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Modern humans share disease-associated genetic variants with Neanderthals
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Modern humans share certain genomic structural variants in common with Neanderthal and Denisovan hominids, according to recent findings.
Modern and ancient humans have deletion variants in common, which have been maintained throughout human evolution and are associated with common diseases such as psoriasis and Crohn’s disease, as well as with growth hormone treatment response, according to the researchers.
“Most of genetics is about reading sequences in our genomes, which is essentially four chemical letters: A, C, T and G. Most of our work as geneticists is focused on identifying single letter changes,” researcher Omer Gokcumen, PhD, assistant professor of biological sciences at the University of Buffalo, told HemOnc Today. “In the last decade, another type of variation is more and more appreciated. These are called copy number variants which, by definition, are not single letter changes, but rather deletions or duplications of large segments of the DNA: so, essentially, some genetic sentences are missing in some individuals.”
Omer Gokcumen
Deletions in common
In the study, which was published in Molecular Biology and Evolution, Gokcumen and colleagues evaluated the genomes of modern humans in relation to Neanderthals and Denisovans. The genomes of these earlier forms of humans were previously sequenced using human remains, according to Gokcumen.
“Denisovans were similar to Neanderthals; humans, Neanderthals and Denisovans had a common ancestor about 500,000 years ago, as far as we can tell,” Gokcumen said. “We don’t know much about Denisovans because there aren’t many remains.”
The researchers used a dataset of 14,422 deletion polymorphisms identified among 1,092 human genomes as part of the 1,000 Genomes Project Phase 1 data release. They found 427 polymorphic deletions that modern humans share with Neanderthals, Denisovans or both.
“We found that the most likely explanation for more than 80% of them is that already in the ancestral population of all humans, Neanderthals and Denisovans, some individuals had these deletions, and some didn’t,” Gokcumen said. “They have been maintained for at least 500,000 years.”
Statistical artifacts
According to Gokcumen, more than 90% of these deletions are “statistical tail of distribution,” with no real function. However, a small percentage of the deletions do appear to have significance, he said.
“In fact, these deletions happen to be associated with several diseases or biomedically relevant phenotypes, including susceptibility to psoriasis and Crohn’s disease, and several drug responses, including responses to growth hormone and several chemotherapy drugs,” he said. “I do not think that these have been maintained for so many years just by chance.”
The question, then, Gokcumen said, is why these disease-associated deletions would be preserved over the years.
“It becomes an issue of understanding the biological scenarios that might cause this to happen,” he said.
Balancing selection
Gokcumen discussed the role of balancing selection, a selective process in which multiple alleles are maintained in a population’s gene pool at frequencies beyond that of gene mutation.
“The best example we know for humans is sickle cell anemia, in which this particular mutation in the hemoglobin creates genetic, inherited anemia. Obviously, this wouldn’t be good for the population,” he said. “If you happen to have the mutation in one of your chromosomes, if you’re heterozygous, you’re slightly anemic and it’s not that bad; and, here is the catch, if you carry that allele you’re protected against malaria.”
In geographic regions where malaria is prevalent, sickle cell anemia may therefore have some genetic benefit, according to Gokcumen.
“If you’re in a malaria-ridden geography like the ancient Middle East or India or some parts of Africa, you have a balance,” he said. “You have a force that actually keeps this so-called ‘bad allele’ in the population.”
Role in autoimmune diseases
Notably, the researchers found that some of the deletions that have been maintained since ancient times are associated with common diseases like Crohn’s disease and psoriasis. While deletions linked to these diseases might seem to be clearly disadvantageous to the population, balancing selection might provide an explanation for their continued existence over the centuries.
“It’s possible that there is a balance between autoimmune diseases and actual immunity to pathogens,” Gokcumen said. “If you have an overactive immune system, this will be good if you have a lot of pathogens around; but, then, if the pathogens aren’t there or you’re oversensitized for external stimuli, suddenly you have inflammation, which is, by the way, what psoriasis and Crohn’s disease are.”
He said in some cases, the advantages of these deletion variants also involve sacrifices.
“Sometimes, everything works out and you have a nice adaptation — it doesn’t really hurt anything, and you’re happy as a clam,” he said. “But it seems there are also some variable traits in the human population, where it’s beneficial on one side and harmful on the other.”
Role in growth hormone receptor
Gokcumen and colleagues found that one of the deletions shared with the ancient humans overlaps with the exon 3 of growth hormone receptor (GHR) gene.
“Some people actually carry a shorter version of this gene, and it’s very common. Apparently, the Neanderthals also carried this,” he said. “There has been some preliminary analysis showing that babies born with the shorter version are smaller, but then they grow up faster. So they catch up later.”
He said when viewed from a balancing selection perspective, this may be a geography-dependent scenario related to seasonal availability of nutrition.
“If you have abundant food and the opportunity for continuous growth, that’s good, but where there’s scarce food, maybe it’s better to grow a little bit slower,” he said. “When you’re thinking about selection in this context, it’s a matter of how many of your children would live, and what kind of alleles they would carry.”
Gokcumen said he and his colleagues plan to investigate this hypothesis by studying this deletion in a mouse model. Additionally, he said, the deletion was analyzed in terms of response to growth hormone treatments by other groups.
“If you have the shorter version of this gene, for some reason — we don’t know the mechanism — you have increased response to growth hormone treatments.” — by Jen Byrne
For more information:
Omer Gokcumen, PhD, can be reached at the Department of Biological Sciences, 641 Cooke Hall, North/Amherst Campus, University at Buffalo, Buffalo, NY 14260; email: omergokc@buffalo.edu.
Disclosure: The researchers report no relevant disclosures.
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