Extraordinary number of genes are required for prenatal mammalian development

A team of scientists led by Cornell University's Dr. John Schimenti reports today that an extraordinary number of genes are required for prenatal mammalian development. The researchers estimate that up to 19% of all genes are vital for embryogenesis in mice.

Their study, which is one of the largest functional genomics projects described to date, is published in the online edition of the journal Genome Research.

In addition to the important implications for understanding mammalian developmental biology and the genetic basis for spontaneous abortions, the impressive scale of the study – an enormous logistical effort spanning the past six years – marks a major step forward in the functional annotation of the mouse genome.

"Due to the availability of whole-genome sequences, we are now in the powerful position of knowing the sequence identity of most genes, their locations in the genome, their expression patterns, and which proteins interact with one another," explains Schimenti. "However, identifying the functions of these genes is a much more difficult challenge. For most genes, direct experimentation in the context of a whole organism will be required."

In an effort to explore the functional content of 50 megabases of mouse chromosome 5, or approximately 2% of the genome, Schimenti and his colleagues generated over 1000 mouse pedigrees with random mutations using a chemical called N-ethyl-N-nitrosourea (ENU). They then screened offspring from these pedigrees for lethality and defects in behavior, fertility, fitness, hearing, and vision.

Of 42 mutations identified, an overwhelming majority – 34 mutations – resulted in embryonic lethality. The scientists attributed the lethality to defects in processes including cellular proliferation, gastrulation, cardiovascular function, craniofacial development, neural tube development, and placental development.

Combining their data with estimates from previous studies, the researchers predicted that between 13.7% and 19% of all mouse genes are necessary for embryonic viability. In comparison, research on other organisms has indicated that 6-10% of zebrafish genes and 7% of C. elegans genes are required for prenatal survival. "The higher percentage of embryonic lethal genes in mice may reflect an inherently more complex or sensitive process of development," report the scientists.

The project included major contributions from Schimenti's collaborators at The University of Pennsylvania School of Medicine (Philadelphia, PA) and The Jackson Laboratory (Bar Harbor, ME), where the study was initiated.

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