Summary
The implications of having a different chromosome complement in males and females are explored in this chapter, with particular reference to X chromosome genes involved in genetic disorders. The epigenetic mechanism for inactivation of an X chromosome in female cells is discussed. Three examples are given of genes on the X chromosome that illustrate some of the consequences of the XX/XY basis of sex determination. All three of these genes (the DMD, FMR1 and AR genes) also show how different mutations in the same gene can give rise to different phenotypes. The utility of testing for these different conditions and some of the genetic counselling aspects are covered briefly. The technical basics of the methods used to detect these different mutations (and of a method for determining patterns of X-inactivation) are introduced. The final part of the chapter discusses to what extent a genetic viewpoint is useful in clarifying wider questions of gender.
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Notes
- 1.
The remaining Y-specific genes include the SRY gene (sex-determining region of the Y chromosome), which is responsible for the cascade of events leading to development as a male, along with other genes related to male development and fertility. The situation as described above ignores the fact that there is a small region of the X and Y chromosomes that is shared, containing some genes present in two copies in both females and males (the pseudoautosomal region). However, the vast majority of X-specific genes are present in two copies in females and one in males, and most genes on the Y chromosome are present in males only.
- 2.
Aneuploidies, instances of an abnormal number of chromosomes in a cell, involve such huge imbalances in gene activity that those affected with the loss or gain of a whole chromosome don’t usually make it to birth. The main exception, (apart from the special case of the X and Y chromosomes) is trisomy 21 (three copies of chromosome 21), more usually known as Down syndrome. Chromosome 21 is the smallest autosome with the lowest number of genes, but the extra copy still has profound effects. The normal chromosome count (44 autosomes in 22 pairs plus XX or XY) is described as diploid. Cells with only one copy of each autosome plus X or Y (such as sperm or egg cells pre-fertilisation) are described as haploid. Some cancer cells have grossly abnormal chromosome complements, with three or more copies of all chromosomes. Such cells are described as polyploid.
- 3.
This is something of an oversimplification, as among other things some genes on the inactivated X do escape inactivation, but it is essentially the case that any imbalances are avoided by switching off genes where a double dose would be harmful.
- 4.
Women in general have longer life spans and better overall health than men. There will be many factors contributing to this, among which is the possession of two X chromosomes, allowing for the possibility that any damaging mutations in a gene on one X chromosome can be compensated for by a functional copy on the other X. This is an option not available to a male, where any sub-optimal X chromosome genes will be exposed. Although in each individual female cell one X chromosome is inactivated, in the absence of significant skewing, both X chromosomes will be active in different tissues, giving the potential for extra resilience. It may also be the case that for any phenotype determined in part by an X-linked gene or genes, males are more likely to be at extreme ends of the spectrum for that particular feature; given that there will be no mitigation from a second copy of those genes.
- 5.
There is potential for confusion between the dystrophin gene name (DMD, always italicised) and the abbreviation for Duchenne muscular dystrophy (DMD, not italicised).
- 6.
There are several alternative promoters for the DMD gene, producing different versions of the dystrophin protein in different tissues. This is a common pattern for human genes, allowing far more proteins to be produced than might be assumed from the total number of genes.
- 7.
The de novo change will have occurred either in the individual egg which gave rise to her affected son, or at some stage in the development of her germline cells. This is a crucial distinction as in the first instance there would be a negligible risk of having another affected child, whereas if her egg-producing cells contain the mutation on one X chromosome it will be present in half of her eggs, and the chance of a male child being affected is 1 in 2 (and any daughters have a 50% chance of being carriers).
- 8.
Prior to the availability of genome-scale sequencing, finding the position of genes including the DMD gene often depended on very rare events such as chromosomal rearrangements which disrupted genes, causing the clinical phenotype, and the location of the rearrangement by chromosome analysis then helped to localise the gene.
- 9.
Other than the disposability of the Y chromosome, this is the only example where lack of an entire chromosome is compatible with life, reflecting the unique situation with respect to the X chromosome. Turner syndrome causes problems with fertility and some other health issues, but in many cases doesn’t prevent individuals having a relatively normal and healthy life.
- 10.
Cascade testing is a general term referring in genetics to the fact that a diagnosis often has immediate implications for other family members, and diagnostic or carrier testing is then cascaded through the family.
- 11.
Premutations are prone to expansion on transmission, and the likelihood of expansion increases with the size of the repeat, and with the purity of the repeat; typically the CGG repeats are periodically interrupted with the sequence AGG in normal alleles, which has a stabilising effect.
- 12.
A syndrome in the context of genetic disorders meaning a collection of clinical effects that (generally) occur together and are ultimately caused by a mutation in a specific gene or genes.
- 13.
In practice it might be difficult to say in any individual case whether (for example) IQ was reduced by a small percentage compared to what might be expected for that particular individual if they were not heterozygous for an FMR1 full mutation.
- 14.
There are laboratory tests for measuring skewing of X-inactivation (see below in the section on the androgen receptor gene). However, these only reflect the pattern of X-inactivation in the tissue from which the DNA is derived, and are usually carried out on DNA prepared from blood cells. This accessible tissue may not be the best one to test for a condition where gene expression in the brain is of central importance.
- 15.
Genes that only show an effect in one sex due to their role are termed sex-limited. Examples would include genes involved in ovarian development in women, or genes controlling prostate development in men.
- 16.
Height is to a significant extent genetically determined: given adequate nutrition, height is highly heritable. Heritability in this sense has a specific technical meaning, roughly speaking the degree to which genes determine the variation within a population for a given environment.
- 17.
As ever there are exceptions: some individuals with male characteristics have two X chromosomes. This may be due to a rearrangement of the genetic material in these individuals. In these rare cases the SRY gene has been moved to another chromosome, usually the X chromosome, and is therefore present in the absence of a full Y chromosome.
- 18.
On such grounds the social practices of contraception or voluntary celibacy could be judged as unnatural as it is possible to be, although both are widely considered as desirable in the right context.
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Bourn, D. (2022). X-linked Inheritance: A Question of Gender. In: Diagnostic Genetic Testing. Springer, Cham. https://doi.org/10.1007/978-3-030-85510-9_4
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