Sex, Dose, and Equality

Abstract

s a rule, genes and chromosomes come in pairs. Sex chromosomes are an exception to this rule. Males of many species have only one X chromosome, a male-specific Y chromosome, and a set of autosomes (AA). Individuals with two X chromosomes and a set of autosomes (XX;AA) are female. Sex chromosomes were first noticed for this distinct unpaired morphology and are now known to have substantially different gene content [1]. These unusual cases have attracted a great deal of attention over the years, not only because of the role they often play in sex determination, but also as windows into more basic features of genes and gene networks. One such feature is the relationship between gene function and dose. Sex chromosomes allow us to question the importance of having a pair of each gene. With current knowledge of gene regulation, one can make an argument that gene dose should not matter. In textbooks and manuscripts, one often finds figures showing the relationship between genes in a pathway or network, replete with elegant feed-back and feed-forward regulatory interactions, parallel pathways, etc. At the transcript level, it seems logical that any inherent 2-fold quantitative difference due to gene dose should be dwarfed, or even nullified, by the high-magnitude changes resulting from transcriptional regulation by proteins that are arrayed at enhancers or silencers. Basic textbook knowledge of genetics also suggests that dose is not very important. Having a single copy of most genes is not deleterious—there are few dominant alleles due to haploinsufficiency. These observations suggest that genes come in pairs to facilitate reproduction, and perhaps to provide a backup in case of spontaneous mutations occurring during the course of somatic development. It seems likely that the dose of most genes is unimportant because of robustness in gene networks, which buffers against noise and mutation [2].Gene regulatory robustness probably makes cells and organisms insensitive to small differences in the dose of components, because such small deviations are also characteristic of more garden-variety noise. However, robustness has limits. Whereas the dose of individual genes does not appear to be very important, altering the doses of many genes is clearly detrimental. Chromosomal rearrangements are associated with many cancers. In some cases, these rearrangements break individual genes, but often there is a duplication or loss resulting in a change in copy number [3]. Monosomy (one rather than two chromosomes) or trisomy (three rather than two chromosomes) occur as a result of errors in meiosis and are highly deleterious during development of the resulting zygote [4]. With the exception of trisomy 21 and the sex chromosomes, altered chromosome dose is generally incompatible with human life. More recently, gene dose polymorphisms have been found to be relatively common in humans [5]. These copy number