Longitudinal changes in the frequency of mosaic chromosome Y loss in peripheral blood cells of aging men varies profoundly between individuals

Abstract

Mosaic loss of chromosome Y (LOY) is the most common somatic genetic aberration and is associated with increased risk for all-cause mortality, various forms of cancer and Alzheimer's disease, as well as other common human diseases. By tracking LOY frequencies in subjects from which blood samples have been serially collected up to five times during up to 22 years, we observed a pronounced intra-individual variation of changes in the frequency of LOY within individual men over time. We observed that in some individuals the frequency of LOY in blood clearly progressed over time and that in other men, the frequency was constant or showed other types of longitudinal development. The predominant method used for estimating LOY is calculation of the median Log R Ratio of probes located in the male specific part of chromosome Y (mLRRY) from intensity data generated by SNP-arrays, which is difficult to interpret due to its logarithmic and inversed scale. We present here a formula to transform mLRRY-values to percentage of LOY that is a more comprehensible unit. The formula was derived using measurements of LOY from matched samples analysed using SNP-array, whole genome sequencing and a new AMELX/ AMELY-based assay for droplet digital PCR. The methods described could be applied for analyses of the vast amount of SNParray data already generated in the scientific community, allowing further discoveries of LOY associated diseases and outcomes.

Genomic alterations in patients with somatic loss of the Y chromosome as the sole cytogenetic finding in bone marrow cells

“…Though these mutations, as with LOY, can be seen in aging populations (so-called age-related clonal hematopoiesis [ARCH] or clonal hematopoiesis of indeterminate potential [CHIP]), the incidence of these frequent alterations was much higher when LOY was ≥ 75% compared to the incidence found in age-matched populations from the literature. These findings suggest that ≥ 75% LOY is associated with an MDS-type mutation signature and therefore likely represents disease-associated clonal proliferation 22 .…”

Loss of Chromosome Y and Its Potential Applications as Biomarker in Health and Forensic Sciences

“…However, bad quality SNP-array data can lead to bias in LOY estimation; thus, accessing the SNP-array quality at the sample level is also required [Dumanski et al, 2016]. Another method that can be used to detect LOY is whole-genome sequencing (WGS) [Danielsson et al, 2020]. This method compares the read depth on the Y chromosome in relation to the full human genome.…”

“…This method compares the read depth on the Y chromosome in relation to the full human genome. The copy number of the male sex chromosome can be estimated by using read counts, resulting in a median ploidy of the Y [Danielsson et al, 2020].…”

“…These proportions mimic different percentages of LOY, and the analysed samples are compared with these proportions to estimate LOY [Noveski et al, 2016;Hirata et al, 2018;Kimura et al, 2018]. On the other hand, Danielsson et al [2020] reported the use of droplet digital PCR (ddPCR) to identify LOY. This method is also based on AMELY/AMELX ratio, but differs in the resources used to achieve this ratio.…”

“…This method is also based on AMELY/AMELX ratio, but differs in the resources used to achieve this ratio. ddPCR is a TaqMan-based method used to relatively quantify the number of Y and X chromosomes in a given sample [Danielsson et al, 2020]. DNA is digested with HindIII enzyme, diluted with ionized water, and mixed with all the needed elements for PCR amplification.…”