The genetic basis of complex traits: from yeast to humans

The National Institute of General Medical Sciences (NIGMS) awarded The Leland Stanford Junior University a $2.117 million Project Grant under the Biomedical Research and Research Training program (CFDA 93.859) to support research on the genetic basis of complex traits. This award, effective September 11, 2025, through August 31, 2029, funds investigator-initiated research aimed at uncovering the evolutionary origins of polygenic traits across multiple organisms. The grant supports the development and application of high-throughput precision genome editing and allele-specific gene expression analysis methods to identify and experimentally validate causal genes and genetic variants underlying complex traits in model organisms ranging from archaea and yeast to humans.

The research deliverables include methodological advances in identifying genes contributing to complex traits with emphasis on evolutionary adaptations involving gene expression regulation, experimental validation of identified genetic variants, and scientific outputs applicable across diverse biological systems. A significant component of the award's impact involves the dissemination of research tools to the broader scientific community, as the principal investigator's laboratory has committed to making code and genetic constructs freely available to researchers. This project aligns with NIGMS's strategic commitment to supporting fundamental biomedical research that advances understanding of biological processes and establishes foundations for advances in disease diagnosis, treatment, and prevention.

Abstract

The evolutionary origins of complex polygenic traits remain an enduring enigma. Although introductory genetics is often taught with simple monogenic examples such as mendel's peas, most traits-including all common human diseases-actually result from multitudes of interacting loci. Genome-wide association studies (gwas) have done a great deal to illustrate this, as well as the fact that variation in gene expression CIS- regulation-such as promoters and enhancers-accounts for most phenotypic variation. However, uncovering the evolutionary origins of complex traits is still a major challenge. My lab has developed experimental and computational methods to pinpoint the genes contributing to complex traits, with a focus on evolutionary adaptations involving gene expression regulation. Our main focus is on two methods: high-throughput precision genome editing and allele-specific gene expression analysis in hybrids. These methods have enabled US to implicate and experimentally validate causal genes and genetic variants underlying complex traits in archaea, yeast, flies, fish, mice, and humans. Moreover, the code and genetic constructs underlying our methods are freely available to the scientific community.