Recombination and de novo mutations During the creation of gametes (egg and sperm cells), recombina- tion occurs through programmed double-stranded breaks and DNA repair. Chromosomal breaks are normal events during meiosis and are reattached to nearby homologous sequences. This breaking and repairing allows for the shuffling of genetic material, leading to biological diversity that ensures the continuity of the species. Some areas of the genome, known as “recombination hotspots,” are more prone to breaks. Failure to properly repair these breaks can result in new genetic variants that cause disease in the offspring. These variants, not inherited from either parent, are called de novo . New research shows that these de novo events are more common than previously thought and occur more frequently in the formation of sperm than eggs. Scientists used data from several large databases of healthy individuals and those with known genetic diseases to identify new disease-causing variants in recombination hotspots. The team then calculated sex-specific rates of these de novo variations. Ultimate- ly, they found that the rate of disease-causing variation due to breakage is much higher than previously thought and is caused by mechanisms beyond simple crossing-over. They estimate that 1 in 4 sperm and 1 in 12 eggs has a de novo variant related to DNA repair during recombination, which could affect the health of offspring. This research provides insight into the origins of disease-caus- ing de novo variation due to human DNA replication. It allows sci- entists to understand better the balance between cellular mecha- nisms of genetic diversity and the burden of genetic disease. n
Practical impacts of knowing your genetic risk As DNA testing improves and costs become even more affordable, testing will be increasingly offered to whole populations. Population-based genomic screening is meant to identify people who harbor DNA changes that increase their risk of developing certain diseases in the future. The goal of this type of testing is to guide healthcare decisions so that those at increased risk can prevent disease or de- tect the disease at an earlier, more treatable stage. Over the past decade, a network of hospital systems offered population-based genomic screen- ing to more than 16,000 adult patients. Patients were then followed over time to track the impact of results on their medical care. Approximately 3% of patients who underwent genomic screening had a positive result, identifying a genetic disease risk. These positive results included risks for several types of heart problems and cancer, as well as high cholesterol. Forty-four percent of patients with positive results got medical care relevant to their results within one year. This was significantly higher than in the year before the results (25.6%) and the amount of care received among patients with negative results (24.9%). This increase in care comes at a cost to patients and the healthcare system. On average, the cost of medical care within a year of receiving genomic results was $149 higher for patients with a positive result. This study provides important insights for patients, health systems, and insurance companies as they consider the benefits, limitations, and consequences of genomic screen- ing in large patient populations. n REFERENCES: Linder, J. E., et al. Prospective, multi-site study of healthcare utilization after actionable monogenic findings from clini- cal sequencing. Am J Human Genetics . (2023) 110 (11): 1950-1958. doi.org/10.1016/j.ajhg.2023.10.006
REFERENCE: Robert Hinch et al., Meiotic DNA breaks drive multifaceted mutagenesis in the human germ line. Science (2023) 382,eadh2531. doi: 10.1126/science.adh253
Risk of adverse drug reactions Nearly 7,000 people across seven European countries took part in a recent study exploring the impact of pharmacogenomic testing on adverse drug reactions. Pharmacogenomics is a field that sits at the intersection of genomics and pharmacology and describes how the medicines that we take are influenced by our DNA. Individuals being prescribed a drug with known pharmacogenomic associations for the first time were eligible for the study. Participants were randomly assigned either to the study group (underwent pharmacogenomic testing) or the control group (did not have testing). The testing looked for genetic changes in 12 genes related to medication response. All the participants were followed for 12 weeks, and any adverse reactions were documented. A quarter of participants who had genetic testing received an actionable result, providing information about their response to a medicine they were taking. The number of adverse drug reactions was reduced in the study group (21.5%) when compared to the control group (28.6%). This large study provides evidence that pharmacog- enomic testing can help reduce the number of adverse drug reac- tions. More information about how a person’s body will respond to a particular medicine makes it easier for doctors to choose the best medicine and dose for a patient. n REFERENCE: Swen JJ, et al., Ubiquitous Pharmacogenomics Consortium. A 12-gene pharmacogenetic panel to prevent adverse drug reactions: an open-label, multicentre, controlled, cluster-randomised crossover implementation study. Lancet . (2023) 401(10374):347-356. doi: 10.1016/S0140-6736(22)01841-4
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