Dosage compensation of the sex chromosomes and autosomes
Introduction
The adaptive advantages of recombination favor sexual reproduction [1], which is often accompanied by differentiation of sex chromosomes. In mammals, males are XY and females XX, while in birds, males are ZZ and females ZW. These systems evolved because sex is genetically determined [2], [3]. Other vertebrates such as reptiles rely on temperature-sensitive systems for sex determination. Muller hypothesized that differentiation of the sex chromosomes would inevitably arise from lack of recombination due to the appearance of a sex-determining gene on the Y or W chromosome [4]. Ohno expanded these ideas by proposing the concept of ancestral sex chromosomes (proto-sex chromosomes) that progressively evolved to the present-day sex chromosomes by degeneration of the Y or W. [5].
Sex chromosomes have evolved independently multiple times: for example, mammalian and avian sex chromosomes derive from different ancestral autosomes. It has been proposed that some chromosomes may be better suited to become sex chromosomes based on their gene content [3], [6]. Both Muller and Ohno predicted that sex chromosome divergence would lead to dosage compensation of the natural type of aneuploidy caused by degeneration of one chromosome in the heterogametic sex. Indeed, a variety of dosage compensation mechanisms that regulate the sex chromosomes have evolved, resulting in a dazzling array of systems throughout the plant and animal kingdoms. The evolution of vertebrate sex chromosomes and of dosage compensation were recently comprehensively reviewed by us and by others [3], [7], [8], [9]. In addition, X chromosome inactivation, one of the main form of X regulation in mammals is discussed in detail by others in this issue.
Here, we summarize salient features of dosage compensation of sex-linked and autosomal genes with a focus on molecular mechanisms of dosage regulation. Two major types of sex chromosome dosage compensation, often confounded in the literature, can be recognized; one type balances gene expression throughout the genome by changing the relative expression of X-linked or Z-linked genes versus autosomal genes or vice versa, and the other equalizes sex-linked gene expression between homogametic and heterogametic sexes. The former type of dosage regulation is critical to maintain fitness. Finally, a narrower definition of dosage compensation has been proposed as representing evolutionary adaptive changes in expression of ancestral autosomal genes that evolved into sex-linked genes [10]. Such definition is necessarily based on a restricted number of conserved genes in different species.
Dosage regulation of the sex chromosomes can be viewed as either global, i.e. employing mechanisms that modify most – but not all – genes on an entire chromosome, or local, i.e. acting on individual genes. This distinction is somewhat fluid as the number of dosage-compensated genes on a given sex chromosome varies between tissues, and also depends on methods of analysis. Intuitively, not all genes need to be regulated by either type of dosage compensation mentioned above. Indeed, balanced expression throughout the genome may be critical only for dosage-sensitive genes implicated in protein complexes and functional networks, but may not apply to dosage-insensitive genes unless they are swept in a global regulatory system. Deleterious effects of copy-number changes may be subtle at the individual gene level, but cumulative effects of large chromosomal imbalance are often severe and yet to be fully understood. Conversely, patchy dosage compensation may be advantageous and selected for in terms of sex-specific traits important in male/female conflicts. This is particularly relevant for testis- or ovary-specific genes abundant on the sex chromosomes.
Section snippets
Evolutionary differentiation of the sex chromosomes
Dosage compensation of sex-linked genes should be considered in light of sex chromosome evolution. One of the best studied systems in which progressive evolutionary steps have been deciphered is represented by the human sex chromosomes that have evolved for about 300 million years [11], [12], [13], [14]. Based on DNA sequence analyses of genes retained on the human sex chromosomes it is apparent that the Y underwent inversions that progressively prevented large regions from undergoing X/Y
Specialized gene content of the sex chromosomes
When studying dosage regulation of the sex chromosomes one must consider their gene content. For example, male-biased genes often expressed in testis are abundant on the Y chromosome, a location predicted to be favorable to the accumulation of sexually antagonistic genes with a male benefit [24]. Interestingly, the X chromosome is also highly enriched in male-biased genes [25]. Hemizygosity in males favors the accumulation of male-advantageous mutations at both X and Y locations. In addition to
Dosage compensation responses to any type of aneuploidy
The heterogametic sex would have had to survive a natural form of aneuploidy. How do organisms respond to any aneuploidy, whether autosomal or sex-linked? Aneuploidy causes significant phenotypic abnormalities and loss of fitness [42]. Duplications are generally better tolerated than deletions. In Drosophila melanogaster, deletions that affect 1% of the genome reduce viability [43], but of course, this very much depends on the gene content of the deleted region (see dosage-sensitive genes
Allele-specific autosomal gene expression
Some genes are normally expressed from a single allele. Do these genes get compensated? While a majority of these genes are X-linked in mammals and will be discussed below, others are autosomal. One category of such autosomal genes is represented by imprinted genes. It should be noted that there are interesting parallels between mechanisms that silence imprinted genes and those that silence genes regulated by X inactivation [62], both types of genes being regulated by cis-acting lncRNAs,
Dosage compensation between sex chromosomes and autosomes
Balanced expression between X/Z-linked and autosomal genes can be attained by increasing X/Z expression or by decreasing autosomal expression in the heterogametic sex. X upregulation is best documented in Drosophila males to increase expression of a large portion of genes [74]. In organisms where dosage adjustment is sex-specific – as in Drosophila – there would be no need for adjustment in the homogametic sex. However, in systems in which X/Z expression is increased relative to autosomal
Molecular evidence of X upregulation
Precise adjustment of X-linked gene expression requires a combination of systems for enhancement and suppression of expression. In Drosophila, upregulation of the male X chromosome is achieved by recruitment of the MSL complex to increase levels of H4K16 acetylation and open chromatin, which results in increased transcription initiation and elongation (Fig. 1) [74]. Recruitment of the MSL complex to the male X is mediated by a 2–4 fold enrichment in specific binding motifs. Heterochromatin
Sex differences due to sex-linked gene dosage
In mammals, gene expression in somatic tissues is fairly similar between sexes except in sex organs. In males, the Y chromosome expresses few genes except for dosage-sensitive X/Y paralogs (see below) and genes implicated in male fertility, while in females, X inactivation effectively silences most genes on one allele, except for genes that escape X inactivation [127], [128]. Escape from X inactivation enhances sex-specific differences via female bias. Such effects can be indirect, as shown for
Dosage-sensitive genes on the sex chromosomes
In human, dosage-sensitive genes, autosomal or sex-linked, have been identified as those causing disease if mutated, deleted, or present in supernumerary copies [138]. A comprehensive list of DNA sequences intolerant to alterations was compiled by considering coding as well as non-coding regions to include regulatory features [139]. Gene expression analysis using expression microarrays in a very large number of tumors has shown that many genes are dosage-sensitive, with their expression usually
Emerging view
Conflicting statements about the existence of dosage compensation in haploid chromosomes such as the sex chromosomes in part result from unclear definition of the term “dosage compensation”. Any adjustment of dosage, partial or global, chromosome-specific or genome-wide, indicates some form of dosage regulation. For sex-linked genes such regulation is in part co-opted from responses to any form of autosomal aneuploidy, with added mechanisms to help restore genome balance. Findings of molecular
Acknowledgements
This work was supported by grants from the National Institutes of Health (GM113943, GM046883, DK107979). I thank X. Deng for helpful discussions.
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