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Evolution of vertebrate sex chromosomes and dosage compensation

Key Points

  • Vertebrate chromosomes and genomes are very conserved, but different genome regions have evolved to trigger the determination of sex in different lineages.

  • The trajectory of independently evolved X and Y (or Z and W) chromosome differentiation from a pair of autosomes is remarkably similar. It involves the degradation of the sex-specific chromosome, leaving much of its partner represented differentially in males and females.

  • Different systems have evolved independently in different lineages to mitigate gene dosage differences between the two sexes and with respect to autosomes.

  • X chromosome inactivation is a whole-X chromosome dosage compensation system that is unique to therian mammals. In birds, reptiles and fish (and even monotreme mammals), dosage compensation is usually partial and gene-specific, although there are some examples of regional control.

  • Many genes on sex chromosomes have evolved sex-biased or sex-specific expression as alternatives to dosage compensation.

  • Mammalian X chromosome inactivation is accomplished by differential binding of DNA to modified histones, which is initiated by coating the majority of the X chromosome that will be inactivated with a non-coding RNA transcribed from an X chromosome locus (independently evolved in placental mammals and marsupials). In placental mammals, but not in marsupials, the silencing chromatin domain is locked into place by DNA methylation. The DNA of the inactive X chromosome is held in a transcriptionally repressive state by long-range genomic interactions.

  • Independently evolved dosage compensation systems in reptiles and fish use many of the same epigenetic silencing mechanisms (non-coding RNA, DNA methylation, and modified and variant histones) as do compensation systems in mammals. The ubiquity of these mechanisms suggests that they are drawn from a common transcriptional regulatory toolbox.

Abstract

Differentiated sex chromosomes in mammals and other vertebrates evolved independently but in strikingly similar ways. Vertebrates with differentiated sex chromosomes share the problems of the unequal expression of the genes borne on sex chromosomes, both between the sexes and with respect to autosomes. Dosage compensation of genes on sex chromosomes is surprisingly variable — and can even be absent — in different vertebrate groups. Systems that compensate for different gene dosages include a wide range of global, regional and gene-by-gene processes that differ in their extent and their molecular mechanisms. However, many elements of these control systems are similar across distant phylogenetic divisions and show parallels to other gene silencing systems. These dosage systems cannot be identical by descent but were probably constructed from elements of ancient silencing mechanisms that are ubiquitous among vertebrates and shared throughout eukaryotes.

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Figure 1: Non-homologous vertebrate sex chromosomes and vertebrate phylogeny.
Figure 2: Differentiation of sex chromosomes from an original autosome as the sex-specific element (Y or W chromosome) degenerates, with examples of animal species that exhibit different extents of sex chromosome differentiation.
Figure 3: Dosage compensation of genes on X or Z chromosomes in mammals, birds, reptiles and fish.
Figure 4: Ohno's hypothesis that Y chromosome degradation drives upregulation of the unpaired region of the X chromosome in males (M) and females (F) and is countered by X chromosome inactivation in females.
Figure 5: Evolution of X chromosome inactivation in mammals.

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Correspondence to Jennifer A. Marshall Graves.

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PowerPoint slides

Glossary

Sex chromosomes

Chromosomes that are different in male and female individuals and defined by a gene that determines sex. Mammals have XX females and XY males (the heterogametic sex, producing two kinds of sperm); birds have ZZ males and ZW females (the heterogametic sex, producing two kinds of eggs).

Sex-determining gene

A gene that turns on the pathway that directs the undifferentiated gonad to form either a testis or an ovary.

Proto-sex chromosomes

The first stage of sex chromosome differentiation from an autosome.

Autosomes

All of the chromosomes that are not sex chromosomes.

X chromosome inactivation

Mechanism to epigenetically silence one X chromosome in the somatic cells of female mammals.

Dosage compensation

Mechanism to equalize the expression of genes on sex chromosomes between males and females, and with respect to autosomes.

Comparative mapping

Mapping orthologous genes in different species.

Pseudoautosomal region

(PAR). Pairing region shared by X and Y, or Z and W chromosomes. PAR genes show an autosomal pattern of inheritance. The boundary between the PAR and the X- and Y- specific (or Z- and W-specific) regions is called the pseudoautosomal boundary.

Synteny

Genes are in synteny when they are on the same chromosome (literally, the “same thread”).

Epigenetic

Epigenetic changes are somatically heritable changes, not in the DNA sequence, but in the level to which the gene is expressed.

RNA-seq

Next-generation sequencing to quantify transcripts of every gene in a particular tissue and/or stage.

Fluorescence in situ hybridization

(FISH). Hybridization of DNA or RNA sequences trapped on a substrate (for example, a microscope slide) with probe sequences specific for a particular gene.

LINE elements

Long Interspersed Elements. A group of repetitive retrotransposed elements widespread throughout eukaryote genomes.

Histone modifications

The post-translational covalent attachment of a chemical group such as acetyl, methyl and ubiquitin groups, to the protruding tail of one of the core histones (H2, H3, H4) around which DNA is wound. Nomenclature (for example, H3K27me3) refers to the amino acid (for example, K) at a specific position (for example, 27) that is modified by the addition of chemical groups (for example, three methyl groups (me3)).

Hi-C

Method for detecting interactions between different sequences by binding DNA with formaldehyde, cutting on either side of the bound sequences and ligating and sequencing the chimeric DNA. This method can be made allele-specific using SNPs that differentiate active and inactive X chromosome DNA.

Homologous

Homology between genes or chromosomes is described as orthology (genes or chromosomes in different species that derived from the same gene or chromosome) or paralogy (genes in the same species that have diverged from a common ancestor, for example, diverged genes on the X and Y chromosomes).

Allele-specific assay

This type of method can be used to distinguish between two alternative forms of a gene by using probes or primers that bind only to one or the other alternative nucleotide sequences.

Quantitative PCR

(qPCR). Quantitative (real-time) PCR measures the amount of a specific sequence in a sample by tracking the production of amplification products over PCR cycles.

Microarray analysis

Expression microarrays assay for the presence of RNA sequences in a sample by binding sample to cDNAs (DNA copies of mRNA) arrayed on a substrate.

Ohno's hypothesis

A hypothesis that states that the first step of the evolution of X chromosome inactivation was the upregulation of X-borne genes in males to maintain parity with the expression of interacting autosomal genes. This resulted in the overexpression of X-borne genes in females, which was countered by X chromosome inactivation.

Meiotic sex chromosome inactivation

(MCSI). Inactivation of the X and Y chromosomes during male meiosis in therian mammals.

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Graves, J. Evolution of vertebrate sex chromosomes and dosage compensation. Nat Rev Genet 17, 33–46 (2016). https://doi.org/10.1038/nrg.2015.2

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