SOURCES — "POV: You're About to Lose the Genetic Lottery" ========================================================= 1. SCN9A — YOU CAN'T FEEL PAIN (2006, northern Pakistan) -------------------------------------------------------- • The gene, the families and the boy (three related families in northern Pakistan; SCN9A builds the Nav1.7 sodium channel that pain nerves fire through; loss of both copies = no pain at all, touch still works; the boy who walked on burning coals and pushed knives through his arms, and died after jumping from a roof around his 14th birthday): - Cox, J.J. et al. (2006). "An SCN9A channelopathy causes congenital inability to experience pain." Nature 444:894-898. https://doi.org/10.1038/nature05413 • The same channel carries smell signals, so people without it are also born without smell: - Weiss, J. et al. (2011). "Loss-of-function mutations in sodium channel Nav1.7 cause anosmia." Nature 472:186-190. https://doi.org/10.1038/nature09975 • Why living without pain is dangerous (unnoticed injuries, burns, broken bones): - MedlinePlus Genetics. "Congenital insensitivity to pain." U.S. National Library of Medicine. https://medlineplus.gov/genetics/condition/congenital-insensitivity-to-pain/ 2. FUT2 — THE NOROVIRUS CRUISE (present day, the Caribbean) ----------------------------------------------------------- • Non-secretors (two broken copies of FUT2) lack certain sugar structures (histo-blood group antigens) in saliva and gut mucus, which some norovirus strains use to attach; volunteers without them were not infected: - Lindesmith, L. et al. (2003). "Human susceptibility and resistance to Norwalk virus infection." Nature Medicine 9(5):548-553. https://doi.org/10.1038/nm860 - Thorven, M. et al. (2005). "A homozygous nonsense mutation (428G→A) in the human secretor (FUT2) gene provides resistance to symptomatic norovirus (GGII) infections." Journal of Virology 79(24):15351-15355. https://doi.org/10.1128/JVI.79.24.15351-15355.2005 • NOTE on "immune": the protection is strong but strain-specific. Some strains still infect non-secretors, and FUT2 does nothing against other stomach bugs: - Nordgren, J. & Svensson, L. (2019). "Genetic Susceptibility to Human Norovirus Infection: An Update." Viruses 11(3):226. https://doi.org/10.3390/v11030226 3. PAX3 — THE UNIBROW (present day, your bathroom) -------------------------------------------------- • PAX3 linked to connected eyebrows (monobrow) in a genome-wide study of 6,000+ people: - Adhikari, K. et al. (2016). "A genome-wide association scan in admixed Latin Americans identifies loci influencing facial and scalp hair features." Nature Communications 7:10815. https://doi.org/10.1038/ncomms10815 • PAX3 guides cells during development (pigment cells, parts of the face); broken PAX3 causes Waardenburg syndrome, where joined eyebrows are a common sign: - Tassabehji, M. et al. (1992). "Waardenburg's syndrome patients have mutations in the human homologue of the Pax-3 paired box gene." Nature 355:635-636. https://doi.org/10.1038/355635a0 • CORRECTION to the on-screen example: Cornelia de Lange syndrome (shown in the video) does come with a unibrow, but it is caused by other genes (mostly NIPBL), not PAX3. The PAX3 condition is Waardenburg syndrome (above). - Kline, A.D. et al. (2018). "Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement." Nature Reviews Genetics 19:649-666. https://doi.org/10.1038/s41576-018-0031-0 • The unibrow as a beauty ideal in Tajikistan, and women drawing it on with usma: - The World (PRX), 2 August 2016. "Where the unibrow reigns." https://theworld.org/stories/2016/08/02/where-unibrow-reigns 4. AR — MALE BALDNESS (present day, your bathroom again) -------------------------------------------------------- • The androgen receptor gene sits on the X chromosome (which men get from their mother) and is the strongest single genetic factor in early male baldness: - Hillmer, A.M. et al. (2005). "Genetic variation in the human androgen receptor gene is the major determinant of common early-onset androgenetic alopecia." American Journal of Human Genetics 77(1):140-148. https://doi.org/10.1086/431425 • Baldness involves many genes from both parents (hundreds of risk loci): - Heilmann-Heimbach, S. et al. (2017). "Meta-analysis identifies novel risk loci and yields systematic insights into the biology of male-pattern baldness." Nature Communications 8:14694. https://doi.org/10.1038/ncomms14694 - Hagenaars, S.P. et al. (2017). "Genetic prediction of male pattern baldness." PLOS Genetics 13(2):e1006594. https://doi.org/10.1371/journal.pgen.1006594 • DHT makes sensitive scalp follicles shrink and grow finer and finer hairs: - Lolli, F. et al. (2017). "Androgenetic alopecia: a review." Endocrine 57(1):9-17. https://doi.org/10.1007/s12020-017-1280-y • Steve's