The somatic cells of multicellular animals are almost exclusively diploid, with haploidy restricted to post-meiotic germ cells. Having two copies of every gene has an obvious advantage. Mutations arise de novo within cells of an organism and within organisms in populations, such that deleterious mutation-free haploid genomes are extremely rare. The wild type alleles of genes tend to be dominant to the recessive loss-of-function alleles, providing a degree of redundancy allowing diploid organisms to survive even with a substantial genetic load of deleterious mutations in each haplotype.
While the dose of most individual genes is of little consequence to the organism, larger scale genomic imbalance, or aneuploidy, is detrimental 
. Chromosomal aneuploidy occurs when whole chromosomes are lost or duplicated and segmental aneuploidy results from deletions, duplications, and unbalanced translocations. In Drosophila
, a systematic genome-wide segmental aneuploidy study 
demonstrated that of all genes (now known to be about 15,000 
), only about 50 are haploinsufficient and just one gene is triplo-lethal. However, these same experiments showed that large deletions and duplications result in reduced viability and fertility that depends on the extent of aneuploidy, and not on any particular region or gene 
. This indicates that the detrimental effect of aneuploidy is a collective function of multiple small effects, not a function of particular genes.
Interestingly, while aneuploidy results in inviability at the organism level, aneuploid cells can out-compete diploid cells for growth in vivo or in vitro. Human cancer cells are a good example of proliferating cells characterized by aneuploidy 
. Most tumors are nearly diploid or tetraploid with extra or lost chromosomes. Even tumors with a normal number of chromosomes contain other rearrangements that result in segmental aneuploidy. It is likely that aneuploidy results in a systems or gene interaction defect. Given that a deleterious effect of aneuploidy is likely to occur at the level of genome balance, understanding the response to aneuploidy requires the exploration of general control mechanisms that operate at the network level.
We have turned to widely used Drosophila
S2 tissue culture cells as an aneuploid model 
. These cells are generally tetraploid 
and studies of gene expression and X chromosome dosage compensation indicate that they are male 
. As a natural consequence of chromosomal sex determination in Drosophila
, females have two X chromosomes and two pairs of autosomes (2X;2A) and males have a single X chromosome (1X;2A) 
. Therefore, male cells can be thought of as naturally occurring chromosomal aneuploids. The response to altered gene dose probably occurs at multiple levels, but transcription is an early step in the flow of information from the genome and is a likely site for control. For example, X chromosome dosage compensation clearly occurs at the transcriptional level 
and is exquisitely precise 
The Male Specific Lethal (MSL) complex regulates the balanced expression of X chromosomes in wild type 1X;2A male flies. MSL is composed of at least four major proteins (Msl1, Msl2, Msl3, and Mof) and two non-coding RNAs (RoX1 and RoX2) 
. Mof is an acetyltransferase responsible for acetylating H4K16 
. Mof is highly enriched on the male X chromosome as a component of the MSL complex. However, Mof also associates with a more limited repertoire of autosomal genes independently of MSL 
. H4K16ac is associated with increased transcription in many systems 
. Therefore, it is widely believed that this acetylation results in increased expression of the X chromosome 
, although an alternative hypothesis suggests that MSL sequesters Mof from the autosomes to drive down autosome expression 
. Determining which of these mechanisms occurs is complicated by the very nature of sampling experiments when much of the transcriptome is altered. The number of X chromosome transcripts sampled from the transcriptome depends on the relative abundance of the X chromosome and autosome transcripts. The salient feature of both models is balanced X chromosome and autosome expression.
While the term dosage compensation is used to describe X chromosome expression, dosage compensation is not restricted to X chromosomes in Drosophila
. Autosomes also show significant, but much less precise, dosage compensation at the expression level 
, suggesting that there is a general dose response genome-wide. Despite the clear role of MSL in X chromosome dosage compensation, the control system rules for MSL function and the contribution of global compensation mechanisms to the specific case of the X chromosome are poorly understood.
There are three basic transcript control mechanisms that could modify the effect of gene dose: buffering, feedback, and feed-forward 
. Here we define buffering as the passive absorption of gene dose perturbations by inherent system properties. For example, if transcription obeys mass-action kinetics and the gene/transcription complex is considered an enzyme 
, then one would not expect a one-to-one relationship between mRNA and gene copy because of the small effect of a change in enzyme concentration at steady-state 
. In addition to the enzymatic properties of transcription, more than a generation of molecular biologists has elegantly described extensive transcriptional regulation networks controlling key phenotypes 
. These regulatory motifs are sensitive to changes in gene dose 
. Feedback is an outstanding error-controlled regulator that detects deviations from the norm and implements corrective action. Feed-forward regulation differs in that it anticipates the possible effect of perturbations on the system rather than correcting the perturbation after the deviation occurs. This could operate if cells detect copy number and correct transcription levels before a quantitative error in transcript abundance is evident.
In male embryos, the sex determination hierarchy detects X chromosome number and leads to association of the MSL complex with the X chromosome before zygotic transcription is activated 
, as expected for a feed-forward regulator. However, MSL is selectively bound to transcribed genes 
, which is also consistent with feedback regulation. By examining the response of X chromosome genes to dose in the presence and absence of MSL, we show that X chromosome dosage compensation results from a combination of MSL-dependent feed-forward regulation based on anticipated effects from unbalanced gene dose and a more general and dynamic response to perceived gene dose. The latter could be due to negative feedback, buffering, or both.