Abundant raw material for cis-regulatory evolution in humans.

Area of Science:

• Genomics
• Evolutionary Biology
• Human Genetics

Background:

• Evolutionary changes in phenotypes are often linked to alterations in gene expression and regulation.
• Cis-regulatory DNA sequences play a crucial role in this process, but their variation in populations is poorly understood.

Purpose of the Study:

• To conduct the first comprehensive survey of experimentally validated functional cis-regulatory polymorphisms in humans.
• To investigate the distribution and impact of cis-regulatory variation on gene expression and human phenotypic diversity.

Main Methods:

• Analysis of over 140 polymorphisms affecting the regulation of 107 human genes.
• Characterization of transcription factor-DNA interactions and their polymorphism.
• Identification of overrepresented variation types, including microsatellites.

Main Results:

• Functional cis-regulatory variation is widespread across the human genome.
• Gene expression variation of twofold or greater was observed in 63% of surveyed genes.
• Humans exhibit higher heterozygosity at functional cis-regulatory sites than at amino acid positions, with microsatellites being a key factor.

Conclusions:

• Cis-regulatory variation significantly contributes to human phenotypic diversity and heritable variation.
• Microsatellites represent a substantial source of rapid, heritable genetic variation impacting gene expression.
• Cis-regulatory variation has complex genotype-phenotype relationships, including epistasis and genotype-by-environment interactions.