You are cordially welcomed to a seminar by Dr. Taru Tukiainen (Molecular Medicine Finland (FIMM), University of Helsinki, Finnish Academy of Sciences) “X chromosome inactivation – from cells to population and phenotypes”.
Time: Wed, Nov 27th 2019 at 12:00 -13:00.
Place: Biomedicum, large auditorium
Abstract: “X chromosome inactivation – from cells to population and phenotypes”
X chromosome inactivation (XCI) serves to balance the X-chromosomal dosage between XX females and XY males by silencing the transcription from one of the two X chromosomes in female cells. The silencing by XCI is, however, largely incomplete, as first established more than a decade ago: up to one third of X chromosome genes escape from XCI, i.e., remain expressed from both X chromosomes in females to some degree. This incompleteness in XCI may be a contributor to male-female differences, yet given technological limitations and lack of suitable data sets, few comprehensive studies on XCI and its downstream effects in human samples have been conducted.
To systematically survey the extent and transcriptome impacts of XCI across human tissues, we have analyzed over 5,500 transcriptomes from the GTEx project set together with ~1000 single-cell transcriptomes, both combined with genomic sequence data. In line with previous work, we find that incomplete XCI affects at least 23% of X-chromosomal genes. Given the unprecedented resolution and breadth of our data, we further demonstrate that XCI is generally uniform across human tissues, but with notable examples of heterogeneity between tissues, individuals and cells, and provide insights into the sources of variability in XCI. Our data also shows that a large majority of escape genes show male-female expression differences detectable at population-level, thus highlighting the potential between-sex diversity introduced by incomplete XCI.
To complement these transcriptome discoveries, we have also undertaken genetic analyses in the UK Biobank data set to determine the impact incomplete XCI on complex trait genetic architecture. Male-female comparisons of genetic associations demonstrate that incomplete XCI is indeed reflected as subtle sex differences in X-chromosomal GWAS that can manifest as sex differences in phenotypic traits.
Overall, these investigations into human XCI, facilitated by the deployment of several complementary genomic approaches, helps to increase our understanding of the extent and impacts of the incompleteness of XCI.
Taru Tukiainen is an Academy Research Fellow and a group leader at the Institute for Molecular Medicine Finland (FIMM) and holds the title of docent in genomics at University of Helsinki. Taru received her D.Sc. (Tech.) degree in computational systems biology from Aalto University, Espoo, Finland, in 2012 for her research on the genetic underpinnings of metabolomics traits in Finnish population cohorts. In 2013-2015, Taru worked as a postdoctoral researcher with Daniel MacArthur at the Massachusetts General Hospital and the Broad Institute, where her work focused on the application of transcriptomics to understand the impacts of genetic variation and epigenetic phenomena. After returning to Finland, Taru completed the three-year Academy of Finland postdoctoral project at FIMM on the role of the X chromosome in human complex traits, prior to launching her own research group in 2018. Taru’s current research interest is in elaborating the biology of sex differences in health and disease using human genomics data sets and tools, with a particular focus on sex chromosomes and X-inactivation.
Selected publications related to the topic of the seminar:
- Tukiainen T, et al. Landscape of X chromosome inactivation across human tissues. Nature 2017; 550(7675):244-248.
- Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, O'Donnell-Luria AH, Ware JS, Hill AJ, Cummings BB, Tukiainen T, et al; Exome Aggregation Consortium. Analysis of protein-coding genetic variation in 60,706 humans. Nature 2016;536(7616):285-91.
- Tukiainen T, et al. Chromosome X-wide association study identifies Loci for fasting insulin and height and evidence for incomplete dosage compensation. PLoS Genet 2014; 10(2):e1004127.
- Kettunen J*, Tukiainen T*, et al. Genome-wide association study identifies multiple loci influencing human serum metabolite levels. Nat Genet 2012;44(3):269-76.