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1. APOBEC mutagenesis is a common process in normal human small intestine

Author

Wang, Yichen, Robinson, Philip S, Coorens, Tim HH, Moore, Luiza, Lee-Six, Henry, Noorani, Ayesha, Sanders, Mathijs A, Jung, Hyunchul, Katainen, Riku, Heuschkel, Robert, Brunton-Sim, Roxanne, Weston, Robyn, Read, Debbie, Nobbs, Beverley, Fitzgerald, Rebecca C, Saeb-Parsy, Kourosh, Martincorena, Iñigo, Campbell, Peter J, Rushbrook, Simon, Zilbauer, Matthias, Buczacki, Simon James Alexander, Stratton, Michael R, ATG - Applied Tumor Genomics, Lauri Antti Aaltonen / Principal Investigator, Research Programs Unit, Wang, Yichen [0000-0001-5122-7545], Robinson, Philip S [0000-0002-6237-7159], Coorens, Tim HH [0000-0002-5826-3554], Moore, Luiza [0000-0001-5315-516X], Lee-Six, Henry [0000-0003-4831-8088], Fitzgerald, Rebecca C [0000-0002-3434-3568], Saeb-Parsy, Kourosh [0000-0002-0633-3696], Martincorena, Iñigo [0000-0003-1122-4416], Campbell, Peter J [0000-0002-3921-0510], Zilbauer, Matthias [0000-0002-7272-0547], Stratton, Michael R [0000-0001-6035-153X], and Apollo - University of Cambridge Repository

Subjects
45, APOBEC-1 Deaminase, Family proteins, Signatures, article, 1184 Genetics, developmental biology, physiology, 45/23, Dna, Stem-cells, 38/91, 631/114/2164, Mutagenesis, Somatic mutations, Child, Preschool, Cytidine Deaminase, Intestine, Small, 631/208/212, Genetics, Humans, RNA, Messenger, Child, Mutational processes, Selection, Apolipoproteins B, Cancer
Abstract

Funder: Core funding from the Wellcome Sanger Institute (Wellcome Trust, No. 206194)., Funder: Wellcome PhD Studentship (Wellcome Trust, No. 206194), Funder: Wellcome Clinical PhD fellowship (Wellcome Trust, No. 206194), Funder: Pathological Society of Great Britain and Ireland; doi: https://doi.org/10.13039/501100000672, Funder: Jean Shank/Pathological Society of Great Britain and Ireland Intermediate Clinical Fellowship(JSPS IF 2019 01), Funder: Finnish Center of Excellence Program 2018–2025, No. 312041, Funder: NIHR Cambridge Biomedical Research Centre, Funder: Core funding from The Pharsalia Trust., APOBEC mutational signatures SBS2 and SBS13 are common in many human cancer types. However, there is an incomplete understanding of its stimulus, when it occurs in the progression from normal to cancer cell and the APOBEC enzymes responsible. Here we whole-genome sequenced 342 microdissected normal epithelial crypts from the small intestines of 39 individuals and found that SBS2/SBS13 mutations were present in 17% of crypts, more frequent than most other normal tissues. Crypts with SBS2/SBS13 often had immediate crypt neighbors without SBS2/SBS13, suggesting that the underlying cause of SBS2/SBS13 is cell-intrinsic. APOBEC mutagenesis occurred in an episodic manner throughout the human lifespan, including in young children. APOBEC1 mRNA levels were very high in the small intestine epithelium, but low in the large intestine epithelium and other tissues. The results suggest that the high levels of SBS2/SBS13 in the small intestine are collateral damage from APOBEC1 fulfilling its physiological function of editing APOB mRNA.

Published
2023

2. Nuclear-embedded mitochondrial DNA sequences in 66,083 human genomes

Author

Wei, Wei, Schon, Katherine R, Elgar, Greg, Orioli, Andrea, Tanguy, Melanie, Giess, Adam, Tischkowitz, Marc, Caulfield, Mark J, Chinnery, Patrick F, Schon, Katherine R [0000-0001-8054-8954], Elgar, Greg [0000-0001-7323-1596], Tischkowitz, Marc [0000-0002-7880-0628], Caulfield, Mark J [0000-0001-9295-3594], Chinnery, Patrick F [0000-0002-7065-6617], and Apollo - University of Cambridge Repository

Subjects
Cell Nucleus, Multidisciplinary, DNA Repair, Genome, Human, article, 45/23, 631/67/69, Sequence Analysis, DNA, DNA, Mitochondrial, Liposarcoma, Myxoid, Mitochondria, 692/420/2489/144, Neoplasms, 631/208/212, 631/443/319/333, Mutation, Humans, DNA Breaks, Double-Stranded, Phylogeny, Germ-Line Mutation
Abstract

DNA transfer from cytoplasmic organelles to the cell nucleus is a legacy of the endosymbiotic event-the majority of nuclear-mitochondrial segments (NUMTs) are thought to be ancient, preceding human speciation1-3. Here we analyse whole-genome sequences from 66,083 people-including 12,509 people with cancer-and demonstrate the ongoing transfer of mitochondrial DNA into the nucleus, contributing to a complex NUMT landscape. More than 99% of individuals had at least one of 1,637 different NUMTs, with 1 in 8 individuals having an ultra-rare NUMT that is present in less than 0.1% of the population. More than 90% of the extant NUMTs that we evaluated inserted into the nuclear genome after humans diverged from apes. Once embedded, the sequences were no longer under the evolutionary constraint seen within the mitochondrion, and NUMT-specific mutations had a different mutational signature to mitochondrial DNA. De novo NUMTs were observed in the germline once in every 104 births and once in every 103 cancers. NUMTs preferentially involved non-coding mitochondrial DNA, linking transcription and replication to their origin, with nuclear insertion involving multiple mechanisms including double-strand break repair associated with PR domain zinc-finger protein 9 (PRDM9) binding. The frequency of tumour-specific NUMTs differed between cancers, including a probably causal insertion in a myxoid liposarcoma. We found evidence of selection against NUMTs on the basis of size and genomic location, shaping a highly heterogenous and dynamic human NUMT landscape., Wellcome, MRC, UKRI, NIHR

Published
2022
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3. Increased somatic mutation burdens in normal human cells due to defective DNA polymerases

Author

Sigurgeir Olafsson, Inigo Martincorena, Bernard C H Lee, Sara Galavotti, Philip S. Robinson, Federico Abascal, Lynn Martin, Michael R. Stratton, Claire Palles, Raheleh Rahbari, James Hewinson, Andrew R. J. Lawson, Luiza Moore, Mathijs A. Sanders, Ian Tomlinson, Emily Mitchell, Tim H. H. Coorens, Peter J. Campbell, Henry Lee-Six, Claudia Maria Assunta Pinna, Robinson, Philip S. [0000-0002-6237-7159], Coorens, Tim H. H. [0000-0002-5826-3554], Abascal, Federico [0000-0002-6201-1587], Lee-Six, Henry [0000-0003-4831-8088], Moore, Luiza [0000-0001-5315-516X], Pinna, Claudia M. A. [0000-0002-5618-7842], Rahbari, Raheleh [0000-0002-1839-7785], Campbell, Peter J. [0000-0002-3921-0510], Martincorena, Iñigo [0000-0003-1122-4416], Tomlinson, Ian [0000-0003-3037-1470], Stratton, Michael R. [0000-0001-6035-153X], Apollo - University of Cambridge Repository, Hematology, Robinson, Philip S [0000-0002-6237-7159], Coorens, Tim HH [0000-0002-5826-3554], Pinna, Claudia MA [0000-0002-5618-7842], Campbell, Peter J [0000-0002-3921-0510], and Stratton, Michael R [0000-0001-6035-153X]

