A brain-development gene found exclusively in humans has an unusual evolutionary history and could contribute to what makes us distinctly human. Equally surprising, this is a partial gene created from an incomplete duplication of its “parent” gene in the prehistoric human genome.
Eichler and his group began studying the evolutionary history of this gene family, located on Chromosome 1, after analysis of hundreds of human genomes revealed that sequence information for SRGAP2 was incorrect or missing. The gene had been misassembled and duplicate copies were not sequenced or characterized. This is not uncommon for genes that are difficult to analyze with standard methods, especially those genes embedded within parts of our genomes holding multiple copies that are nearly identical.
Eichler and his team decided to complete the missing data with genetic information from a human hydatidiform mole, a rare product of the fertilization of an empty egg by a sperm. Because the collection of cells that make up the mole has but half of each pair of human chromosomes, geneticists refer to it as haploid.
“The data we leveraged from the haploid mole allowed us to reconstruct the complex evolutionary history of the SRGAP2 gene family since about 6 million years ago when humans diverged from non-human primates,” the researchers reported.
By identifying nearly identical sequences not recorded in the reference human genome, the researchers confirmed that the SRGAP2 gene had duplicated three times. Although many mammals have the gene, the segmental duplications occurred exclusively in humans. The promoter and a few other parts of the gene were first duplicated about 3.4 million years ago. Later, larger duplications copied this partial gene to nearby locations on Chromosome 1 about 2.4 million years ago, and then again 1 million years ago.
The second duplicate seemed most promising to the scientists because their analysis suggested that it was likely to produce a viable protein.
Unlike many of the mutations that created the approximately two-dozen human-specific genes discovered so far, the partial gene is no longer located in a hotspot of change. Perhaps, the researchers surmise, it was transported to a more stable location during the second duplication event, or the product became indispensable to human adaptation and evolution. The relocation permitted it to function over the long haul.
“This gene is among the most fixed of human-specific genes,” Dennis said. “There’s almost no variation in the number of copies from one human genome to another. Just about everyone has two copies, she explained, which is unusual for such a recently duplicated gene segment.
Evidence for the role of this gene family in human brain development and intellectual capacity comes from the Eichler group’s study of mutations in children with developmental delays, certain types of epilepsy, and brain malformations.
“Final proof of the functional significance of this gene family will rest on the discovery of disruptive mutations associated with these types of disorders,” Dennis said. In turn, such studies may uncover the molecular mechanisms of these conditions and perhaps improve their diagnosis and treatment.
The researchers emphasized that the SRGAP2 gene duplications are a few of several that are specific to humans and yet whose duplicates are missing or incompletely assembled in the reference human genome. Several remaining uncharacterized human-specific genes are believed to have a role in brain development, the growth of connections between brain cells, and behavior.
“Uncharacterized human-specific genes,” the researchers proposed,” are important pieces in the puzzle of the genetic basis of human brain evolution.”
The project “Evolution of Human-Specific Neural SRGAP2 Genes by Incomplete Segmental Duplication” was funded by the National Institutes of Health grants and support from the Howard Hughes Medical Institute.
In addition to Dennis, Nuttle, and Eichler, other scientists on the project were Peter Sudmant, Francesca Antonacci, Saba Sajjadian, and Maika Malig, all of the UW Department of Genome Sciences; Tina Graves, Holland Kotkiewicz and Richard Wilson, all of the Genome Institute at Washington University School of Medicine in St. Louis, Mo.; Mikhail Nefedov and Pieter J. de Jong of the Children’s Hospital Oakland Research Group in California; Jill Rosenfeld and Lisa Shaffer of the Signature Genomic Laboratories, Perkin Elmer, Inc., Cynthia Curry of Genetic Medicine Central California, University of California San Francisco, and Susan Shafer, Carle Clinic Association, Urbana, Ill. Eichler is also on the scientific advisory boards for Pacific Biosciences, Inc., DNANexus, and SynapticDx Corp.