SARS-CoV-2 and Mouse Genetics

Computer generated SARS-CoV-2 virions.
Avatar

By IMPC

Published 2nd April 2020

What is SARS-CoV-2 and How Can Mice Help?

Viruses are infective agents that cause disease. They are different from other pathogens, such as bacteria, fungi and parasites, because most scientists don’t technically classify them as alive. They’re not 100% an organism as they cannot grow and reproduce by themselves. They’re made of the same building blocks of life (DNA, RNA and nucleic acids) as other organisms (such as bacteria or our own cells) but are unable to read and use this information. They reproduce by infecting host cells and hijacking the host’s processes. By inserting its genetic information into a cell’s DNA, when the cell begins to produce proteins it reads the viral DNA instead of its own, producing viral components that assemble into a new virion which can then infect a new cell.

Scientists classify viruses in several ways because they vary so widely, such as whether they have DNA or RNA or by their size and shape. Coronaviruses have single-stranded RNA genetic material encased in a viral envelope – a layer of protein usually made up of host cell and viral proteins that allows a virion to bind to a new host cell and fuse with it, starting the viral replication process. Coronaviruses have many club-shaped viral spike proteins attached to its envelope that creates a crown or corona-like appearance when viewed under a microscope.

Transmission Electron Microscope image of SARS-CoV with its characteristic corona. Credit: CDC/ Dr. John Hierholzer

There are a number of different coronaviruses that infect different animal species and cause widely varying severity of respiratory disease. There are seven known human coronavirus species (HCoVs), including the recent MERS-CoV and SARS-CoV. ‘COVID-19’ actually refers to the disease caused, not the virus that causes the disease, and stands for ‘coronavirus disease 2019’. COVID-19 is caused by the most recent novel coronavirus, first known as 2019-nCoV and now known as SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2.) SARS-CoV-2 is more infective than SARS-CoV and MERS-CoV and therefore spreads more easily but is less fatal(1).

It is SARS-CoV-2’s spike protein that allows it to bind to human cells via the ACE2 (angiotensin converting enzyme 2) receptor(2). This receptor is found on lung, artery, heart, kidney and intestine cells. Normally, human angiotensin, a protein, will attach to the ACE2 receptor, causing a lowering of blood pressure. The viral spike protein’s shape also fits ACE2 like angiotensin does, allowing a virion to bind to the receptor and enter cells.

SARS-CoV-2 and spike protein 3D models. Credit: NIAID / CC BY (https://creativecommons.org/licenses/by/2.0)

Mice also have an ACE2 receptor but its shape is different from the human version and SARS-CoV-2 doesn’t bind to it as easily. This means mice can be naturally infected with the virus but the severity of the disease is less than in humans(3). A mammalian model is vital for studying the virus and the disease it causes, as well as validating possible treatments and vaccines. Institutions such as our consortium member The Jackson Laboratory (JAX) are breeding a mouse colony with humanised ACE2 receptors (K18-hACE2 transgenic mouse model(3).) By genetically altering the mice to produce human ACE2 instead of mouse ACE2 we can create a much more applicable mouse model for the study of SARS-CoV-2. This will enable scientists to complete the research needed to treat the outbreak.

Main image credit: Felipe Esquivel Reed / CC BY-SA (https://creativecommons.org/licenses/by-sa/4.0)

Sources

Singhal, T. A Review of Coronavirus Disease-2019 (COVID-19). Indian J Pediatr 87, 281–286 (2020). https://doi.org/10.1007/s12098-020-03263-6

Letko, M., Marzi, A. & Munster, V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat Microbiol 5, 562–569 (2020). https://doi.org/10.1038/s41564-020-0688-y

McCray PB Jr, Pewe L, Wohlford-Lenane C, et al. Lethal infection of K18-hACE2 mice infected with severe acute respiratory syndrome coronavirus. J Virol. 81(2), 813–821 (2007.) https://doi:10.1128/JVI.02012-06

The International Mouse Phenotyping Consortium (IMPC) is a collaboration between world-leading research institutions that specialise in mouse genetics to identify the function of every protein-coding gene in the mouse genome. In recent years, many projects have aimed to sequence the entire genome of numerous species, such as the Human Genome Project, but for many of these projects, the function of these genes remains unknown. The IMPC aims to complete an open-access database that describes what each gene does and how it can affect a mouse physically when it doesn’t work properly.

A map of IMPC collaborators

All organisms have two versions of each gene called alleles. Genes control the production of proteins within organisms, which are vital for cell structure and function. Mutations can cause genes to stop working, which changes the function of the protein or the amount produced. These changes can disrupt development and cause physical and chemical abnormalities.

