Denisovan Genes Responsible for Modern Depression, Says New Study

Ancient humans inter-breeding with extinct Denisovans have created a genetic make-up and subsequent adaptations that have left many of us predisposed to certain mental health issues like depression, a new study claims. Tracing the evolution of a specific gene most predominantly found amongst East Asians left researchers with the findings that a certain subvariant responsible for zinc regulation and thereby metabolism might be responsible for this slight in evolution.

Introgressions and Genetic Profiles: A Study

Around 60,000 years ago, modern humans embarked on the notable event now known as the "Out-of-Africa" migration. As they ventured into Asia, they encountered the Denisovans, a distinct human species, which likely resulted in a mix of interactions including crossbreeding between the two groups, according to the study published in PLoS Genetics.

Throughout the course of human history, various branches of our family tree have engaged in interbreeding and gene exchange, a phenomenon referred to as 'introgression,' which has occurred on multiple occasions.

Geographical distribution of the substitution identified in the SLC30A9 gene in current human populations and possible scenarios of Denisovan introgression. SLC30A9 ancestral corresponds to the version of the gene prior to the crossing between Denisovans and Sapiens. SLC30A9 variant refers to the version shared with Denisovans. (Jorge Garcia and Elena Bosch. Created in mapchart/CC BY SA 4.0)

The research is conducted by the Institute of Evolutionary Biology (IBE), a collaborative institution of the Spanish National Research Council (CSIC) and Pompeu Fabra University (UPF). It is further supported by the UPF Department of Medicine and Life Sciences (MELIS). They noted that while breeding with Denisovans bestowed modern humans with genes that have potentially facilitated adaptation to the cold, they have also heightened the susceptibility to conditions like schizophrenia, depression, anorexia nervosa, amongst others.

They analyzed the genetic profiles of 26 present-day human populations and compared them to the genomes of our extinct relatives. Through this investigation, the scientists identified one of the most widespread traces of Denisovan DNA in modern humans.

"Through genomic analysis, we noted that the genetic variant observed came from our interbreeding with archaic humans in the past, possibly the Denisovans," says evolutionary biologist Ana Roca-Umbert, from UPF, according to a press-release.

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Denisovan SLC30A9: It’s All in the Zinc!

The researchers' analysis revealed that contemporary populations in regions outside of Africa possess a specific variant of a gene called SLC30A9, which appears to have been acquired through interbreeding with Denisovans in the distant past. This gene encodes a protein known as ZnT9, responsible for transporting zinc across cell membranes.

Demonstration that part of the transporter is located in mitochondria by superresolution STED microscopy imaging with HEZ293 cells transfected with the zinc transporter ZnT9 (in green). In magenta the mitochondrial protein TOM 20 and in white the localization to mitochondria. ( Rubén Vicente/ UPF)

This variant is absent in the Neanderthal genome, eliminating Neanderthals as the source of this gene. Simultaneously, the study found that modern African genomes typically contain an older variant of SLC30A9 that predates the introduction of the Denisovan allele.

“Apparently, the change was beneficial and proved a selective advantage for humans. As a consequence, this variation in the SLC30A9 gene was selected and has reached current populations”, added co-author Jorge Garcia-Calleja.

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To investigate the impact of the Denisovan genetic variant on human physiology, the research team introduced this DNA into human embryonic kidney cells. They observed that this genetic material modified the amount of zinc entering crucial cellular structures, including mitochondria and the endoplasmic reticulum. Consequently, these alterations in zinc levels resulted in changes in mitochondrial metabolism, preventing an "overload" of zinc and providing an overall "gain of function."

Based on these findings, the authors of the study speculate that the genetic variant inherited from Denisovans may have played a role in enhancing the adaptability of ancient Homo sapiens to cold environments. At the same time, imbalances in zinc levels potentially contribute to neurological disorders, raising the possibility that the DNA acquired by our ancestors during interbreeding could have had both advantageous and detrimental consequences, reports IIFL Science.

Essentially, the variant discovered in this zinc transporter, expressed in all tissues of the body, is linked to an increased susceptibility to various psychiatric disorders. These conditions encompass anorexia nervosa, hyperactivity disorder, autism spectrum disorder, bipolar disorder, depression, obsessive-compulsive disorder, and schizophrenia.

"In the future, expanding this study to animal models could shed light on this predisposition to suffering from mental illnesses," concluded molecular biologist Rubén Vicente, from UPF.

Top image: Study reveals Denisovan genetic make-up may be responsible for modern day depression. Source: Bartek/Adobe Stock, Woraphon/Adobe Stock

By Sahir Pandey