"Although mutation is random, the relative rate of mutation at each position is not uniform across the genome. Variation in mutability has been demonstrated at multiple scales and the rate mutations occur at can vary from site to site across the genome more than 100-fold...

" As expected, our mutability model shows that CpG
trinucleotides have on average 10-fold higher mutability than non-CpG trinucleotides."

"Non-CpG bearing trinucleotides still show considerable variation, with a 3.7-fold difference between the lowest and highest..."

"The premise of our model was that low mutability sequences will become more common because they tend to be retained for a longer time in the genome; however, the observed pattern was more complex..."

"When mutations occur, they also alter the mutability of the flanking trinucleotides. This can further obscure the relationship of mutability with equilibrium frequency when, say, a low mutability trinucleotide is not stable because its flanks have a high mutability..."

"These processes are further complicated over time as mutations occur on top of each other. This creates an
effect where later in the simulation the number of times a triplet is mutated no longer correlates to its mutability...

"The result being that it is not necessarily true that low mutability trinucleotides will be at higher frequency at equilibrium."

"Even low-mutability exons demonstrate that coding sequences are limited in their ability to evolve towards a lower mutability state..."

"When we used our mutation model to estimate mutability in intergenic vs. coding regions within the human genome, we found that exons had ~40% higher mutability than intergenic regions..."

"At equilibrium, the mutability of coding exons in our simulations was within 22% of true coding sequences in the genome, despite experiencing more complex functional constraints and evolutionary forces not
represented in our model."


• • •

Missing some Tweet in this thread? You can try to force a refresh

Keep Current with Harvard2TheBigHouse

Harvard2TheBigHouse Profile picture

Stay in touch and get notified when new unrolls are available from this author!

Read all threads

This Thread may be Removed Anytime!


Twitter may remove this content at anytime! Save it as PDF for later use!

Try unrolling a thread yourself!

how to unroll video
  1. Follow @ThreadReaderApp to mention us!

  2. From a Twitter thread mention us with a keyword "unroll"
@threadreaderapp unroll

Practice here first or read more on our help page!

More from @Harvard2H

20 Jul
"Among SARS-CoV-2's mutations, three were considered stabilizing to the respective protein structures, while six mutations were destabilizing. The significance of these mutations in evolutionary selection cannot be solely predicted by ΔΔG, or change in free energy..."

"Computational prediction to understand the effect of amino acid substitutions in SARS-CoV-2 revealed a balance of stabilization and destabilization of the proteins."

"The most frequent amino acid substitutions were observed in the nucleocapsid (N) protein..."

"The increased rigidities of the structure may provide a stable conformation to the protein that may positively influence the binding of spike protein to the ACE2 receptor..."

Read 4 tweets
19 Jul
"The coevolutionary analysis identified a number of 28 coevolving sites that were found not to be conditionally independent, such as the couple E484K - N501Y from P.1 and B.1.351 lineages..."

"There were structural stabilizing effect and the higher impact of E484K for the improvement of the binding affinity between the spike RBD and the hACE2 in P.1 and P.2 lineages."

"P.1 emerged in a region with up to 75% demonstrated previous seroprevalence
of SARS-CoV-2..."

"Taken together this evidence supports the role of consecutive accumulation of mutations rather than recombinations in order to explain the emergence of multiple lineages with specific sets of mutations, characteristic of the VOC viruses."

Read 4 tweets
19 Jul
Imagine your immune system is a pachinko machine, where the balls are meant to reach the bottom and stack to the top 10% of the pegs, representing penetrating the cell.

The physical mechanics are reversed, but this is about probabilities and not mechanical action...

Without a vaccine, the process of the balls bouncing down is randomized as the immune system is able to partially fight-off some virions due to the natural configuration of the little pegs.

But some have mutations that help them or otherwise get through due to chance...

And so it's an unpredictable and imperfect process, but it does follow the reality of immunological math.

Everyone has some innate protection from the natural configuration of their immune system's pegs...

Read 15 tweets
18 Jul


"Before immunity or antibody prophylaxis is widely established in the population, there is no transmission advantage..."

"... for viruses with immune escape mutations since most people are equally susceptible to infection from wild-type and mutant SARS-CoV-2."

"Once neutralizing antibodies are common in the population, these mutants will have a selective advantage..."

"...If they already exist at sufficient frequency in the population, the escape mutants will expand deterministically and lead to widespread SARS-CoV-2 resistance to nAbs."

Read 4 tweets
17 Jul
"We detected 15 minor variants that had an allele frequency (AF) of >5% in at least one sample of the passage series. These changes mapped to several genes and proteins of SARS-CoV-2, including ORF1AB, Spike, E, N, and ORF10..."

"There's significant standing genetic diversity in viral populations in vitro that can be acted upon by rapid evolutionary processes.

"It was revealed that the virus readily diversifies during culture with the most evident being mutations mapping to the PBCS of Spike..."

" One striking finding of our work, is that on several occasions for both isolates we observed a rapid increase in frequency of specific mutations in the PBCS and independently of it to near fixation over the course of a couple of passages in Vero cells..."

Read 7 tweets
17 Jul
"The Delta variant is less sensitive to neutralising antibodies in sera from recovered individuals, with higher replication efficiency as compared to the Alpha variant. In an analysis of vaccine breakthrough in over 100 healthcare workers across three centres in India...

"The Delta variant not only dominates vaccine-breakthrough infections with higher respiratory viral loads compared to non-delta infections (Ct value of 16.5 versus 19), but also generates greater transmission between HCW as compared to B.1.1.7 or B.1.617.1..."

"The Delta variant contains several spike mutations that are located at positions within the structure that are predicted to alter its function... This analysis showed that the B.1.617.2 spike was predominantly in the cleaved form, in contrast to WT and B.1.1.7..."

Read 8 tweets

Did Thread Reader help you today?

Support us! We are indie developers!

This site is made by just two indie developers on a laptop doing marketing, support and development! Read more about the story.

Become a Premium Member ($3/month or $30/year) and get exclusive features!

Become Premium

Too expensive? Make a small donation by buying us coffee ($5) or help with server cost ($10)

Donate via Paypal Become our Patreon

Thank you for your support!

Follow Us on Twitter!