Subjects
Premature aging, Adult, Adolescent, DNA polymerase, Somatic cell, Embryonic Development, medicine.disease_cause, Germline, Article, Gastrointestinal cancer, Young Adult, Germline mutation, SDG 3 - Good Health and Well-being, Intestinal Neoplasms, Genetics, medicine, Humans, Germ-Line Mutation, Phylogeny, Aged, DNA Polymerase III, Mutation, POLD1, biology, Genome, Human, Stem Cells, 631/443/7, Genomics, DNA Polymerase II, Mutation Accumulation, Middle Aged, 631/67/1504, Intestines, Ageing, Mutagenesis, 631/208/212, biology.protein
Abstract

Funder: Wellcome Clinical PhD fellowship, Funder: Wellcome PhD Studentship, Funder: Jean Shank/Pathological Society Intermediate Fellowship, Mutation accumulation in somatic cells contributes to cancer development and is proposed as a cause of aging. DNA polymerases Pol ε and Pol δ replicate DNA during cell division. However, in some cancers, defective proofreading due to acquired POLE/POLD1 exonuclease domain mutations causes markedly elevated somatic mutation burdens with distinctive mutational signatures. Germline POLE/POLD1 mutations cause familial cancer predisposition. Here, we sequenced normal tissue and tumor DNA from individuals with germline POLE/POLD1 mutations. Increased mutation burdens with characteristic mutational signatures were found in normal adult somatic cell types, during early embryogenesis and in sperm. Thus human physiology can tolerate ubiquitously elevated mutation burdens. Except for increased cancer risk, individuals with germline POLE/POLD1 mutations do not exhibit overt features of premature aging. These results do not support a model in which all features of aging are attributable to widespread cell malfunction directly resulting from somatic mutation burdens accrued during life.

Published
2021

4. The genome and lifestage-specific transcriptomes of a plant-parasitic nematode and its host reveal susceptibility genes involved in trans-kingdom synthesis of vitamin B5

Author

Shahid Siddique, Zoran S. Radakovic, Clarissa Hiltl, Clement Pellegrin, Thomas J. Baum, Helen Beasley, Andrew F. Bent, Oliver Chitambo, Divykriti Chopra, Etienne G. J. Danchin, Eric Grenier, Samer S. Habash, M. Shamim Hasan, Johannes Helder, Tarek Hewezi, Julia Holbein, Martijn Holterman, Sławomir Janakowski, Georgios D. Koutsovoulos, Olaf P. Kranse, Jose L. Lozano-Torres, Tom R. Maier, Rick E. Masonbrink, Badou Mendy, Esther Riemer, Mirosław Sobczak, Unnati Sonawala, Mark G. Sterken, Peter Thorpe, Joris J. M. van Steenbrugge, Nageena Zahid, Florian Grundler, Sebastian Eves-van den Akker, Siddique, Shahid [0000-0001-7503-4318], Baum, Thomas J [0000-0001-9241-3141], Grenier, Eric [0000-0002-2260-1101], Habash, Samer S [0000-0002-4493-1451], Hewezi, Tarek [0000-0001-5256-8878], Holbein, Julia [0000-0001-5146-9907], Lozano-Torres, Jose L [0000-0002-0021-5947], Mendy, Badou [0000-0002-5767-9638], Riemer, Esther [0000-0001-8097-8997], Sterken, Mark G [0000-0001-7119-6213], Thorpe, Peter [0000-0001-8572-4654], Zahid, Nageena [0000-0002-9015-2061], Grundler, Florian [0000-0001-8101-0558], Eves-van den Akker, Sebastian [0000-0002-8833-9679], Apollo - University of Cambridge Repository, The Wellcome Trust, University of St Andrews. School of Medicine, University of St Andrews. Institute of Behavioural and Neural Sciences, and University of St Andrews. St Andrews Bioinformatics Unit

Subjects
Tylenchida, General Physics and Astronomy, 631/337/2019, 45/23, QH426 Genetics, General Biochemistry, Genetics and Molecular Biology, QK Botany, Pantothenic Acid, 38/91, 38/89, Genetics, 2.2 Factors relating to the physical environment, Life Science, Animals, 631/449/2676/2677, Parasites, QR180 Immunology, Aetiology, QH426, Laboratorium voor Nematologie, Nutrition, MCC, Multidisciplinary, Cysts, Prevention, Human Genome, QK, article, DAS, General Chemistry, 631/158/2456, 96/63, Infectious Diseases, QR180, 631/208/212, EPS, Laboratory of Nematology, Infection, Transcriptome
Abstract

Funding: The work at University of Bonn was supported by the Federal Ministry of Education and Research, Germany (BMBF) (Grant 031A326B to FMWG) and by the German Research Foundation (DFG) (Grant SI1739/3–1 and SI1739/5-1 to S.S.). M.S.H. was supported by a fellowship from German Academic Exchange Service (DAAD; Grant 91525252)). The work at University of California Davis was supported by the National Science Foundation (NSF) (Grant IOS-1954929) and National Institute of Food and Agriculture (NIFA) (Grant 20-3994). Work on plant-parasitic nematodes at the University of Cambridge is supported by DEFRA license 125034/359149/3, and funded by BBSRC grants BB/R011311/1, BB/N021908/1, and BB/S006397/1. C.P. received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 882941. P.T. was supported by the University of St Andrews Bioinformatics Unit, funded by Wellcome Trust ISSF awards 105621/Z/14/Z and 204821/Z/16/Z. Work at Iowa State University was supported by Hatch and State of Iowa funds and a grant from the North Central Soybean Research Program. J.L.L.-T. was supported by an NWO domain Applied and Engineering Sciences VENI grant (14250) and a Wageningen University & Research Experimental Plant Sciences strategic funds grant. M.G.S. was supported by NWO domain Applied and Engineering Sciences VENI grant (17282). Plant-parasitic nematodes are a major threat to crop production in all agricultural systems. The scarcity of classical resistance genes highlights a pressing need to find new ways to develop nematode-resistant germplasm. Here, we sequence and assemble a high-quality phased genome of the model cyst nematode Heterodera schachtii to provide a platform for the first system-wide dual analysis of host and parasite gene expression over time, covering all major parasitism stages. Analysis of the hologenome of the plant-nematode infection site identified metabolic pathways that were incomplete in the parasite but complemented by the host. Using a combination of bioinformatic, genetic, and biochemical approaches, we show that a highly atypical completion of vitamin B5 biosynthesis by the parasitic animal, putatively enabled by a horizontal gene transfer from a bacterium, is required for full pathogenicity. Knockout of either plant-encoded or now nematode-encoded steps in the pathway significantly reduces parasitic success. Our experiments establish a reference for cyst nematodes, further our understanding of the evolution of plant-parasitism by nematodes, and show that congruent differential expression of metabolic pathways in the infection hologenome represents a new way to find nematode susceptibility genes. The approach identifies genome-editing-amenable targets for future development of nematode-resistant crops. Publisher PDF

Published
2022

5. Transmission history of SARS-CoV-2 in humans and white-tailed deer

Author

Willgert, Katriina, Didelot, Xavier, Surendran-Nair, Meera, Kuchipudi, Suresh V, Ruden, Rachel M, Yon, Michele, Nissly, Ruth H, Vandegrift, Kurt J, Nelli, Rahul K, Li, Lingling, Jayarao, Bhushan M, Levine, Nicole, Olsen, Randall J, Davis, James J, Musser, James M, Hudson, Peter J, Kapur, Vivek, Conlan, Andrew, Willgert, Katriina [0000-0003-3586-1997], Conlan, Andrew [0000-0002-2593-6353], and Apollo - University of Cambridge Repository

