Sex Chromosome Evolution The fly genus Drosophilia has repeatedly generated evolutionarily new sex chromosomes. To understand the changes shaping the X and Y chromosomes, Zhou and Bachtrog (p. 341), sequenced the genome of D. miranda, which formed neo-X and neo-Y chromosomes approximately 1 million years ago. The data illuminate the ongoing conflict between selection for male and female function on the sex chromosomes and show that Y chromosome evolution is characterized both by a loss of gene function and selection for male-specific adaptations in genes beneficial to male functions. Evolutionarily new X and Y chromosomes evidence how selection for sexual function shapes sex chromosomes. Most species’ sex chromosomes are derived from ancient autosomes and show few signatures of their origins. We studied the sex chromosomes of Drosophila miranda, where a neo-Y chromosome originated only approximately 1 million years ago. Whole-genome and transcriptome analysis reveals massive degeneration of the neo-Y, that male-beneficial genes on the neo-Y are more likely to undergo accelerated protein evolution, and that neo-Y genes evolve biased expression toward male-specific tissues—the shrinking gene content of the neo-Y becomes masculinized. In contrast, although older X chromosomes show a paucity of genes expressed in male tissues, neo-X genes highly expressed in male-specific tissues undergo increased rates of protein evolution if haploid in males. Thus, the response to sex-specific selection can shift at different stages of X differentiation, resulting in masculinization or demasculinization of the X-chromosomal gene content.

Sex-Specific Adaptation Drives Early Sex Chromosome Evolution In Drosophila

It is well known that women live longer than men. This gap is observed in most human populations and can even reach 10–15 years. In addition, most of the known super centenarians (i.e., humans who lived for > 110 years) are women. The differences in life expectancy between men and women are often attributed to cultural differences in common thinking. However, sex hormones seem to influence differences in the prevalence of diseases, in the magnitude of aging, and in the longevity between men and women. Moreover, far from being human specific, the sex gap in longevity is extremely common in non-human animals, especially in mammals. Biological factors clearly contribute to such a sex gap in aging and longevity. Different hypotheses have been proposed to explain why males and females age and die differently. The cost of sexual selection and sexual dimorphism has long been considered the best explanation for the observed sex gap in aging/longevity. However, the way mitochondria are transmitted (i.e., through females in most species) could have an effect, called the mother’s curse. Recent data suggest that sex chromosomes may also contribute to the sex gap in aging/longevity through several potential mechanisms, including the unguarded X/Z, the toxic Y/W and the loss of Y/W. We discuss future research directions to test these ideas.

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Sex gap in aging and longevity: can sex chromosomes play a role?

Many taxa show substantial differences in lifespan between the sexes. However, these differences are not always in the same direction. In mammals, females tend to live longer than males, while in b...

https://royalsocietypublishing.org/doi/pdf/10.1098/rsbl.2019.0867

The sex with the reduced sex chromosome dies earlier: a comparison across the tree of life.

Although aging is a conserved phenomenon across evolutionary distant species, aspects of the aging process have been found to differ between males and females of the same species. Indeed, observations across mammalian studies have revealed the existence of longevity and health disparities between sexes, including in humans (i.e. with a female or male advantage). However, the underlying mechanisms for these sex differences in health and lifespan remain poorly understood, and it is unclear which aspects of this dimorphism stem from hormonal differences (i.e. predominance of estrogens vs. androgens) or from karyotypic differences (i.e. XX vs. XY sex chromosome complement). In this review, we discuss the state of the knowledge in terms of sex dimorphism in various aspects of aging and in human age-related diseases. Where the interplay between sex differences and age-related differences has not been explored fully, we present the state of the field to highlight important future research directions. We also discuss various dietary, drug or genetic interventions that were shown to improve longevity in a sex-dimorphic fashion. Finally, emerging tools and models that can be leveraged to decipher the mechanisms underlying sex differences in aging are also briefly discussed.

