POPULATION GENETICS OF RARE VARIANTS

“𝕋𝕙𝕖 𝕧𝕒𝕤𝕥 𝕓𝕦𝕣𝕕𝕖𝕟 𝕠𝕗 𝕕𝕖𝕝𝕖𝕥𝕖𝕣𝕚𝕠𝕦𝕤 𝕞𝕦𝕥𝕒𝕥𝕚𝕠𝕟𝕤 𝕚𝕟 𝕙𝕦𝕞𝕒𝕟𝕤 𝕝𝕚𝕖𝕤 𝕚𝕟 𝕣𝕒𝕣𝕖 𝕧𝕒𝕣𝕚𝕒𝕟𝕥𝕤, 𝕨𝕙𝕚𝕔𝕙 𝕞𝕒𝕜𝕖𝕤 𝕥𝕙𝕖𝕞 𝕔𝕣𝕚𝕥𝕚𝕔𝕒𝕝 𝕗𝕠𝕣 𝕦𝕟𝕕𝕖𝕣𝕤𝕥𝕒𝕟𝕕𝕚𝕟𝕘 𝕘𝕖𝕟𝕖𝕥𝕚𝕔 𝕝𝕠𝕒𝕕 𝕒𝕟𝕕 𝕕𝕚𝕤𝕖𝕒𝕤𝕖 𝕤𝕦𝕤𝕔𝕖𝕡𝕥𝕚𝕓𝕚𝕝𝕚𝕥𝕪.” - Professor James F. Crow (Emeritus)

🧬 Population genetics has been transformed by next-generation sequencing, revealing the critical role of rare variants-mutations occurring in <1% of individuals. While often overlooked compared to common variants, rare variants provide unique insights into evolution, disease, and genetic diversity.

           🔹 Rare variants arise through mutation, genetic drift, and demographic events such as bottlenecks. In small or isolated populations, drift and founder effects can increase their frequency, sometimes conferring adaptive advantages.

          🔹 Rare variants underlie many monogenic disorders (e.g., cystic fibrosis, sickle cell anemia) and also contribute to complex traits like cancer, infertility, and cardiovascular disease. However, their detection requires large cohorts and deep sequencing, as their effects are often subtle and population-specific.

          🔹 The distribution of rare variants reflects historical migrations, demographic events, and environment. Studying their geography not only informs human population history but also aids precision medicine by uncovering population-specific disease risks.

          ➡️ Projects like the 1000 Genomes Project and "gnomAD" have expanded catalogs of rare variation, enabling more powerful association studies. Integration with functional genomics, transcriptomics, and proteomics is helping clarify biological consequences.

          ➡️ In conservation biology, rare alleles can be essential for adaptive resilience in endangered species, guiding strategies to preserve biodiversity against disease, habitat loss, and climate change.

⚠️ In an Oystershell, the population genetics of rare variants is a frontier connecting evolutionary biology, medicine, and conservation. As sequencing scales and interdisciplinary collaboration grow, rare variants will be central to decoding disease, guiding precision medicine, and safeguarding biodiversity.

Abubakar Abubakar ✍🏻

• Tennessen, J. A. et al. (2012). Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science, 337(6090), 64–69.

• Lek, M. et al. (2016). Analysis of protein-coding genetic variation in 60,706 humans. Nature, 536, 285–291.

• 1000 Genomes Project Consortium. (2015). A global reference for human genetic variation. Nature, 526, 68–74.

• Fu, W. et al. (2013). Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants. Nature, 493, 216–220.

#PopulationGenetics #RareVariants #HumanGenetics #Evolution #PrecisionMedicine #MedicalGenetics
#NGS #GeneticVariation #Biodiversity #CRISPR #PublicHealth 💊🔬⚕️