Subjects
QL, Multidisciplinary, SARS-CoV-2, Deer, article, COVID-19, Risk Assessment, Viral Zoonoses, 631/208/212, 631/326/596/2562, Animals, Humans, 692/699/255, RA, 631/326/596/4130, RC, Environmental Monitoring
Abstract

Funder: National Institute for Health Research, Funder: USDA National Institute of Food and Agriculture (NIFA) Award, Funder: NSF Ecology and Evolution of Infectious Diseases program grant, Funder: National Institute of Allergy and Infectious Diseases, National Institutes of Health grants, Funder: United States National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, The emergence of a novel pathogen in a susceptible population can cause rapid spread of infection. High prevalence of SARS-CoV-2 infection in white-tailed deer (Odocoileus virginianus) has been reported in multiple locations, likely resulting from several human-to-deer spillover events followed by deer-to-deer transmission. Knowledge of the risk and direction of SARS-CoV-2 transmission between humans and potential reservoir hosts is essential for effective disease control and prioritisation of interventions. Using genomic data, we reconstruct the transmission history of SARS-CoV-2 in humans and deer, estimate the case finding rate and attempt to infer relative rates of transmission between species. We found no evidence of direct or indirect transmission from deer to human. However, with an estimated case finding rate of only 4.2%, spillback to humans cannot be ruled out. The extensive transmission of SARS-CoV-2 within deer populations and the large number of unsampled cases highlights the need for active surveillance at the human–animal interface.

Published
2022

6. Transferability of genetic risk scores in African populations

Author

Kamiza, Abram B, Toure, Sounkou M, Vujkovic, Marijana, Machipisa, Tafadzwa, Soremekun, Opeyemi S, Kintu, Christopher, Corpas, Manuel, Pirie, Fraser, Young, Elizabeth, Gill, Dipender, Sandhu, Manjinder S, Kaleebu, Pontiano, Nyirenda, Moffat, Motala, Ayesha A, Chikowore, Tinashe, Fatumo, Segun, Vujkovic, Marijana [0000-0003-4924-5714], Machipisa, Tafadzwa [0000-0002-4882-9067], Corpas, Manuel [0000-0002-4417-1018], Gill, Dipender [0000-0001-7312-7078], Nyirenda, Moffat [0000-0003-2120-4806], Chikowore, Tinashe [0000-0002-6743-751X], Fatumo, Segun [0000-0003-4525-3362], and Apollo - University of Cambridge Repository

Subjects
Population Groups, Risk Factors, 631/208/212, brief-communication, Black People, Humans, 631/208/1516, Cholesterol, LDL, General Medicine, Brief Communication, General Biochemistry, Genetics and Molecular Biology, Genome-Wide Association Study
Abstract

The poor transferability of genetic risk scores (GRSs) derived from European ancestry data in diverse populations is a cause of concern. We set out to evaluate whether GRSs derived from data of African American individuals and multiancestry data perform better in sub-Saharan Africa (SSA) compared to European ancestry-derived scores. Using summary statistics from the Million Veteran Program (MVP), we showed that GRSs derived from data of African American individuals enhance polygenic prediction of lipid traits in SSA compared to European and multiancestry scores. However, our GRS prediction varied greatly within SSA between the South African Zulu (low-density lipoprotein cholesterol (LDL-C), R2 = 8.14%) and Ugandan cohorts (LDL-C, R2 = 0.026%). We postulate that differences in the genetic and environmental factors between these population groups might lead to the poor transferability of GRSs within SSA. More effort is required to optimize polygenic prediction in Africa.

Published
2022

7. Long-read-sequenced reference genomes of the seven major lineages of enterotoxigenic Escherichia coli (ETEC) circulating in modern time

Author

Åsa Sjöling, Ann-Mari Svennerholm, Christine J. Boinett, Astrid von Mentzer, Enrique Joffré, Derek Pickard, Gordon Dougan, Grace A. Blackwell, Andrew J. Page, Dougan, Gordon [0000-0003-0022-965X], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Diarrhea, Virulence Factors, Science, 030106 microbiology, Virulence, Genomics, Antineoplastic Agents, Biology, medicine.disease_cause, Microbiology, Genome, 03 medical and health sciences, Plasmid, Enterotoxigenic Escherichia coli, Drug Resistance, Bacterial, medicine, Humans, Clinical microbiology, Gene, Illumina dye sequencing, 631/326, Escherichia coli Infections, Phylogeny, Synteny, Genetics, 631/326/107, Multidisciplinary, 631/326/325, 631/326/421, Escherichia coli Proteins, article, 631/208/325, Reference Standards, bacterial infections and mycoses, 030104 developmental biology, 631/208/212, Medicine, Pathogens, Microbial genetics, Genome, Bacterial
Abstract

Enterotoxigenic Escherichia coli (ETEC) is an enteric pathogen responsible for the majority of diarrheal cases worldwide. ETEC infections are estimated to cause 80,000 deaths annually, with the highest rates of burden, ca 75 million cases per year, amongst children under 5 years of age in resource-poor countries. It is also the leading cause of diarrhoea in travellers. Previous large-scale sequencing studies have found seven major ETEC lineages currently in circulation worldwide. We used PacBio long-read sequencing combined with Illumina sequencing to create high-quality complete reference genomes for each of the major lineages with manually curated chromosomes and plasmids. We confirm that the major ETEC lineages all harbour conserved plasmids that have been associated with their respective background genomes for decades, suggesting that the plasmids and chromosomes of ETEC are both crucial for ETEC virulence and success as pathogens. The in-depth analysis of gene content, synteny and correct annotations of plasmids will elucidate other plasmids with and without virulence factors in related bacterial species. These reference genomes allow for fast and accurate comparison between different ETEC strains, and these data will form the foundation of ETEC genomics research for years to come.

Published
2021

8. Somatic mutation rates scale with lifespan across mammals

Author

Alex Cagan, Adrian Baez-Ortega, Natalia Brzozowska, Federico Abascal, Tim H. H. Coorens, Mathijs A. Sanders, Andrew R. J. Lawson, Luke M. R. Harvey, Shriram Bhosle, David Jones, Raul E. Alcantara, Timothy M. Butler, Yvette Hooks, Kirsty Roberts, Elizabeth Anderson, Sharna Lunn, Edmund Flach, Simon Spiro, Inez Januszczak, Ethan Wrigglesworth, Hannah Jenkins, Tilly Dallas, Nic Masters, Matthew W. Perkins, Robert Deaville, Megan Druce, Ruzhica Bogeska, Michael D. Milsom, Björn Neumann, Frank Gorman, Fernando Constantino-Casas, Laura Peachey, Diana Bochynska, Ewan St. John Smith, Moritz Gerstung, Peter J. Campbell, Elizabeth P. Murchison, Michael R. Stratton, Iñigo Martincorena, Cagan, Alex [0000-0002-7857-4771], Abascal, Federico [0000-0002-6201-1587], Coorens, Tim H. H. [0000-0002-5826-3554], Lawson, Andrew R. J. [0000-0003-3592-1005], Bhosle, Shriram [0000-0002-7638-2899], Jones, David [0000-0002-0407-0386], Butler, Timothy M. [0000-0001-5803-1035], Spiro, Simon [0000-0002-9621-2192], Milsom, Michael D. [0000-0002-3567-254X], Bochynska, Diana [0000-0003-0219-8818], Smith, Ewan St. John [0000-0002-2699-1979], Gerstung, Moritz [0000-0001-6709-963X], Campbell, Peter J. [0000-0002-3921-0510], Murchison, Elizabeth P. [0000-0001-7462-8907], Stratton, Michael R. [0000-0001-6035-153X], Martincorena, Iñigo [0000-0003-1122-4416], Apollo - University of Cambridge Repository, Hematology, Coorens, Tim HH [0000-0002-5826-3554], Lawson, Andrew RJ [0000-0003-3592-1005], Butler, Timothy M [0000-0001-5803-1035], Milsom, Michael D [0000-0002-3567-254X], Smith, Ewan St John [0000-0002-2699-1979], Campbell, Peter J [0000-0002-3921-0510], Murchison, Elizabeth P [0000-0001-7462-8907], Stratton, Michael R [0000-0001-6035-153X], Smith, Ewan [0000-0002-2699-1979], and Murchison, Elizabeth [0000-0001-7462-8907]

