Image credit: Wellcome Sanger Institute
2021 has been another year in which COVID-19 has dominated headlines and scientific journals around the world. We have taken a leading role in sequencing positive SARS-CoV-2 samples, and identifying and tracking new variants of the virus so that we can assist public health officials.
However, in no way is COVID research all that our scientists have achieved this year. We would like to bring you 21 things that we have learned in the year 2021.
1. The inside story of the Covid-19 pandemic in England
The COVID-19 pandemic has gripped the world for almost two years now, and has been studied in detail by the COVID-19 Genomics UK (COG-UK) consortium. In a detailed analysis of genomic surveillance of SARS-CoV-2 in England, researchers found that the pandemic is in fact a series of epidemics, rather than one single extended event.
Researchers from the Wellcome Sanger Institute and EMBL-EBI analysed genomic data collected in England between September 2020 and June 2021, and characterised the growth rates and geographic spread of 21 lineages. They studied the behaviours of the Alpha, Beta, Gamma, Kappa and Delta variants, mapping when, where and how each of them flourished, and how their effects unfolded in local populations.
These data have provided near real time epidemiological reporting to inform the government’s health response.
Research paper: Vöhringer, H.S., Sanderson, T., Sinnott, M. et al. Genomic reconstruction of the SARS-CoV-2 epidemic in England. Nature (2021). DOI: https://doi.org/10.1038/s41586-021-04069-y
2. The developmental origins of eczema and psoriasis
The Human Cell Atlas is a global initiative to map every cell type in the human body, and in January 2021 the team published the Skin Cell Atlas. This highly detailed map of human skin revealed cellular processes in eczema and psoriasis patients that had never been seen before.
The diseased skin cells shared many of the same cellular mechanisms as developing skin cells. Cellular processes from developing cells are re-activated in cells from patients with inflammatory skin disease. Knowing these pathways offers potential new drug targets for treating painful skin conditions.
Research paper: Gary Reynolds, Peter Vegh, James Fletcher & Elizabeth F.M. Poyner et al. (2021). Developmental cell programs are co-opted in inflammatory skin disease. Science. DOI: 10.1126/science.aba6500
3. A potential biomarker for Irritable Bowel Syndrome treatment
Half of people with Irritable Bowel Syndrome (IBS) have a microbiome that includes specific gut bacteria that could be used as biomarkers. Those with these biomarkers could greatly benefit from a low FODMAP diet.
The study used in-depth microbiome analysis to gain insight into IBS, and found that those with the condition can be divided into two groups based on the make-up of their gut bacteria. Approximately half of IBS patients had a distinctive profile to their gut bacteria, and these are the patients that benefited greatly from avoiding high FODMAP foods such as milk, wheat, and some fruits and vegetables.
Research paper: Vervier, S. Moss, N. Kumar, et al. Two microbiota subtypes identified in irritable bowel syndrome with distinct responses to the low FODMAP diet. (2021). Gut. DOI: 10.1136/gutjnl-2021-325177
4. Your DNA can overcome harmful genetic mutations
A person’s DNA is able to suppress undesirable genetic changes that might threaten their survival. This is called a “rescue mutation”. If confirmed in humans, it could explain why some patients suffer more from severe disease than others.In this study, the researchers looked at yeast cells, and exposed them to an unfavourably high temperature. A much higher than expected 26 per cent of the yeast were able to suppress their temperature-sensitive allele and overcome the tough conditions. In ten instances more closely examined, the researchers found that a single mutation was responsible for enabling the yeast to survive and reproduce.
Research paper: Leopold Parts, Amandine Batté and Maykel Lopes et al. (2021). Natural variants suppress mutations in hundreds of essential genes. Molecular Systems Biology. DOI: https://doi.org/10.15252/msb.202010138
5. 16 new high-quality vertebrate reference genomes published
The Vertebrate Genomes Project (VGP) reached a significant milestone this year, releasing a flagship study that included 16 high quality vertebrate reference genomes. The species represent the top level groups of animals with backbones, including the Canada lynx, platypus, greater horseshoe bat, zig-zag eel and Anna’s hummingbird.
Producing these high quality reference genomes without considerable time and expense has only been possible in the last five years. The VGP has taken advantage of enormous improvements in sequencing technologies, and is working to produce high quality reference genomes for approximately 70,000 vertebrate species globally.
