A confluence of rare mutations

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Three decades ago, a neuroscientist at UC Santa Barbara Kenneth S. Kosik began studying a Colombian family with a genetic form of early Alzheimer’s disease. He and his fellow researchers realized they were only scratching the surface of the largely unseen, yet profound, consequences of Spanish-led colonization nearly five centuries ago.

“When my colleagues were running this clinical trial on individuals from this very large rural family carrying this mutation, they needed as many participants as possible,” Kosik said, recalling efforts to recruit people for the study. . The family in question, which numbers several thousand people, was unique. Members carrying the so-called Paisa mutation would, like clockwork, begin to develop the characteristic forgetfulness of Alzheimer’s disease – what they called the bobera — in his forties. Together with Colombian neuroscientist Francisco Lopera, the researchers tried to expand their network as much as possible to find even in remote parts of the country people with early dementia that has caused so much undue suffering in Colombia.

The extent of the disease was far greater than they had anticipated – their investigation yielded genetic results that date back millennia and span multiple continents. The work of researchers is published in the journal Genome Medicine.

distant origins
Juliana Acosta-Uribe remembers the beginnings of this study. Then a medical student, she was finishing her studies to become a doctor-researcher with a year devoted to social work.

“We were getting over a thousand phone calls from people with early dementia in their families,” said Acosta-Uribe, now a project scientist at Kosik Lab and lead author of the paper. “And we were testing them to see if they were part of the family with the Paisa mutation.”

But as they tested these people for the PSEN1 E280 mutation, as it is officially known, the researchers’ assumptions that their new patients were somehow a subset of the original family evaporated. The vast majority of tests came back negative. Further testing revealed that the researchers had a concentration of unrelated families with different mutations that resulted in the same observable characteristics.

“We have become quite good at identifying different mutations that lead to neurodegenerative diseases – their genotype.” Kosik said. “But we don’t really understand the relationship between genotype and their phenotype – i.e. what they look like clinically, what type of dementia they get, how it happens, what mechanisms are affected.”

The genomic tests only told part of the story, with information that at first seemed to only deepen the mystery. The famous Paisa mutation, for example, traces back to a single founder in early Habsburg Spain, while another mutation traces back to West Africa. Yet another has been identified with Native American roots. How did they all emerge in the rural Colombian countryside?

Hints of this phenomenon can be found in the history of Colombia and the movement of people around the world.

“So many different factors in demographics and the history of the population and its movements have shaped the current risk burden for Alzheimer’s disease,” Acosta-Uribe said. At the time of the conquest of the Americas by Spain, Europeans landed for the first time on the northern shores of what would become Colombia at the beginning of the 16e century, making efforts to settle and colonize the region. Later in that century, West Africans would be added to the mix as enslaved labor.

However, people weren’t the only ones mixing in Colombia at this time.

“People don’t travel alone,” Acosta-Uribe said. “People travel with their bugs.” According to the researchers, people traded their insects with others who had never encountered them before and the population “suffered massive mortality from many infectious diseases including smallpox, influenza, syphilis, hepatitis, measles, encephalitis, tuberculosis, diphtheria, cholera, typhus, scarlet fever and meningitis.

The population collapse caused a shrinking of the gene pool – a genetic bottleneck in which the few remaining survivors, who also possessed these rare mutations, became the founders of subsequent populations, passing their mutations on to their offspring. A long period of settlement followed during which migration slowed and people mostly stayed put. The lack of new genes, isolated pockets of people, and large families have helped establish the mutations in the population.

“If they have multiple generations of large families, those mutations amplify, and they amplify locally, because people aren’t moving around,” Kosik explained. “And what we’re starting to see in Colombia is that the genetic map overlaps the geographic map, because you can actually match people with a mutation to a certain region.”

This mechanism explains how mutations were able to proliferate in the population over generations. But the researchers’ investigations raised another question, one that’s hard to ignore.

“When you put selective pressure, such as pathogens, on a population, the question arises: do the survivors have an advantage over those who died?” said Acosta-Uribe. Could these mutations – in particular variants of the PSEN1 (presenilin) ​​gene – have conferred some kind of protection on their carriers against the onslaught of infectious diseases at the start of colonization, thus ensuring their survival?