Subjects
Scale (anatomy), Somatic cell, Longevity, Normal tissue, 45/23, 631/67/69, Biology, 13, 14, Oxidative damage, Germline mutation, Mutation Rate, SDG 3 - Good Health and Well-being, Animals, Humans, 631/208/212/748, Mammals, Multidisciplinary, 45, Mutagenesis, 631/443/7, article, 45/77, Ageing, Evolutionary biology, Mutation, 631/208/212, 14/63, Trait
Abstract

The rates and patterns of somatic mutation in normal tissues are largely unknown outside of humans1–7. Comparative analyses can shed light on the diversity of mutagenesis across species, and on long-standing hypotheses about the evolution of somatic mutation rates and their role in cancer and ageing. Here we performed whole-genome sequencing of 208 intestinal crypts from 56 individuals to study the landscape of somatic mutation across 16 mammalian species. We found that somatic mutagenesis was dominated by seemingly endogenous mutational processes in all species, including 5-methylcytosine deamination and oxidative damage. With some differences, mutational signatures in other species resembled those described in humans8, although the relative contribution of each signature varied across species. Notably, the somatic mutation rate per year varied greatly across species and exhibited a strong inverse relationship with species lifespan, with no other life-history trait studied showing a comparable association. Despite widely different life histories among the species we examined—including variation of around 30-fold in lifespan and around 40,000-fold in body mass—the somatic mutation burden at the end of lifespan varied only by a factor of around 3. These data unveil common mutational processes across mammals, and suggest that somatic mutation rates are evolutionarily constrained and may be a contributing factor in ageing.

Published
2022

9. Precise identification of cancer cells from allelic imbalances in single cell transcriptomes

Author

Mi K. Trinh, Clarissa N. Pacyna, Gerda Kildisiute, Christine Thevanesan, Alice Piapi, Kirsty Ambridge, Nathaniel D. Anderson, Eleonora Khabirova, Elena Prigmore, Karin Straathof, Sam Behjati, Matthew D. Young, Trinh, Mi K [0000-0003-4185-0071], Pacyna, Clarissa N [0000-0002-4404-8183], Kildisiute, Gerda [0000-0002-5314-2294], Anderson, Nathaniel D [0000-0003-4523-6327], Khabirova, Eleonora [0000-0002-5891-6789], Behjati, Sam [0000-0002-6600-7665], Young, Matthew D [0000-0003-0937-5290], and Apollo - University of Cambridge Repository

Subjects
45/91, Genotype, article, Medicine (miscellaneous), 631/114/1314, 631/208/514, 45/23, 631/67/69, Allelic Imbalance, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Neoplasms, 631/208/212, Humans, RNA, Messenger, General Agricultural and Biological Sciences, Transcriptome
Abstract

A fundamental step of tumour single cell mRNA analysis is separating cancer and non-cancer cells. We show that the common approach to separation, using shifts in average expression, can lead to erroneous biological conclusions. By contrast, allelic imbalances representing copy number changes directly detect the cancer genotype and accurately separate cancer from non-cancer cells. Our findings provide a definitive approach to identifying cancer cells from single cell mRNA sequencing data.

Published
2022

10. Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women

Author

Kamil Sicinski, B. Gwen Windham, Nathalie van der Velde, Luigi Ferrucci, Jian'an Luan, Fernando Rivadeneira, Thuy Vy Duong, Ryan Cvejkus, David A. Bennett, José A. Carnicero, Megan L. Grove, Stefan Walter, Cheryl L. Ackert-Bicknell, Joshua R. Lewis, Adam J. Santanasto, David Melzer, Aron S. Buchman, Janice L. Atkins, Garan Jones, Joanne M. Murabito, Shengjun Hong, Stefania Bandinelli, Michelle C. Odden, Leocadio Rodríguez-Mañas, Magnus Karlsson, Erika Kague, Najada Stringa, Francisco J. Garcia, Chia-Ling Kuo, Dominik Spira, Maria Nethander, André G. Uitterlinden, Claes Ohlsson, Jingyun Yang, Sahar Ghasemi, George A. Kuchel, Dan Mellström, Eric Boerwinkle, Pamela Herd, Lisette C. P. G. M. de Groot, Alexander Teumer, M. Carola Zillikens, Alison E. Fohner, Dan E. Arking, Douglas P. Kiel, Kathryn L. Lunetta, Claudia Langenberg, Toshiko Tanaka, David Karasik, Natasja M. van Schoor, Thomas Kocher, Luke C. Pilling, Lars Bertram, Bruce M. Psaty, Philip L. De Jager, Katerina Trajanoska, Martijn Huisman, Joseph M. Zmuda, Mary L. Biggs, Misa Graff, Qihua Tan, Ilja Demuth, Mary K. Wojczynski, Nicholas J. Wareham, Uwe Völker, Chloé Sarnowski, Jones, Garan [0000-0002-8917-3930], Trajanoska, Katerina [0000-0002-3792-4296], Santanasto, Adam J. [0000-0002-6912-2909], Stringa, Najada [0000-0001-6350-452X], Atkins, Janice L. [0000-0003-4919-9068], Lewis, Joshua R. [0000-0003-1003-8443], Luan, Jian’an [0000-0003-3137-6337], Sarnowski, Chloe [0000-0002-6090-7099], Lunetta, Kathryn L. [0000-0002-9268-810X], Cvejkus, Ryan [0000-0001-5287-5341], Nethander, Maria [0000-0003-3688-906X], Yang, Jingyun [0000-0002-3495-3710], Walter, Stefan [0000-0002-6010-7550], Kague, Erika [0000-0002-0266-9424], Graff, Misa [0000-0001-6380-1735], de Groot, Lisette C. P. G. M. [0000-0003-2778-2789], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas J. [0000-0003-1422-2993], Tan, Qihua [0000-0003-3194-0030], Buchman, Aron S. [0000-0002-6426-2742], De Jager, Philip L. [0000-0002-8057-2505], Uitterlinden, Andre G. [0000-0002-7276-3387], Völker, Uwe [0000-0002-5689-3448], Kocher, Thomas [0000-0001-9605-2822], Teumer, Alexander [0000-0002-8309-094X], Bertram, Lars [0000-0002-0108-124X], Melzer, David [0000-0002-0170-3838], Kuchel, George A. [0000-0001-8387-7040], Ferrucci, Luigi [0000-0002-6273-1613], Karasik, David [0000-0002-8826-0530], Rivadeneira, Fernando [0000-0001-9435-9441], Kiel, Douglas P. [0000-0001-8474-0310], Pilling, Luke C. [0000-0002-3332-8454], Apollo - University of Cambridge Repository, Epidemiology, Internal Medicine, VU University medical center, General practice, Epidemiology and Data Science, APH - Aging & Later Life, APH - Personalized Medicine, APH - Societal Participation & Health, Geriatrics, AMS - Ageing & Vitality, Santanasto, Adam J [0000-0002-6912-2909], Atkins, Janice L [0000-0003-4919-9068], Lewis, Joshua R [0000-0003-1003-8443], Luan, Jian'an [0000-0003-3137-6337], Lunetta, Kathryn L [0000-0002-9268-810X], de Groot, Lisette CPGM [0000-0003-2778-2789], Wareham, Nicholas J [0000-0003-1422-2993], Buchman, Aron S [0000-0002-6426-2742], De Jager, Philip L [0000-0002-8057-2505], Uitterlinden, Andre G [0000-0002-7276-3387], Kuchel, George A [0000-0001-8387-7040], Kiel, Douglas P [0000-0001-8474-0310], and Pilling, Luke C [0000-0002-3332-8454]

