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Understanding the dynamics of human DNA across generations is crucial for assessing genetic disease risks and tracing our evolutionary journey. Recent advancements have enabled researchers to analyze some of the most fluctuating segments of our genetic makeup.
A collaborative effort involving experts from the University of Utah Health, the University of Washington, PacBio, and other institutions has culminated in the creation of a detailed atlas that maps genetic variations across generations. This groundbreaking study unveils that numerous areas within the human genome exhibit a far more rapid rate of change than previously recognized, potentially reshaping our comprehension of genetic disorders and human evolution.
“Mutations are what set us apart from other species,” comments Lynn Jorde, PhD, a lead author. “We are tapping into fundamental aspects that define our humanity.”
The biological “speed of light”
By juxtaposing the DNA of parents with that of their offspring, the team was able to quantify the frequency of new mutations being inherited. Jorde emphasizes that this rate is as pivotal to understanding human biology as the speed of light is in physics. “This knowledge is essential for grasping how variability within our species emerges,” explains Jorde, who holds a professorship in human genetics at the Spencer Fox Eccles School of Medicine (SFESOM) at the University of Utah. “The genetic diversity we observe among individuals stems from these mutations.” Over time, such variations have influenced traits ranging from eye color to lactose digestion and the incidence of rare genetic disorders.
The researchers estimate that nearly every individual possesses close to 200 new genetic alterations that are not found in either parent. Many of these modifications arise from segments of DNA that have traditionally proven challenging to investigate.
Aaron Quinlan, PhD, chair of human genetics at SFESOM and a co-author of the research, points out that earlier studies tended to focus on the most stable parts of the genome. The current study, however, employed cutting-edge sequencing technologies to uncover areas of DNA that are highly mutable, regions that Quinlan describes as “previously off-limits.”
“We observed sections of our genome that mutate at astonishing rates, almost once every generation,” he notes, contrasting them with more stable regions of genetic material.
According to Jorde, the findings provide critical insights for genetic counseling, particularly in determining whether a genetic disorder in a child is likely inherited from a parent or is the result of a new mutation. Conditions linked to rapidly changing mutation hotspots are often specific to the child and less likely to recur in siblings, thus providing reassurance to parents about the genetic risks to future offspring. Conversely, if a genetic alteration is passed down, it increases the likelihood that future children will also be affected.
The platinum pedigree
The researchers’ groundbreaking findings were significantly bolstered by their work with a Utah family that has collaborated with geneticists since the 1980s as part of the Centre d’étude du polymorphisme humain, significantly contributing to the Human Genome Project.
This family’s extensive participation across four generations, allowing for analysis of their DNA, enabled a meticulous examination of how novel genetic changes develop and are transmitted from one generation to the next. “The unique breadth and depth of this large family provide an unparalleled resource,” states Deborah Neklason, PhD, an associate professor of internal medicine at SFESOM and co-author. “It allows for an in-depth understanding of genomic variation and changes across generations.”
The best of both worlds
To attain a comprehensive, high-resolution view of genetic variations over time, the research team utilized multiple DNA sequencing technologies. Some methods excel at identifying minute changes, while others can scan vast regions of DNA to detect substantial alterations in hard-to-sequence parts of the genome. By marrying these different approaches, the researchers achieved a versatile understanding of genetic variation at both micro and macro levels.
Looking ahead, the team aims to apply their thorough sequencing techniques to a broader population to determine whether the rate of genetic change differs among families. “Our findings within this one family were intriguing,” Quinlan remarks. The next logical inquiry is how universally applicable these results might be for predicting disease risk or tracing genomic evolution across varied familial contexts.
The sequencing data generated from this research will be made publicly accessible, inviting other scholars to leverage the information for further studies, potentially enhancing our understanding of human evolution and genetic disorders.
This research received support from the National Institutes of Health and other notable funding agencies, whose grants facilitated this significant endeavor. However, the authors and their affiliations do not necessarily reflect the official positions of the funding bodies.
Additionally, some researchers acknowledged potential conflicts of interest, with certain authors holding advisory roles or investments related to relevant biotech firms, while others reported no such competing interests.
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