After the California bubonic plague case, where a resident who went camping at South Lake Tahoe area tested positive for plague, lot has been talked about the disease. The bubonic plague is often remembered as one of the deadliest pandemics in human history. Today, with the California resident case, we all know that it still lingers in scattered regions, but antibiotics make it far less threatening.What is less widely known is that the plague may have permanently altered human biology, leaving an imprint on the immune system that persists even now.Also Read: Bubonic Plague California Resident: Here's All That You Need To Know About The DiseaseThe Bacterium Behind the PlagueThe plague is caused by Yersinia pestis, a rod-shaped bacterium carried by fleas that thrive on rodents and other wild animals. While unremarkable in appearance under a microscope, this microbe has shaped centuries of human history. At its peak during the 14th century, the Black Death killed tens of millions across Europe, with entire towns and communities wiped out in a matter of months.Earlier outbreaks of plague are believed to stretch back thousands of years, with traces of the bacterium found in ancient human remains. Yet the medieval Black Death was unlike anything before, spreading rapidly through trade routes and devastating Europe within a few short years.Natural Selection in the Wake of the Black DeathThe scale of mortality during plague outbreaks raised an intriguing question: could survival have been influenced by genetics? If certain individuals carried genetic variations that helped them fight off the infection, those traits might have been passed on to their descendants. In essence, the plague may have acted as a brutal filter, altering the genetic makeup of future generations.Modern genetic studies now provide evidence for this idea. By comparing DNA from plague victims with that of later populations, researchers have observed that people who lived through the plague era and passed on their genes tended to carry variants that supported stronger immune defenses. This suggests that the catastrophe of the Black Death created a surge of natural selection across affected regions.Unlocking Clues from Ancient BonesFor a long time, studying the genetic impact of plague was extremely difficult. DNA preserved in centuries-old skeletons is often degraded and contaminated by soil and microbes. However, advances in ancient DNA sequencing opened new doors. Scientists discovered that the inner ear’s bony labyrinth, one of the densest parts of the human body, preserves intact DNA remarkably well. Extracting genetic material from this area has allowed researchers to examine how plague survivors may have differed from those who succumbed.With these methods, mass graves of plague victims have become key resources for understanding how the disease influenced human biology. By sequencing genomes from skeletons buried before, during, and after outbreaks, scientists can track changes across generations.The Role of HLA GenesOne of the clearest examples of plague-driven selection lies in the human leukocyte antigen (HLA) system. This group of genes is essential for immune defense, helping the body recognize and destroy cells infected by pathogens. Even subtle differences in HLA variants can determine whether someone is more resilient against a particular disease.Evidence suggests that during the plague years, people carrying certain HLA variants were more likely to survive. These protective versions of the genes became more common in descendants over time. This mirrors what scientists have observed in more recent pandemics, such as Covid-19, where some people showed natural resistance thanks to genetic variations in immune-regulating genes.A Gene Called ERAP2Another key discovery centers on a gene known as ERAP2. This gene produces a protein that helps immune cells break down foreign invaders, including bacteria like Yersinia pestis. Researchers studying remains from plague cemeteries in London and Denmark found that individuals who carried a particular version of ERAP2 were twice as likely to survive the Black Death.By the end of the 14th century, this protective variant had become widespread among Europeans, appearing in roughly half the population in London and even more frequently in Denmark. It is one of the strongest pieces of evidence showing how a pandemic can reshape human genetics in just a few generations.Balancing Benefits and RisksHowever, the story is not entirely one of benefit. Genes that protect against deadly infections may also carry hidden costs. For example, some of the same immune-system variations that helped ancestors survive plague outbreaks are now associated with autoimmune disorders, where the immune system mistakenly attacks healthy tissue. This illustrates the trade-offs of evolution: what once ensured survival may create vulnerabilities in a very different modern environment.Why More Research is NeededWhile the genetic evidence is compelling, scientists caution that we are only beginning to understand the full scope of plague’s impact. To get a clearer picture, thousands more ancient genomes from across Europe and Asia need to be analyzed. Only then can researchers determine how widespread these adaptive changes really became.There is also debate over whether plague was the most significant driver of immune evolution. Diseases like smallpox, which persisted for centuries and claimed hundreds of millions of lives, may have exerted an even greater influence. The challenge is teasing apart the effects of different pathogens across different time periods.What To RememberYou May Like To Read: What History Teaches Us About Plague? Are There More Than One Type?Despite its reputation as a medieval killer, plague has not disappeared. Small numbers of cases are still reported each year in parts of the world, from the western United States to Madagascar. Thanks to antibiotics, survival rates are far higher today, but the fact that the disease persists is a reminder of its enduring presence in nature.Rodents and fleas continue to serve as reservoirs for Yersinia pestis. Outbreaks in isolated communities highlight the delicate balance between human society and the microbial world. While the scale of devastation seen during the Black Death is unlikely to return, the evolutionary lessons it left behind remain relevant.Centuries later, the legacy of plague survives in our DNA. Some of the same genetic defenses that once meant the difference between life and death still influence how our immune systems function today.