Fig 1.
Overview of chromosome-wide to gene-by-gene dosage alterations.
Artistic representation of the beneficial and the disadvantageous aspects of gene dosage alterations. Examples of naturally occurring and disease-causing phenomena are shown in the illustration. Such gene dosage alterations can occur from any level, from the chromosome-wide, i.e., mega-base scale, down to the individual gene level, i.e., a single-nucleotide change. Dosage can be modulated by genetic and epigenetic mechanisms.
Fig 2.
(Top left) Sex chromosomes are highly dynamic and show recurrent turnovers illustrated by gray arrows. They typically evolve from a pair of regular autosomes after acquisition of a sex-determining locus. Recombination starts to be repressed and the future Y (in the case of a male heterogametic species) or W (in the case of a female heterogametic species) acquire more and more protein truncating mutations. This process results in gradual functional heterozygosity of the X or Z chromosome (pink). In some organisms, the sex chromosomes then become fully degenerated and are sometimes even entirely lost, but there are also many species, where sex chromosomes do not decay [37]. Despite degeneration, some genes can be retained [41] or even become expanded on the degenerating Y/W [108]. (Top right) Evolutionary tree showing multiple species across the animal and plant kingdom, where DC has been studied. XY and ZW sex chromosome systems are colored in blue and orange, respectively, and the presence of chromosome-wide versus gene by gene/absence of DC are illustrated with black and gray boxes. Pictograms (images: phylopic.org) are only shown for illustrative purposes and do not depict the actual species in the tree; also see references and comments in S1 File. (Bottom) Comparison of the 3 known molecular mechanisms achieving DC by up-regulation of the X in males (Drosophila), inactivation of the X in females (mammals) or dampening of the 2 X by half in hermaphrodites (nematodes) are compared in the table. In Drosophila, both X-to-autosome as well as male-to-female DC is reached. Mammalian females undergo X chromosome inactivation, where besides selection to correct for dosage imbalance, sexual antagonism has been proposed as an alternative mechanism shaping X inactivation during evolution [109]. Whether the remaining, active X and the single male X are globally up-regulated by 2-fold remains ambiguous to date. While transcriptional mechanisms have been broadly investigated [110–112], a recent study comparing different vertebrates suggests that this second level of compensation according to Ohno’s hypothesis is achieved via translational regulation [113]. DC, dosage compensation.
Fig 3.
Molecular consequences upon gene dosage alterations.
If gene dosage alterations reduce gene quantity, insufficient amounts of a protein (blue chain) can be produced (top). If the affected protein is rate limiting, for example, an enzyme, this can lead to fitness defects. Increases and reductions in gene quantity can also result in disrupted stoichiometry (bottom), if the affected protein (blue chain) interacts with other cellular macromolecules (illustrated as a complex consisting of a dimeric subunit A (purple), a dimeric subunit C (yellow) and the affected protein functioning as a bridge subunit B (blue)). This can lead to (a) change in the amount of functional complexes; (b) aggregation of uncomplexed subunits; and (c) overload of the chaperones and proteostasis network. Copy number increases can also lead to the aggregation of the protein products simply by reaching a critical, abnormally high concentration, promoting pathological transitions due to the protein’s physical properties.
Fig 4.
Comparison of genetic compensation and X chromosome DC.
The illustration shows the genetic compensation mechanism, where a premature termination codon in the DNA, produces an RNA, which is exported to the cytoplasm. Upon translation, the premature termination codon-containing transcript is recognized as “faulty” by the NMD pathway and degraded. It is assumed that the degradation products (small RNAs?) can signal back to the corresponding locus in the nucleus, which promotes an increase of Histone H3 Lysine 4 trimethylation (H3K4me3) at the promoter of the (a) unaffected allele; and (b) of gene paralogues that have sequence similarity to the original locus. This can then enhance transcription, which functionally rescues the effects of the original mutation. In Drosophila DC, noncoding RNAs are produced in cis from the hemizygous X chromosome in males. This induces the recruitment of the MSL2 protein of the MSL complex. The MSL complex acetylates Histone H4 Lysine 16 (H4K16ac), which triggers the chromatin decompaction and promotes transcription of expressed genes on the X. DC, dosage compensation; NMD, nonsense mediated decay.