The quality of the VGP genome assemblies has enabled new discoveries that have implications for biodiversity and conservation, as well as human health and disease. The first reference genomes of six bat species, for example, revealed selection and loss of immunity-related genes that may underlie bats’ unique tolerance to viral infection. This finding opens up new avenues of research that are particularly relevant for emerging infectious diseases such as COVID-19.
Research paper: Rhie, A., McCarthy, S.A., Fedrigo, O. et al. Towards complete and error-free genome assemblies of all vertebrate species. Nature 2021; 592: 737–746. DOI: https://doi.org/10.1038/s41586-021-03451-0
6. The placenta is a dumping ground for genetic defects
A study this year was the first investigation of the genomic architecture of the human placenta. The researchers found that the structure of the placenta is different to any other human organ, and actually more resembles that of a tumour. It harbours many of the same genetic mutations found in childhood.
The placenta gives the foetus access to the mother’s circulation, as well as oxygen and nutrients to support the foetus’ health and growth. Genetic errors found in the placenta are corrected by the baby, and further studies could help to uncover the causes of complications and diseases that arise during pregnancy.
Research paper: Tim H. H. Coorens, Thomas R. W. Oliver and Rashesh Sanghvi et al. (2021). Inherent mosaicism and extensive mutation of human placentas. Nature. DOI: https://doi.org/10.1038/s41586-021-03345-1
7. A new potential drug target was identified for treating advanced colorectal cancer
Researchers used state-of-the-art patient-derived organoid models to study a gene that is found in some colorectal cancers. This gene, known as Werner Helicase (WRN), is crucial for the cancer’s survival, and so targeting drugs at this gene could lead to new treatments for this disease.
Research paper: Gabriele Picco, Emile E. Voest, Alberto Bardelli, Mathew J. Garnett, et al. (2021) Werner helicase is a synthetic-lethal vulnerability in Mismatch Repair–Deficient Colorectal Cancer Refractory to Targeted Therapies, Chemotherapy and Immunotherapy. Cancer Discovery. DOI: 10.1158/2159-8290.CD-20-1508
8. Inactivation of the MAGEE2 gene results in increased brain size in men and decreased brain size in women
The MAGEE2 gene is found in the region of the brain responsible for memory, navigation, and spatial information processing.
Inactivation of the MAGEE2 gene is found mainly in East Asia and the Americas. Researchers studied this gene in mice, discovering that when there is loss of function, adult male mice had enlarged brains compared to their counterparts with the normally functioning variant. Using brain scans, the researchers investigated human brains and found the same effect in males with the corresponding human gene.
It appears that the inactivation of this gene has no detectable impact on health or disease, but further research is needed to fully understand the role of MAGEE2 and its role in cognitive function.
Research paper: Szpak, S. Collins, Y. Li, X. Liu, et al. (2021) A positively-selected MAGEE2 LoF allele is associated with sexual dimorphism in human brain size, and shows similar phenotypes in Magee2 null mice. Molecular Biology and Evolution. DOI: 10.1093/molbev/msab243
9. Differences in immune system responses were identified between those who have no symptoms and those who have severe symptoms of COVID-19
Researchers identified differences in the immune response to COVID-19 between people who experienced no symptoms and those who had a serious reaction to the virus. They found that people with asymptomatic cases of COVID-19 had raised levels of B-cells - immune cells that produce antibodies. In people with severe symptoms, these B-cells were not found, though there was an uncontrolled increase in inflammatory cells.
This research uncovered potential therapeutic targets to help protect patients against inflammation and severe disease.
This was the largest study of its type in the UK - a Human Cell Atlas collaboration between the Wellcome Sanger Institute, Newcastle University, University College London, University of Cambridge, and EMBL’s European Bioinformatics Institute (EMBL-EBI).
Research paper: Emily Stephenson, Gary Reynolds, Rachel A Botting, Fernando J Calero-Nieto, Michael D. Morgan, Zewen Kelvin Tuong, Karsten Bach, Waradon Sungnak, et al. (2021) The immune response in COVID-19 detailed by single cell multi-omics. Nature Medicine. DOI: 10.1038/s41591-021-01329-2
10. The oesophagus can carry many mutations, but tumours are rare due to competition between cells
The normal human oesophagus is a patchwork of cells containing mutations, known as mutant clones, which create a highly competitive environment. This means that many early tumours are prevented from becoming cancers.
Before this research, it wasn’t understood how the cells in the oesophagus could carry so many cancer-driving mutations and not have a higher rate of tumours. This study unravels part of this mystery by showing, in single-cell resolution, that these mutant clones can engulf and remove early tumours, leading to a protective effect. If these interactions are more fully understood, it could lead to new ways to prevent early tumours from growing into cancers.
