Emily G. Mitchell

Bio: Emily G. Mitchell is an academic researcher from University of Cambridge. The author has contributed to research in topics: Haematopoiesis & Medicine. The author has an hindex of 10, co-authored 37 publications receiving 481 citations. Previous affiliations of Emily G. Mitchell include Wellcome Trust Sanger Institute & University of St Andrews.

Somatic mutation landscapes at single-molecule resolution

Abstract: Somatic mutations drive the development of cancer and may contribute to ageing and other diseases1,2. Despite their importance, the difficulty of detecting mutations that are only present in single cells or small clones has limited our knowledge of somatic mutagenesis to a minority of tissues. Here, to overcome these limitations, we developed nanorate sequencing (NanoSeq), a duplex sequencing protocol with error rates of less than five errors per billion base pairs in single DNA molecules from cell populations. This rate is two orders of magnitude lower than typical somatic mutation loads, enabling the study of somatic mutations in any tissue independently of clonality. We used this single-molecule sensitivity to study somatic mutations in non-dividing cells across several tissues, comparing stem cells to differentiated cells and studying mutagenesis in the absence of cell division. Differentiated cells in blood and colon displayed remarkably similar mutation loads and signatures to their corresponding stem cells, despite mature blood cells having undergone considerably more divisions. We then characterized the mutational landscape of post-mitotic neurons and polyclonal smooth muscle, confirming that neurons accumulate somatic mutations at a constant rate throughout life without cell division, with similar rates to mitotically active tissues. Together, our results suggest that mutational processes that are independent of cell division are important contributors to somatic mutagenesis. We anticipate that the ability to reliably detect mutations in single DNA molecules could transform our understanding of somatic mutagenesis and enable non-invasive studies on large-scale cohorts. NanoSeq is used to detect mutations in single DNA molecules and analyses show that mutational processes that are independent of cell division are important contributors to somatic mutagenesis.

Integrated records of environmental change and evolution challenge the Cambrian Explosion

Abstract: The 'Cambrian Explosion' describes the rapid increase in animal diversity and abundance, as manifest in the fossil record, between ~540 and 520 million years ago (Ma). This event, however, is nested within a far more ancient record of macrofossils extending at least into the late Ediacaran at ~571 Ma. The evolutionary events documented during the Ediacaran-Cambrian interval coincide with geochemical evidence for the modernisation of Earth's biogeochemical cycles. Holistic integration of fossil and geochemical records leads us to challenge the notion that the Ediacaran and Cambrian worlds were markedly distinct, and places biotic and environmental change within a longer-term narrative. We propose that the evolution of metazoans may have been facilitated by a series of dynamic and global changes in redox conditions and nutrient supply, which, potentially together with biotic feedbacks, enabled turnover events that sustained multiple phases of radiation. We argue that early metazoan diversification should be recast as a series of successive, transitional radiations that extended from the late Ediacaran and continued through the early Palaeozoic. We conclude that while the Cambrian Explosion represents a radiation of crown-group bilaterians, it was simply one phase amongst several metazoan radiations, some older and some younger.

Life histories of myeloproliferative neoplasms inferred from phylogenies

Abstract: Mutations in cancer-associated genes drive tumour outgrowth, but our knowledge of the timing of driver mutations and subsequent clonal dynamics is limited1–3. Here, using whole-genome sequencing of 1,013 clonal haematopoietic colonies from 12 patients with myeloproliferative neoplasms, we identified 580,133 somatic mutations to reconstruct haematopoietic phylogenies and determine clonal histories. Driver mutations were estimated to occur early in life, including the in utero period. JAK2V617F was estimated to have been acquired by 33 weeks of gestation to 10.8 years of age in 5 patients in whom JAK2V617F was the first event. DNMT3A mutations were acquired by 8 weeks of gestation to 7.6 years of age in 4 patients, and a PPM1D mutation was acquired by 5.8 years of age. Additional genomic events occurred before or following JAK2V617F acquisition and as independent clonal expansions. Sequential driver mutation acquisition was separated by decades across life, often outcompeting ancestral clones. The mean latency between JAK2V617F acquisition and diagnosis was 30 years (range 11–54 years). Estimated historical rates of clonal expansion varied substantially (3% to 190% per year), increased with additional driver mutations, and predicted latency to diagnosis. Our study suggests that early driver mutation acquisition and life-long growth and evolution underlie adult myeloproliferative neoplasms, raising opportunities for earlier intervention and a new model for cancer development. Whole-genome sequencing of 1,013 clonal haematopoietic colonies from myeloproliferative neoplasms of 12 individuals reveals haematopoietic phylogenies and indicates that driver mutations are acquired sequentially, starting early in life.

