One of the most anticipated returns to normalcy following the pandemic is the in-person conference. Like the mythical Phoenix bird arising from…
Determining the sequence of building blocks of entire genomes – aka genomics – first came to public attention in the 1990s, with the race to decode the first human genomes. Today, smartphones can carry our personal genome sequences.
Genomics applies to all species, revealing evolution in action, because we all use the same genetic code – that is, the correspondence between DNA sequences and the amino acid sequences of proteins. Many popular uses of “genetic code” actually mean “genome sequence.”
Analysis of environmental DNA (eDNA) catalogs the DNA in specific places, from microorganisms inhabiting a human armpit to vast ecosystems. Several recent DNA Science posts describe eDNA:
- A Glimpse of The Ocean’s “Twilight Zone” Through Environmental DNA
- A 2-million-year-old Ecosystem in the Throes of Climate Change Revealed in Environmental DNA
- DNA in Strange Places: Hippo Poop, Zoo Air and Cave Dirt
- Microbiome Analysis of Ancient Feces
Genome sequencing was critical from the start of COVID, as the first SARS-CoV-2 sequences were posted for researchers just days after initial case reports. That information led, thanks to vaccine shelved from the first SARS circa 2003, to the rapid development and deployment of mRNA vaccines against the new infectious disease.
I tracked the numbers of sequenced SARS-CoV-2 genomes posted at GISAID every few days during the pandemic, contributed by researchers everywhere. Right now it’s just below 16 million variations of the tiny genome. New mutations continue to arise and recombine into new viral variants. Evolution never ceases.
Recently, I’ve noticed an uptick in technical reports on eclectic applications of genome sequencing – so here are a few, followed by a brief historical perspective.
Cats and Bird Flu
Comparing DNA sequences is a little like linguistic research that connects languages. Consider a study of cats in Poland that have died recently from H5N1 bird flu. Cats (and humans) don’t typically contract bird flu. The owners of the felines all reported feeding their pets raw meat, and samples of the meat revealed not only flu virus genetic material, but also infectious virus.
Genomic sequencing of the viruses in the Polish cats indicated a strain found in a white stork in the Tarnów region in early June. The “highly pathogenic avian influenza” strain (H5N1 clade 18.104.22.168) emerged in late 2021. The first cat case was reported in December 2022, in a feline living near a duck farm in southern France.
So far at least 6 cats in the U.S. have died of H5N1. All had contact with birds, which anyone who has an outdoor cat knows is unavoidable. One of the first, a barn cat in Wyoming, ate wild waterfowl.
H5N1 infects many mammals – bears, feral cats, dogs, dolphins, foxes, otters, raccoons, seals, sea lions, and skunks. The fear is that a variant of the deadly virus might emerge that infects people, and, worst-case-scenario, passes from person to person.
Dolphins Adapt to Climate Change
The warming planet will sculpt future genomes as natural selection guides which individuals adapt to conditions well enough to contribute to the next generation. For sea inhabitants, climate change can alter salinity patterns, water depth, and the locations of predator and prey species.
Emergence of new coastal areas may entice dolphins to swim closer to shore, which may affect their physiology and behaviors, but at the same time, enable sharks to hunt closer to shore. Bottlenose dolphins today so far seem to be adapting to environmental warming. A report in Nature Communications on DNA from dolphins that lived millennia ago uncovers clues to the possible future as global temperatures continue to rise.
Marie Louis from the University of St. Andrews in the UK and colleagues analyzed DNA from four dolphin bones dredged from the North Sea radiocarbon dated to 8,610–5,626 years ago, a time when coastal habitats emerged in northern European waters. Genomic evidence indicates that not only did ancient dolphins adapt quickly to the new coastal habitats, but that natural selection has retained the genetic changes associated with coastal adaptation – good news for today’s dolphins facing warming waters.