Subjects
Male, 0301 basic medicine, Aging, Sarcopenia, 45/43, General Physics and Astronomy, Arthritis, Bioinformatics, Cohort Studies, Grip strength, 0302 clinical medicine, Growth Differentiation Factor 5, Genetics research, Aged, 80 and over, Geriatrics, Muscle Weakness, Multidisciplinary, article, Genomics, 631/208/205, Middle Aged, Nutritional Biology, Europe, Meta-analysis, 631/208/212, Medical genetics, Female, medicine.symptom, Cohort study, medicine.medical_specialty, Science, Predictive markers, Polymorphism, Single Nucleotide, HLA-DQ alpha-Chains, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Diabetes mellitus, 692/53/2423, Mendelian randomization, medicine, Life Science, Humans, Genetic Predisposition to Disease, Muscle Strength, Genetic association study, Aged, VLAG, Autoimmune disease, 45, business.industry, 692/308/2056, Muscle weakness, General Chemistry, medicine.disease, 030104 developmental biology, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10−17), arthritis (GDF5 p = 4 × 10−13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing., Muscle weakness has been associated with morbidity and mortality in older people. Here, the authors have investigated this trait further by performing a genome-wide meta-analysis of grip strength and Mendelian randomization to discover causal relationships between muscle weakness and other diseases.

