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Genetics

From left, Joshua Rest and Jackie Collier. The blurred image in the background shows the genome structure of Aurantiochytrium limacinum, including the arrays of rDNAs at the chromosome ends, and the two mirusvirus elements that were discovered. Photo by Donna DiGiovanni

By Daniel Dunaief

They were trying for two years to solve a puzzle that didn’t make sense. Then, a combination of another discovery, some extensive analysis, and a deep dive into the past helped them put the pieces together.

Jackie Collier, Associate Professor at the School of Marine and Atmospheric Sciences at Stony Brook University and Joshua Rest, also an Associate Professor in the Department of Ecology and Evolution at Stony Brook, had been looking closely at the genetic sequence of a marine protist called Aurantiochytrium limacinum. A circular section and pieces at the end of the chromosome seemed inconsistent with the rest of the genes and with the specific type of single-celled organism.

But then, they saw a preprint of a paper in 2022 that the prestigious journal Nature published earlier this year that described a new type of virus, called a mirusvirus, which appeared to have genetic similarities and a signature that matched what they saw in their protist.

Mirus means “strange” or unknown in Latin, which was a way to describe the unusual evolutionary traits of these viruses.

Collier and Rest, working with a group of collaborators, found that a high copy circular structure and genetic elements that integrated at the end of one chromosome resembled this mirusvirus.

“From the perspective of the virus folks, ‘mirus’ was apt because the mirusviruses contain features of the two very distinct ‘realms’ of viral diversity,” Collier explained. “Our results confirm that strangeness, and add more strangeness in terms of two different ways to maintain themselves (circular episomes or integrated into a chromosome) in the same host genome.”

Researchers had discovered the mirusvirus by sequencing DNA they took from the ocean. “What our findings do is connect to a host and hopefully eventually prove that there is a protist that contains a mirusvirus genome,” said Collier.

The Aurantiiochytrium protist, which is part of the Thraustochytrids order, intrigues researchers in part because it produces essential omega-3 fatty acids and carotenoids, which enhances its biotechnology potential. This protist also intrigues Collier because it is involved in decomposing dead mangrove leaves in mangrove forests.

Dormant virus

The Stony Brook scientists have been working on analyzing the genome for a paper they recently published in the journal Current Biology since 2019.

“We had been struggling to figure out what that was,” said Collier. “We had a lot of hints that it had some relationship to some kind of viruses, but it wasn’t similar enough to any known virus. We were struggling to figure out what to call this thing,” which they had tentatively designated CE1, for circular element one.

Identifying viral elements provided the “hook” for the paper.

Rest suggested that the different confounding elements in the protist genome came from two different viruses.

At this point, Collier and Rest think the virus may be something like the herpesvirus, which hides out in human nerve cells. That virus enters a latent phase, remaining quiescent until a host becomes stressed.

John Archibald, Lucie Gallot-Lavallee and others from Dalhousie University in Canada, who are collaborators on this study, are creating the kind of conditions, such as lower food or colder temperatures, that might reactivate the viral DNA, causing it to release viral particles.

The research team has detected similar mirusvirus proteins in other Aurantiochytrium isolates and in four other Thraustochytrid genomes. 

Focusing on this protist

Collier started working on thraustochytrids in 2002, after the first outbreak of QPX disease in Raritan Bay hard clams.

Bassem Allam, who is now the Marinetics Endowed professor in Marine Sciences at SBU asked Collier if she would help understand what was going on with the clams which had QPX disease. That was caused by another Thraustochytrid.

The organism that caused QPX is a relative of the protist that interested Collier.  She chose Aurantiochytrium in part because it was the easiest to grow.

When the Gordon and Betty Moore Foundation started a program to develop molecular genetic methods for diverse marine protists about seven years ago, Collier approached Rest for a potential collaboration.

A key piece, half a century old

In her informatics work, Collier followed a path that Google or artificial intelligence might otherwise have missed.

Like traveling back hand over hand in time through older research, Collier pulled up the references from one study after another. Finally, she found an intriguing study from 1972 that had overlaps with their work.

Scientists had isolated a Thraustochytrid from an estuary in Virginia using the same kinds of methods Collier and Rest used to grow Aurantiochytrium. Using electron microscopy, these earlier researchers characterized its ultrastructure. Along the way, these 1970’s scientists noticed that starved cells released viral particles, which Collier and Rest believe might be the first record of a mirusvirus.

