Table ED.1 ∣.

Med-PaLM 2 answers to questions about phenotypes cataract, diabetes, and chronic pain.

Candidate gene set 1: Cataract Input prompt: You are a helpful genetic assistant. The following is a question about genetic discovery. Which of the following genes is most likely associated with phenotype Cataract. Gene candidates: Miox, Nid1, Trappc1, Pi4ka, Adgrv1, Slc8b1

Med-PaLM 2 output: Of the genes listed, the most likely candidate for association with cataract is **Nid1**. Nid1 encodes nidogen-1, a protein that is a major component of the extracellular matrix in the eye. Mutations in Nid1 have been shown to cause a variety of eye disorders, including cataracts. For example, a study of families with autosomal dominant cataracts found that mutations in Nid1 were responsible for the condition in some of the families. The other genes listed are not known to be associated with cataracts. Miox encodes a protein that is involved in the metabolism of iodine. Trappc1 encodes a protein that is involved in the transport of proteins. Pi4ka encodes a protein that is involved in the production of phosphatidylinositol 4-phosphate. Adgrv1 encodes a protein that is involved in the development of blood vessels. Slc8b1 encodes a protein that is involved in the transport of calcium. While it is possible that mutations in any of these genes could contribute to the development of cataracts, there is no evidence to suggest that they are directly involved in the condition. Therefore, the most likely candidate for association with cataract is Nid1.

Candidate gene set 2: Diabetes Input prompt: You are a helpful genetic assistant. The following is a question about genetic discovery. Which of the following genes is most likely associated with phenotype Diabetes. Gene candidates: Krtap5-1, Act1, Act2, Act3, Actb, Abra, Tlr5, Myh1, Myh2, Myh8, Unc45a, Cdc102a

Med-PaLM 2 output: Of the genes listed, the most likely candidate for association with diabetes is **Tlr5**. Tlr5 is a Toll-like receptor that is involved in the innate immune system. It is known to play a role in the recognition of bacterial flagellin, a component of bacterial flagella. Activation of Tlr5 can lead to the production of inflammatory cytokines, which can contribute to the development of insulin resistance. Insulin resistance is a condition in which the body’s cells become less responsive to insulin. This can lead to high blood sugar levels, which is a hallmark of diabetes. Studies have shown that mice lacking Tlr5 are protected from developing insulin resistance. Additionally, polymorphisms in the Tlr5 gene have been associated with an increased risk of developing type 2 diabetes in humans. The other genes listed are not known to be directly involved in the development of diabetes. However, it is possible that they could play a role in the development of complications associated with diabetes. For example, Krtap5-1 is a gene that is involved in the formation of keratin, a protein that is found in hair, skin, and nails. People with diabetes are at increased risk of developing skin problems, so it is possible that Krtap5-1 could play a role in these complications. Overall, the evidence suggests that Tlr5 is the most likely candidate gene for association with diabetes. However, it is important to note that genetic factors are only one part of the puzzle when it comes to understanding the development of diabetes. Environmental factors, such as diet and lifestyle, also play a role.

Candidate Gene Set 3: Chronic Pain Input prompt: You are a helpful genetic assistant. The following is a question about genetic discovery. Which of the following genes is most likely associated with phenotype Chronic pain. Gene candidates: P2rx7, Arntl, Pttg1, Kcnk2, Clcn4-2, Mhrt, Mh7b, Cttnb1, Dact, Cdh2

Med-PaLM 2 output: Of the genes listed, P2rx7 is the most likely to be associated with chronic pain. P2rx7 is a gene that encodes for a receptor protein that is involved in the transmission of pain signals. Studies have shown that mutations in the P2rx7 gene can lead to increased pain sensitivity. Additionally, P2rx7 has been shown to be upregulated in the spinal cord of patients with chronic pain. The other genes listed are not as well-studied in the context of chronic pain. However, some of them have been implicated in other pain-related conditions. For example, Arntl has been linked to migraine headaches, and Kcnk2 has been linked to neuropathic pain. Overall, the evidence suggests that P2rx7 is the most likely of the listed genes to be associated with chronic pain. However, it is important to note that chronic pain is a complex condition that is likely influenced by multiple genes. Therefore, it is possible that other genes on the list may also play a role in chronic pain. If you are interested in learning more about the genetics of chronic pain, I would be happy to provide additional information.