News from the 2013 American Society of Human Genetics conference
INVESTIGATING THE GENETIC MECHANISM BEHIND DELUSIONS IN SCHIZOPHRENICS
SESSION 15 - Psychiatric Disease: GWAS to Genes
Speaker: Mariela Zeledon, Predoctoral Training Program in Human Genetics, Johns Hopkins University School of Medicine
Johns Hopkins researchers say they have identified changes in a person's DNA sequence that can affect what kinds of schizophrenia symptoms they experience. The DNA changes either ramp up or down a gene associated with delusions. The researchers still aren't sure how having too much and too little of the gene's product triggers delusions, but they have taken a step toward determining why people with schizophrenia can have very different symptoms.
Single DNA letter changes, or mutations, in the gene NRG3 have been linked to susceptibility to delusions in schizophrenic patients. But these mutations don't affect the portion of the gene used as a template to make NRG3 protein, so the researchers initially didn't know how the mutations were having an effect.
To home in on the cause, researchers first looked at whether single DNA letter variations could change NRG3 expression levels - how many times the gene is "read" to make protein. One NRG3 variant was turned on too high, meaning the gene makes too much NRG3 protein, and another too low, meaning it doesn't make enough. Next, the researchers looked at what proteins stick to the NRG3 DNA sequence of the variants associated with delusion compared to the normal version, specifically searching for proteins that turn genes on or off. They did this in two ways: by using a computer program to predict which DNA sequence would stick to which proteins, and by taking a whole slew of gene control proteins spotted individually onto a chip and seeing which DNA sequences bound to which spots. The computer program predicted one set of gene-activating proteins, which the researchers are confirming with the chip analysis. The physiological mechanism has yet to be fully elucidated, but the researchers say that knowing how each genetic variant causes delusions could yield information about disease progression and what treatments will be most effective.
DISCORDANT DATA BETWEEN GENETIC DATABASES
Study suggests case for standardization of data storage and information-sharing policies for genetic diseases
SESSION 32 - Genetic Testing for Neurodevelopmental Disease: Genotype: Phenotype Challenges
Speaker: Julie Jurgens, Predoctoral Training Program in Human Genetics, Johns Hopkins University School of Medicine
Geneticists at Johns Hopkins have found discrepancies between several genetic databases in the records of disease-causing DNA variants. They say their results argue for a single, comprehensive international genetic database compiling the most up-to-date information, which would allow doctors and clinicians to give better patient care.
To look for disease-causing genetic variants in the 56 genes recommended by the American College of Medical Genetics and Genomics, researchers analyzed the gene sequences of 2,443 individuals sequenced in the Baylor-Hopkins Center for Mendelian Genomics. They identified 6,477 rare variants in these patients within the 56 genes. Then the researchers looked for these variants in three different genetic databases and found that 50 percent of the genetic variants weren't listed in any of the databases. The researchers argue that the databases' lack of comprehensiveness stems from there not being a central standardized repository for the data, which could contribute to improper diagnoses if physicians can't find the information on the patient's variant.
The researchers also found that about 1.7 percent of the individuals had one incidental finding, or genetic variant besides the one responsible for the primary disease being investigated. As sequencing of entire genomes becomes more common, the researchers point out that there isn't a standard policy in place about whether and how to inform patients or their primary care providers of these findings, or to decide which data is worth sharing and which will do more harm than good. They suggest that geneticists decide as a group which genetic information to share with patients and their caregivers as a way to manage disease.
'JUMPING GENES' ASSOCIATED WITH COLON CANCER
SESSION 46 - Cancer Genomics
Speaker: Szilvia Solyom, Ph.D., Postdoctoral Fellow, McKusick-Nathans Institute of Genetic Medicine
Researchers at Johns Hopkins have discovered "jumping genes" in colon cancer cells. They say these jumping genes could eventually be used as biomarkers to monitor the progression of colon cancer.
Jumping genes - pieces of DNA that spontaneously copy themselves from the genome and reinsert in another location - make up a large portion of the human genome, but it is thought that jumps occur fairly infrequently. Since the majority of colon cancer cases occur without a known underlying genetic cause, the researchers decided to investigate whether jumping genes might be involved.
To test this, the researchers sequenced the DNA from four colon cancer patients with polyps, primary cancers and metastases, and the DNA from five people with inflammatory bowel disease (IBD) - a disease that increases colon cancer risk - specifically looking for jumping genes. Many cancer and precancerous samples contained large amounts of a certain jumping gene called Long Interspersed Element-1 retrotransposon, or L1 for short, but none of the healthy tissue samples contained L1s. The L1s had inserted in and around known cancer genes, but also in some genes with unknown functions, providing insight into other potential colon cancer-causing genes. The researchers caution that they haven't yet proved that L1s cause colon cancer; they say that jumping genes could either be an unexplored cancer-causing phenomenon or may be a side effect of some other malignant process.