The researchers wrote a short paper that the prestigious journal Science published.

A cat connection

While Collier, who lives in Lake Grove, and Rest, who is a resident of Port Jefferson, are collaborators at Stony Brook, they have also have a feline connection.

In the beginning of the pandemic, a feral cat delivered kittens in Rest’s garage. Rest’s family initially tried to raise them, but allergies made such a pet arrangement untenable. 

A cat lover, Collier was searching for kittens. She adopted two of the kittens, bottle feeding them starting at three days old. When Collier and Rest speak by zoom, Rest’s children Julia, nine, and Jonah, five, visit with the cats virtually.

As for their work, Collier and Rest are intrigued by the possibility of gathering additional pieces to answer questions about this virus.

“For me, the most intriguing question is how common our observations will turn out to be — do many Thraustochytrids have latent mirusviruses?” she explained.

Linda Van Aelst. Photo from CSHL

By Daniel Dunaief

Different people respond to the same level of stress in a variety of ways. For some, a rainy Tuesday that cancels a picnic can be a minor inconvenience that interrupts a plan, while others might find such a disruption almost completely intolerable, developing a feeling of helplessness.

Scientists and clinicians have been working from a variety of perspectives to determine the cause of these different responses to stress.

From left, graduate student Nick Gallo, Linda Van Aelst and Postdoctoral Researcher Minghui Wang. Photo by Shanu George

Cold Spring Harbor Laboratory Professor Linda Van Aelst and a post doctoral researcher in her lab, Minghui Wang, recently published a collaborative work that also included graduate student Nicholas Gallo, postdoctoral researcher Yilin Tai and Professor Bo Li in the journal Neuron that focused on the gene Oligophrenin-1, which is also implicated in intellectual disability.

As with most X-linked diseases, the OPHN1 mutation primarily affects boys, who have a single X chromosome and a Y chromosome. Girls have two X chromosomes, giving them a backup gene to overcome the effect of an X-linked mutation.

In addition to cognitive difficulties, people with a mutation in this gene also develop behavioral challenges, including difficulty responding to stress.

In a mouse model, Wang and Van Aelst showed that the effect of mutations in this gene mirrored the stress response for humans. Additionally, they showed that rescuing the phenotype enabled the mouse to respond more effectively to stress.

“For me and [Wang], it’s very exciting,” Van Aelst said. “We came up with this mouse model” and with ways to counteract the effect of this mutated analogous gene.

As with many other neurological and biological systems, Oligophrenin1 is involved in a balancing act in the brain, creating the right mix of excitation and inhibition.

When oligophrenin1 was removed from the prelimbic region of the medical prefrontal cortex, a specific brain area that influences behavioral responses and emotion, mice expressed depression-like helpless behaviors in response to stress. They then uncovered two brain cell types critical for such behavior: the inhibitory neurons and excitatory pyramidal neurons. The excitatory neurons integrate many signals to determine the activity levels in the medial prefrontal cortex.

The inhibitory neurons, meanwhile, dampen the excitatory signal so they don’t fire too much. Deleting oligophrenin1 leads to a decrease in these inhibitory neurons, which Van Aelst found resulted from elevated activity of a protein called Rho kinase.

“The inhibitor keeps the excitatory neurons in check,” Van Aelst said. “If you have a silencing of the inhibitory neurons, you’re going to have too much excitatory response. We know that contributes to this maladaptive behavior.”

Indeed, Wang and Van Aelst can put their metaphorical finger on the scale, restoring the balance between excitation and inhibition with three different techniques.

The scientists used an inhibitor specific for a RhoA kinase, which mimicked the effect of the missing Oligophrenin1. They also used a drug that had the same effect as oligophrenin1, reducing excess pyramidal neuron activity. A third drug activated interneurons that inhibited pyramidal neurons, which also restored the missing inhibitory signal. All three agents reversed the helpless phenotype completely.

Japanese doctors have used the Rho-kinase inhibitor fasudil to treat cerebral vasospasm. which Van Aelst said does not appear to produce major adverse side effects. It could be a “promising drug for the stress-related behavioral problems” of oligophrenin1 patients, Van Aelst explained in an email. “It has not been described for people with intellectual disabilities and who also suffer from high levels of stress.”