Published
2021

11. Genetic association study of childhood aggression across raters, instruments, and age

Author

Nicholas G. Martin, S. Alexandra Burt, Louise Arseneault, Fazil Aliev, Luke M. Evans, Hill F. Ip, Beate St Pourcain, Michel G. Nivard, William E. Copeland, Rebecca K. Vinding, Scott Gordon, Koen Bolhuis, Christian J. Hopfer, Gun Peggy Knudsen, Stefan Johansson, Avshalom Caspi, Richard Border, Chandra A. Reynolds, Pål R. Njølstad, Liisa Keltikangas-Järvinen, Dorret I. Boomsma, Klaus Bønnelykke, Teemu Palviainen, Marta Ribasés, Alina Rodriguez, Catharina A. Hartman, Ilkka Seppälä, Christel M. Middeldorp, Rosa Bosch, Jan Haavik, Gail M. Williams, Andrea G. Allegrini, Ruth Ks, John R. B. Perry, Hadi Zafarmand, Chang Jiang, Elizabeth J. Costello, Camiel M. van der Laan, Olli T. Raitakari, Miquel Casas, Isabell Brikell, William G. Iacono, Jaakko Kaprio, John K. Hewitt, Andrew C. Heath, Eero Vuoksimaa, Xiaoran Tong, Gemma Español, Erik A. Ehli, Richie Poulton, Gareth E. Davies, Albertine J. Oldehinkel, Hans Bisgaard, Naomi R. Wray, Ted Reichborn-Kjennerud, Robert Plomin, Michael C. Stallings, Qing Lu, Jackob M. Najman, Daniel E. Adkins, Yi Lu, Harold Snieder, Sally J. Wadsworth, Alexander Neumann, Alexandra Havdahl, Karen Sugden, Kelly L. Klump, Andrew Smolen, Henrik Larsson, Toos C. E. M. van Beijsterveldt, Kenneth Krauter, Tarunveer S. Ahluwalia, Tellervo Korhonen, Andrey A. Shabalin, Joachim Heinrich, Anke R. Hammerschlag, Shelby Marrington, Lærke Sass, Pamela A. F. Madden, Henning Tiemeier, Tanja Vrijkotte, Paul Lichtenstein, Terho Lehtimäki, Ville Karhunen, Cristina Sánchez-Mora, Robin P. Corley, Anna A. E. Vinkhuyzen, Richard J. Rose, Per Magnus, Sabrina Llop, Ilja M. Nolte, S.A. Brown, Christian Hakulinen, Anjali K. Henders, Marie Standl, Silvia Alemany, Gretchen R.B. Saunders, Jouke-Jan Hottenga, Eveline L. de Zeeuw, Meike Bartels, Elisabeth Thiering, José J. Morosoli, Fiona A. Hagenbeek, Laura Pulkki-Råback, Frank C. Verhulst, Martin A. Kennedy, Craig E. Pennell, Eva Krapohl, Kaili Rimfeld, Tetyana Zayats, Lucía Colodro-Conde, Judith B.M. Ensink, André G. Uitterlinden, Natalia Vilor-Tejedor, Felix R. Day, Jennifer R. Harris, George Davey Smith, Qi Chen, Sebastian Lundström, Marjo-Riitta Järvelin, Alyce M. Whipp, Katrina L. Grasby, L. John Horwood, John Pearson, Judy L. Silberg, Paula Rovira, Hermine H. Maes, Carol A. Wang, Roseann E. Peterson, Tamara L. Wall, Andrew J. O. Whitehouse, Maria-Jose Lopez-Espinosa, Najaf Amin, Jess Tyrrell, Danielle M. Dick, Sarah E. Medland, Allison L. Miller, Øyvind Helgeland, Josep Antoni Ramos Quiroga, Joseph M. Boden, Abdullah Mamun, James Scott, María Soler Artigas, Joseph A. Prinz, Lindon J. Eaves, Terrie E. Moffitt, Matt McGue, Jordi Sunyer, Joanna Martin, Tampere University, Clinical Medicine, Department of Clinical Chemistry, Apollo-University Of Cambridge Repository, Ip, Hill F [0000-0003-1991-5019], Sánchez-Mora, Cristina [0000-0003-4211-1107], Nolte, Ilja M [0000-0001-5047-4077], St Pourcain, Beate [0000-0002-4680-3517], Palviainen, Teemu [0000-0002-7847-8384], Colodro-Conde, Lucía [0000-0002-9004-364X], Gordon, Scott [0000-0001-7623-328X], Aliev, Fazil [0000-0001-8357-4699], Karhunen, Ville [0000-0001-6064-1588], Border, Richard [0000-0002-6293-2968], Ahluwalia, Tarunveer S [0000-0002-7464-3354], Day, Felix R [0000-0003-3789-7651], Hottenga, Jouke-Jan [0000-0002-5668-2368], Rimfeld, Kaili [0000-0001-5139-065X], Lu, Yi [0000-0001-9933-3654], Soler Artigas, María [0000-0002-3213-1107], Bosch, Rosa [0000-0002-7596-183X], Ramos Quiroga, Josep Antoni [0000-0003-1622-0350], Neumann, Alexander [0000-0001-6653-3203], Grasby, Katrina [0000-0001-8539-0228], Middeldorp, Christel [0000-0002-6218-0428], Evans, Luke M [0000-0002-7458-1720], Alemany, Silvia [0000-0002-7925-6767], Sass, Lærke [0000-0002-5217-7014], Ruth, Kate [0000-0003-4966-9170], Ehli, Erik A [0000-0002-7865-3015], Hagenbeek, Fiona A [0000-0002-8773-0430], Snieder, Harold [0000-0003-1949-2298], Uitterlinden, André G [0000-0002-7276-3387], Haavik, Jan [0000-0001-7865-2808], Johansson, Stefan [0000-0002-2298-7008], Knudsen, Gun Peggy S [0000-0002-6193-4291], Njolstad, Pal Rasmus [0000-0003-0304-6728], Rodriguez, Alina [0000-0003-1209-8802], Brown, Sandy [0000-0001-8780-0323], Miller, Allison [0000-0003-3816-2251], Keltikangas-Järvinen, Liisa [0000-0002-7977-3852], Havdahl, Alexandra [0000-0002-9268-0423], Perry, John RB [0000-0001-6483-3771], Lehtimäki, Terho [0000-0002-2555-4427], Arseneault, Louise [0000-0002-2938-2191], Boden, Joseph [0000-0003-1502-1608], Pearson, John [0000-0001-5607-4517], Kennedy, Martin [0000-0002-6445-8526], Poulton, Richie [0000-0002-1052-4583], Copeland, William E [0000-0002-1348-7781], Wray, Naomi [0000-0001-7421-3357], Järvelin, Marjo-Riitta [0000-0002-2149-0630], McGue, Matt [0000-0002-5580-1433], Pennell, Craig E [0000-0002-0937-6165], Dick, Danielle M [0000-0002-1636-893X], Martin, Nicholas G [0000-0003-4069-8020], Medland, Sarah E [0000-0003-1382-380X], Kaprio, Jaakko [0000-0002-3716-2455], Tiemeier, Henning [0000-0002-4395-1397], Davey Smith, George [0000-0002-1407-8314], Oldehinkel, Albertine J [0000-0003-3925-3913], Ribasés, Marta [0000-0003-1039-1116], Lichtenstein, Paul [0000-0003-3037-5287], Plomin, Robert [0000-0002-0756-3629], Bartels, Meike [0000-0002-9667-7555], Nivard, Michel G [0000-0003-2015-1888], Boomsma, Dorret I [0000-0002-7099-7972], Apollo - University of Cambridge Repository, Life Course Epidemiology (LCE), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Child and Adolescent Psychiatry / Psychology, Epidemiology, Internal Medicine, Institute for Molecular Medicine Finland, Genetic Epidemiology, Helsinki Institute of Life Science HiLIFE, University of Helsinki, Tellervo Korhonen / Principal Investigator, Cognitive and Brain Aging, Faculty Common Matters (Faculty of Medicine), Medicum, Doctoral Programme in Cognition, Learning, Instruction and Communication, Department of Psychology and Logopedics, Helsinki Inequality Initiative (INEQ), Faculty Common Matters (Faculty of Education), Psychosocial factors and health, Behavioural Sciences, Department of Public Health, Adult Psychiatry, Epidemiology and Data Science, APH - Aging & Later Life, APH - Methodology, ARD - Amsterdam Reproduction and Development, Graduate School, Child Psychiatry, ACS - Pulmonary hypertension & thrombosis, ANS - Cellular & Molecular Mechanisms, ANS - Compulsivity, Impulsivity & Attention, Public and occupational health, APH - Health Behaviors & Chronic Diseases, Institut Català de la Salut, [Ip HF] Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. [van der Laan CM] Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. Netherlands Institute for the Study of Crime and Law Enforcement, Amsterdam, The Netherlands. [Krapohl EML] Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK. [Brikell I] Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. [Sánchez-Mora C, Soler Artigas M, Rovira P, Ribasés M] Servei de Psiquiatria, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Barcelona, Spain. Unitat de Genètica Psiquiàtrica, Grup de Recerca en Psiquiatria, Salut Mental i Addicció, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Nolte IM] Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. [Bosch R] Servei de Psiquiatria, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Barcelona, Spain. Servei de Psiquiatria i Medicina Legal, Universitat Autònoma de Barcelona, Bellaterra, Spain. [Español G] Servei de Psiquiatria, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Ramos Quiroga JA, Ribasés M] Servei de Psiquiatria, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Barcelona, Spain. Unitat de Genètica Psiquiàtrica, Grup de Recerca en Psiquiatria, Salut Mental i Addicció, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Servei de Psiquiatria i Medicina Legal, Universitat Autònoma de Barcelona, Bellaterra, Spain, Vall d'Hebron Barcelona Hospital Campus, Biological Psychology, APH - Personalized Medicine, APH - Mental Health, Amsterdam Reproduction & Development, Perry, John R B [0000-0001-6483-3771], Ip, Hill F. [0000-0003-1991-5019], Nolte, Ilja M. [0000-0001-5047-4077], Ahluwalia, Tarunveer S. [0000-0002-7464-3354], Day, Felix R. [0000-0003-3789-7651], Evans, Luke M. [0000-0002-7458-1720], Ehli, Erik A. [0000-0002-7865-3015], Hagenbeek, Fiona A. [0000-0002-8773-0430], Uitterlinden, André G. [0000-0002-7276-3387], Knudsen, Gun Peggy S. [0000-0002-6193-4291], Perry, John R. B. [0000-0001-6483-3771], Copeland, William E. [0000-0002-1348-7781], Pennell, Craig E. [0000-0002-0937-6165], Dick, Danielle M. [0000-0002-1636-893X], Martin, Nicholas G. [0000-0003-4069-8020], Medland, Sarah E. [0000-0003-1382-380X], Oldehinkel, Albertine J. [0000-0003-3925-3913], Nivard, Michel G. [0000-0003-2015-1888], and Boomsma, Dorret I. [0000-0002-7099-7972]

Subjects
0301 basic medicine, DISORDER, 45/43, Genome-wide association study, 3124 Neurology and psychiatry, 0302 clinical medicine, Child, Psychiatry, 0303 health sciences, trastornos mentales [PSIQUIATRÍA Y PSICOLOGÍA], HERITABILITY, Mental Disorders, Cognition, Genomics, Explained variation, Justice and Strong Institutions, Aggression, Psychiatry and Mental health, Meta-analysis, ADOLESCENCE, Child, Preschool, conducta y mecanismos de la conducta::conducta::síntomas conductuales::agresión [PSIQUIATRÍA Y PSICOLOGÍA], 631/208/212, Female, Biological psychiatry, medicine.symptom, Life Sciences & Biomedicine, Investigative Techniques::Genetic Techniques::Genetic Association Studies [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], BEHAVIOR, RC321-571, Childhood aggression, Clinical psychology, SDG 16 - Peace, Adolescent, Mental Disorders [PSYCHIATRY AND PSYCHOLOGY], Neurosciences. Biological psychiatry. Neuropsychiatry, Single-nucleotide polymorphism, Biology, 3121 Internal medicine, Malalties mentals - Aspectes genètics, Genetic correlation, Article, 1117 Public Health and Health Services, Cellular and Molecular Neuroscience, 03 medical and health sciences, 631/477/2811, SDG 3 - Good Health and Well-being, Human behaviour, medicine, SNP, Humans, GENOME-WIDE ASSOCIATION, Biological Psychiatry, Genetic Association Studies, 030304 developmental biology, Genetic association, Retrospective Studies, técnicas de investigación::técnicas genéticas::estudios de asociación genética [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Science & Technology, SDG 16 - Peace, Justice and Strong Institutions, Infant, Behavior and Behavior Mechanisms::Behavior::Behavioral Symptoms::Aggression [PSYCHIATRY AND PSYCHOLOGY], 1103 Clinical Sciences, Agressivitat en els infants, Heritability, 030104 developmental biology, 1701 Psychology, ORIGINS, Research Programm of Donders Centre for Neuroscience, 3111 Biomedicine, TRAJECTORIES, 030217 neurology & neurosurgery, Demography, Genome-Wide Association Study
Abstract

Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E–06), PCDH7 (P = 2.0E–06), and IPO13 (P = 2.5E–06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from rg = 0.46 between self- and teacher-assessment to rg = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range $$\left| {r_g} \right|$$ r g : 0.19–1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg = ~−0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range $$\left| {r_g} \right|$$ r g : 0.46–0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.

