>>12598398Yeah, so pathways involved in responding to DNA strand breaks, the main cancer mechanism, control cell proliferation and apoptosis. p53 for example induces apoptosis in cells which experience DNA damage, downregulation of that gene is associated with significantly decreased cell apoptosis in the brain and other areas of the body, predisposing you to some types of cancer, but we've also found it can have significant effects on anthropometrics, like brain size.
>https://pubmed.ncbi.nlm.nih.gov/30664637/There are more subtle effects associated with mutations like that, the cancer risk isn't particularly deterministic, i.e. the genes have to enter linkage disequilibrium with alleles that essentially "negate" the carcinogenic risk. We see it all the time, so pathogenic BRCA mutations aren't technically "pathogenic" in a strict sense, they're just in extremely high linkage disequilibrium with SNPs which remove the associated cancer risk. In fact, about 30% of BRCA positive individuals don't even have a family history of cancer, and have cancer risk approximately the same as the rest of the population. That's why it's important to go off family history, rather than DNA testing, as there's a moral gray area with traditionally "deleterious" alleles like that, which can cause a scare when there really isn't one.
With high effect alleles, like hereditary hemochromatosis for example, there's always a genetic "reshuffling" that happens in populations, which substantially reduces the penetrance of the disease, which consequently is what allows 6% of Jews to be positive for Gaucher disease, or about 15% of Europeans to carry a hereditary hemochromatosis gene. Those populations have lower frequencies of the polygenic alleles which cause disease, which is why hereditary hemochromatosis genes in Africans/Asians are substantially more deleterious than in whites.
