Evolutionary and genomic perspectives of brain aging and neurodegenerative diseases.

This chapter utilizes genomic concepts and evolutionary perspectives to further understand the possible links between typical brain aging and neurodegenerative diseases, focusing on the two most prevalent of these: Alzheimer's disease and Parkinson's disease. Aging is the major risk factor for these neurodegenerative diseases. Researching the evolutionary and molecular underpinnings of aging helps to reveal elements of the typical aging process that leave individuals more vulnerable to neurodegenerative pathologies. Very little is known about the prevalence and susceptibility of neurodegenerative diseases in nonhuman species, as only a few individuals have been observed with these neuropathologies. However, several studies have investigated the evolution of lifespan, which is closely connected with brain size in mammals, and insights can be drawn from these to enrich our understanding of neurodegeneration. This chapter explores the relationship between the typical aging process and the events in neurodegeneration. First, we examined how age-related processes can increase susceptibility to neurodegenerative diseases. Second, we assessed to what extent neurodegeneration is an accelerated form of aging. We found that while at the phenotypic level both neurodegenerative diseases and the typical aging process share some characteristics, at the molecular level they show some distinctions in their profiles, such as variation in genes and gene expression. Furthermore, neurodegeneration of the brain is associated with an earlier onset of cellular, molecular, and structural age-related changes. In conclusion, a more integrative view of the aging process, both from a molecular and an evolutionary perspective, may increase our understanding of neurodegenerative diseases.

Rats exhibit age-related mosaic loss of chromosome Y.

Mosaic loss of the Y chromosome (LOY) is the most frequent chromosomal aberration in aging men and is strongly correlated with mortality and disease. To date, studies of LOY have only been performed in humans, and so it is unclear whether LOY is a natural consequence of our relatively long lifespan or due to exposure to human-specific external stressors. Here, we explored whether LOY could be detected in rats. We applied a locus-specific PCR and target sequencing approach that we used as a proxy to estimate LOY in 339 samples covering eleven tissues from young and old individuals. We detected LOY in four tissues of older rats. To confirm the results from the PCR screening, we re-sequenced 60 full genomes from old rats, which revealed that the Y chromosome is the sole chromosome with low copy numbers. Finally, our results suggest that LOY is associated with other structural aberrations on the Y chromosome and possibly linked to the mosaic loss of the X chromosome. This is the first report, to our knowledge, demonstrating that the patterns of LOY observed in aging men are also present in a rodent, and conclude that LOY may be a natural process in placental mammals.

Expression Evolution of Ancestral XY Gametologs across All Major Groups of Placental Mammals.

Placental mammals present 180 million-year-old Y chromosomes that have retained a handful of dosage-sensitive genes. However, the expression evolution of Y-linked genes across placental groups has remained largely unexplored. Here, we expanded the number of Y gametolog sequences by analyzing ten additional species from previously unexplored groups. We detected seven remarkably conserved genes across 25 placental species with known Y repertoires. We then used RNA-seq data from 17 placental mammals to unveil the expression evolution of XY gametologs. We found that Y gametologs followed, on average, a 3-fold expression loss and that X gametologs also experienced some expression reduction, particularly in primates. Y gametologs gained testis specificity through an accelerated expression decay in somatic tissues. Moreover, despite the substantial expression decay of Y genes, the combined expression of XY gametologs in males is higher than that of both X gametologs in females. Finally, our work describes several features of the Y chromosome in the last common mammalian ancestor.

Deciphering Ancestral Sex Chromosome Turnovers Based on Analysis of Male Mutation Bias.

The age of sex chromosomes is commonly obtained by comparing the substitution rates of XY gametologs. Coupled with phylogenetic reconstructions, one can refine the origin of a sex chromosome system relative to specific speciation events. However, these approaches are insufficient to determine the presence and duration of ancestral sex chromosome systems that were lost in some species. In this study, we worked with genomic and transcriptomic data from mammals and squamates and analyzed the effect of male mutation bias on X-linked sequences in these groups. We searched for signatures indicating whether monotremes shared the same sex chromosomes with placental mammals or whether pleurodonts and acrodonts had a common ancestral sex chromosome system. Our analyses indicate that platypus did not share the XY chromosomes with placental mammals, in agreement with previous work. In contrast, analyses of agamids showed that this lineage maintained the pleurodont XY chromosomes for several million years. We performed multiple simulations using different strengths of male mutation bias to confirm the results. Overall, our work shows that variations in substitution rates due to male mutation bias could be applied to uncover signatures of ancestral sex chromosome systems.