Jamie Blundell: The Evolutionary Dynamics and Fitness Landscape of Clonal Expansions in Our Blood
- Date: Nov 13, 2019
- Time: 04:00 PM - 05:00 PM (Local Time Germany)
- Speaker: Jamie Blundell from University of Cambridge, UK
- For more information on Jamie Blundell please see: https://crukcambridgecentre.org.uk/users/jrb7511916
- Location: MPI Plön
- Room: Lecture hall
- Host: Loukas Theodosiou
Abstract:
Somatic mutations acquired in healthy
tissues as we age are major
determinants of cancer risk. Whether variants confer a fitness
advantage or
rise to detectable frequencies by chance, however, remains
largely unknown.
Here, by combining blood sequencing data from ∼50,000 individuals, we reveal how mutation,
genetic drift and fitness
differences combine to shape the genetic diversity of healthy
blood (‘clonal
haematopoiesis’). By analysing the spectrum of variant allele
frequencies we
quantify fitness advantages for key pathogenic variants and
genes and provide
bounds on the number of haematopoietic stem cells. Positive
selection, not
drift, is the major force shaping clonal haematopoiesis. The
remarkably wide
variation in variant allele frequencies observed across
individuals is driven
by chance differences in the timing of mutation acquisition
combined with
differences in the cell-intrinsic fitness effect of variants.
Contrary to the
widely held view that clonal haematopoiesis is driven by
ageing-related
alterations in the stem cell niche, the data are consistent with
the age
dependence being driven simply by continuing risk of mutations
and subsequent
clonal expansions that lead to increased detectability at older
ages.