Contributions
Abstract: EP754
Type: E-Poster Presentation
Session title: Hematopoiesis, stem cells and microenvironment
Background
Clonal haematopoiesis (CH) is apparent in the general population from age 60 with a steady increase to 18-20% over age 90 driven by somatic mutations in leukaemic driver genes, leading to reduced diversity of the blood pool. CH carries an increased risk for leukaemia.
Aims
We investigated CH in the Lothian Birth Cohort through targeted error-corrected sequencing of blood samples taken from aged participants every 3 years for 15 years.
Methods
Study Cohorts
The Lothian Birth Cohorts (LBCs) of 1921 and 1936 are two longitudinal studies of ageing. Participants have been followed up every ~3 years, each for five waves, from the age of 70 (LBC1936) and 79 (LBC1921). MPN patient material was derived from the Cambridge Stem Cell Bank.
Error corrected sequencing
Genomic variants were determined in 1,148 LBC participants with error corrected sequencing. CH variants were classified as per Jaiswal et al.
Results
We identified 73 participants with CH (6.2%). The gene-specific prevalence ranged between 1-37 cases with CH-variant allele frequencies ranging from 0.034-0.677. Mathematical modelling of the population dynamics of clones shows that, at old age, the commonly used threshold to diagnose CH can be reached as the result of neutral drift in synonymous mutations. This clinically implemented detection method therefore leads to a ~50% false discovery rate of fit mutations. Using our longitudinal data, we can better detect clones whose growth cannot be explained by neutral drift by considering the measured distribution of fluctuations of neutral mutations. This method allows us to uncover fitness-inducing mutations with high sensitivity as well as uncover highly fit variants before they achieve the threshold-based definition of CH.
Conclusion
Longitudinal data allow for more accurate modelling and detection of fitness effects of CH in an aged population.
Keyword(s):
Abstract: EP754
Type: E-Poster Presentation
Session title: Hematopoiesis, stem cells and microenvironment
Background
Clonal haematopoiesis (CH) is apparent in the general population from age 60 with a steady increase to 18-20% over age 90 driven by somatic mutations in leukaemic driver genes, leading to reduced diversity of the blood pool. CH carries an increased risk for leukaemia.
Aims
We investigated CH in the Lothian Birth Cohort through targeted error-corrected sequencing of blood samples taken from aged participants every 3 years for 15 years.
Methods
Study Cohorts
The Lothian Birth Cohorts (LBCs) of 1921 and 1936 are two longitudinal studies of ageing. Participants have been followed up every ~3 years, each for five waves, from the age of 70 (LBC1936) and 79 (LBC1921). MPN patient material was derived from the Cambridge Stem Cell Bank.
Error corrected sequencing
Genomic variants were determined in 1,148 LBC participants with error corrected sequencing. CH variants were classified as per Jaiswal et al.
Results
We identified 73 participants with CH (6.2%). The gene-specific prevalence ranged between 1-37 cases with CH-variant allele frequencies ranging from 0.034-0.677. Mathematical modelling of the population dynamics of clones shows that, at old age, the commonly used threshold to diagnose CH can be reached as the result of neutral drift in synonymous mutations. This clinically implemented detection method therefore leads to a ~50% false discovery rate of fit mutations. Using our longitudinal data, we can better detect clones whose growth cannot be explained by neutral drift by considering the measured distribution of fluctuations of neutral mutations. This method allows us to uncover fitness-inducing mutations with high sensitivity as well as uncover highly fit variants before they achieve the threshold-based definition of CH.
Conclusion
Longitudinal data allow for more accurate modelling and detection of fitness effects of CH in an aged population.
Keyword(s):