From left, graduate student Nick Gallo, Linda Van Aelst and Postdoctoral Researcher Minghui Wang. Photo by Shanu George

Van Aelst said she has been studying this gene for several years. Initially, she found that it is a regulator of rho proteins and has linked it to a form of intellectual disability. People with a mutation in this gene had a deficit in cognitive function that affected learning and memory.

From other studies, scientists learned that people who had this mutation also had behavioral problems, such as struggling with stressful situations.

People with intellectual difficulties have a range of stressors that include issues related to controlling their environment, such as making decisions about the clothing they wear or the food they eat.

“People underestimate how many [others] with intellectual disabilities suffer with behavioral problems in response to stress,” Van Aelst said. “They are way more exposed to stress than the general population.”

Van Aelst said she and Wang focused on this gene in connection with a stress response.

Van Aelst wanted to study the underlying cellular and molecular mechanism that might link the loss of function of oligophrenin1 with the behavioral response to stress.

At this point, Van Aelst hasn’t yet studied how the mutation in this gene might affect stress hormones, like cortisol, which typically increase when people or mice are experiencing discomfort related to stress. She plans to explore that linkage in future studies.

Van Aelst also plans to look at some other genes that have shown mutations in people who battle depression or other stress-related conditions. She hopes to explore a genetic link in the brain’s circuitry to see if they can “extend the findings.” She would also like to connect with clinicians who are studying depression among the population with intellectual disabilities. Prevalence studies estimate that 10 to 50 percent of individuals with intellectual disability have some level of behavioral problems and/or mood disorders.

Reflecting the reality of the modern world, in which people with various conditions or diseases can sequence the genes of their relatives, Van Aelst said some families have contacted her because their children have mutations in oligophrenin1.

“It’s always a bit tricky,” she said. “I don’t want to advise them yet” without any clinical studies.

A resident of Huntington, Van Aelst arrived at CSHL in the summer of 1993 as a post doctoral researcher in the lab of Michael Wigler. She met Wigler when he was giving a talk in Spain.

After her post doctoral research ended, she had planned to return to her native Belgium, but James Watson, who was then the president of the lab, convinced her to stay.

Outside of work, Van Aelst enjoys hiking, swimming and running. Van Aelst speaks Flemish, which is the same as Dutch, French, English and a “bit of German.” 

She is hopeful that this work may eventually lead to ways to provide a clinical benefit to those people with intellectual disabilities who might be suffering from stress disorders.

By Elof Axel Carlson

Elof Axel Carlson

Why is the term race rarely used by geneticists? The term race is not a scientific one. It is largely cultural when applied to humans. It is too ambiguous a term for describing a population of any one species.

For example, suppose I were a breeder of dachshunds and I specialized in two varieties — one that had a black coat of fur and the other that had a tan coat of fur. I would not call them black or tan races. I would call them varieties of a specific breed called dachshunds of dogs who are described by biologists as the species Canis vulgaris.

The term race is vague. Is it the varietal difference? Is it the collection of traits that we use for dogs, cats, horses, cattle and other domesticated animals? If it is applied to the color of dachshunds, does that mean humans are divided into thousands of races if I were to use McKusick’s online reference work on Mendelian inheritance in humans?

That work describes thousands of genetic traits caused by single gene malfunctions. Geneticists use the term breed for genetically manipulated traits or collections of traits by human selection or breeding. They use the term varieties or naturally occurring variations in a population or for new varieties arising by mutation in a sperm or egg.

Racism is used to describe a social application of race to designate rights and to assign attributes to other races by members of a specific race. There is far more genetic variation within a single race than there is between any two races. The criteria for classifying human races are often arbitrary and are based on skin color, facial appearance, hair texture and other visually distinctive traits. Many of these traits involve quantitative factors (like skin color), and thus racial mixture quickly obliterates the sharp racial traits initially used to describe a person of a specific race.

Quite a few people who have considered themselves and their immediate family as white are surprised when they send off DNA to be analyzed and discover they have percentages of African, Asian, Hispanic, Native American or Jewish ancestry along with their majority Caucasian Western European ancestry.

Racism is particularly destructive in assigning behavioral traits (personality, intelligence and social failure or inadequacy) to race. Most of those traits are determined by how we are raised and not by a roll of genes in forming our parents’ sperm or eggs. If they were to follow their own criteria, racists would find that white Catholics and Protestants are inferior to Jews and Orientals in intelligence measured by intelligence tests or IQs.

