Average human genome characterised for first time from nearly one million sequences

An international team led by researchers at the University of Exeter has produced the first systematic characterisation of the “average” human genome, published in Genome Medicine and presented at the American Society of Human Genetics annual meeting. Drawing on whole-genome sequencing data from UK Biobank in the United Kingdom and the All of Us study in the United States, the observational study surveyed sequences from nearly one million individuals to establish what a typical genome actually contains. The work, supported by the Medical Research Council, Wellcome and the NIHR Biomedical Research Centre Exeter, provides a reference baseline that the team says can help clinicians and patients interpret genomic findings in context.

The survey found that every person’s genome includes around five million variants, meaning locations in the DNA that differ between individuals. Of these, roughly 10,000 alter gene sequences, with effects that range from lactose intolerance to drug response, although many are biologically neutral. Beyond this common variation, every individual carries between one and three rare variants that have previously been shown to cause serious genetic diseases, together with another 50 rare variants whose clinical relevance is currently uncertain. The researchers emphasise that carrying such variants is part of normal genetic variation, and that many will not actually cause disease in the individual who carries them.

The team also calculated polygenic risk scores, which combine all known genetic factors to estimate a person’s future risk of developing a disease. Examining scores for 28 common conditions, including diabetes, cardiovascular disease and schizophrenia, they found that most people would be categorised as at high genetic risk for around three conditions. Crucially, the study did not investigate the health status of any participants, so many of these individuals might have no diseases at all. The findings underline that a high polygenic score can fall within normal genetic variation, and that other clinical and environmental factors are crucial in whether disease actually develops.

Senior author Professor Caroline Wright, of the University of Exeter, said: “Whole genome sequencing has become such an important tool in diagnosing genetic disease, and we’re increasingly moving towards 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. For the first time, our study outlines what to expect in the average human genome, which can benefit clinicians and patients across the world in understanding, interpreting and contextualising genomics.” She added: “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.”

Among the additional findings, individuals in the two biobanks who were recruited alongside their parents carried around 63 “de novo” variants in their genome that were not present in either parent. These new mutations arose mostly in the fathers’ sperm and some in the mothers’ eggs, and their number increased particularly with the age of the father, at around 1.2 more mutations per year, a pattern the researchers note has important implications for reproductive decision-making. The team also acknowledges a key limitation: although the two biobanks are large, participation is skewed towards people of Western European origin, and the researchers recognise the need for data on more diverse populations to continue evolving understanding and impact. The paper, titled ‘The average individual genome: a survey of nearly 1 million whole-genome sequences’, concludes that the study’s findings provide important context for professionals interpreting genetic testing results or commissioning genetic screening programmes, and that everyone, regardless of their current health status, could potentially be told they are at risk for numerous conditions based on their genetics alone.

Subject of Research: Characterisation of the average human genome using whole-genome sequencing data from nearly one million individuals in UK Biobank and the All of Us study.

Article Title: “Average” human genome described for first time, with implications for disease risk

Article References: “Average” human genome described for first time, with implications for disease risk. Original publication (Bibliographic details unavailable.)

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Keywords: human genome, whole genome sequencing, genetic variation, polygenic risk scores, rare variants, de novo mutations, Genome Medicine, University of Exeter, UK Biobank, All of Us, genetic disease risk, genetic screening