Table ED.3 ∣.

Chain-of-Thought prompt and Med-PaLM 2 answer to the question of identifying 5 genes for hearing loss.

CoT prompt: You are a helpful genetic assistant. You need to identify genes with causal mutations for chronic pain. You are provided with a set of genes that contain causal genetic factors in mice that might cause chronic pain. You need to determine which of the following genes have causal mutations that are directly associated with chronic pain in mice or humans. Output top 3 options in the final answer. (1) P2rx7 (2) Arntl (3) Pttg1 (4) Kcnk2 (5) Clcn4-2 (6) Mhrt (7) Mh7b (8) Cttnb1 (9) Dact (10) Cdh2 (11) Gabrg2 (12) Slco3a1 (13) Scn8a (14) Clbp (15) Ctgf.

Based on the available evidence, the majority of the genes listed are not directly associated with chronic pain in mice or humans. However, the top 3 most likely genes in the list to have causal mutations that are directly associated with chronic pain are: **P2rx7**: 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. P2X7 receptor antagonists have been considered as potential treatments for chronic pain. **Kcnk2**: Also known as TREK-1, this gene encodes a member of the superfamily of potassium channel proteins containing two pore-forming P domains. Changes in its activity have been associated with pain perception. TREK-1 channel modulators have been studied as potential analgesic drugs. **Arntl**: Also known as BMAL1, is mainly known for its role in the circadian rhythm. There is indirect evidence suggesting that disruptions in circadian rhythms can influence pain processing, but the direct causal relationship of Arntl mutations to chronic pain isn’t well-established. 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. Newer studies might have identified more direct links or clarified associations for the genes mentioned. Always refer to recent literature for the most up-to-date scientific evidence.

You are a helpful genetic assistant. You need to identify genes with causal mutations for hearing loss or deafness. You are provided with a set of genes that contain causal genetic factors in mice that might cause hearing loss or deafness. You need to determine which of the following genes have causal mutations that are directly associated with hearing loss or deafness in mice or humans. Output top 5 options in the final answer. (1) Zfp629 (2) Sdc2 (3) Gtpbp10 (4) Adgrb1 (5) Mettl7a1 (6) Il23r (7) Crym (8) Med1 (9) Stk38 (10) Fcgr1 (11) Armt1 (12) Mast4 (13) Spertl (14) Ifi27l2b (15) Tmem242 (16) Stxbp4 (17) Eppk1.

Med-PaLM 2 output: Based on the available evidence, the top 5 genes in the list that are most likely to have causal mutations that are directly associated with hearing loss or deafness in mice or humans are: **Crym**: Crym encodes a protein called α-crystallin, which is a major structural component of the lens. Mutations in Crym can lead to cataracts, which can cause hearing loss. **Med1**: Med1 encodes a protein that is involved in the development of the inner ear. Mutations in Med1 can lead to sensorineural hearing loss. **Mast4**: Mast4 encodes a protein that is involved in the transmission of sound signals from the inner ear to the brain. Mutations in Mast4 can lead to nonsyndromic hearing loss. **Tmem242**: Tmem242 encodes a protein that is involved in the development of the inner ear. Mutations in Tmem242 can lead to sensorineural hearing loss. **Stk38**: Stk38 encodes a protein that is involved in the development of the inner ear. Mutations in Stk38 can lead to sensorineural hearing loss. It is important to note that hearing loss 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 hearing loss. Newer studies might have identified more direct links or clarified associations for the genes mentioned. Always refer to recent literature for the most up-to-date scientific evidence.