The Y chromosome and its impact on health and disease

Abstract

The Y chromosome is the most gene-deficient chromosome in the human genome (though not the smallest chromosome) and has largely been sequestered away from large-scale studies of the effects of genetics on human health. Here I review the literature, focusing on the last 2 years, for recent evidence of the role of the Y chromosome in protecting from or contributing to disease. Although many studies have focused on Y chromosome gene copy number and variants in fertility, the role of the Y chromosome in human health is now known to extend too many other conditions including the development of multiple cancers and Alzheimer's disease. I further include the discussion of current technology and methods for analyzing Y chromosome variation. The true role of the Y chromosome and associated genetic variants in human disease will only become clear when the Y chromosome is integrated into larger studies of human genetic variation, rather than being analyzed in isolation.

Figure 1

Mechanisms of Y chromosome affecting human health and disease. Typical genetic male cells will have one X chromosome (blue with stripes) and one Y chromosome (solid green). Although there are many genes that are unique to the X or Y chromosome, there are some that have a functional copy on both the X (e.g. UTX/KDM6A, shown here as a dark blue band) and the Y (e.g. UTY, dark green band) chromosomes. These genes will express transcripts (blue or green squiggles, respectively) in typical cells. In a bulk tissue sample, early in life, all of the cells will show expression from the Y chromosome (bottom left square). However, as individuals age, they can lose functionality of the Y in two main ways. First, their cells could start to lose the Y chromosome completely, a process called loss of Y, in which a portion of cells loses the Y chromosome during cell division and all daughter cells no longer have the Y chromosome at all (top right box). In this case, the proportion of cells in a bulk sample that exhibit loss of Y can range from 0 to 100%. The second primary way to lose functionality on the Y is for the genes to be methylated (or as happens on the Y chromosome with aging, hyper-methylated). In this case, the Y chromosome will still be present, but individual genes will be silenced via methylation (bottom left box). The approaches will be different for distinguishing these two mechanism of loss of Y functionality.