AI Analyzes Brain Tumors
Artificial intelligence may have entered the news cycle only recently, but it’s been around in genetics and genomics for years, because DNA sequences are information, which reveals microevolutionary change. AI is especially insightful in comparing the DNA in cells of a tumor that are at different stages of evolution – that is, cells in the same tumor may have different sets of mutations in tumor suppressor genes and oncogenes. These patterns can foretell which treatments will likely work and which won’t, how likely and quickly the cancer will spread, and its path in the body.
Harvard Medical School researchers recently described an “AI tool” that “Decodes Brain Cancer’s Genome During Surgery,” in the journal Med. The real-time tumor profiling system can guide surgical and treatment decisions as the patient lies on the table, eliminating the weeks-long waits to detect the often multiple genetic inclinations of the parts of a tumor. The report describes “in-surgery genomic profiling of gliomas, the most aggressive and most common brain tumors.” A surgeon guided to key parts of the tumor to remove can then place tiny chemo-coated wafers directly into the brain. This “real-time precision oncology” can uncover critical details destroyed when tissue is frozen, detecting beyond what a human eye can discern.
A similar AI tool was the star of the most recent season of the network TV show Chicago Med, featuring an AI-based operating theater called OR-2.0, or just 2.0 as the docs became accustomed to it. Duke University neurosurgeon Oren Gottfried voiced 2.0, which spit out information guiding the trimming of tumors in real time, a bit reminiscent of its ancestor Hal the computer from 2001: A Space Odyssey.
The AI tool, called CHARM (for Cryosection Histopathology Assessment and Review Machine) was trained on 2,334 brain tumor samples from 1,524 patients. When tested on other samples, CHARM distinguished tumors with specific mutation sets with 93% accuracy, classifying them into three subtypes with different prognoses and treatment responses. CHARM also detected non-genetic characteristics with prognostic value, such as the shapes of tumor cell nuclei, the extent and location of cell death in the tumor, and regions of greater cell density.
CHARM wilI join AI-based systems already used to interrogate tumors of the colon, lung, and breast. Gliomas have been challenging to analyze due to their great variability. Next up: testing in real-world settings and submission of clinical trial findings to the FDA.
Speeding Diagnostic Odysseys for Rare Diseases
I’ve written much about the “diagnostic odysseys” that parents undertake upon finally learning a name for a child’s unusual collection of symptoms. A spellbinding such tale is “8 fingers 8 toes,” in Human Genetics and Genomics Advances. In the essay, Debbie Jorde recalls the birth of her daughter Heather, in 1977, and her feelings upon first glimpsing her newborn’s 8 fingers, 8 toes, oddly bent arms, and small eyes and ears. She and her husband were rattled when asked to sign an autopsy consent form before one diagnostic procedure.
A spectrum of seemingly unrelated symptoms suggests a genetic condition. When Heather was 18 months old, a geneticist suspected Miller syndrome, but only 3 cases were known, and those were due to a mutation that the child didn’t have. The parents were assured that it wouldn’t happen again. But it did, 18 months later when their son was born with the same traits.
An answer didn’t emerge until the family was one of the first to participate in a government program in exome and genome sequencing. Heather and her brother indeed had Miller syndrome, but with different mutations than the known cases. Plus, they had a second genetic condition that affected their lungs. The dual diagnosis was a game changer, suggesting treatments. Debbie concludes:
“Being part of ground-breaking genome and exome sequencing research positively changed our lives and was exciting. We feel we have contributed something important to the world and that we are helping other families receive answers. We also enjoy knowing we are the first family worldwide to have our exomes and genomes sequenced to discover a gene for a Mendelian condition.”
Genome Sequencing for All Newborns? BabySeq
A newborn with oddities and anomalies could obviously benefit from the information that genome (or exome, the part of the genome that encodes protein) sequencing could provide. But what about seemingly healthy newborns? That’s the goal of the BabySeq initiative, at Brigham and Women’s Hospital and Boston Children’s Hospital.