Published
2021

12. Distinct genetic architectures and environmental factors associate with host response to the γ2-herpesvirus infections

Author

Denise Whitby, Alexander T. Dilthey, Deepti Gurdasani, Martin L. Hibberd, Wendell Miley, Manjinder S. Sandhu, Cristina Pomilla, Paul Kellam, Nazzarena Labo, Robert U. Newton, Gershim Asiki, Elena M. Cornejo Castro, Vickie Marshall, Alexander J. Mentzer, Elizabeth H. Young, Martin O. Pollard, Inês Barroso, Neneh Sallah, Tommy Carstensen, Segun Fatumo, Sallah, Neneh [0000-0002-2953-5311], Pollard, Martin O [0000-0001-8738-0920], Dilthey, Alexander T [0000-0002-6394-4581], Mentzer, Alexander J [0000-0002-4502-2209], Cornejo Castro, Elena M [0000-0003-1480-1397], Asiki, Gershim [0000-0002-9966-1153], Hibberd, Martin L [0000-0001-8587-1849], Sandhu, Manjinder [0000-0002-2725-142X], Kellam, Paul [0000-0003-3166-4734], Barroso, Inês [0000-0001-5800-4520], Apollo - University of Cambridge Repository, Pollard, Martin O. [0000-0001-8738-0920], Dilthey, Alexander T. [0000-0002-6394-4581], Mentzer, Alexander J. [0000-0002-4502-2209], Cornejo Castro, Elena M. [0000-0003-1480-1397], and Hibberd, Martin L. [0000-0001-8587-1849]

Subjects
0301 basic medicine, Male, Rural Population, Epstein-Barr Virus Infections, Herpesvirus 4, Human, Urban Population, viruses, 45/43, General Physics and Astronomy, Gene Expression, Genome-wide association study, Disease, Antibodies, Viral, 0302 clinical medicine, hemic and lymphatic diseases, Uganda, lcsh:Science, Antigens, Viral, Disease Resistance, Henipavirus Infections, Multidisciplinary, 631/208/729, Transmission (medicine), Coinfection, Incidence, virus diseases, Genomics, 631/208/721, 631/208/248, Middle Aged, 631/208/727, 030220 oncology & carcinogenesis, 631/208/212, Herpesvirus 8, Human, Host-Pathogen Interactions, Female, 82/1, 141, Adult, HIV Positivity, Genotype, Adolescent, Science, 45/23, Human leukocyte antigen, Biology, General Biochemistry, Genetics and Molecular Biology, Virus, Article, HLA-DQ alpha-Chains, 03 medical and health sciences, Antigen, medicine, Immunogenetics, Humans, Sarcoma, Kaposi, HIV, General Chemistry, medicine.disease, 030104 developmental biology, Epstein-Barr Virus Nuclear Antigens, Immunology, Genetic markers, lcsh:Q, Heritable quantitative trait, Capsid Proteins, Genome-Wide Association Study
Abstract

Kaposi’s sarcoma-associated herpesvirus (KSHV) and Epstein-Barr Virus (EBV) establish life-long infections and are associated with malignancies. Striking geographic variation in incidence and the fact that virus alone is insufficient to cause disease, suggests other co-factors are involved. Here we present epidemiological analysis and genome-wide association study (GWAS) in 4365 individuals from an African population cohort, to assess the influence of host genetic and non-genetic factors on virus antibody responses. EBV/KSHV co-infection (OR = 5.71(1.58–7.12)), HIV positivity (OR = 2.22(1.32–3.73)) and living in a more rural area (OR = 1.38(1.01–1.89)) are strongly associated with immunogenicity. GWAS reveals associations with KSHV antibody response in the HLA-B/C region (p = 6.64 × 10−09). For EBV, associations are identified for VCA (rs71542439, p = 1.15 × 10−12). Human leucocyte antigen (HLA) and trans-ancestry fine-mapping substantiate that distinct variants in HLA-DQA1 (p = 5.24 × 10−44) are driving associations for EBNA-1 in Africa. This study highlights complex interactions between KSHV and EBV, in addition to distinct genetic architectures resulting in important differences in pathogenesis and transmission., Disease prognosis after infection with Kaposi’s sarcoma-associated herpesvirus and Epstein-Barr Virus is highly variable. Here the authors carry out epidemiological and genetic analysis of a Ugandan cohort and suggest complex interactions may influence pathogenesis and transmission.

Published
2020

13. Comprehensive molecular characterization of mitochondrial genomes in human cancers

Author

Inigo Martincorena, Keunchil Park, Yang Yang, Yanxun Xu, Yuan Yuan, Han Liang, Hidewaki Nakagawa, Hyung Lae Kim, Leng Han, Chad J. Creighton, Yumeng Wang, Christopher J. Yoon, Young-Wook Kim, Peter J. Campbell, Jun Li, Young Seok Ju, John N. Weinstein, Yuan, Yuan [0000-0003-4706-7897], Ju, Young Seok [0000-0002-5514-4189], Kim, Youngwook [0000-0002-1106-3037], Li, Jun [0000-0002-1171-7141], Creighton, Chad J. [0000-0002-6090-703X], Weinstein, John N. [0000-0001-9401-6908], Han, Leng [0000-0002-7380-2640], Park, Keunchil [0000-0002-4846-7449], Campbell, Peter J. [0000-0002-3921-0510], Liang, Han [0000-0001-7633-286X], and Apollo - University of Cambridge Repository

Subjects
631/67, Whole genome sequencing, 0303 health sciences, Mitochondrial DNA, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], DNA repair, Sequence analysis, 45/23, Genomics, Computational biology, Mitochondrion, Biology, Genome, Human genetics, 3. Good health, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, 631/208/212, Genetics, Gene, Analysis, Cancer, 030304 developmental biology
Abstract

Mitochondria are essential cellular organelles that play critical roles in cancer. Here, as part of the International Cancer Genome Consortium/The Cancer Genome Atlas Pan-Cancer Analysis of Whole Genomes Consortium, which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumor types, we performed a multidimensional, integrated characterization of mitochondrial genomes and related RNA sequencing data. Our analysis presents the most definitive mutational landscape of mitochondrial genomes and identifies several hypermutated cases. Truncating mutations are markedly enriched in kidney, colorectal and thyroid cancers, suggesting oncogenic effects with the activation of signaling pathways. We find frequent somatic nuclear transfers of mitochondrial DNA, some of which disrupt therapeutic target genes. Mitochondrial copy number varies greatly within and across cancers and correlates with clinical variables. Co-expression analysis highlights the function of mitochondrial genes in oxidative phosphorylation, DNA repair and the cell cycle, and shows their connections with clinically actionable genes. Our study lays a foundation for translating mitochondrial biology into clinical applications., Analysis of mitochondrial genomes (mtDNA) by using whole-genome sequencing data from 2,658 cancer samples across 38 cancer types identifies hypermutated mtDNA cases, frequent somatic nuclear transfer of mtDNA and high variability of mtDNA copy number in many cancers.