The revival of racist ideology among groups like the KKK, neo-Nazis and white supremacy groups is not based on biology or genetics. It is based on prejudice passed down by people who feel victimized if people different from them are treated with justice, fairness and equal opportunity.

The Civil War was fought over slavery. Thousands of abolitionists participated to hide escaped slaves, write books and pamphlets denouncing slavery and demanded the freedom of all slaves. The Confederacy seceded from the U.S. and fought to keep its slaves, many slave owners justifying slavery on biblical grounds — that it was a divine punishment for the descendants of a son who laughed at his drunken naked father.

Most ministers and priests in the North denounced that interpretation. We are not born with a knowledge of our past history. It has to be learned and it has to be taught. It is easier to avoid talking about our past errors than to ignore them.

Germany made a special effort after World War II to teach the racism of its Nazi past to all its school children so that error would never again be repeated. Let us hope that we teach our youth that we are one living species, Homo sapiens, and in the Judeo-Christian tradition we all have one ancestor in common.

In the scientific tradition we also have one human species in recorded history and enormous genetic variation that is constantly changing as humans migrate around the world, settle down or move on to new areas of the Earth. Most of that variation is in Africa where our species first arose.

It is ironic that whites who enslaved or colonized Africa diminished, in their minds, this genetic variation and reduced it to racist formulas of a handful of physical or behavioral traits. I hope this revived racism will recede and our focus will shift to problems that can and should be solved by our elected representatives. Those problems are overwhelmingly caused by our social and economic conditions and not by our genes.

Elof Axel Carlson is a distinguished teaching professor emeritus in the Department of Biochemistry and Cell Biology at Stony Brook University.

'A trip to the American Museum of Natural History was my idea of being in heaven.' - Elof Carlson

By Elof Axel Carlson

The life sciences are vast in the number of specialties that exist for those pursuing a career as a biologist. A majority of college biology majors are premedical or seek some sort of health-related field. As much as possible they hope the biology they learn will find its way into the health field they seek to enter. Persons who want to be scholars in biology are often motivated by a desire to know as much about life as they can. I was one of those from early childhood when a trip to the American Museum of Natural History was my idea of being in heaven.

Elof Axel Carlson

I loved learning about evolution and the diversity of life. I knew I wanted to be a geneticist when I was in ninth grade and learned about Paul Müller’s Nobel Prize work on inducing mutations. Like a duckling, I felt imprinted and wanted to work with Müller someday.

Graduate work was different. As a teaching assistant I got to see about 90 different specimens each week for the various organ systems displayed by students. Unlike the textbook perfect illustrations, veins and arteries could be slightly off in the specimens I looked at. Their colors differed. Their texture differed.

I also learned how much we didn’t know about life. For my specialty of genetics (with Müller, as I had hoped) I felt steeped in experimental design, techniques and ways of thinking. Doing a Ph.D. allowed me to examine a gene using the tools of X-raying to produce mutations of a particular gene and subtle genetic design to combine pieces of a gene — taking it apart and combining pieces that were slightly different. It gave me an insight into that gene (dumpy, in fruit flies) that for a short time (until I published my work) I was the only person in the world that knew its structure.

In my career I have taught biology for majors, biology for nonscience majors, genetics, human genetics and the history of genetics. I have taught lower division and upper division courses, graduate courses and first-year medical classes. I learned that sharing new knowledge with students excited their imaginations. I learned that the human disorders I discussed led to office visits; and if I didn’t know the information they sought, I went with them to the medical library and we looked up articles in the Index Medicus and discussed their significance.

Often that student was married and had a child with a birth defect (born without a thyroid, having a family trait that might appear like cystic fibrosis). I would prepare a genetic pedigree and give it to the student to stick in a family bible for future generations to read. I also delighted in going to meetings to discuss genetics with colleagues whose work I had read.

I was pleased that I shared a body plan with other mammals. I liked comparative anatomy, which taught me how other body plans work (mollusks, arthropods, worms, coelenterates, echinoderms). As a graduate student taking a vertebrate biology course, I went into a cave and plucked hibernating bats from a ceiling.

The world under a microscope is very different. To see amoebas, ciliated protozoans, rotifers and other organisms invisible to the naked eye or as mere dust-like specks is a thrill. I can go back in time and imagine myself as a toddler, a newborn, an embryo in my mother’s uterus or an implanting blastocyst rolling out of her fallopian tube. I can imagine myself as a zygote, beginning my journey as a one-celled potential organism typing this article into a computer. I can go back in time to my prehistoric ancestors and trace my evolution back to the first cellular organism (bacteria-like) more than 3 billion years ago.

