NEW FINDINGS — EPIGENETICS
Exercise, motivation and genes If you’ve ever lacked motivation to hit the gym, it turns out your genes could be to blame. A recent study suggests that voluntary exercise behavior is influenced by epigenetic changes in early development. These changes, such as DNA methylation, are chemical modifications to DNA that affect gene activity without altering the DNA sequence. In the study, scientists deleted, or knocked out, a DNA methylation gene in a subset of neurons in the hypothalamus of mice thought to be responsible for regulating the amount of food that animals eat. Genome sequencing of hypothalamic neurons showed altered meth- ylation patterns in several genes, some of which could be involved in exercise motivation. Although they weighed more, juvenile knockout mice ate the same amount of food as the normal mice. But, when the mice were offered an exercise wheel, the knockout mice exercised far less than their counterparts. While it still requires translation to humans, the study suggests a possible epigenetic-driven developmental connection between motivation and exercise. REFERENCE: MacKay H. et al. DNA methylation in AgRP neurons regulates vol- untary exercise behavior in mice. Nature Communications (2019) 10:5364 doi: 10.1038/ s41467-019-13339-3.
Researchers assemble database of cancer genomes Cancer is a genetic disease that is characterized by the uncontrollable growth of abnormal cells that often travel to and invade other parts of the
NEW FINDINGS — CANCER
tumor sequencing project to date. The team performed whole- genome sequencing and analysis on more than 2,500 samples from 38 different primary cancers and matching normal tissue samples, including brain, skin, esophagus and liver. An interesting finding was that about 95% of the tumors had at least one identifiable DNA mutation in their genome that appeared to drive the cancer. These mutations, known as driver mutations, are responsible for cancer development and progression. About 13% of the driver mutations occurred in those non-coding portions of DNA that are not regularly analyzed. Many cancer drugs are designed to target specific proteins affected by driver mutations. Unearthing driver mutations in non-coding regions of a patient’s tumor genome could open the door to new avenues of treatment that would other- wise be missed. These studies represent a big step toward uncovering and under- standing all of the major cancer-causing mutations. In an effort to continue the momentum of this collaborative endeavor, the Project team has made all of its data and analytic tools freely available to the research community. REFERENCE: The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. Pan-cancer analysis of whole genomes. Nature . 578:82-93 (2020) doi: 10.1038/s41586- 020-1969-6. Genomic analysis of childhood cancer patients identifies potential targets for treatment The availability of targeted therapeutics for pediatric cancers pales in comparison to those available for adults. However, a recent study suggests that some FDA-approved drugs could be repurposed to treat pediatric cancer. Solid tumors account for about 50% of pediatric cancers. They are generally assumed to be heavily influenced by germline DNA variants, mutations inherited from the parent’s germ cells and present in all of the child’s cells, in addition to somatic mu- tations that only occur in the cancer cells. However, germline genomic analysis is not regularly used when determining the course of therapy for such patients. Scientists at the Cleveland Clinic have shown that such an analysis could be valuable when selecting a treatment strategy for these young cancer patients. During the study, scientists analyzed germline DNA from over 1,500 patients under the age of 29. They found that many of them carried germline mutations in known cancer-causing genes. Some of the mutations are known to be treatable with drugs already approved by the FDA for adult patients. In fact, thirty-four percent of the patients had at least one mutation that was potentially druggable. This study highlights the importance of sequence analysis of both germline and cancer genomes in pediatric and adolescent patients. By detecting more druggable targets, more approved drugs could be available, giving these young patients a wider range of therapeutic options in their battle against cancer. REFERENCE: Akhavanfard S, et al. Comprehensive germline genomic profiles of children, adolescents and young adults with solid tumors. Nature Communications (2020) 11:2206 doi: 10.1038/s41467-020-16067-1.
