By Grant Keddie
Genetics, diseases, modern humans and our close relatives.
Our Developing Nervous system
One of the keys to understanding modern diseases is through their genetic evolution and how that can contribute to where we focus research to eliminate them. One of the latest fascinating discoveries may be relevant to the study of modern common neurological diseases such as parkinson’s, dementia, seizures, strokes and migraine headaches.
There is a new field of study that involves a combination of stem cell biology, neuroscience and paleogenomics. This involves the ability to apply the comparative approach of modern human genetics to our closest extinct relatives, the Neanderthals and Denisovans, using brain organoids.
A brain organoid is an artificially grown miniature organ resembling the brain. It is essentially a mini brain in a laboratory dish composed of stem cells – the self-renewing precursors of other cell types.
The NOVO1 Gene
Although there a number of gene differences between modern humans Neanderthals and Denisovans, one unique gene, a neuro-oncological central antigen 1 (NOVA1) is now the focus of study. This gene is active during brain development and influences the development of our nervous system.
This gene variant found in all modern humans differed from that of Neanderthals and Denisovans by only one base pair. The newer CRISPR gene editing was used to change the modern NOVA1 in human stems cells to mimic the older Neanderthal and Denisovan version. These cells were developed into a brain organoid and compared with modern human stem cells in the same process.
As they matured the ancient human organoids were visibly different than modern ones. They were smaller, structurally different and their cells multiplied more slowly and differed in the way their synapses — the connections between neurons — form.
This single alteration of this ancient version of the gene changed the expression of 277 other genes compared with modern organoids, and caused 113 alternate splicing events – a process that causes one gene to code for multiple proteins. Many of these proteins were linked to brain development.
The “Extinct” Hominins
We currently know that many hominin lineage branches existed in the past. We are the only one that has survived to the present. Modern humans all have 99.9 % the same genes and cannot be divided into any separate groups. Neanderthals and Denisovans are two of the extinct branches that are our closest evolutionary relatives. They provide the most subtle genetic contrast to our species.
Comparison of the genes of Neanderthals and Denisovans with modern genomes has shown that many humans today carry genes introduced through past intermixture events. I have several hundred genes that I inherited from Neanderthals and Denisovans. This comparison allows us to see which of the human-specific genetic differences have become important in recent evolution.
This new mutation variant of NOVA1 is an important gene difference between the modern human brain and that of our immediate extinct ancestors. It has a different gene expression that results in greater regional network complexity in the brain. There are exciting prospects as to where this will lead modern medicine in the control or elimination of some modern diseases.
Image. Reconstruction of Neanderthal woman.
