Data from a new study links a pair of duplicated genes to human brain features. The research provides a roadmap for scientists to gain a deeper understanding of brain function and evolution, as well as the roots of language disorders and conditions like autism spectrum disorders. Full details are available in a Cell paper titled “Human-specific gene expansions contribute to brain evolution.”
According to the scientists, the newly characterized genes are found among what’s considered the “dark matter” of the human genome—regions of DNA with duplicated or repeat sequences. Though difficult to study, DNA repeats are also thought to be important for evolution as they can generate new versions of existing genes for selection to act on. However, with the release of the telomere-to-telomere reference genome, which includes difficult regions left out of the draft of the human genome, scientists now have a place to start to make new discoveries.
For the current Cell study, senior author Megan Dennis, PhD, associate director of genomics and associate professor in the department of biochemistry and molecular medicine at the University of California, Davis, and her team used data from the telomere-to-telomere (T2T) human reference genome T2T-CHM13. Dennis is one of the investigators on the T2T consortium, which aimed to fill gaps in the genome left by earlier drafts. The T2T genome was generated using a cell line derived from a bundle of cells called a hydatidiform mole. These form when an egg in the uterus loses its genome but gets fertilized by a sperm. The resulting cells end up with two identical copies of each chromosome.
Armed with a short list of duplicated genes from the T2T reference, the scientists sorted them based on specific criteria. Specifically, they focused on genes that are expressed in the brain, present in all humans, based on sequences from the 1000 Genomes Project, and conserved, meaning they did not show much variation among individuals.
The result was about 250 candidate gene families. Of these, they picked some for further study in a zebrafish model. To understand the roles of these genes in brain development, the scientists generated “zebrafish CRISPR ‘knockout’ models of nine orthologs and introduced mRNA-encoding paralogs, effectively ‘humanizing’ larvae,” according to the paper. By both deleting genes and introducing human-duplicated genes into zebrafish, they showed that at least two of these genes might contribute to features of the human brain. In the models, one gene, called GPR89B, led to slightly bigger brain size, and another, FRMPD2B, led to altered synapse signaling.
The data and findings reported in the paper are intended to provide a resource for the scientific community, Dennis said. Specifically, it should make it easier to screen duplicated regions for mutations that, for example, are related to language deficits or autism, that might have been missed in previous genome-wide screening.
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