Research paper: Colom, A. Herms, M.W.J Hall, et al. Mutant clones in normal epithelium outcompete and eliminate emerging tumours. (2021). Nature. DOI: 10.1038/s41586-021-03965-7
11. Non-coding regions of DNA could hold the key to diagnosing developmental disorders in children
Researchers conducted a study in which they found mutations in parts of the genome that do not code for proteins, and were the cause of in developmental disorders in children. This research helped in giving ten families a named diagnosis, allowing them to predict risk for other family members but also potentially offer a pathway to treatment.
Untranslated regions of DNA, or UTRs, do not code for proteins, but can regulate processes such as controlling how much protein is made, and where the protein ends up in the cell. By looking at these parts of the genome, they were able to identify multiple variants that cause developmental disorders and would have been missed by current clinical screening.
Research paper: Caroline Wright, Nicholas Quaife, Laura Ramos-Hernández, et al. (2021) Non-coding region variants upstream of MEF2C cause severe developmental disorder through three distinct loss-of-function mechanisms. American Journal of Human Genetics. DOI: 10.1016/j.ajhg.2021.04.025
12. Some malaria parasites can overcome sickle cell haemoglobin defence
People who carry the sickle haemoglobin gene have historically been known to be protected from malaria, as the parasites struggle to invade these blood cells.
However, for the first time, some malaria parasites have been found that have adapted to overcome this red blood cell mutation that offers humans protection from malaria. Further studies are needed to understand the biological mechanisms behind this.
Research paper: Band, et al. (2021) Malaria protection due to sickle haemoglobin depends on parasite genotype. Nature. DOI: 10.1038/s41586-021-04288-3
13. Genome notes for insects, amphibians, fish, echinoderms and a wolf were released
The Darwin Tree of Life project has seen a flurry of activity this year, with teams collecting species samples from the mountains of Scotland, to the sea caves of Wales, and the forests of Oxfordshire. The team has assembled over 200 genomes and published more than 50 of those as Genome notes.
The Darwin Tree of Life Project is a nationwide collaboration, led by the Sanger Institute. Collaborators plan to sequence and openly publish the genomes of 70,000 known species of animals, plants, fungi, and protists in Britain and Ireland.
14. The full evolutionary journey of a hospital superbug was mapped for the first time
The full genetic timeline of the bacterium, Enterococcus faecalis was published this year, showing the influence of human behaviour on the development of its different strains.
Researchers discovered this bacterium has the ability to adapt very quickly to selection pressures, such as the use of chemicals in farming as well as the development of new medications. This has resulted in different strains of the same bacterium being found in many places worldwide, from the majority of people’s guts to many wild birds. As it is so widespread, the researchers suggest people should be screened for this type of bacterium when entering the hospital, in the same way they are for other superbugs, to help reduce the possibility of developing and spreading infections within healthcare.
E. faecalis is a common bacterium that, in most people, is found in the intestinal tract and does not cause harm to the host. However, if someone is immunocompromised and this bacterium gets into the bloodstream, it can cause a serious infection.
Research paper: Anna K. Pöntinen, Janetta Top and Sergio Arredondo-Alonso, et al. (2021) Apparent nosocomial adaptation of Enterococcus faecalis predates the modern hospital era. Nature Communications. DOI: https://doi.org/10.1038/s41467-021-21749-5
15. How ageing works may be more complicated than we thought
One of the current models of ageing suggests that accumulation of mutations in the DNA of healthy cells results in the changes that we see as the body grows older. However, this new research shows that human cells and tissues can function apparently normally with many more mutations than are usually present, suggesting that ageing may not be due to build-up of these types of genetic changes alone.
Understanding why our cells age and the mechanisms behind ageing may help us find new ways to protect against age-related disease. Further studies are therefore required to understand what changes that occur in cells during life cause the behaviours associated with ageing.
Research paper: P Robinson, T. Coorens, C. Palles, et al. (2021) Increased somatic mutation burdens in normal human cells due to defective DNA polymerases. Nature Genetics. DOI: 10.1038/s41588-021-00930-y
16. The transmission stages of malaria parasites have been mapped for the first time
Mosquitoes are increasingly becoming resistant to pesticides, and some of the Plasmodium parasites that cause malaria are also becoming increasingly resistant to antimalarial drugs. This has created an urgent need for new ways to fight malaria, which in 2019 caused an estimated 229 million cases and 409,000 deaths, most of which were young children in sub-Saharan Africa.
