de Goede, O. | Search bioRxiv

bioRxiv2019

Genetic dysregulation of gene expression and splicing during a ten-year period of human aging

Molecular and cellular changes are intrinsic to aging and age-related diseases. Prior cross-sectional studies have investigated the combined effects of age and genetics on gene expression and alternative splicing; however, there has been no long-term, longitudinal characterization of these molecular changes, especially in older age. We performed RNA sequencing in whole-blood from the same individuals from the PIVUS study at ages 70 and 80 to quantify how gene expression, alternative splicing, and their genetic regulation are altered during this 10-year period of advanced aging. We observe that individuals are more similar to their own expression profiles later in life than profiles of other individuals their own age; 93% of samples cluster with their own measurement at another age, and there is a strong correlation of genetic effects on expression between the two ages (median{rho} G = 0.96). Despite this, we identify 1,291 and 294 genes differentially expressed and alternatively spliced with age, as well as 529 genes with outlying individual trajectories of aging. Further, 7.8% and 9.6% of tested genes show a reduction in genetic associations with expression and alternative splicing in older age, with impacted genes enriched in DNA repair pathways. Together these findings indicate that, although gene expression and alternative splicing and their genetic regulation are mostly stable late in life, a small subset of genes is dynamic and is characterized by changes in expression and splicing and a reduction in genetic regulation.

genomics↗

bioRxiv2018

Differences in DNA methylation of white blood cell types at birth and in adulthood reflect postnatal immune maturation and influence accuracy of cell type prediction

BackgroundDNA methylation profiling of peripheral blood leukocytes has many research applications, and characterizing the changes in DNA methylation of specific white blood cell types between newborn and adult could add insight into the maturation of the immune system. As a consequence of developmental changes, DNA methylation profiles derived from adult white blood cells are poor references for prediction of cord blood cell types from DNA methylation data. We thus examined cell-type specific differences in DNA methylation in leukocyte subsets between cord and adult blood, and assessed the impact of these differences on prediction of cell types in cord blood.\n\nResultsThough all cell types showed differences between cord and adult blood, some specific patterns stood out that reflected how the immune system changes after birth. In cord blood, lymphoid cells showed less variability than in adult, potentially demonstrating their naive status. In fact, cord CD4 and CD8 T cells were so similar that genetic effects on DNA methylation were greater than cell type effects in our analysis, and CD8 T cell frequencies remained difficult to predict, even after optimizing the library used for cord blood composition estimation. Myeloid cells showed fewer changes between cord and adult and also less variability, with monocytes showing the fewest sites of DNA methylation change between cord and adult. Finally, including nucleated red blood cells in the reference library was necessary for accurate cell type predictions in cord blood.\n\nConclusionChanges in DNA methylation with age were highly cell type specific, and those differences paralleled what is known about the maturation of the postnatal immune system.

genetics↗