Inference of Evolutionary Forces Acting on Human Biological Pathways

Area of Science:

• Evolutionary biology
• Human genetics
• Bioinformatics

Background:

• Natural selection often targets multiple genes for a single phenotypic trait.
• Genes within biological pathways exhibit stronger selective constraints and correlated evolutionary responses compared to other genes.

Purpose of the Study:

• To investigate the impact of past and ongoing selection on the genetic diversity of human biological pathways.
• To introduce a novel method for detecting selection at the gene set level.

Main Methods:

• Developed a new procedure, 2DNS (Two-Dimensional Null Distribution of Selection), extending the McDonald-Kreitman test for multiple genes.
• Analyzed genetic diversity and selective constraints within human gene sets.
• Applied the 2DNS test to identify outlier gene sets and assess demographic effects.

Main Results:

• Genes in gene sets are under stronger selective constraints and show correlated evolutionary responses.
• The 2DNS test successfully identified outlier gene sets indicating positive, balancing, purifying selection, and relaxation of constraints.
• Comparison of African and non-African populations revealed higher nonsynonymous mutations in non-Africans, suggesting differing demographic histories and selective pressures.

Conclusions:

• Biological pathways are shaped by complex selective pressures.
• The 2DNS method provides a powerful tool for detecting selection at the pathway level.
• Human population genetic diversity reflects distinct evolutionary trajectories and selective forces.