In this study, Sanger Institute researchers used single-cell RNA sequencing to map the transmission stages of Plasmodium falciparum, the most prevalent malaria parasite in humans. Researchers identified key genes, tracked when they are turned on, and highlighted which are specific to the human version of the parasite.
Knowing in detail how malaria parasites develop and transmit, both when hosted by mosquitoes and humans, could lead to new treatments to block the parasite in action.
Research paper: Eliana Real, et al. (2021) A single-cell atlas of Plasmodium falciparum transmission through the mosquito. Nature Communications. DOI: 10.1038/s41467-021-23434-z
17. We are molecular mosaics
As we age, the DNA in all our cells accumulates changes, or mutations. The mutations that cause cancer are well studied: Which are dangerous? What effects do they have? How do they accumulate, and how quickly? Genome sequencing has been helping scientists answer these questions for decades. But for the mutations in healthy cells, the picture was much hazier.
Previous studies by Sanger Institute researchers have shown that our genome is not a fixed entity, and that our tissues are made up of different populations of cells, each with a slightly different genome to its neighbours.
This year, researchers published the most comprehensive study ever of DNA mutations in healthy cells. They have used the data to help understand how we develop from a single cell, and how our cells, tissues and organs age. The data will form the basis of a new understanding of how our genomes change over lifetimes, and influence health and disease.
18. Higher levels of amino acid, fMet are associated with an increased risk of a wide range of late-onset diseases
Published this year, researchers carried out one of the first population-scale studies on how common genetic traits are influenced by variations in the DNA of mitochondria, the powerhouse of the human cell.
They found a link between higher levels of the amino acid, N-formylmethionine (fMet) being present and late-onset illnesses, demonstrating fMet’s potential as a biomarker of ageing and disease risk.
Research paper: Na Cai, Aurora Gomez-Duran and Ekaterina Yonova-Doing et al. (2021). Mitochondrial DNA variants modulate N-formylmethionine, proteostasis and risk of late-onset human diseases Nature Medicine. DOI: https://doi.org/10.1038/s41591-021-01441-3
19. The first reference map of the human uterus was published
Researchers published the most comprehensive cell atlas of the human uterus to date, and identified two new epithelial cell states that can be used to distinguish between two forms of uterine cancer. The team also identified the genetic pathways that determine two main endometrial cell types.
Although around one in three women will suffer from some form of reproductive disease during their lifetime, we know very little about these conditions, partly due to the challenges in analysing this highly dynamic and complex tissue. This Uterine Cell Atlas, and the sophisticated organoid models that have been created using these data, will help us to better understand the healthy endometrium and how things go wrong in disease.
This work was carried out as part of the Human Cell Atlas consortium.
Research paper: Luz Garcia-Alonso, Louis-François Handfield, Kenny Roberts and Konstantina Nikolakopoulou et al. (2021). Mapping the temporal and spatial dynamics of the human endometrium in vivo and in vitro. Nature Genetics. DOI: https://doi.org/10.1038/s41588-021-00972-2
20. Syphilis is back, and this time it’s global
The most comprehensive genomic study of syphilis has mapped the recent resurgence of the disease around the world. Researchers found almost identical syphilis samples between 14 countries, showing there is widespread international transmission of the disease, particularly within the last 20 years.
This study found that the global population of syphilis is made up of two lineages. Detailed analysis of these lineages provides important insights into the genetic diversity of syphilis, with implications for vaccine design and anti-microbial resistance.
Research paper: Mathew A. Beale, Michael Marks and Michelle J. Cole et al. (2021). Global phylogeny of Treponema pallidum lineages reveals recent expansion and spread of contemporary syphilis. Nature Microbiology. DOI: https://doi.org/10.1038/s41564-021-01000-z
21. How blood and immune systems form in developing bone marrow
Researchers found that in the space of just a few weeks, numerous blood and immune cell types emerge from developing bone marrow, including key white blood cells that protect against bacteria.
The study will be an important reference for understanding how the blood and immune systems develop in bone marrow, and how this can go wrong in disorders such as leukaemia. With more research, this could provide valuable insights that could lead to new treatments and therapies for these types of illnesses.
Research paper: Laura Jardine and Simone Webb et al. (2021) Blood and immune development in human fetal bone marrow and Down syndrome. Nature. DOI: https://doi.org/10.1038/s41586-021-03929-x