Dosage compensation

Dosage Compensation is the equalization of gene expression between the males and females of a species. Because sex chromosomes contain different numbers of genes, different species of organisms have developed different mechanisms to cope with this inequality. Replicating the actual gene is impossible; thus organisms instead equalize the expression from each gene. In humans, the females (XX) silence the transcription of one X chromosome of each pair, and transcribe all information from the other, expressed X chromosome. Thus, human females have the same number of expressed X-linked genes as do human males (XY), both genders having essentially one X chromosome per cell, from which to transcribe and express genes.

XX/XY System

Several different dosage compensation methods are included in the XX/XY sex system. In the mammalian version, the females (XX) silence their extra X chromosome so gene expression matches that of the males (XY). In Drosophila flies, the males (XY) double the expression from their single X chromosome to match that of the females (XX).

In the mammalian XX/XY sex system, the X chromosome has more genetic information than the Y chromosome, and organisms have two (known) approaches to rectifying this. In humans, the females silence their extra X chromosome into inactive Barr bodies using the X-ist gene. This condenses almost all of the genetic material into untranscribable heterochromatin, leaving only pseudoautosomal portions free. These portions are similar to portions on the Y chromosome and allow division in meiosis.

In Drosophila flies, the opposite occurs. Instead of the females silencing their extra X chromosomes, the males double the expression from their X chromosomes. Several binding sites exist on the Drosophila X chromosome for the dosage compensation complex (DCC), a ribonucleoprotein complex; these binding sites have varying levels of affinity, presumably for varying expression of specific genes. The Male Specific Lethal complex, composed of protein and RNA binds and selectively modifies hundreds of X-linked genes, increasing their transcription to levels comparable to female D. melanogaster. This over-expression on the sole male X chromosome is particularly remarkable, as it has yet to be observed in another species.

In addition to humans and flies, some plants also make use of the XX/XY dosage compensation systems. Silene latifolia plants are also either male (XY) or female (XX), with the Y chromosome being smaller, with fewer genes expressed, than the X chromosome. Two separate studies have shown male S. latifolia expression of X-linked genes to be about 70% of the expression in females. If the S. latifolia did not practice dosage compensation, the expected level of X-linked gene expression in males would be 50% that of females, thus the plant practices some degree of dosage compensation but, because male expression is not 100% that of females, it has been suggested that S. latiforia and its dosage compensation system is still evolving. Additionally, in plant species that lack dimorphic sex chromosomes, dosage compensation can occur when aberrant meiotic events or mutations result in either aneuploidy or polyploidy. Genes on the affected chromosome may be upregulated or down-regulated to compensate for the change in the normal number of chromosomes present.

Monotremes

Platypus, a type of monotreme

Monotreme is an order of mammals that includes platypuses and four species of echidna, all of which are egg-laying mammals. While monotremes use an XX/XY system, unlike other mammals, monotremes have more than two sex chromosomes. The male short-beaked echidna, for example, has nine sex chromosomes—5 Xs and 4 Ys, and the male platypus has 5 Xs and 5 Ys. A recent study revealed that four platypus X chromosomes, as well as a Y chromosome, are homologous to some regions on the avian Z chromosome. Specifically, platypus X1 shares homology with the chicken Z chromosome, and both share homology with the human chromosome 9. This homology is important when considering the mechanism of dosage compensation in monotremes. In 50% of female platypus cells, only one of the alleles on these X chromosomes is expressed while in the remaining 50% multiple alleles are expressed. This, combined with the portions that are homologous to chicken Z and human 9 chromosomes imply that this level of incomplete silencing may be the ancestral form of dosage compensation.

ZZ/ZW System

The ZZ/ZW sex system is used by most birds, as well as some reptiles and insects. In this system the Z is the larger chromosome so the males (ZZ) must silence some genetic material to compensate for the female’s (ZW) smaller W chromosome. Instead of silencing the entire chromosome as humans do, male chickens (the model ZZ organism) seem to engage in selective Z silencing, in which they silence only certain genes on the extra Z chromosome. Thus, male chickens express an average of 1.4-1.6 of the Z chromosome DNA expressed by female chickens. The Z chromosome expression of male zebra finches and chickens is higher than the autosomal expression rates, whereas X chromosome expression in female humans is equal to autosomal expression rates, illustrating clearly that both male chickens and male zebra finches practice incomplete silencing. Few other ZZ/ZW Systems have been analyzed as thoroughly as the chicken; however a recent study on silkworms revealed similar levels of unequal compensation across male Z chromosomes. Z-specific genes were over-expressed in males when compared to females, and a few genes had equal expression in both male and female Z chromosomes.

In chickens, most of the dosage compensated genes exist on the Zp, or short, arm of the chromosome while the non-compensated genes are on the Zq, or long, arm of the chromosome. The compensated (silenced) genes on Zp resemble a region on the primitive platypus sex chromosome, suggesting an ancestor to the XX/XY system

Epigenetic Mechanisms of Dosage Compensation in Chickens

While the epigenetic mechanisms behind dosage compensation in birds are poorly understood, especially in comparison to the well-studied mechanisms of dosage compensation in humans and drosophila, several recent studies have revealed promising sequences. One example is MHM (male hypermethylated) RNA, an Xist-like long noncoding RNA that is expressed only in female chickens (ZW). It is associated with female-specific hyper-acetylation of lysine 16 on histone 4 near the MHM locus on the Z chromosome. This MHM locus is heavily studied as a site of dosage compensation because male Z chromosomes are hypermethylated and thus underexpress genes in this area in comparison to female Z chromosomes which are hyperacetylated and overexpress these genes. There has been debate on whether the MHM locus constitutes dosage compensation, however, since scientists claim that even if the MHM locus has been found to have significantly greater expression in females than in males, it could not even be considered to be a dosage compensation mechanism since it does not balance gene dose between the Z chromosome and autosomes in the heterogametic sex.

Similar to mammals, chickens seem to use CpG islands (segments of Cytosine-phosphate-Guanine that are more readily methylated and silenced than other DNA segments) to regulate gene expression. One study found that CpG islands were found primarily in compensated areas of the Z chromosome—areas that are differentially expressed in male and female chickens. Thus it is likely that these CpG islands are locations where genes on the male Z chromosome are methylated and silenced, but which stay functional on the female Z chromosome.

See also

• 2R hypothesis
• Barr body
• Gene dosage
• X-inactivation
• Tsix
• XY sex-determination system
• epigenetics

Further reading

• Casci, T. Dosage compensation: What dosage compensation? Nature Reviews Genetics (2011).
• Orr, H.A. (1990). The American Naturalist. 136(6):759-770.
• Mable, B.K. (2004). Biological Journal of the Linnean Society. 82:453-466.de:Gonosom#Dosiskompensation