Widespread sex dimorphism in aging and age-related diseases.

San Diego is facing significant challenges to its future development. How do the some of the region's leading lights think it will cope? Ken Howard finds out.

/pdf/the-view-from-the-top-345n2szxjd.pdf

The view from the top.

Heterochromatin suppresses repetitive DNA, and a loss of heterochromatin has been observed in aged cells of several species, including humans and Drosophila. Males often contain substantially more heterochromatic DNA than females, due to the presence of a large, repeat-rich Y chromosome, and male flies generally have a shorter average lifespan than females. Here we show that repetitive DNA becomes de-repressed more rapidly in old male flies relative to females, and repeats on the Y chromosome are disproportionally mis-expressed during ageing. This is associated with a loss of heterochromatin at repetitive elements during ageing in male flies, and a general loss of repressive chromatin in aged males away from pericentromeric regions and the Y. By generating flies with different sex chromosome karyotypes (XXY females and X0 and XYY males), we show that repeat de-repression and average lifespan is correlated with the number of Y chromosomes. This suggests that sex-specific chromatin differences may contribute to sex-specific ageing in flies.

/pdf/the-y-chromosome-may-contribute-to-sex-specific-ageing-in-1q7uu1snuu.pdf

The Y chromosome may contribute to sex-specific ageing in Drosophila.

The Drosophila Y chromosome is gene poor and mainly consists of silenced, repetitive DNA. Nonetheless, the Y influences expression of hundreds of genes genome-wide, possibly by sequestering key components of the heterochromatin machinery away from other positions in the genome. To test the influence of the Y chromosome on the genome-wide chromatin landscape, we assayed the genomic distribution of histone modifications associated with gene activation (H3K4me3) or heterochromatin (H3K9me2 and H3K9me3) in fruit flies with varying sex chromosome complements (X0, XY, and XYY males; XX and XXY females). Consistent with the general deficiency of active chromatin modifications on the Y, we find that Y gene dose has little influence on the genomic distribution of H3K4me3. In contrast, both the presence and the number of Y chromosomes strongly influence genome-wide enrichment patterns of repressive chromatin modifications. Highly repetitive regions such as the pericentromeres, the dot, and the Y chromosome (if present) are enriched for heterochromatic modifications in wildtype males and females, and even more strongly in X0 flies. In contrast, the additional Y chromosome in XYY males and XXY females diminishes the heterochromatic signal in these normally silenced, repeat-rich regions, which is accompanied by an increase in expression of Y-linked repeats. We find hundreds of genes that are expressed differentially between individuals with aberrant sex chromosome karyotypes, many of which also show sex-biased expression in wildtype Drosophila. Thus, Y chromosomes influence heterochromatin integrity genome-wide, and differences in the chromatin landscape of males and females may also contribute to sex-biased gene expression and sexual dimorphisms.

/pdf/the-drosophila-y-chromosome-affects-heterochromatin-4gkg61r1jk.pdf

The Drosophila Y Chromosome Affects Heterochromatin Integrity Genome-Wide.

Sex-specific differences in lifespan are prevalent across the tree of life and influenced by heteromorphic sex chromosomes. In species with XY sex chromosomes, females often outlive males. Males and females can differ in their overall repeat content due to the repetitive Y chromosome, and repeats on the Y might lower survival of the heterogametic sex (toxic Y effect). Here, we take advantage of the well-assembled young Y chromosome of Drosophila miranda to study the sex-specific dynamics of chromatin structure and repeat expression during aging in male and female flies. Male D. miranda have about twice as much repetitive DNA compared to females, and live shorter than females. Heterochromatin is crucial for silencing of repetitive elements, yet old D. miranda flies lose H3K9me3 modifications in their pericentromere, with heterochromatin loss being more severe during aging in males than females. Satellite DNA becomes de-repressed more rapidly in old vs. young male flies relative to females. In contrast to what is observed in D. melanogaster, we find that transposable elements (TEs) are expressed at higher levels in male D. miranda throughout their life. We show that epigenetic silencing via heterochromatin formation is ineffective on the TE-rich neo-Y chromosome, presumably due to active transcription of a large number of neo-Y linked genes, resulting in up-regulation of Y-linked TEs already in young males. This is consistent with an interaction between the evolutionary age of the Y chromosome and the genomic effects of aging. Our data support growing evidence that "toxic Y chromosomes" can diminish male fitness and a reduction in heterochromatin can contribute to sex-specific aging.