The BabySeq initiative “will help us better understand how we can appropriately use this information to improve health and prevent disease in infants and children,” said Eric Green, then director of the National Human Genome Research Institute, when the agency solicited plans for pilot programs in universal newborn genome sequencing a decade ago. Initially BabySeq is enrolling 500 babies in Boston, New York City, and Birmingham, Alabama.
The overall approach is termed “newborn genomic sequencing (NBSeq).” It’s expected to reveal the 11% of newborns with dominant mutations, the 88% who are carriers of recessive mutations, and the 5% with atypical responses to pediatric drugs
While NBSeq can speed diagnosis of genetic syndromes, it can also open a proverbial can of worms if the penetrance of specific mutations isn’t known – that is, how often a genotype (mutation) predicts phenotype (health). Too much genetic information could, in some cases, lead to “patients-in-waiting” as parents and practitioners await predicted symptoms that may or may not materialize. Sometimes, mutation in a second gene can counter the symptoms, so algorithms should ultimately account for gene-gene interactions as we discover them.
Once a diagnosis has been made via genome or exome sequencing of a newborn, the major issue is actionability – can the associated symptoms be treated, or avoided?
To examine follow-through, a report in a recent American Journal of Human Genetics from BabySeq used a shortcut: exome sequencing in 127 apparently healthy infants and 32 infants in intensive care. Seventeen of the entire group (10.7%) had “unanticipated monogenic disease risks (uMDRs).” The investigators followed the 17 children for 3 to 5 years, and assessed whether identified genetic conditions could be managed and/or treated, using a standard metric. All 17 children had conditions that were “moderately or highly actionable.”
For three infants, the findings put a name on mysterious sets of symptoms. For the other 14, the results enabled “risk stratification for future medical surveillance.” Identifying newborns who have disease-causing mutations also led to testing family members. Three had surgery to reduce hereditary cancer risk based on findings in newborn relatives.
The practicality of the pilot study gives a thumbs-up to further BabySeq efforts.
CODA: A Brief History of Genome Sequencing
It is remarkable to live through the birth and development of a technology as rich as genome sequencing and interpretation. The field began with viruses, so streamlined that they’re considered “infectious particles,” neither cells nor organisms. But, they have genomes, built of RNA or DNA.
I was in graduate school for my PhD in genetics when the first virus genome sequences were published. First came RNA bacteriophage MS2, a mere four genes, sequenced in 1976. (A bacteriophage is a virus that infects bacteria.)
A year later, improvements in sequencing revealed the 10-gene genome of another bacteriophage, ϕX174.
In 1982 came phage lambda, boasting a bigger genome of 70 genes that encode its proteins. Lambda was a classic tool of the fledgling field of molecular genetics.
Other viral genomes joined the roster of the sequenced. A landmark was the 1995 publication of the first bacterial genome, that of Hemophilus influenzae, which causes ear and other infections.
In 1996 came the first eukaryotic genome, that of baker’s yeast (Saccharomyces cerevisiae). (A eukaryotic cell has a nucleus and other organelles). The yeast genome has 12 million DNA bases splayed across 16 chromosomes.
Then in 1998 the tiny roundworm Caenorhabditis elegans had its 97 million bases revealed, encoding more than 19,000 proteins. It is a classic model organism in developmental biology because we can follow the fates of all 959 of its initial cells as they divide, fold, and unfurl into organs, building the larval body.
Next, in 1999, came the genome of the fruit fly Drosophila melanogaster, with 215 to 220 million base pairs, females with the higher number because of their two X chromosomes.
And then in 2001 came us. I recently recounted the history of human genome sequencing, here at DNA Science.
I am privileged to have been able to chronicle the emerging field of human genomics, in many articles and in the fourteen editions of my human genetics textbook. With the avalanche of information now coming from genomics research, I can’t help but wonder what we have yet to ponder!