-8, (1993)
