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Genome of Galapagos Gentle Giant Lonesome George Leaves Clues to Longevity

I have a special fondness for tortoises.

Many years ago I bought a baby Sulcata tortoise at a reptile show. Unbeknownst to me, as I brought the Oreo-sized Speedy home in a McDonald’s burger container, she could live 100+ years.

Speedy grew. Fast. For amusement, she took to moving the furniture around at night. The weekly bowel movement took me several hours to clean up and the culprit hated the bathtub. She loved being outdoors in the summer, a reptilian lawn mower, but come winter, she’d grow depressed stuck inside, stalling herself in a corner of my office like a misplaced file box.

Speedy Lewis

I despaired. Then googling led to articles disparaging idiot northeasterners who take in the likes of iguanas and giant tortoises, then have to deal with the inevitable growth.

I had to rehome my beloved Speedy.

I read the explicit directions posted online and placed her in the required two plastic tubs with lots of room and a label “I am not a snake,” and off she went to the mail store. I’d ascertained that Airborne Express would send her on her way, but FedX and DHL wouldn’t touch a live reptile. But I was 5 minutes late, and the Airborne guy had come and gone.

It was Monday, September 10, 2001.

Had Speedy left on schedule, she’d no doubt have perished on a tarmac somewhere as the U.S. shut down in the wake of the terror attacks. The owner of the mail store, to this day, tells the tale of his most intriguing package, Speedy the tortoise.

I kept her an extra month, then sent her off. I heard soon that the Airborne guy in California, after ascertaining that she was not a snake, took her out and let her sit on the seat next to him. She ended up on a tortoise farm in Apple Valley, California, with other large, rehomed Yankee reptiles. Speedy soon had a boyfriend, a wealthy Sulcata flown in by private jet from Sonoma. But we lost touch.

The Genomic Legacy of Lonesome George

I was intrigued to discover a paper in in the December 3 Nature Ecology & Evolution, “Giant tortoise genomes provide insights into longevity and age-related disease,” from researchers at Yale University, the University of Oviedo in Spain, the Galapagos Conservancy, and the Galapagos National Park Service. The subject was the most famous resident of the Galapagos islands, Lonesome George. The researchers compared George’s genome to that of the Indian Ocean’s Aldabra giant tortoise (Aldabrachelys gigantea) and a few genes from other species, including of course our own.

The project took a long time. In 2010, Adalgisa Caccone of Yale began the sequencing, and Carlos Lopez-Otin at the University of Oviedo in Spain led the analysis of the data to hunt for gene variants associated with longevity.

When Lonesome George died in 2012, he was the last living member of Chelonoidis abingdonii. He lived on the island of Pinta and weighed 195 pounds when he died, at approximately a century old.

Comparison of specific DNA sequences considering known mutation rates reveal that the two types of torts shared their last common ancestor about 40 million years ago, and both diverged from the human lineage more than 300 million years ago. Arrival of people in the Galapagos accelerated the decline of the populations of Lonesome George’s kin – the sailors aboard the Beagle, on which Darwin famously sailed, are said to have eaten at least 30 of the animals.

The new report, unfortunately, uses the term “evolutionary strategies,” as if the creatures lumbered about considering what, exactly, to do or not do to stick around for another day. That’s not how evolution by natural selection works. Instead, those individuals lucky enough to have inherited decent gene variants that render them well enough to reproduce leave behind more offspring, hence perpetuating those genes.

Today researchers track evolution through beneficial changes rooted in the genes. Specifically, they look for signs of “positive selection” – amino acid sequences in the proteins that genes encode that differ from those in related species and that are associated with an advantage (an adaptation).

The example of positive selection that I use in my human genetics textbook is the high-altitude adaptation of the human natives of the Tibetan plateau, who live more than two miles above sea level. These highlanders have a version of a gene called EPAS1 (hypoxia inducible factor 2), plus variants in two other genes, that enable them to thrive in thin air.

The types of adaptive genetic changes include replacing amino acids in the corresponding proteins, deleting gene parts, and, simpler, duplicating key genes. Copying genes that work is a persistent theme in evolution.

Lonesome George’s Genome Secrets

The new study found 43 genes in Lonesome George’s species that show evidence of “giant-tortoise-specific positive selection.” They’ve enabled the animals to live a century or more, avoid or easily combat infection and injury, and never get cancer. “Lonesome George is still teaching us lessons,” said Dr. Caccone in a news release.

Not surprisingly, the tort had lots of genes for the scaly keratin proteins that formed his shell, and no genes for teeth. I’ve never seen a tortoise with teeth.

A whopping 891 genes that provide the immune response are duplicated in Lonesome George compared to their counterparts in mammals. He had a dozen copies of the perforin gene, whose protein shatters the cells of pathogens, and extra granzymes, enzymes that kill pathogens. Other immune system genes overrepresented in Lonesome George’s genome specifically wallop viruses, bacteria, fungi, and parasites. And the major histocompatibility complex (HMC) genes are duplicated.

The genes that regulate blood sugar and DNA repair are different from counterparts in other species. Lonesome George and his brethren had the 8 types of globin molecules common to all vertebrates, but with variants that protected them against low-oxygen conditions. It was a trait likely handed down from their aquatic turtle ancestors.

When screened against a large “census” of known cancer genes, Lonesome George’s genome revealed 5 expanded genes that encode tumor suppressor proteins, and their identities suggest a role in immunosurveillance – an immune system that actively fought cancer. The immune endowment might help to explain Peto’s paradox: the lower incidence of cancer in larger animal species.

Lonesome George’s genome also revealed an enzyme variant that suggests a possible protection against the sort of protein aggregation that lies behind Parkinson’s disease and Alzheimer’s disease. Variants of the gene TDO2 are associated with regulation of alpha-synuclein aggregation in worms. The gene variant in Lonesome George inhibits the enzyme that breaks down tryptophan, which protects against protein aggregation.

Most interesting to me was the scrutiny of genes associated with longevity in other species. “We had previously described nine hallmarks of aging, and after studying 500 genes on the basis of this classification, we found interesting variants potentially affecting six of those hallmarks in giant tortoises, opening new lines for aging research,” Dr. Lopez-Otin said.

Lonesome George’s half dozen aging-associated genes that have unique variants promote genome integrity, DNA repair (base excision), and a resistance to double-stranded DNA breaks, meaning that CRISPR probably wouldn’t work on a giant tortoise. Lonesome George also managed to keep his chromosome tips, his telomeres, long, extending the biological cell division clock. Plus, unique gene variants point to superior cell-cell communication, a robust cytoskeleton, and mitochondria especially good at detoxification.

The lonesome one shared key aging gene variants with the naked mole rat, the longest-lived rodent. Plus, George’s genome show positive selection in the genes AHSG and FGF19, which encode biomarkers of healthy longevity in humans.

Conclude the researchers, “Lonesome George—the last representative of C. abingdonii, and a renowned emblem of the plight of endangered species—left a legacy including a story written in his genome whose unveiling has just started.”

Speedy would be proud.



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