A new study by one of China’s top scientists has found the ability of
Professor Li Lanjuan and her colleagues from Zhejiang University found within a small pool of patients many mutations not previously reported. These mutations included changes so rare that scientists had never considered they might occur.
They also confirmed for the first time with laboratory evidence that
“Sars-CoV-2 has acquired mutations capable of substantially changing its pathogenicity,” Li and her collaborators wrote in a non-peer reviewed paper released on preprint service medRxiv.org on Sunday.
Li took an unusual approach to investigate the virus mutation. She analysed the viral strains isolated from 11 randomly chosen Covid-19 patients from Hangzhou in the eastern province of Zhejiang, and then tested how efficiently they could infect and kill cells.
The deadliest mutations in the Zhejiang patients had also been found in most patients across Europe, while the milder strains were the predominant varieties found in parts of the United States, such as Washington state, according to their paper.
A separate study had found that New York strains had been imported from Europe. The death rate in New York was similar to that in many European countries, if not worse.
But the weaker mutation did not mean a lower risk for everybody, according to Li’s study. In Zhejiang, two patients in their 30s and 50s who contracted the weaker strain became severely ill. Although both survived in the end, the elder patient needed treatment in an intensive care unit.
This finding could shed light on differences in regional mortality. The pandemic’s infection and death rates vary from one country to another, and many explanations have been proposed.
The issue was further complicated because survival rates depended on many factors, such as age, underlying health conditions or even blood type.
“Drug and vaccine development, while urgent, need to take the impact of these accumulating mutations … into account to avoid potential pitfalls,” they said.
according to state media reports. The government followed her advice and in late January, the city of more than 11 million residents was shut down overnight.
The sample size in this most recent study was remarkably small. Other studies tracking the virus mutation usually involved hundreds, or even thousands, of strains.
Li’s team detected more than 30 mutations. Among them 19 mutations – or about 60 per cent – were new.
They found some of these mutations could lead to functional changes in the virus’ spike protein, a unique structure over the viral envelope enabling the coronavirus to bind with human cells. Computer simulation predicted that these mutations would increase its infectivity.
To verify the theory, Li and colleagues infected cells with strains carrying different mutations. The most aggressive strains could generate 270 times as much viral load as the weakest type. These strains also killed the cells the fastest.
It was an unexpected result from fewer than a dozen patients, “indicating that the true diversity of the viral strains is still largely underappreciated,” Li wrote in the paper.
The mutations were genes different from the earliest strain isolated in Wuhan, where the virus was first detected in late December last year.
The coronavirus changes at an average speed of about one mutation per month. By Monday, more than 10,000 strains had been sequenced by scientists around the globe, containing more than 4,300 mutations, according to the China National Centre for Bioinformation.
Most of these samples, though, were sequenced by a standard approach that could generate a result quickly. The genes were read just once, for instance, and there was room for mistakes.
Li’s team used a more sophisticated method known as ultra-deep sequencing. Each building block of the virus genome was read more than 100 times, allowing the researchers to see changes that could have been overlooked by the conventional approach.
The researchers also found three consecutive changes – known as tri-nucleotide mutations – in a 60-year-old patient, which was a rare event. Usually the genes mutated at one site at a time. This patient spent more than 50 days in hospital, much longer than other Covid-19 patients, and even his faeces were infectious with living viral strains.
“Investigating the functional impact of this tri-nucleotide mutation would be highly interesting,” Li and colleagues said in the paper.
Professor Zhang Xuegong, head of the bioinformatics division at the National Laboratory for Information Science and Technology at Tsinghua University, said ultra-deep sequencing could be an effective strategy to track the virus’ mutation.
“It can produce some useful information,” he said.
But this approach could be much more time consuming and costly. It was unlikely to be applied to all samples.
“Our understanding of the virus remains quite shallow,” Zhang said. Questions such as where the virus came from, why it could kill some healthy young people while generating no detectable symptoms in many others still left scientists scratching their heads.
“If there is a discovery that overturns the prevailing perception, don’t be surprised.”
Why? Is it genes, hormones, the immune system – or behaviour – that makes men more susceptible to the disease?
I see it as an interaction of all of these factors and it isn’t unique to the SARS-Cov-2 virus – the different response of men and women is typical of many diseases in many mammals.