back: the same hormones grow body and beard hair while shrinking scalp follicles (the "androgen paradox"): - Randall, V.A. (2008). "Androgens and hair growth." Dermatologic Therapy 21(5):314-328. https://doi.org/10.1111/j.1529-8019.2008.00214.x • "No real proof that bald men are hairier": we found no study showing it. The closest is a small Japanese study where a DHT-blocking pill worked better in balding men who were hairy elsewhere (89%) than in smooth ones (32%). That says the same hormone may drive both, not that baldness makes you hairy: - Inadomi, T. (2014). "Efficacy of finasteride for treating patients with androgenetic alopecia who are pileous in other areas: A retrospective study." Indian Journal of Dermatology 59(2):163. https://doi.org/10.4103/0019-5154.127677 • Looks: balding men tend to be rated as older and less attractive, but shaved heads are seen as more dominant: - Muscarella, F. & Cunningham, M.R. (1996). "The evolutionary significance and social perception of male pattern baldness and facial hair." Ethology and Sociobiology 17(2):99-117. https://doi.org/10.1016/0162-3095(95)00130-1 - Mannes, A.E. (2013). "Shorn scalps and perceptions of male dominance." Social Psychological and Personality Science 4(2):198-205. https://doi.org/10.1177/1948550612449490 5. AS3MT — ARSENIC IN THE WATER (1000 BC, the Andes, northern Argentina) ----------------------------------------------------------------------- • People in the Argentinian Andes (San Antonio de los Cobres) have lived on naturally arsenic-rich water for thousands of years, and carry AS3MT variants that process arsenic into a less toxic form that leaves in the urine; signs of natural selection: - Schlebusch, C.M. et al. (2013). "Possible positive selection for an arsenic-protective haplotype in humans." Environmental Health Perspectives 121(1):53-58. https://doi.org/10.1289/ehp.1205504 - Schlebusch, C.M. et al. (2015). "Human adaptation to arsenic-rich environments." Molecular Biology and Evolution 32(6):1544-1555. https://doi.org/10.1093/molbev/msv046 - Apata, M. et al. (2017). "Human adaptation to arsenic in Andean populations of the Atacama Desert." American Journal of Physical Anthropology 163(1):192-199. https://doi.org/10.1002/ajpa.23193 • Arsenic from the local rock, and what long exposure does (skin changes, cancer, death): - World Health Organization. "Arsenic" fact sheet. https://www.who.int/news-room/fact-sheets/detail/arsenic 6. GULO — SCURVY AT SEA (May 1747, HMS Salisbury) ------------------------------------------------- • James Lind's trial: 12 men with scurvy in six pairs (cider, elixir of vitriol, vinegar, seawater, two oranges and a lemon a day, a spicy paste); one citrus man fit for duty within six days, the other well enough to nurse the sick: - Lind, J. (1753). "A Treatise of the Scurvy." Edinburgh: Sands, Murray and Cochran. (text at the James Lind Library) https://www.jameslindlibrary.org/lind-j-1753/ - Bartholomew, M. (2002). "James Lind's Treatise of the Scurvy (1753)." Postgraduate Medical Journal 78:695-696. https://doi.org/10.1136/pmj.78.925.695 • Most mammals make their own vitamin C; our primate ancestors lost the ability tens of millions of years ago when GULO broke, and every human carries the broken copy: - Nishikimi, M. et al. (1994). "Cloning and chromosomal mapping of the human nonfunctional gene for L-gulono-gamma-lactone oxidase, the enzyme for L-ascorbic acid biosynthesis missing in man." Journal of Biological Chemistry 269(18):13685-13688. https://doi.org/10.1016/S0021-9258(17)36884-9 - Drouin, G., Godin, J.-R. & Pagé, B. (2011). "The genetics of vitamin C loss in vertebrates." Current Genomics 12(5):371-378. https://doi.org/10.2174/138920211796429736 • Vitamin C is needed to make collagen; without it tissues break down (scurvy): - NIH Office of Dietary Supplements. "Vitamin C — Fact Sheet for Health Professionals." https://ods.od.nih.gov/factsheets/VitaminC-HealthProfessional/ EXTENDED CUT (members) ---------------------- • FUT2 is no shield against food poisoning or salmonella, and other norovirus strains still get through: Nordgren & Svensson 2019 (above). • Why only the top goes bald: side and back follicles are less sensitive to DHT and keep that resistance when moved ("donor dominance"), which is why hair transplants work: - Orentreich, N. (1959). "Autografts in alopecias and other selected dermatological conditions." Annals of the New York Academy of Sciences 83:463-479. https://doi.org/10.1111/j.1749-6632.1960.tb40920.x • Why seawater: it was one of the scurvy remedies of the day, based on the idea that scurvy came from bad digestion and decay inside the body. Lind's real contribution was the comparison of groups with the same symptoms, all kept on the same diet: Lind 1753 and Bartholomew 2002 (above).