The Sequence 2/20-2/26
Why Elephants Rarely Get Cancer, Diagnosing Genetic Conditions Using 3D Images, Genetic Factors Associated with White Matter in the Brain, New Genes Associated with Suicidal Thoughts or Behaviors
Why elephants rarely get cancer
Image credit: Canva
In a beautiful follow up to last week's post discussing the TP53 gene and why mutations in the gene, or harmful changes in genetic code, increase susceptibility to cancer, this week I am discussing the TP53 gene in elephants. Recently, the UK-based Institute of Cancer Research spoke to Professor Joshua Schiffman about the TP53 gene and why elephants rarely get cancer.
Tell me more.
In humans, TP53 is responsible for keeping us safe from cancer and has two main roles in terms of cancer prevention: It stops mutated cells from dividing so they don’t spread, or eliminates those cells through cell suicide if they cannot be repaired. This is why if the TP53 gene has a mutation and it no longer works properly, tumors grow.
But what happens when we look at the role of the TP53 gene in an animal that rarely gets cancer? This is what Dr. Schiffman and his team are studying, in hopes of finding ways to prevent cancer in humans.
What did the team find?
In conjunction with cancer researcher Professor Carlo Maley, Dr. Schiffman’s team found some answers. They began by working with zoos and a circus company to successfully obtain blood samples from 644 elephants.
The first major results: Elephants have 40 copies of the TP53 gene instead of the two copies humans carry. FYI these TP53 genes are the only genes in elephants with significant extra copies.
The second major results: Elephant TP53 genes have evolved to work more effectively than TP53 genes in humans. Above, we talked about how TP53 genes stops mutated cells from dividing so they don’t spread, and so that they can be fixed. Well in elephants, mutated cells self-destruct rather than try to fix their mutations.
The third (and newest) set of results: Schiffman’s team tried this mechanism out in human cells, and it worked. By growing human cells with cancer in the lab and adding the elephant TP53 gene, Professor Schiffman showed the cancer cells began to rapidly self-destruct.
What’s the takeaway?
Understanding the unique properties of elephant TP53 can help us to understand how other animals have evolved to resist cancer. This can help us to replicate nature’s processes, and eventually create targeted medicines to protect humans from cancer in the way that elephants’ bodies have naturally over time.
Full Article 1 (interview w/ Dr. Schiffman), Full Article 2 (Preston et al. 2023)
Diagnosing genetic conditions using 3D images
Speaking of AI, Bannister et al. studied 3D images of patients in order to understand the accuracy of diagnosing conditions based on 3D images.
Why? Well, many genetic conditions have certain expected facial characteristics. Think: especially short or long distance between the pupils of the eyes, shape of the upper lip, placement of the ears, etc.
Interesting. How did they study that?
To begin, the team took 3D surface scans for more than 1,900 faces from individuals affected by 43 genetic syndromes. They then created different 3D and 2D facial representations for each subject, and used them in comparative analyses.
Cool. What did they find?
Generally speaking, 3D surface-based syndrome classification models significantly outperformed 2D image-based models trained and evaluated on the same subject.
Additionally, 2D color representations outperformed 2D colorless representations that had surface color information removed. One interpretation of this result is that facial complexion carries relevant information for some genetic syndromes. Makes sense, because some syndromes are associated with features that manifest in the complexion of the skin. For example, neurofibromatosis is characterized by café au lait spots, and Prader-Willi syndrome is characterized by hypopigmentation.
What’s the takeaway?
Although the 3D model outperformed 2D models for most syndromes, this was certainly not the case for all of them, suggesting 3D facial phenotype modeling can improve. Although facial imaging to assist in diagnosing in genetic disorders is not a new concept, 3D imaging has not really been studied. This technology may help diagnose patients more accurately and efficiently, and earlier in life.
Genetic factors associated with white matter in the brain
Sha et al. studied the data from 31,000 participants from the UK Biobank in order to identify correlations with genetics and the development of white matter in the brain.
Tell me more.
Let’s start with the importance of white matter in the brain. Neural signals move along white matter connections in the brain. These neural signals support cognitive functions and behaviors. So, it’s important to understand which genes and mutations affect white matter connections in the human brain, since they’re likely to influence cognition and behavior.
This study is the first time researchers have used a combination of data from a type of white matter imaging called nerve fiber tractography with data from GWAS studies (see my post explaining GWAS here) to understand how genetics affects white matter structure and function.
So what did they find?
The analysis included performing fiber tractography on all 30,810 participants with diffusion magnetic resonance imaging (MRI) and genetic data after quality control. By analyzing the data on these individuals, the researchers found 325 genetic loci (i.e. position in a gene) potentially implicated in neurodevelopmental processes including neurogenesis, neural differentiation, neural migration, neural projection guidance, and axon development, as well as prenatal brain expression.
What’s the takeaway?
This cohort study expands what we knew about genetic involvement in white matter connectivity, and provides evidence that neural signals supporting cognitive functions and behaviors are especially influenced by genes that are
1- active in the prenatal developing brain
2- up-regulated in stem cells and neurons of the fetal brain; and
3- involved in neurodevelopmental processes including neural migration, neural projection guidance, and axon development
Finally, it suggested the use of nerve fiber tractography is totally feasible and useful by using it to analyze brain connectivity in more than 30,000 individuals.
New genes associated with suicidal thoughts or behaviors identified
Kimbrel et al. studied the genome (entire set of DNA) of 633,778 US veterans from the US Million Veteran Program, 121,211 of whom had had suicidal thoughts or behaviors. The purpose was to identify whether there are certain changes in the DNA that are tied to suicidal thoughts or behaviors.
The results?
Using GWAS (see my post explaining GWAS here), the team identified four genes that were strongly tied to suicidal thoughts or behaviors. These four genes — ESR1, DRD2, TRAF3, and DCC — have each previously been linked to other psychiatric conditions. Makes sense.
Interesting. Is any of this different from what we already knew?
Yes! To begin, although these genes have all been implicated in other psychiatric conditions, they have never been associated with suicidal thoughts or behaviors. For instance, ESR1 has been identified as a causative gene for post-traumatic stress disorder and depression. DRD2 has been linked to schizophrenia and mood disorders. TRAF3 has been tied to antisocial behavior, substance use, and attention-deficit/hyperactivity disorder. Finally, DCC has been linked to multiple psychiatric disorders.
Additionally, the research uncovered two dozen additional ‘cross-ancestry’ risk genes. In ancestry-specific analyses, they identified seven mutations unique to the European-ancestry cohort, and one each within the African ancestry and Hispanic ancestry cohorts.
What’s the takeaway here?
It’s surprising to have found single genetic changes potentially responsible for suicidal thoughts or behaviors. Generally, behavioral traits like this are considered complex inheritance, meaning genetic differences in multiple genes likely work together, along with environmental factors, to affect a person’s behavior. Genes are just part of the picture. But, this study points to one genetic variant being very relevant.
Interested in reading more on genetics and mental health? This article describes single genetic variants associated with neurodevelopmental psychiatric disorders like intellectual disability, schizophrenia, and bipolar disorder.