Published
2020

14. A practical guide for mutational signature analysis in hematological malignancies

Author

Elias Campo, Daniel Leongamornlert, Bachisio Ziccheddu, Peter J. Campbell, Helen Davies, Nikhil C. Munshi, Andrea Degasperi, Serena Nik-Zainal, Hervé Avet-Loiseau, Niccolo Bolli, Francesco Maura, Romina Royo, Ferran Nadeu, Xose S. Puente, Luiza Moore, Degasperi, Andrea [0000-0001-6879-0596], Moore, Luiza [0000-0001-5315-516X], Nik-Zainal, Serena [0000-0001-5054-1727], Apollo - University of Cambridge Repository, Barcelona Supercomputing Center, Universitat de Barcelona, Nadeu, Ferran [0000-0003-2910-9440], and Puente, Xose S. [0000-0001-9525-1483]

Subjects
0301 basic medicine, Computer science, Chronic lymphocytic leukemia, ADN, DNA Mutational Analysis, General Physics and Astronomy, Datasets as Topic, Myeloma, 02 engineering and technology, Cancer--Immunological aspects, Hematological malignancies, Cancer genomics, Leukaemia, lcsh:Science, 45/70, Multidisciplinary, BRCA1 Protein, article, Myeloid leukemia, High-Throughput Nucleotide Sequencing, Genomics, 021001 nanoscience & nanotechnology, Signature (logic), 3. Good health, Leukemia, Leukemia, Myeloid, Acute, 631/208/212, Practice Guidelines as Topic, 0210 nano-technology, Multiple Myeloma, 631/67/1990/804, Leucèmia mieloide, Science, Mutational signatures, 45/23, 631/67/69, Computational biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 631/67/1990/283, 631/67/1990, medicine, Humans, Càncer -- Aspectes immunològics, BRCA2 Protein, Haematological cancer, Whole Genome Sequencing, Mutació (Biologia), Computational Biology, General Chemistry, DNA, Mutation (Biology), medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, 030104 developmental biology, Mutation, lcsh:Q, Treatment decision making, Analysis tools, Homologous Recombination Deficiency, Ciències de la salut [Àrees temàtiques de la UPC]
Abstract

Analysis of mutational signatures is becoming routine in cancer genomics, with implications for pathogenesis, classification, prognosis, and even treatment decisions. However, the field lacks a consensus on analysis and result interpretation. Using whole-genome sequencing of multiple myeloma (MM), chronic lymphocytic leukemia (CLL) and acute myeloid leukemia, we compare the performance of public signature analysis tools. We describe caveats and pitfalls of de novo signature extraction and fitting approaches, reporting on common inaccuracies: erroneous signature assignment, identification of localized hyper-mutational processes, overcalling of signatures. We provide reproducible solutions to solve these issues and use orthogonal approaches to validate our results. We show how a comprehensive mutational signature analysis may provide relevant biological insights, reporting evidence of c-AID activity among unmutated CLL cases or the absence of BRCA1/BRCA2-mediated homologous recombination deficiency in a MM cohort. Finally, we propose a general analysis framework to ensure production of accurate and reproducible mutational signature data., Mutational signature analysis provides important information about the mutational processes underpinning different stages of tumorigenesis. Here, the authors compare publicly available signature extraction tools and suggest a framework for the generation of accurate and reproducible signature data.

Published
2019
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15. Clonal dynamics of haematopoiesis across the human lifespan

Author

Mitchell, Emily, Spencer Chapman, Michael, Williams, Nicholas, Dawson, Kevin J, Mende, Nicole, Calderbank, Emily, Jung, Hyunchul, Mitchell, Thomas, Coorens, Tim HH, Spencer, David H, Machado, Heather, Lee-Six, Henry, Davies, Megan, Hayler, Daniel, Fabre, Margarete A, Mahbubani, Krishnaa, Abascal, Federico, Cagan, Alex, Vassiliou, George, Baxter, Joanna, Martincorena, Inigo, Stratton, Michael R, Kent, David G, Chatterjee, Krishna, Parsy, Kourosh Saeb, Green, Tony, Nangalia, Jyoti, Laurenti, Elisa, Campbell, Peter J, Spencer Chapman, Michael [0000-0002-5320-8193], Williams, Nicholas [0000-0003-3989-9167], Mende, Nicole [0000-0002-5078-2333], Calderbank, Emily [0000-0002-9559-6593], Coorens, Tim HH [0000-0002-5826-3554], Lee-Six, Henry [0000-0003-4831-8088], Mahbubani, Krishnaa [0000-0002-1327-2334], Abascal, Federico [0000-0002-6201-1587], Cagan, Alex [0000-0002-7857-4771], Vassiliou, George [0000-0003-4337-8022], Martincorena, Inigo [0000-0003-1122-4416], Stratton, Michael R [0000-0001-6035-153X], Kent, David G [0000-0001-7871-8811], Chatterjee, Krishna [0000-0002-2654-8854], Parsy, Kourosh Saeb [0000-0002-0633-3696], Green, Tony [0000-0002-9795-0218], Nangalia, Jyoti [0000-0001-7122-4608], Laurenti, Elisa [0000-0002-9917-9092], Campbell, Peter J [0000-0002-3921-0510], Apollo - University of Cambridge Repository, Calderbank, Emily F [0000-0002-9559-6593], and Vassiliou, George S [0000-0003-4337-8022]

Subjects
Adult, Male, Aging, Adolescent, education, Longevity, 45/23, 631/208/737, Young Adult, Humans, Child, health care economics and organizations, Aged, Aged, 80 and over, Multidisciplinary, CambridgeStemCellInstitute, 45, Multipotent Stem Cells, Infant, Newborn, article, Infant, Middle Aged, Hematopoietic Stem Cells, 631/250/232, humanities, Clone Cells, 631/532/7, Child, Preschool, Hematologic Neoplasms, 631/208/212, Female, Clonal Hematopoiesis, 692/499
Abstract

Funder: Medical Research Council, Age-related change in human haematopoiesis causes reduced regenerative capacity1, cytopenias2, immune dysfunction3 and increased risk of blood cancer4-6, but the reason for such abrupt functional decline after 70 years of age remains unclear. Here we sequenced 3,579 genomes from single cell-derived colonies of haematopoietic cells across 10 human subjects from 0 to 81 years of age. Haematopoietic stem cells or multipotent progenitors (HSC/MPPs) accumulated a mean of 17 mutations per year after birth and lost 30 base pairs per year of telomere length. Haematopoiesis in adults less than 65 years of age was massively polyclonal, with high clonal diversity and a stable population of 20,000-200,000 HSC/MPPs contributing evenly to blood production. By contrast, haematopoiesis in individuals aged over 75 showed profoundly decreased clonal diversity. In each of the older subjects, 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 the subject was 40 years old, but only 22% had known driver mutations. Genome-wide selection analysis estimated that between 1 in 34 and 1 in 12 non-synonymous mutations were drivers, accruing at constant rates throughout life, affecting more genes than identified in blood cancers. Loss of the Y chromosome conferred selective benefits in males. Simulations of haematopoiesis, with constant stem cell population size and constant acquisition of driver mutations conferring moderate fitness benefits, entirely explained the abrupt change in clonal structure in the elderly. Rapidly decreasing clonal diversity is a universal feature of haematopoiesis in aged humans, underpinned by pervasive positive selection acting on many more genes than currently identified.

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