Reconstructing the reproductive mode of an Ediacaran macro-organism

Abstract: Enigmatic macrofossils of late Ediacaran age (580–541 million years ago) provide the oldest known record of diverse complex organisms on Earth, lying between the microbially dominated ecosystems of the Proterozoic and the Cambrian emergence of the modern biosphere1. Among the oldest and most enigmatic of these macrofossils are the Rangeomorpha, a group characterized by modular, self-similar branching and a sessile benthic habit2, 3, 4. Localized occurrences of large in situ fossilized rangeomorph populations allow fundamental aspects of their biology to be resolved using spatial point process techniques5. Here we use such techniques to identify recurrent clustering patterns in the rangeomorph Fractofusus, revealing a complex life history of multigenerational, stolon-like asexual reproduction, interspersed with dispersal by waterborne propagules. Ecologically, such a habit would have allowed both for the rapid colonization of a localized area and for transport to new, previously uncolonized areas. The capacity of Fractofusus to derive adult morphology by two distinct reproductive modes documents the sophistication of its underlying developmental biology.

Atmospheric Evolution on Inhabited and Lifeless Worlds

Abstract: As the search for Earth-like exoplanets gathers pace, in order to understand them, we need comprehensive theories for how planetary atmospheres form and evolve. Written by two well-known planetary scientists, this text explains the physical and chemical principles of atmospheric evolution and planetary atmospheres, in the context of how atmospheric composition and climate determine a planet's habitability. The authors survey our current understanding of the atmospheric evolution and climate on Earth, on other rocky planets within our Solar System, and on planets far beyond. Incorporating a rigorous mathematical treatment, they cover the concepts and equations governing a range of topics, including atmospheric chemistry, thermodynamics, radiative transfer, and atmospheric dynamics, and provide an integrated view of planetary atmospheres and their evolution. This interdisciplinary text is an invaluable one-stop resource for graduate-level students and researchers working across the fields of atmospheric science, geochemistry, planetary science, astrobiology, and astronomy.

Cambrian Small Bilaterian Fossils from 40 to 55 Million Years Before the Cambrian

Abstract: Ten phosphatized specimens of a small (<180 micrometers) animal displaying clear bilaterian features have been recovered from the Doushantuo Formation, China, dating from 40 to 55 million years before the Cambrian. Seen in sections, this animal (Vernanimalcula guizhouena gen. et sp. nov.) had paired coeloms extending the length of the gut; paired external pits that could be sense organs; bilateral, anterior-posterior organization; a ventrally directed anterior mouth with thick walled pharynx; and a triploblastic structure. The structural complexity is that of an adult rather than a larval form. These fossils provide the first evidence confirming the phylogenetic inference that Bilateria arose well before the Cambrian.

The origin of the animals and a 'Savannah' hypothesis for early bilaterian evolution.

