Y Chromosome

Apes possess two sex chromosomes-the male-specific Y chromosome and the X chromosome, which is present in both males and females. The Y chromosome is crucial for male reproduction, with deletions being linked to infertility1. The X chromosome is vital for reproduction and cognition2. Variation in mating patterns and brain function among apes suggests corresponding differences in their sex chromosomes. However, owing to their repetitive nature and incomplete reference assemblies, ape sex chromosomes have been challenging to study. Here, using the methodology developed for the telomere-to-telomere (T2T) human genome, we produced gapless assemblies of the X and Y chromosomes for five great apes (bonobo (Pan paniscus), chimpanzee (Pan troglodytes), western lowland gorilla (Gorilla gorilla gorilla), Bornean orangutan (Pongo pygmaeus) and Sumatran orangutan (Pongo abelii)) and a lesser ape (the siamang gibbon (Symphalangus syndactylus)), and untangled the intricacies of their evolution. Compared with the X chromosomes, the ape Y chromosomes vary greatly in size and have low alignability and high levels of structural rearrangements-owing to the accumulation of lineage-specific ampliconic regions, palindromes, transposable elements and satellites. Many Y chromosome genes expand in multi-copy families and some evolve under purifying selection. Thus, the Y chromosome exhibits dynamic evolution, whereas the X chromosome is more stable. Mapping short-read sequencing data to these assemblies revealed diversity and selection patterns on sex chromosomes of more than 100 individual great apes. These reference assemblies are expected to inform human evolution and conservation genetics of non-human apes, all of which are endangered species.

Epidemiological investigations show that mosaic loss of chromosome Y (LOY) in leukocytes is associated with earlier mortality and morbidity from many diseases in men. LOY is the most common acquired mutation and is associated with aberrant clonal expansion of cells, yet it remains unclear whether this mosaicism exerts a direct physiological effect. We studied DNA and RNA from leukocytes in sorted- and single-cells in vivo and in vitro. DNA analyses of sorted cells showed that men diagnosed with Alzheimer's disease was primarily affected with LOY in NK cells whereas prostate cancer patients more frequently displayed LOY in CD4 + T cells and granulocytes. Moreover, bulk and single-cell RNA sequencing in leukocytes allowed scoring of LOY from mRNA data and confirmed considerable variation in the rate of LOY across individuals and cell types. LOY-associated transcriptional effect (LATE) was observed in ~ 500 autosomal genes showing dysregulation in leukocytes with LOY. The fraction of LATE genes within specific cell types was substantially larger than the fraction of LATE genes shared between different subsets of leukocytes, suggesting that LOY might have pleiotropic effects. LATE genes are involved in immune functions but also encode proteins with roles in other diverse biological processes. Our findings highlight a surprisingly broad role for chromosome Y, challenging the view of it as a "genetic wasteland", and support the hypothesis that altered immune function in leukocytes could be a mechanism linking LOY to increased risk for disease.

Somatic cells of human males and females have 45 chromosomes in common, including the "active" X chromosome. In males the 46th chromosome is a Y; in females it is an "inactive" X (Xi). Through linear modeling of autosomal gene expression in cells from individuals with zero to three Xi and zero to four Y chromosomes, we found that Xi and Y impact autosomal expression broadly and with remarkably similar effects. Studying sex chromosome structural anomalies, promoters of Xi- and Y-responsive genes, and CRISPR inhibition, we traced part of this shared effect to homologous transcription factors-ZFX and ZFY-encoded by Chr X and Y. This demonstrates sex-shared mechanisms by which Xi and Y modulate autosomal expression. Combined with earlier analyses of sex-linked gene expression, our studies show that 21% of all genes expressed in lymphoblastoid cells or fibroblasts change expression significantly in response to Xi or Y chromosomes.

The loss of chromosome Y (LOY) in leukocytes is the most prevalent form of clonal mosaicism observed in older men. Previous studies provided multiple pieces of evidence for the effect of LOY on the immune system and connected LOY to elevated risk of all major causes of mortality, including cardiovascular diseases and cancer. Despite these associations, the dynamic effects of LOY across the developmental trajectories of immune cell populations remain unclear. We utilized single-cell RNA-sequencing data from the peripheral blood mononuclear cells of 416 male donors (median age = 68) from the OneK1K cohort. LOY was identified in 45,304 cells (8.76%) and exhibited cell type-specific effects on immune cells along the differentiation trajectories. The largest frequency was detected in monocytes (18.6% in classical and 17.1% in nonclassical) with a progressive decrease along the transition trajectory from 22.6% to 15.8% (padj = 2.00 × 10-11), and a gradual reduction in the expression of nonclassical markers LYPD2 and C1QA. LOY is associated with a profibrotic signature in classical monocytes marked by downregulation of IL1B (log FC = -0.22, pfdr = 2.84 × 10-6) and MYC-regulated genes (log FC = -0.25, pfdr = 2.22 × 10-5), consistent with previous observations that LOY-associated macrophages are polarized toward a fibrotic rather than inflammatory phenotype in cardiac and pulmonary injury. Notably, we detected aberrant expression of XIST, the essential X-chromosome-inactivation lncRNA that is not normally expressed in males, and upregulation of genes known to escape X-inactivation, including male-biased cancer-related genes KDM6A, DDX3X, KDM5C, and ZRSR2. Our results indicate associations between LOY and cell type-specific transcriptional changes, including aberrant X-inactivation features.