To find the function of each gene, the IMPC genetically alters mice by turning off one or both alleles for each protein-coding gene, creating a knockout mouse line. The IMPC then conducts a series of tests to find what effect the alteration has had, such as testing grip strength, body weight, blood content, behaviour, sleeping and eating patterns, sight, hearing and much more. The IMPC then analyses the test data for significance and uploads findings into the open-access database. The knockout mouse lines are deposited in publicly funded repositories so researchers can obtain mouse lines for their studies.

How Does Mouse Genetics Apply to Humans?

We share 97% of our DNA with mice, as well as being biologically and behaviourally very similar to humans. They are also very well understood, convenient, and reproduce quickly so that we can observe and study the genetics of several generations. This makes mice a reliable model for human disease and researchers have used them to study cancer and inherited diseases such as diabetes, heart disease, Parkinson’s and Alzheimer’s for decades.

Queen Mary University of London (QMUL) takes IMPC data and analyses it to find associations to human disease. One method used is the study of ‘orthologs.’ These are genes in different species that share an ancestor gene and are therefore more likely to have a similar function. Another method is through data analysis – comparisons are made between the physical changes seen in the mouse after a gene has been turned off to the disease characteristics listed in human rare disease databases, such as OMIM and Orphanet, to see if there are any significant similarities. Through this, genetic mutations in mice can be related to disease in humans.

In 2017, experts from the IMPC and QMUL analysed 3,328 genes in the database and identified models for 360 diseases, including possibly the first models for type C Bernard-Soulier, Bardet-Biedl-5 and Gordon Holmes syndromes.

A disease is usually considered rare if less than 1 in 2,000 people is affected within the population, meaning most genetic conditions are classed as rare diseases. Some of the more well-known genetic diseases, such as Cystic Fibrosis, Muscular Dystrophy and Multiple Sclerosis are well studied but others are not. The less researched a condition is, the harder it is to treat and manage. Some mutations, and the disease they cause, are so rare that there are only clinical records of one or a few families with shared symptoms.

A major aim of the IMPC database is to assist research into rare disease, building a starting point for novel research into the mechanisms of rare disease, new possible treatments and precision medicine – allowing doctors to choose personalised treatments on a genetic basis. Through this, patients can receive accurate and effective healthcare for their conditions.

IMPC Resource Use

Data experts within the IMPC find new ways of analysing the IMPC database (and other open access rare disease databases) to find new ‘candidate genes’ – genes that have not previously been related to disease but have a high chance of causing disease. Recent IMPC screens include finding possible genetic causes behind hearing disorders, metabolic diseases, integumentary and oculocutaneous (hair, skin, eyes and pigmentation) conditions, sleeping and eating disorders and neurodegenerative disease.

Externally, researchers are constantly using IMPC resources for their work. Recent examples of how IMPC alleles have been used are:

  • Clear cell sarcomas, a rare soft tissue cancer.
  • Bardet-Biedl syndrome (BBS) which causes vision loss, obesity, extra fingers and toes and learning problems, among other symptoms.
  • Primary familial brain calcification (PFBC), in which deposits of calcium accumulate in the basal ganglia – structures found deep within the centre of the brain. This can cause movement disorders and psychiatric problems like psychosis, dementia and vertigo.
  • Aicardi-Goutières syndrome (AGS) which causes severe brain dysfunction leading to fevers, seizures, developmental issues and muscle issues. Symptoms start very early, around one year of age, and due to the severity of the condition, most do not reach adulthood.
  • Gray platelet syndrome (GPS), a bleeding disorder that can cause easy bruising, nosebleeds and heavy bleeding after an injury.
  • Karyomegalic interstitial nephritis (KIN), a hereditary, progressive and chronic form of kidney disease.

Researchers can source mice, embryonic stem cells and data for each processed gene on the IMPC website and database. Start searching genes by using our search function above.

For the Future

Since data release 11, the IMPC has now fully tested 6,440 protein-coding genes, but there are still over 11,000 mouse orthologs to be processed and their association to disease still needs to be analysed. The IMPC’s key aim is to complete the analysis of every protein-coding gene in the mouse genome. Having a complete database will only further the use and applications of IMPC resources in rare disease research, opening possibilities for new treatments and better healthcare for patients.

Avatar

By IMPC

Published 28th February 2020

The IMPC Newsletter

Get highlights of the most important data releases, news and events, delivered straight to your email inbox

Subscribe to newsletter