Neuroscience presents unique genetics challenges. Genetics of the brain means studying an enormous number of mutations. In addition, many loci encode proteins that interact with each other, so a mutation that affects one protein could, in fact, affect the function of other proteins in a given pathway, even if the other proteins are not mutated.
And as if that isn’t complicated enough, many neurological diseases, like neuropathies or cognitive disorders, may appear to be similar- but are genetically very distinct.
NGS has yielded valuable insights into how the brain works, as well as new ways to diagnose and treat neurological disease. For example;
- Earlier this year, whole-exome sequencing studies linked mutations in three new genes to autism spectrum disorders.
- Another whole-exome study discovered that variants of one single gene were linked to two rare diseases—Perrault Syndrome (which causes loss of hearing and ovarian function) and D-bifunctional protein (DBP) deficiency (a severe metabolic disorder).
But, NGS techniques have run into obstacles once the focus shifts to the brain. One new technique, the genome-wide association study, has uncovered many new genes and mutations in other body parts. However, it has come up short in uncovering the genetic links to psychiatric disorders. One problem is the way we characterize these disorders. Schizophrenia and autism, for example, are characterized by symptoms. The “phenotype” of these diseases is so genetically diverse that any genome-wide study simply won’t be able to read the signal through all that heterogeneous genetic noise! Another issue is that diseases in the brain may have epigenetic causes—genetic interactions with other proteins and the environment could lead to different disease states in different individuals.
For students of evolution, there’s more confoundment. Only a few hundred genes separate our brains from those of non-human primates. Aside from fodder for stand-up comedy acts, this fact also means genome-wide studies won’t illustrate how the human brain evolved. However, developmental biologists are applying NGS techniques to fetal neural development, where evolutionary traits may be traced as the brain develops (remember “ontology recapitulates phylogeny”?).
We’ve come a long way in a few years, and the future of neurobiology and genetics will be aided by NGS techniques. This couldn’t come soon enough- according to the National Institutes of Health Undiagnosed Diseases Program, more than half of the people enrolled in the program suffered from an undiagnosed neurological disorder.
ScienceDaily (April 4, 2012). Mutations in three genes linked to autism spectrum disorders.
Bras, J., Guerreiro, R., Hardy, J. (2012). Use of next-generation sequencing and other whole-genome strategies to dissect neurological disease. Nature Reviews: Neuroscience, 13, 453-464.
Konopka, G. (2012). The fetal brain provides a raison d’être for the evolution of new human genes. Brain Behavior and Evolution. DOI: 10.1159/000336723.
Zoghbi, H. and Warren, S. (2010). Neurogenetics: advancing the “next-generation” of brain research. Neuron, 68, 165-173.