The Grim Figures
In Italy and China deaths of men are more than double those of women. In New York city men constitute about 61% of patients who die. Australia is shaping up to have similar results, though here it’s mostly in the 70-79 and 80-89 age groups.
One major variable in severity of COVID-19 is age. But this can’t explain the sex bias seen globally because the increased male fatality rate is the same in each age group from 30 to 90+. Women also live on average six years longer than men, so there are more elderly women than men in the vulnerable population.
But then we must ask why men are more vulnerable to the diseases that put them at greater risk of COVID-19.
Men and Women Are Biologically Different
Men and women differ in their sex chromosomes and the genes that lie on them. Women have two copies of a mid-sized chromosome (called the X). Men have only a single X chromosome and a small Y chromosome that contains few genes.
One of these Y genes (SRY) directs the embryo to become male by kick-starting the development of testes in an XY embryo. The testes make male hormones and the hormones make the baby develop as a boy.
In the absence of SRY an ovary forms and makes female hormones.
It’s the hormones that control most of the obvious visible differences between men and women – genitals and breasts, hair and body type – and have a large influence on behaviour.
The Y Chromosome and Hormones
The Y chromosome contains hardly any genes other than SRY but it is full of repetitive sequences (“junk DNA”).
Perhaps a “toxic Y” could lose its regulation during ageing. This might hasten ageing in men and render them more susceptible to the virus.
But a bigger problem for men is the male hormones unleashed by SRY action. Testosterone levels are implicated in many diseases, particularly heart disease, and may affect lifespan.
Men are also disadvantaged by their low levels of estrogen, which protects women from many diseases, including heart disease.
Male hormones also influence behaviour. Testosterone levels have been credited with major differences between men and women in risky behaviours such as smoking and drinking too much alcohol, as well as reluctance to heed health advice and to seek medical help.
The extreme differences in smoking rate between men and women in China (almost half the men smoke and only 2% of women) may help to account for their very high ratio of male deaths (more than double female). Not only is smoking a severe risk factor for any respiratory disease, but it also causes lung cancer, a further risk factor.
Smoking rates are lower and not as sex-biased in many other countries, so risky behaviour can’t by itself explain the sex difference in COVID-19 deaths. Maybe sex chromosomes have other effects.
Two X Chromosomes Are Better Than One
The X chromosome bears more than 1,000 genes with functions in all sorts of things including routine metabolism, blood clotting and brain development.
The presence of two X chromosomes in XX females provides a buffer if a gene on one X is mutated.
XY males lack this X chromosome backup. That’s why boys suffer from many sex-linked diseases such as haemophilia (poor blood clotting).
The number of X chromosomes also has big effects on many metabolic characters that are separable from sex hormone effects, as studies of mice reveal.
Females not only have a double dose of many X genes, but they may also have the benefit of two different versions of each gene.
This X effect goes far to explain why males die at a higher rate than females at every age from birth.
And another man problem is the immune system.
We’ve known for a long time that women have a stronger immune system than men. This is not all good, because it makes women more susceptible to autoimmune diseases such as lupus and multiple sclerosis.
But it gives women an advantage when it comes to susceptibility to viruses, as many studies in mice and humans show. This helps to explain why men are more susceptible to many viruses, including SARS and MERS.
There are at least 60 immune response genes on the X chromosome, and it seems that a higher dose and having two different versions of these gives women a broader spectrum of defences.
Sex Differences in Diseases – the Big Picture
Sex differences in the frequency, severity and treatment efficacy for many diseases were pointed out long ago. COVID-19 is part of a larger pattern in which males lose out – at every age.
This isn’t just humans – it is true of most mammals.
Are sex differences in disease susceptibility simply the by-catch of genetic and hormone differences? Or were they, like many other traits, selected differently in males and females because of differences in life strategy?
It’s suggested that male mammals spread their genes by winning competitions for mates, hence hormone control of risky behaviour is a plus for men.
It’s also suggested female mammals are selected for traits that enhance their ability to care for young, hence their stronger immune system. This made sense for most mammals through the ages.
So the sex bias in COVID-19 deaths is part of a much larger picture – and a very much older picture – of sex differences in genes, chromosomes and hormones that lead to very different responses to all sorts of disease, including COVID-19.
The views in this article may not reflect editorial policy of The Mind Unleashed.