Abstract: The earliest evolution of the animals remains a taxing biological problem, as all extant clades are highly derived and the fossil record is not usually considered to be helpful. The rise of the bilaterian animals recorded in the fossil record, commonly known as the ‘Cambrian explosion’, is one of the most significant moments in evolutionary history, and was an event that transformed first marine and then terrestrial environments. We review the phylogeny of early animals and other opisthokonts, and the affinities of the earliest large complex fossils, the so-called ‘Ediacaran’ taxa. We conclude, based on a variety of lines of evidence, that their affinities most likely lie in various stem groups to large metazoan groupings; a new grouping, the Apoikozoa, is erected to encompass Metazoa and Choanoflagellata. The earliest reasonable fossil evidence for total-group bilaterians comes from undisputed complex trace fossils that are younger than about 560 Ma, and these diversify greatly as the Ediacaran–Cambrian boundary is crossed a few million years later. It is generally considered that as the bilaterians diversified after this time, their burrowing behaviour destroyed the cyanobacterial mat-dominated substrates that the enigmatic Ediacaran taxa were associated with, the so-called ‘Cambrian substrate revolution’, leading to the loss of almost all Ediacara-aspect diversity in the Cambrian. Why, though, did the energetically expensive and functionally complex burrowing mode of life so typical of later bilaterians arise? Here we propose a much more positive relationship between late-Ediacaran ecologies and the rise of the bilaterians, with the largely static Ediacaran taxa acting as points of concentration of organic matter both above and below the sediment surface. The breaking of the uniformity of organic carbon availability would have signalled a decisive shift away from the essentially static and monotonous earlier Ediacaran world into the dynamic and burrowing world of the Cambrian. The Ediacaran biota thus played an enabling role in bilaterian evolution similar to that proposed for the Savannah environment for human evolution and bipedality. Rather than being obliterated by the rise of the bilaterians, the subtle remnants of Ediacara-style taxa within the Cambrian suggest that they remained significant components of Phanerozoic communities, even though at some point their enabling role for bilaterian evolution was presumably taken over by bilaterians or other metazoans. Bilaterian evolution was thus an essentially benthic event that only later impacted the planktonic environment and the style of organic export to the sea floor.

Integrated records of environmental change and evolution challenge the Cambrian Explosion

Abstract: The 'Cambrian Explosion' describes the rapid increase in animal diversity and abundance, as manifest in the fossil record, between ~540 and 520 million years ago (Ma). This event, however, is nested within a far more ancient record of macrofossils extending at least into the late Ediacaran at ~571 Ma. The evolutionary events documented during the Ediacaran-Cambrian interval coincide with geochemical evidence for the modernisation of Earth's biogeochemical cycles. Holistic integration of fossil and geochemical records leads us to challenge the notion that the Ediacaran and Cambrian worlds were markedly distinct, and places biotic and environmental change within a longer-term narrative. We propose that the evolution of metazoans may have been facilitated by a series of dynamic and global changes in redox conditions and nutrient supply, which, potentially together with biotic feedbacks, enabled turnover events that sustained multiple phases of radiation. We argue that early metazoan diversification should be recast as a series of successive, transitional radiations that extended from the late Ediacaran and continued through the early Palaeozoic. We conclude that while the Cambrian Explosion represents a radiation of crown-group bilaterians, it was simply one phase amongst several metazoan radiations, some older and some younger.

Increase of litter at the Arctic deep-sea observatory HAUSGARTEN – indirect effect of global warming?

Abstract: Although recent research has shown that marine litter has made it even to the remotest parts of our planet, little information is available about temporal trends on the deep ocean floor. To quantify litter on the deep seafloor over time, we analysed images from the HAUSGARTEN observatory (79°N) taken in 2002, 2004, 2007, 2008 and 2011 (2500 m depth). Our results indicate that litter increased from 3635 to 7710 items km⁻² between 2002 and 2011 and reached densities similar to those reported from a canyon near the Portuguese capital Lisboa. Plastic constituted the majority of litter (59%) followed by a black fabric (11%) and cardboard/paper (7%). Sixty-seven percent of the litter was entangled or colonised by invertebrates such as sponges (41%) or sea anemones (15%). The changes in litter could be an indirect consequence of the receding sea ice, which opens the Arctic Ocean to the impacts of man's activities.