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What Do Non-identical Identical Twins Have to do with COVID-19? Mutation!

Identical twins Stella and Desiree Vignes were born in 1938 in a Louisiana town so small that it wasn’t on any maps. Light-skinned Blacks, the girls left town together at the age of 16 to head to New Orleans to work and escape a bleak future. Stella was mistaken for White at a job interview and continued the deception to get the position, eventually marrying her boss and leaving her sister behind. Stella experienced adulthood as White, Desiree as Black.

The Vignes sisters were born in the imagination of Brit Bennett, an extraordinary young writer. Her bestseller “The Vanishing Half,” traces the experiences of the twins in a world where what happens to them depends upon how others perceive them – as Black or White. Of course, they go on to live starkly different lives, Stella in wealthy Brentwood, California, and Desiree back in her hometown waitressing in a diner. The drama intensifies when their grown daughters meet, one a pale blonde, the other “a dark girl” black as ebony.

Identical twins and higher multiples are, indeed, fascinating. The 2018 film Three Identical Strangers tells the tale of triplet brothers who met by chance at age 19 in 1980. It echoes the fictional film The Parent Trap, from 1961 with Hayley Mills and reborn in 1998 with Lindsay Lohan, each in dual roles.

Twin Studies

Twins have for decades provided a handy tool in genetics research. It’s straightforward. Characteristics more often shared between identical twins than between fraternal twins are presumed to have a greater inherited component. The flip side is that differences between identical twins are assumed to have arisen from environmental factors.

Twin studies are often used to scrutinize the underpinnings of behavioral traits, including conditions such as anxiety and depression. But the approach is also applied to less-well-defined characteristics, such as the ability to make wise investment decisions, altruism, trust, and even cell phone call and texting frequencies.

An entire literature is devoted to what twin studies reveal about the inheritance of political persuasion. The investigations are rigorous – I can’t follow the math – but explaining how, exactly, a gene-encoded protein causes a trait like loyalty seems elusive.

“The Heritability of Duty and Voter Turnout,” for example, considers “belief that voting is a duty” as a trait that a gene or genes influence. (Heritability is a measure of the proportion of a trait’s variance that is inherited, not the degree that the trait itself is inherited.) I’m more comfortable with traits that arise from abnormal or missing proteins like clotting factors and enzymes, rather than from harder-to-define feelings and beliefs.

The Biology of Twinning

Fraternal twins result from two sperm fertilizing two eggs. The twins share a uterus, but are no more closely related genetically than are any two full siblings. Fraternal twins are termed dizygotic, or DZ – two zygotes, aka fertilized ova.

For identical, or monozygotic (MZ), twins, a single sperm fertilizes a single egg, which then splits. But that can happen at different points very early in development, leading to different types of identical twins.

The split may occur as soon as the fertilized ovum divides, or over the first three days and resulting, eventually, in development of separate placentas. But if an initial collection of cells (the inner cell mass) chugs along until day 7 before separating into two clumps, then the resulting twins may share a placenta and possibly their amniotic sac too. Examining these structures reveals when the twinning took place.

The timing of twinning is important because as cells divide, DNA replicates (copies itself), and that’s when mutations can occur, like cutting and pasting an error in a document and then making many copies. A mutation that happens before the inner cell mass has sorted itself into two clumps will persist in both twins. But a mutation happening after the split results in discordance – that is, a mutation in one twin but not the other, even though they are called identical.

Tracking Mutations That Distinguish Identical Twins

A team from deCODE genetics in Iceland has cleverly identified a few mutations that distinguish supposedly genetically identical twins. They deduced events in development by comparing genome sequences of living individuals, not by harming embryos. The findings are published in a recent Nature Genetics.

(deCODE is the company founded in 1996 that established the first national biobank. It caused quite a fuss then, when genome projects were launching, about government control of genetic information. But deCODE went on to become and remain a leader in identifying genetic risk factors. Today deCODE is a subsidiary of Amgen.)