I learned, too, that I contain multitudes of ancestors who gave me one or more of their genes for the 20,000 I got from my father’s sperm and the matching 20,000 genes in my mother’s egg nucleus. I contain some 37 trillion (that is, 37,000,000,000,000) cells or 2 to the 45th power, which means some 45 mitotic cell divisions since I was a zygote. I know that the warmth of my body is largely a product of the mitochondrial organelles in my cells that using the oxygen from the air I breathe and converting small molecules of digested food to provide energy that runs the metabolism of my body and disposes carbon dioxide that eventually is expelled from my lungs. This knowledge makes me aware of my vulnerability at the cellular level, the chromosome level and the genetic level of my DNA to the agents around me that can lead to birth defects cancers, and a premature aging.

Knowing my biology allows me to know my risks as well as new ways to celebrate my life.

Elof Axel Carlson is a distinguished teaching professor emeritus in the Department of Biochemistry and Cell Biology at Stony Brook University.

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By Elof Carlson

Fossils are relatively rare because most of the animals and plants that have died in nature have been eaten or decomposed. Fossils are often found in sedimentary rocks, and those dead organisms were buried after drowning, caught by volcanic ash, buried in a mudslide or sucked down by quicksand or some other event less likely than falling on a field or in the underbrush of a forest, or left as scattered bones by hungry predators. Only in the past few ten thousand years have humans buried their dead, improving the chances that their remains will someday be unearthed and studied by paleontologists.

DNAUntil the last half of the twentieth century, the only way to use human fossils to work out a historical association was through comparative anatomy and a variety of chemical and physical tools to determine the age of the sediments in which they were unearthed. The idea of a paleogenetics arose in 1963, with the use of that term by Linus Pauling and his colleagues, who studied the amino acid sequences in hemoglobin molecules of numerous organisms, from sipunculoid worms to humans, that use hemoglobin to carry oxygen to body tissues.

In 1964, the first sequence of fragments of the DNA of an extinct quagga were worked out using the skin of an extinct specimen in a museum. The quagga was an animal that looked like a chimera of giraffe and a zebra.

Once DNA sequencing was worked out, especially by Fred Sanger and his colleagues, viruses, bacteria, single-celled organisms, and then more complex worms and flies were sequenced. By 2000, the human genome was being worked out. Svante Pääbo and his colleagues are leaders in the working out of fossil human DNA.

This is what has been found so far. Four contenders for species status lived about 40,000 years ago. Three populations of humans arose after an initial origin in Africa. Of these three, the Neandertals (Homo neanderthalis) left Africa earlier than our own Homo sapiens. The Neandertals were named for the Neander river valley where they found in Germany. We were named by Linnaeus as Man (Homo) the Thinker (sapiens).

Two additional populations were found, one in western Siberia and the other in Indonesia. The Siberian humans are called Denisovans (Homo denisova). They were named for the Denis cave in which they were found and they also had an exit from Africa. The Indonesian humans are called Homo floresiensis and are named for the island Flores in Indonesia where they were found. Where they came from is not yet known. They are unusual for their small size, a Hobbit-like three- and-a-half feet tall.

The DNAs of three forms of humanity have been sequenced. The complete sequence of DNA of an organism’s cell is called a genome. The Indonesian form went extinct about 12,000 years ago, but no DNA has been extracted from their remains. Neandertals and Denisovans went extinct about 40,000 years ago.

Analysis of the three available genomes shows that most Europeans have about 4 percent Neandertal DNA. Living people in Melanesia and Australian aborigines have about 4 percent H. denisova DNA. About 17 percent of Denisovan DNA is from Neandertals. The human branch Homo bifurcated and one branch split into H. neanderthalis and H. denisova. The other branch from Homo produced us, H. sapiens. We are 99.7 percent alike for H. sapiens and H. neanderthalis.

Since we have 3 billion nucleotides to our genome, there remain 9 million mutations between us, most of it in our junk DNA. There are, nevertheless, hundreds of gene differences between our two species. It also means that where these populations came into contact, fertile matings occurred, and remain in our DNA from our ancestral “kissing cousins.”

Elof Axel Carlson is a distinguished teaching professor emeritus in the Department of Biochemistry and Cell Biology at Stony Brook University.