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Clonal dynamics of haematopoiesis across the human lifespan



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Mitchell, Emily 


The haematopoietic system manifests several age-associated phenotypes including anaemia; loss of regenerative capacity, especially in the face of insults such as infection, chemotherapy or blood loss; and increased risk of clonal haematopoiesis and blood cancers. The cellular alterations that underpin these age-related phenotypes, which typically manifest in individuals aged over 70, remain elusive. In my thesis I have aimed to investigate whether changes in HSC population structure with age might underlie any aspects of haematopoietic system ageing. In addition, I have investigated the impact of chemotherapeutic perturbations on haematopoietic stem cell mutation burden and clonal dynamics.

To answer the ageing question, I have sequenced 3579 genomes from single-cell-derived colonies of haematopoietic stem cell/multipotent progenitors (HSC/MPPs) from 10 haematologically normal subjects aged 0-81 years. HSC/MPPs accumulated 17 somatic mutations/year after birth with no increased rate of mutation accumulation in the elderly. HSC/MPP telomere length declined by 30 bp/yr. To interrogate changes in HSC population structure with age, I used the pattern of unique and shared mutations between the sampled cells from each individual to reconstruct their phylogenetic relationships. I found that haematopoiesis in adults aged <65 was polyclonal, with high indices of clonal diversity. In contrast, haematopoiesis in individuals aged >75 showed profoundly decreased clonal diversity. In each elderly subject, 30-60% of haematopoiesis was accounted for by 12-18 independent clones, each contributing 1-34% of blood production. Most clones had begun their expansion before age 40, but only 22% had known driver mutations.

I used the ratio of non-synonymous to synonymous mutations (dN/dS) to identify any excess of non-synonymous (driver) mutations in the dataset. This genome-wide selection analysis estimated that the set of 300 - 400 HSC/MPPs sampled from each adult individual harboured around 100 driver mutations, over 10-fold higher than the number of known drivers we could identify. Novel drivers affected a wider pool of genes than identified in blood cancers. Simulations from a simple model of haematopoiesis, with constant HSC population size and constant acquisition of driver mutations conferring moderate fitness benefits, entirely explained the abrupt change in clonal structure observed over the age of 70. By old age the majority of HSCs harbour at least one driver mutation. Our data supports the view that dramatically decreased clonal diversity is a universal feature of haematopoiesis in elderly humans, underpinned by pervasive positive selection acting on many more genes than currently known.

Finally, I also sequenced haematopoietic progenitor cells from individuals exposed to a wide range of chemotherapeutic agents. I was able to identify an increased mutation burden associated with a number of chemotherapeutic agents, including platinum and alkylating agents, some of which conferred thousands of excess mutations. There was a wide variation in mutation burden conferred from agents within the same class, meaning that there are potential patient benefits from switching drugs in commonly used regimens. I show that chemotherapy given in childhood can profoundly impact clonal dynamics in later life.





Laurenti, Elisa
Campbell, Peter


haematopoiesis, ageing, clonal dynamics, haematopoietic stem cells, chemotherapy


Doctor of Philosophy (PhD)

Awarding Institution

Wellcome Sanger Institute
Wellcome Harrison Foundation