Dosage compensation of the sex chromosomes and autosomes

Abstract

Males are XY and females are XX in most mammalian species. Other species such as birds have a different sex chromosome make-up: ZZ in males and ZW in females. In both types of organisms one of the sex chromosomes, Y or W, has degenerated due to lack of recombination with its respective homolog X or Z. Since autosomes are present in two copies in diploid organisms the heterogametic sex has become a natural "aneuploid" with haploinsufficiency for X- or Z-linked genes. Specific mechanisms have evolved to restore a balance between critical gene products throughout the genome and between males and females. Some of these mechanisms were co-opted from and/or added to compensatory processes that alleviate autosomal aneuploidy. Surprisingly, several modes of dosage compensation have evolved. In this review we will consider the evidence for dosage compensation and the molecular mechanisms implicated.

Keywords: Aneuploidy; Dosage compensation; Sex chromosome evolution; Sex differences; X chromosome.

Figure 1. Types of mechanisms that can modulate dosage responses to imbalance

From top: 1. Copy-number adjustments occur, for example, in the case of multi-copy ribosomal genes or mouse sex-linked genes engaged in a meiotic conflict; 2. Move to a different genomic location occurs in the case of genes lost from the mammalian Y but translocated to the X or to an autosome to preserve function; 3. Increased initiation of transcription can represent a feedback mechanism or a feedforward mechanism, as in mammalian and Drosophila X upregulation; 4. Increased elongation of transcription represents a feedforward mechanism in Drosophila X upregulation; 5. Increased efficiency of splicing have been observed in aneuploid yeast; 6. Increased number of ribosomes on RNA to enhance translation occurs in mammalian X upregulation; 7. Increased RNA stability has been associated with mammalian X upregulation; 8. Adjustment at the protein level, for example, by changing stability has been reported in Drosophila aneuploidy. Note that all types of adjustments can work in reverse to decrease gene/protein products, for example to adjust genome-wide expression in response to a deficiency (inverse effects). The mechanisms included here have been implicated in dosage responses, but this does not exclude other mechanisms known to change gene expression (e.g. miRNA, lncRNA) and protein production. Epigenetic mechanisms including chromatin and nuclear organization associated with enhancement or repression of gene expression are not included in this figure. See text for further details and references.