Abstract
With the accumulation of scientific knowledge of the genetic causes of common diseases and continuous advancement of gene-editing technologies, gene therapies to prevent polygenic diseases may soon become possible. This study endeavored to assess population genetics consequences of such therapies. Computer simulations were used to evaluate the heterogeneity in causal alleles for polygenic diseases that could exist among geographically distinct populations. The results show that although heterogeneity would not be easily detectable by epidemiological studies following population admixture, even significant heterogeneity would not impede the outcomes of preventive gene therapies. Preventive gene therapies designed to correct causal alleles to a naturally-occurring neutral state of nucleotides would lower the prevalence of polygenic early- to middle-age-onset diseases in proportion to the decreased population relative risk attributable to the edited alleles. The outcome would manifest differently for late-onset diseases, for which the therapies would result in a delayed disease onset and decreased lifetime risk; however, the lifetime risk would increase again with prolonging population life expectancy, which is a likely consequence of such therapies. If the preventive heritable gene therapies were to be applied on a large scale, the decreasing frequency of risk alleles in populations would reduce the disease risk or delay the age of onset, even with a fraction of the population receiving such therapies. With ongoing population admixture, all groups would benefit over generations.
Highlights
Research into the causality and liability of diseases primarily based on familial and populational observations greatly pre-dates the discovery of DNA structure and the genetic code in 1953 by Watson and Crick [1]
The simulations in this research demonstrated that, even if relatively large heterogeneity in the causal allele set for Early- to Middle-age-Onset Diseases (EMODs) existed between populations, it will not be detectable by epidemiological studies in admixed populations
While the simulation results show that a large heterogeneity would be hypothetically possible, genome-wide association studies (GWASs) findings indicate the existence of a discernible commonality of causal SNPs for polygenic diseases between geographically distinct populations, and the extent of the risk differences between populations due to unique causal SNPs is likely not extreme
Summary
Research into the causality and liability of diseases primarily based on familial and populational observations greatly pre-dates the discovery of DNA structure and the genetic code in 1953 by Watson and Crick [1]. It was only possible to estimate the frequency of highly malignant mutations in human populations [2] It took several decades for experimental techniques to develop sufficiently to sequence the human genome [3]. The search for singular genetic mutations started decades ago and continued with GWASs and WGS, which led to the discovery of many thousands of highly malignant so-called Mendelian conditions. Among such conditions are sickle-cell anemia, Tay–Sachs disease, cystic fibrosis, hemophilia, thalassemia, Huntington disease, early-onset Alzheimer’s disease, and macular degeneration, as well as mutations in the BRCA1/2 genes, which are causally linked to multiple types of cancer, especially breast cancer [5]. In aggregate, less malignant diseases caused by rare mutations affect a noticeable fraction of the population, with approximately 8% of individuals affected [7,10]
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