/pdf/toxic-y-chromosome-increased-repeat-expression-and-age-1jwzy62bs3.pdf

Toxic Y chromosome: Increased repeat expression and age-associated heterochromatin loss in male Drosophila with a young Y chromosome.

Sex‐specific differences in lifespan are prevalent across the tree of life and influenced by heteromorphic sex chromosomes. In species with XY sex chromosomes, females often outlive males. Males and females can differ in their overall repeat content due to the repetitive Y chromosome, and repeats on the Y might lower survival of the heterogametic sex (toxic Y effect). Here, we take advantage of the well‐assembled young Y chromosome of Drosophila miranda to study the sex‐specific dynamics of chromatin structure and repeat expression during aging in male and female flies. Male D. miranda have about twice as much repetitive DNA compared to females, and live shorter than females. Heterochromatin is crucial for silencing of repetitive elements, yet old D. miranda flies lose H3K9me3 modifications in their pericentromere, with heterochromatin loss being more severe during aging in males than females. Satellite DNA becomes de‐repressed more rapidly in old vs. young male flies relative to females. In contrast to what is observed in D. melanogaster , we find that transposable elements (TEs) are expressed at higher levels in male D. miranda throughout their life. We show that epigenetic silencing via heterochromatin formation is ineffective on the large TE‐ rich neo‐Y chromosome, resulting in up‐regulation of Y‐linked TEs already in young males. This is consistent with an interaction between the age of the Y chromosome and the genomic effects of aging. Our data support growing evidence that “toxic Y chromosomes” can diminish male fitness and a reduction in heterochromatin can contribute to sex‐specific aging.

### Competing Interest Statement

The authors have declared no competing interest.

/pdf/toxic-y-chromosome-increased-repeat-expression-and-age-1ijwgm7rrl.pdf

Toxic Y chromosome: increased repeat expression and age-associated heterochromatin loss in male Drosophila with a young Y chromosome

Heterochromatin suppresses repetitive DNA, and a loss of heterochromatin has been observed in aged cells of several species, including humans and Drosophila. Males often contain substantially more heterochromatic DNA than females, due to the presence of a large, repeat-rich Y chromosome, and male flies generally have shorter average life spans than females. Here we show that repetitive DNA becomes de-repressed more rapidly in old male flies relative to females, and repeats on the Y chromosome are disproportionally mis-expressed during aging. This is associated with a loss of heterochromatin at repetitive elements during aging in male flies, and a general loss of repressive chromatin in aged males away from pericentromeric regions and the Y. By generating flies with different sex chromosome karyotypes (XXY females; X0 and XYY males), we show that repeat de-repression and average lifespan is directly correlated with the number of Y chromosomes. Thus, sex-specific chromatin differences contribute to sex-specific aging in flies.

/pdf/the-y-chromosome-contributes-to-sex-specific-aging-in-33p23aatru.pdf

Alison H. Nguyen

Papers

The Y chromosome may contribute to sex-specific ageing in Drosophila.

The Drosophila Y Chromosome Affects Heterochromatin Integrity Genome-Wide.

Toxic Y chromosome: Increased repeat expression and age-associated heterochromatin loss in male Drosophila with a young Y chromosome.

Toxic Y chromosome: increased repeat expression and age-associated heterochromatin loss in male Drosophila with a young Y chromosome

The Y chromosome contributes to sex-specific aging in Drosophila