body. It is commonly caused by the accumulation of many different types of DNA mutations. Cancer is an extremely diverse disease, meaning that one person’s cancer genome can look entirely different from another person’s cancer genome. As we move closer to an era of precision medicine and personalized cancer treatment, it is critical to understand the thousands of different types and combinations of mutations that can cause cancer. To date, cancer research has mainly focused on well-known can- cer-associated genes, specifically mutations in the protein-coding components of those genes. However, this only represents a mere 1% of the entire genome. Therefore, a majority of the genome has been largely unstudied and unsequenced as it relates to mutations associated with cancer. However, the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Project team recently completed the largest whole-genome
Skewing X inactivation may activate autoimmune disorders Many autoimmune diseases disproportionately affect women more than men. One such disease, systemic lupus erythematosus (SLE), affects women nearly ten times more frequently than men. However, the molecular basis for the sex disparity is poorly understood. A recent study published in Human Molecular Genetics suggests that X chromosome inactivation could be to blame. Because females carry two X chromosomes compared to men who carry one, mammals evolved X chromosome inac- tivation to randomly silence, or turn off, genes on one of the X chromosomes in females. This allows XX females and XY males to have equal expression of X-linked genes, or genes located on the X chromosome. X chromosome inactivation is largely mediated by a molecule called XIST which recruits multiple proteins to the inactivated X chromosome to initiate and maintain gene silencing. By using RNA sequencing technology, scientists compared expression patterns of X-linked alleles in immune cells from female SLE patients and healthy subjects. They found that SLE patients had skewed X chromosome inactivation in T and B cells, meaning that the inactivation of one X chromosome occurs more frequently than the other. Offering a potential mechanism for the skewed X chromo- some inactivation, the scientists also observed that XIST was upregulated in the immune cells of patients with SLE. Because the process of X chromosome inactivation is limited to female cells, these findings may explain the female predisposition to autoimmune diseases like SLE. The skewed silencing of certain X-linked genes in SLE patients could increase the generation of immune cells that attack the patient’s own tissue, or reduce a patient’s ability to eliminate such cells.
Increasing mutation rates generates treatment resistant cancer cells
Genetic patterns of mimicry: the same… only different In South America, there are many Heliconius butterflies that have identical wing coloration and markings, despite belonging to different
Imagine the devastation that patients feels when they are told the cancer treatment that was working wonders for them for a year is now ineffective
because their cancer is no lon- ger responding to the treatment. This phenomenon, known as drug resistance, is a major setback in many patient’s cancer treat- ment plans. The current understanding is that within the tumor’s population of millions or billions of cancer cells, one or more already contain drug resistance mutations prior to treatment. However, a group of scientists challenged this understanding by turning to an unlikely source: bacteria. An increased DNA mutation rate has been observed in bacteria exposed to stress, like antibiotic treatment. This improves their odds of developing a mutation that will cause resistance to the antibiotic and increase their chance of survival. In a recent Science study, the scientists provide evidence that cancer cells may use a similar mechanism that generates resistance to drug treatment. As in the bacteria, colon cancer cells that survived drug treatment had a stress-induced increase in DNA mutation rate. Specifically, they had shifted gene expression from efficient repair systems towards error-prone repair pathways. The higher mutation rates increased the chance of acquiring drug resistance. In future studies, the scientists hope to determine the mechanism the cells use to increase their mutation rate and find a drug target to stop or delay drug resistance.
species. The bright black, red and white wing color patterns serve as a warning that the butterflies are poisonous, affording them a survival advantage in the face of hungry predators. Over time, some species have evolved and more closely resemble the poisonous species in a process called mimicry. These lookalike butterflies provide evolution- ary biologists with a unique opportunity to study the evolutionary and genetic basis of mimicry. A recent study published in Current Biology aimed to answer the question: Do distantly related species of butterflies use the same genetic path to evolve identical wing-color patterns? An internation- al group of scientists used CRISPR/Cas9 genome editing to knock out an important wing patterning gene, WntA , from the butterflies’ genomes. WntA is known to be important for the generation of Heliconius butterfly stripes. The scientists thought that if WntA played the same role in each of the butterfly species, inactivating it would lead to identical knockout butterflies. However, the knockout butterflies were not identical, having notice- able differences in their wing patterning and coloration. Although evolution of color patterns in the butterflies was driven by similar forces, such as survival and mating success, the study suggests that there are several different genetic pathways that can lead to identical color patterns in butterflies. REFERENCE: Concha, C. et al. Interplay between Developmental Flexibility and Determinism in the Evolution of Mimetic Heliconius Wing Patterns. Current Biology (2019) 29:3996-4009 doi:10.1016/j.cub.2019.10.010.
The laboratory of HudsonAlpha faculty researcher Devin Absher, PhD, contributed to this research.
REFERENCE: Zhang, Y. et al. Skewed allelic expression on X chromosome associated with aberrant expression of XIST on systemic lupus erythematosus lymphocytes. Human Molecular Genetics (published online ahead of print, 2020 Jul 6) doi: 10.1093/hmg/ddaa131.
REFERENCE: Russo M, et al. Adaptive mutability of colorectal cancers in response to targeted therapies. Science (2019) 366:1473-1480 doi: 10,1126/science.aav4474.
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SCIENCE FOR LIFE
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