Analysis of molecular data for health and disease

National Human Genome Research Institute

Investigators

Abstract

One fundamental challenge in assessing new methods for detecting variation in the genome is the lack of a “gold standard” set of variants – such that one could be confident that an approach is identifying true positives, and not false positives. This distinction is incredibly important in human disease studies, where clinicians must be especially sensitive to interpretation of possible causal genetic mutations. To aide in these efforts, we contributed our expertise in sex chromosome genomics to develop a set of benchmark variants on the X and Y chromosomes (ref 1). This set will be a gold standard for researchers to use to test their new methodology for accurately identifying small mutations on the sex chromosomes. In our efforts to study gene expression and the effects of sex chromosome complement in early life, we collaborated to combine gene expression data we have generated in the placenta with methylation data our collaborators generated, to show that the expected relationship between patterns of DNA methylation and allele-specific expression are not conserved on the X chromosome, suggesting that future research will need to be more intentional with using methylation data to infer expression on the X chromosome (ref 2). On the other end of the lifespan, we contributed our methodological expertise in assessing genes that have functional partners on the X and Y chromosomes in aged individuals with Alzheimer’s disease. We showed, for the first time, that the expression of one of these pairs of genes on the X and Y chromosomes correlates with the functional microglia differences observed between men and women with Alzheimer’s disease (ref 3). The final two papers we had published this year were the result of collaborative efforts to identify regulators of gene expression – in genomic regions that respond to wounding (ref 4) and that vary between species (ref 5). Since joining the NIH on December 29, 2024, we have had five papers formally accepted for publication, and the section has posted three preprints based on analysis we conducted during our time at the NIH: one on a new method to identify sex chromosomes from a single assembled genome, one demonstrating sex-specific gene expression in preeclampsia, and one that outlines best practices for improving variant detection on human sex chromosomes.