The researchers used the formation of identical twins as “a unique window into early embryonic development,” they write. Explained first author Hákon Jónsson, “Mutations can be formed when cells divide and the daughter cells may carry a mutation that marks the descendants of the mutated cell within an individual. Mutations that are present in only one of the twins allow us therefore to backtrack to the cell divisions that lead to the development of the twins.”

To find the mutations, the team compared full genome sequences from fat cells, white blood cells, and cheek lining cells among 387 pairs of identical twins and their parents, offspring, and spouses to identify twins that aren’t exact clones. Comparison to spouses enabled elimination of mutations inherited from that parent, and comparison to a twin’s offspring made it possible to infer the gene variants that passed from the twin’s sperm or egg.

The degree to which the identical twin pairs differ varied quite a lot, with some twins by more than 100 mutations, yet others, none at all. In about 15% of the pairs, one twin had many mutations that the other didn’t. The average is 5.2 mutations.

The mutations that distinguish identical twins occurred during the first days of development – that explains why the mutations tend to be in large percentages of the sampled cells from an individual. “These two groups of monozygotic twins give insight into development of the embryo only a few divisions after conception, when the embryo consists of several cells,” said Kari Stefansson, CEO and founder of deCODE genetics.

The finding may be important in understanding the origin of conditions such as autism and developmental disorders that are assumed to be due to an environmental factor if only one identical twin is affected. The conditions may instead be due to genetic differences between the twins, perhaps suggesting novel treatment approaches.

The Bigger Picture: COVID

The new view of identical twins illustrates the fundamental changeability of the informational molecules that are genetic material, DNA and RNA.

DNA changes, mutates, because it is an informational molecule. Triplets of the building blocks A, C, T, and G are transcribed into a molecule of RNA, which is then translated into sequences of 20 types of amino acids, the building blocks of proteins. Traits come from the proteins. That’s molecular biology in a nutshell.

SARS-CoV-2, the virus that causes COVID-19, has RNA. And the sequence of that RNA’s building blocks changes, as does the genetic material within our own cells. That is, mutation is part of nature, lying at the intersection of chemistry and biology.

If a mutation leads to a new characteristic, or modifies an existing one, in a way that benefits the organism or virus, the change will persist. This is natural selection, aka “survival of the fittest.” The word “fittest” in the context of evolution means reproductive success, not physical fitness. And that’s why certain new variants of SARS-CoV-2 are potentially worrisome.

The new “variants” are actually a set of genetic changes. Because they enable SARS-CoV-2 to spread more readily, which in turn increases the reproduction number (R naught) of how many people an infected person in turn infects, the mutants will take over the population of viruses – I think, no matter what we do.

Because new variants are present before we’re aware of them, and because some countries have prioritized sequencing viral genomes while others, like the U.S., have not, the proverbial cat is out of the bag. Efforts to block the spread of new viral variants by restricting human travel are almost without doubt too little too late.

Resistance may indeed be futile. For mutations will continue to happen. That’s what nucleic acids – RNA and DNA – do.

Adam Lauring, MD, PhD, from the University of Michigan Division of Infectious Diseases and an expert in the evolutionary biology of RNA viruses, put the new mutations into practical perspective in a JAMA audio clinical review on January 2 and published a related Viewpoint in JAMA, “Genetic Variants of SARS-CoV-2—What Do They Mean?” with Emma B. Hodcroft, PhD. Said he:

“Lots of mutations have happened around the world that haven’t affected transmissibility. We don’t have evidence that they are more virulent and cause more severe disease or death. Mutation happens. Some are important and help the virus do what viruses do – spread. The trick is figuring out which of these mutations are important and which ones aren’t. What is allowing it to spread and how do we get on top of that? I’m optimistic mutations won’t affect vaccinations, but there will be a lot of work over the next weeks and months and in the future, because we’ll have more mutations to contend with.”

Stay tuned …

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