Figure: Diagram of the eye mosaic.
Recent advances in genetics research may have led to the discovery of new genes that underlie common mental illnesses. Schizophrenia and bipolar disorder affect more than 64 million people worldwide. These disorders are strongly influenced by genetics. However, there is no gene that determines a person’s risk of developing schizophrenia or bipolar disorder. Rather, many genes may contribute to risk. Researchers at Stanford University used artificial intelligence to discover complex variations across the human genome that may contribute to these mental illnesses. This new study suggests that mutations that occur after fertilization, such as genetic mosaicism, may be the cause of many mental illnesses, including bipolar disorder and schizophrenia.
Think of your genome as a living book that contains instructions for every cell in your body. Our genes are chapters. We have approximately 20,000 genes that provide instructions for making proteins, the building blocks of life. However, most of our genes are non-coding genes, meaning they do not provide instructions to proteins. Nevertheless, these genes play important roles in the regulation of genetics and cellular function.
Genetic mutations or spelling changes in coding or non-coding regions can interfere with how cells translate certain instructions. Small typos can have little effect on how the book reads. However, significant spelling changes can lead to the deletion of sentences or even entire chapters. Without the correct instructions to produce a particular protein, such spelling changes can cause diseases that affect different aspects of our bodies.
Our genes are a combination of the DNA we inherited from our parents. We have two copies of each gene. One from the mother and one from the father. These randomly combined pairs of genes determine traits such as hair texture, eye color, and even health risks. Some traits are dominant, meaning that only one copy of the variant is required for expression. Others are recessive and only appear if both copies are the same. This is called Mendelian inheritance, named after Dr. Gregor Mende’s first observation of how genes are inherited in the pea plant.
During the early stages of life, DNA undergoes multiple replications. Trillions of cell divisions occur, during which one cell splits into two identical daughter cells. However, DNA replication is prone to mistakes. Every time a cell divides, small misspellings occur in the genome. Therefore, rapid replication during the first trimester of pregnancy can introduce many genetic changes not seen in the mother or father. This is known as genetic mosaicism, where two or more genetically distinct cell populations are expressed in the body. The mosaic may appear as two different colored eyes or alternating skin patterns, as shown below. Many conditions are also associated with mosaicism, including developmental delays, autism, epilepsy, and some cancers. We all have some degree of genetic mosaic within our bodies. This is why identical twins can have different fingerprints.
Figure: Depiction of a skin mosaic.
Genetic mutations are acquired throughout an individual’s lifetime and can further alter the genomic mosaic. Changes in DNA can result from exposure to chemicals or radiation, or from infections such as hepatitis B and hepatitis C, which destroy the genetic material of host cells. Other variants are obtained randomly. DNA can make errors during replication and other normal cellular functions. This damage is exacerbated by inflammation, aging, and lifestyle choices such as smoking and poor diet. Therefore, pinpointing which mutations contribute to a particular disease can be a very complex process.
Whole genome sequencing (WGS) helps identify small changes in DNA. This genetic test uses samples taken from blood or swab tests to map an individual’s entire genome. Whole genome sequencing extracts the precise sequences that make up each chapter of DNA. The extracted sequences are compared to reference genes from a typical human genome. Differences between an individual’s genome and a reference genome reveal potential mutations that may be associated with disease.
“The study’s senior author, Alexander Urban, an associate professor at Stanford University, said: You’ll overlook that words are scrambled, duplicated, or out of order, and you might even miss that half the chapter is gone. ” In fact, certain diseases can be associated with long and complex spelling changes in an individual’s genes. Things are further complicated by the fact that mutations across multiple genes can overlap with multiple diseases.
Many psychiatric disorders are influenced by multiple changes across similar genes. Bipolar disorder and schizophrenia are prime examples of the complexity of the human genome. Hundreds of genetic mutations that contribute to risk have been identified. Many of these genes are involved in brain development, immune system regulation, and neuronal signaling pathways. The AKAP11 gene in particular has been shown to be a strong risk factor for bipolar disorder, but recent studies in mice suggest that this gene may also be involved in schizophrenia. are. Understanding how changes in the spelling of this gene interact with other high-risk mutations could help decipher what triggers the development of psychiatric symptoms.
In Zhou et al.’s study, they compared the genomes of more than 4,000 individuals around the world. Their entire DNA sequences were extracted using whole genome sequencing. The data was then uploaded to an AI algorithm trained to recognize dozens of genomes across different ancestry. This approach has allowed researchers to match large, complex genetic variations to specific health conditions.
The study specifically recruited people diagnosed with bipolar disorder or schizophrenia and compared them with healthy controls. This type of approach is known as genome-wide association studies (GWAS). Genome-wide association studies compare the genes of individuals with a particular disease to a large cohort of controls. This approach allows us to know where the variants are located, but this information is often not accurate. For example, you can see that there are spelling changes on pages 122, 296, and 731 of this book, but you don’t know what type of mistakes they contain. The AI algorithm developed by Zhou et al. al adds further specificity. Words and sentences that have changed are highlighted and reported whether they have been scrambled, duplicated, or deleted.
The AI tool identified over 8,000 complex variants with over 85% accuracy. Many of these spelling changes were found in genomic regions that provide instructions for brain function. To determine whether these mutations may be associated with mental illness, they extracted DNA from brain tissue samples of individuals with schizophrenia or bipolar disorder. The complex mutations they identified appeared to overlap with single mutations found in other genome-wide association studies of these diseases. For example, one of the complex mutations found to be correlated with schizophrenia and bipolar disorder was 4,700 base pairs long, the basic unit of DNA. Using a book analogy, base pairs are like words in a book.
New innovations in genetic research are deepening our understanding of the human genome. By analyzing vast amounts of genetic data, AI technology is uncovering complex relationships between large mutations and specific mental disorders. This not only improves our understanding of the genetic basis of these diseases, but also paves the way for personalized medicine. As we learn more about the human genome, future studies may reveal deeper insights into the genetic basis of various diseases.
