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Saturday, July 11, 2020

The coronavirus life cycle

The coronavirus life cycle is depicted in a figure from Fung and Liu (2019). See below for a brief description.
The virus particle attaches to receptors on the cell surface (mostly ACE2 in the case of SARS-CoV-2). It is taken into the cell by endocytosis and then the viral membrane fuses with the host membrane releasing the viral RNA. The viral RNA is translated to produce the 1a and 1ab polyproteins, which are cleaved to produce 16 nonstructural proteins (nsps). Most of the nsps assemble to from the replication-transcription complex (RTC). [see Structure and expression of the SARS-CoV-2 (coronavirus) genome]

RTC transcribes the original (+) strand creating (-) strands that are subsequently copied to make more viral (+) strands. RTC also produces a cluster of nine (-) strand subgenomic RNAs (sgRNAs) that are transcribed to make (+) sgRNAs that serve as mRNAs for the production of the structural proteins. N protein (nucleocapsid) binds to the viral (+) strand RNAs to help form new viral particles. The other structural proteins are synthesized in the endoplasmic reticulum (ER) where they assemble to form the protein-membrane virus particle that engulfs the viral RNA.

New virus particles are released when the vesicles fuse with the plasma membrane.

The entire life cycle takes about 10-16 hours and about 100 new virus particles are released before the cell commits suicide by apoptosis.

Fung, T.S. and Liu, D.X. (2019) Human coronavirus: host-pathogen interaction. Annual review of microbiology 73:529-557. [doi: 10.1146/annurev-micro-020518-115759]

Thursday, July 09, 2020

Structure and expression of the SARS-CoV-2 (coronavirus) genome

Coronaviruses are RNA viruses, which means that their genome is RNA, not DNA. All of the coronaviruses have similar genomes but I'm sure you are mostly interested in SARS-CoV-2, the virus that causes COVID-19. The first genome sequence of this virus was determined by Chinese scientists in early January and it was immediately posted on a public server [GenBank MN908947]. The viral RNA came from a patient in intensive care at the Wuhan Yin-Tan Hospital (China). The paper was accepted on Jan. 20th and it appeared in the Feb. 3rd issue of Nature (Zhou et al. 2020).

By the time the paper came out, several universities and pharmaceutical companies had already constructed potential therapeutics and several others had already cloned the genes and were preparing to publish the structures of the proteins.1

By now there are dozens and dozens of sequences of SARS-CoV-2 genomes from isolates in every part of the world. They are all very similar because the mutation rate in these RNA viruses is not high (about 10-6 per nucleotide per replication). The original isolate has a total length of 29,891 nt not counting the poly(A) tail. Note that these RNA viruses are about four times larger than a typical retrovirus; they are the largest known RNA viruses.

Wednesday, July 08, 2020

Where did your chicken come from?

Scientists have sequenced the genomes of modern domesticated chickens and compared them to the genomes of various wild pheasants in southern Asia. It has been known for some time that chickens resemble a species of pheasant called red jungle fowl and this led Charles Darwin to speculate that chickens were domesticated in India. Others have suggested Southeast Asia or China as the site of domestication.

The latest results show that modern chickens probably descend from a subspecies of red jungle fowl that inhabits the region around Myanmar (Wang et al., 2020). The subspecies is Gallus gallus spadiceus and the domesticated chicken subspecies is Gallus gallus domesticus. As you might expect, the two subspecies can interbreed.

The authors looked at a total of 863 genomes of domestic chickens, four species of jungle fowl, and all five subspecies of red jungle fowl. They identified a total of 33.4 million SNPs, which were enough to genetically distinguish between the various species AND the subspecies of red jungle fowl. (Contrary to popular belief, it is quite possible to assign a given genome to a subspecies (race) based entirely on genetic differences.)

The sequence data suggest that chickens were domesticated from wild G. g. spadiceus about 10,000 years ago in the northern part of Southeast Asia. The data also suggest that modern domesticated chickens (G. g. domesticus) from India, Pakistan, and Bangladesh interbred with another subspecies of red jungle fowl (G. g. murghi) after the original domestication. These chickens from South Asia contain substantial contributions from G. g. murghi ranging from 8-22%.

Next time you serve chicken, if someone asks you where it came from you won't be lying if you say it came from Myanmar.

Image credits: BBQ chicken, Creative Common License [Chicken BBQ]
Red Jungle Fowl, Creative Commons License [Red_Junglefowl_-Thailand]
Map: Lawler, A. (2020) Dawn of the chicken revealed in Southeast Asia, Science: 368: 1411.

Wang, M., Thakur, M., Peng, M. et al. (2020) 863 genomes reveal the origin and domestication of chicken. Cell Res (2020) [doi: 10.1038/s41422-020-0349-y]

Monday, July 06, 2020

A storm of cytokines

Cytokines are a diverse groups of small signal proteins that act like hormones to turn on genes in blood cells and cells of the immune system. In COVID-19 the production of cytokines can be over-stimulated to produce a cytokine storm that activates immune cells producing all kinds of severe, sometimes lethal, effects. There are dozens of different cytokines but they all act in a similar manner. Each one binds to a receptor on the membrane of a target cell and this stimulates the cytoplasmic side of the receptor to activate a transcription factor that enters the nucleus and turns on a specific set of genes. The activation step requires phosphorylation just like dozens of other signalling pathways. (See Morris et al. (2018) for a recent review.)

I was curious about the structures of these cytokines so I looked up a few of them on PDB. Here are three fairly representative structures.

Morris, R., Kershaw, N.J., and Babon, J.J. (2018) The molecular details of cytokine signaling via the JAK/STAT pathway. Protein Science 27: 1984-2009. [doi:]