It wouldn’t be an unusual situation, according to Acosta-Uribe.

“There are many examples of selection for people who have a genetic variant that in other conditions could be detrimental,” she said. For example, she pointed out, people who are heterozygous (one copy of a mutated gene from one parent and a normal copy from the other) for sickle cell anemia are resistant to severe malaria. The mutation that leads to the sickle-shaped cells “also interferes with the reproductive cycle of the malaria parasite.”

Unfortunately, the idea that having these PSEN1 mutations helped their carriers ward off deadly infectious diseases may forever be in the realm of speculation, Kosik said.

“We can’t replay the tape of life,” he said. “You can’t replay everything that happened there to prove it, but it’s pretty believable.” Two tantalizing circumstantial pieces of evidence in this mystery: a total of 13 PSEN1 gene mutations found in the Colombian cohort alone (a “statistically unusual” concentration of such rare mutations for a country the size and population of Colombia), and the antimicrobial properties of the peptides responsible for the insoluble sticky plaques characteristic of Alzheimer’s disease.

“It turns out that the beta-amyloid peptide could have an antimicrobial function; there’s this very old system of protection against invading organisms where an antimicrobial peptide attaches to the invading organism and separates it from the rest of the body,” Kosik said. Speculation is that this particular mutation may have been positively selected, perhaps because it protected people from disease. His lab is investigating this effect with an even closer examination of their cohort’s genomes, but at best it may remain a statistical argument, Kosik added.

As the Kosik Lab continues its work, with the results of a major clinical trial fast approaching, it is clear that the huge genomic dataset they have generated is just the tip of the iceberg. regarding the genetics of diseases in the world. population.

“We generated a unique dataset that can help us understand disease genetics in non-white populations,” Acosta-Uribe said. The majority of genomic data focuses on European genomes, which can obscure much of the picture when it comes to gene-linked diseases in the human population, she added. This is especially true of the links between mutations and their physical outcomes.

For example, in his survey of genomes for this project, Acosta-Uribe found that the same mutations and pathologies that present in the European context as ALS (also known as Lou Gehrig’s disease) are present in the Native American lineage as frontotemporal dementia. Moreover, tracing the Native American mutation through time, she discovered that it originated from the first population of the Americas.

“We compared the Colombian carriers of these variants with the Asian carriers of this variant,” Acosta-Uribe said, “and we identified that indeed the Colombians had picked it up from their ancestors who migrated across the strait. of Bering and populated the Americas with over 30,000 people years ago.”

Back in the present, this new knowledge may provide clues to members of the Colombian cohort as to why the genetic form of Alzheimer’s disease is so prevalent in their families. It also underscores the value of collaboration in efforts to understand and eventually treat this as yet incurable disease. One bright spot: A female relative with the Paisa mutation lived her entire life without developing Alzheimer’s disease, possibly because a second copy of the rare genetic mutation uncoupled the two hallmark signs of the disease : beta-amyloid plaques (which were found in his brain after his death), and tau tangles (which were not found).

“This article has led us to develop close ties with the scientific community and with families in Colombia,” said Acosta-Uribe. “We were able to explain to the families why this was happening to them and tell them that even though we may not be able to cure them yet, we will be there with them.”

Research in this project was also conducted by Bradley W. Killingsworth, Rijul Singhal, Sarah Labib, and Nithesh Perumal at UCSB; David Agillón, Margarita Giraldo, Lucía Madrigal, Diana Alzate, Lina Velilla, Sonia Moreno, Gloria P. García, Amanda Saldarriaga, Francisco Piedrahita, Liliana Hincapié, Hugo E. López, Dionis Vallejo, Juan Marcos Solano and Andrés Villegas-Lanau at the University of Antioquia; Ezquiel I. Surace, Tatiana Itzcovich and Ricardo Allegri in Fleni-CONICET; Eric M. Reiman at the Banner Alzheimer Institute; Raquel Sánchez-Valle at the University of Barcelona; Charles L. White III of the University of Texas Southwestern Medical Center; Diana Matallana at the Pontifical Xaverian University; Richard Meyers of the HudsonAlpha Institute of Biotechnology; and Sharon R. Browning of the University of Washington.

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