Yale Researchers Find Genetic Home of Some of Life’s Diversity

Almost a decade after the first draft of the human genome was published, scientists now know that many differences among individuals arise not only from the content of their genes but where and when those genes are expressed.

Now a Yale-led team of scientists, using advanced DNA sequencing technology, has for the first time pinpointed individual variations of where, along the chain of 3 billion letters that make up the human genome, important gene regulatory elements do their jobs.

The findings — both in humans, as reported online March 18 in the journal Science Express, and in yeast, detailed in a complementary paper by Yale scientists published March 17 in the journal Nature — shed new light on the mechanisms that contribute to life’s diversity.

“Differences in how our genes are regulated may provide a better understanding of disease, advance the cause of personalized medicine and even help explain how species evolved,” said Maya Kasowski, an M.D./Ph.D. candidate in Yale’s Department of Molecular, Cellular and Developmental Biology. Kasowski is co-lead author of the paper with Fabian Grubert, formerly a postdoctoral researcher at Yale now a post-doc at Stanford.

Michael Snyder, formerly the Lewis B. Cullman Professor of Molecular, Cellular and Developmental Biology launched both studies at Yale. Snyder is now professor and chair of genetics at Stanford University.

In the Science paper, the researchers analyzed genomes of several individuals and a chimpanzee to look for variations in areas along the genome where proteins called transcription factors bind to specific sites of DNA. Transcription factors are crucial for life because they control the activity of multiple genes by regulating the transfer, or transcription, of information from DNA into RNA molecules, which in turn carry the information to the cell’s protein-making machinery. The location of these binding sites is crucial to determining the function of genes that are regulated.

Researchers found individuals differed in 25 percent of binding sites that regulate RNA polymerases II, one of the molecules crucial in the transcriptions of genes to proteins. The differences between humans and chimps were also pronounced, suggesting they may play a key role in creating variation between the species. When researchers looked at a well-known immune system pathway, only 7.5 percent of the binding sites were found to differ among individual humans.

In the Nature paper, a Yale team led by Wei Zheng, now a biostatistician in the University’s Keck Laboratory, analyzed a big family of yeast cells, including a sample from the lung of an AIDS patient.

“We now can do molecular analysis that was unimaginable a couple of years ago,” Zheng said. “The analysis of sequencing data revealed two previously unknown regulatory genes that help govern mating and other functions in yeast.”

She said the work may also help explain why usually harmless yeast becomes a pathogen in AIDS patients whose immune system has been compromised.

“We believe it will be essential to monitor differences in regulatory information in order to understand both how we are different from one another as well as the underlying basis of many diseases,” Snyder said.
Other Yale authors on the Science paper were Christopher Heffelfinger, Akwasi Asabere, Joel Rozowsky, Alexander E. Urban, Mi-Young Hong, Lukas Habegger, Sherman M. Weissman, and Mark Gerstein. Grubert, Manoj Hariharan, Minyi Shi worked on the project at Yale and are now at Stanford.

Researchers from the Genome Biology Research Unit of the European Molecular Biology Laboratory in Heidelberg, Germany, also contributed to the research.

The other Yale author of the Nature paper is Hongyu Zhao. Researchers from the Genome Biology Research Unit of the European Molecular Biology Laboratory in Heidelberg, Germany, also contributed to the paper.

The National Institutes of Health funded the research on both papers.