Genome-wide selection inference at short tandem repeats

Area of Science:

• Population genetics
• Human genetics
• Evolutionary biology

Background:

• Short tandem repeats (STRs) are a major source of human genetic variation.
• STRs contribute to various diseases, including Mendelian disorders, complex traits, and cancer.
• Mutations in STRs can negatively impact reproductive fitness over evolutionary timescales.

Purpose of the Study:

• To extend the SISTR framework (SISTR2) for joint estimation of selection coefficients across multiple STRs.
• To enable more accurate analysis of a broader range of STRs, including those with low mutation rates.
• To estimate the relative burden of de novo and inherited variation at STRs compared to single nucleotide variants (SNVs).

Main Methods:

• Development of SISTR2, an extension of the SISTR population genetics framework.
• Joint estimation of selection coefficient distributions across sets of STRs.
• Exploration of mutation parameters and comparison of variation burden between STRs and SNVs.

Main Results:

• SISTR2 allows for more accurate analysis of diverse STRs, including low-mutation-rate loci.
• Substantial variation in mutation and selection parameters was observed across different STR classes.
• De novo mutations at STRs contribute a greater burden than those at SNVs, while SNVs contribute more inherited variation.

Conclusions:

• SISTR2 provides a more robust framework for analyzing selection at STRs.
• STRs exhibit significant variation in mutation and selection parameters.
• The burden of de novo STR mutations is higher than de novo SNVs, impacting evolutionary and disease studies.