A new study from the University of Exeter has characterized what counts as an “average” human genome, offering a reference point for normal genetic variation and genetic disease risk. Published in Genome Medicine, the research drew on nearly one million whole genome sequences from two major population biobanks, UK Biobank and the U.S.-based All of Us program, funded by the Medical Research Council, Wellcome and the NIHR Biomedical Research Centre: Exeter.
The analysis points to an uncomfortable conclusion: based on genetics alone, virtually anyone, whatever their current health, could be flagged as at risk for multiple conditions. Each genome, the team found, contains roughly five million variants, about 10,000 of which alter gene sequences—ranging from traits like lactose intolerance to drug response, though most such changes are biologically neutral. Everyone also carries one to three rare variants previously linked to serious genetic disease, plus around 50 more of uncertain clinical significance.
The team also calculated polygenic risk scores—which combine many genetic factors into an overall disease-risk estimate—across 28 common conditions, including diabetes, cardiovascular disease and schizophrenia, and found most participants fell into the high genetic risk category for about three of them. Since the researchers didn’t assess participants’ actual health status, many of those flagged this way may have no disease at all, underscoring that such results can reflect ordinary genetic variation rather than a looming diagnosis, with other factors playing a major role in whether disease ever develops.
Senior author Professor Caroline Wright said the findings fill a gap in how genomic results get interpreted: “Whole genome sequencing has become such an important tool in diagnosing genetic disease, and we’re increasingly moving toward genetic screening for predicting disease. Yet most people are unaware of just how much genetic variation is present in every genome. Actually, variation is the norm.”
Both biobanks skew toward participants of Western European ancestry, and the researchers note a continued need for more diverse population data. Among participants recruited alongside their parents, the team also found around 63 new, or “de novo,” variants in each genome that weren’t present in either parent, arising mostly from mutations in fathers’ sperm and, to a lesser extent, mothers’ eggs. The number of these new variants rose with paternal age, by about 1.2 additional mutations per year —a finding the researchers say carries implications for reproductive decision-making.
Wright added that context remains essential when acting on genetic test results: “Importantly, we found that everyone carries a small number of genetic variants linked to disease, although many of these will not actually cause disease in that individual. It is therefore crucial to consider context when interpreting findings from genetic testing, including symptoms or family history of disease as well as other clinical and environmental risk factors. Our findings also provide important context for professionals who are interpreting genetic testing results or commissioning genetic screening programs.”
The analysis points to an uncomfortable conclusion: based on genetics alone, virtually anyone, whatever their current health, could be flagged as at risk for multiple conditions. Each genome, the team found, contains roughly five million variants, about 10,000 of which alter gene sequences—ranging from traits like lactose intolerance to drug response, though most such changes are biologically neutral. Everyone also carries one to three rare variants previously linked to serious genetic disease, plus around 50 more of uncertain clinical significance.
The team also calculated polygenic risk scores—which combine many genetic factors into an overall disease-risk estimate—across 28 common conditions, including diabetes, cardiovascular disease and schizophrenia, and found most participants fell into the high genetic risk category for about three of them. Since the researchers didn’t assess participants’ actual health status, many of those flagged this way may have no disease at all, underscoring that such results can reflect ordinary genetic variation rather than a looming diagnosis, with other factors playing a major role in whether disease ever develops.
Senior author Professor Caroline Wright said the findings fill a gap in how genomic results get interpreted: “Whole genome sequencing has become such an important tool in diagnosing genetic disease, and we’re increasingly moving toward genetic screening for predicting disease. Yet most people are unaware of just how much genetic variation is present in every genome. Actually, variation is the norm.”
Both biobanks skew toward participants of Western European ancestry, and the researchers note a continued need for more diverse population data. Among participants recruited alongside their parents, the team also found around 63 new, or “de novo,” variants in each genome that weren’t present in either parent, arising mostly from mutations in fathers’ sperm and, to a lesser extent, mothers’ eggs. The number of these new variants rose with paternal age, by about 1.2 additional mutations per year —a finding the researchers say carries implications for reproductive decision-making.
Wright added that context remains essential when acting on genetic test results: “Importantly, we found that everyone carries a small number of genetic variants linked to disease, although many of these will not actually cause disease in that individual. It is therefore crucial to consider context when interpreting findings from genetic testing, including symptoms or family history of disease as well as other clinical and environmental risk factors. Our findings also provide important context for professionals who are interpreting genetic testing results or commissioning genetic screening programs.”