Deep resequencing reveals excess rare recent variants consistent with explosive population growth

Area of Science:

• Human Genetics
• Population Genetics
• Genomic Sequencing

Background:

• Accurate determination of rare variant distribution is crucial in human genetics.
• Previous resequencing efforts were limited by sample size, hindering comprehensive analysis.
• Understanding rare variants is key to assessing disease risk and population health.

Purpose of the Study:

• To determine the distribution of rare variants in diabetes-associated genes.
• To assess the feasibility of large-scale resequencing for rare variant discovery.
• To investigate the genetic signal of population growth through variant analysis.

Main Methods:

• Sanger sequencing of genomic PCR amplicons for KCNJ11 and HHEX genes.
• Resequencing of 13,715 individuals (European Americans and African Americans).
• Validation of rare variant amplicons using 454 pyrosequencing.

Main Results:

• Observed significantly more variation than predicted by common variant surveys (expected variant-site count ~578).
• Identified a substantial number of rare variants, challenging previous estimates.
• Genetic modeling indicated a signal of accelerating population growth.

Conclusions:

• Human populations harbor a vast number of rare, potentially deleterious variants.
• Rare variants significantly influence contemporary disease risk and burden.
• Large-scale sequencing is now feasible for comprehensive rare variant distribution studies.