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In this graph, two unaffected parents each carry one copy of a gene mutation for an autosomal recessive disorder. They have one affected child and three unaffected children, two of which carry one copy of the gene mutation. Image Credit: US National Library of Medicine

Most People Carry Recessive Disease Mutations

Humans carry an average of one or two mutations per person that can cause severe genetic disorders or prenatal death.

These new numbers were made possible by a long-term collaboration between medical research and a unique community which maintains detailed family histories.

"These records offered a fantastic opportunity to estimate disease mutation carrier rates in a new way that disentangles the effects of genetics from socioeconomic factors," said lead author Ziyue Gao, graduate student at the University of Chicago.

Estimate results are published in the journal GENETICS.

Most genetic disorders that result in sterility or childhood death are caused by recessive mutations, DNA sequence variations (variants) that are harmless when a person carries only one copy. But when the same mutation is inherited — meaning one mutation from each parent — recessive mutations can cause devastating diseases like cystic fibrosis.

Recessive disease mutations are much more common than those that are harmful only in a single copy. That is because single copy dominant mutations are more easily eliminated by natural selection. But exactly how common are recessive disease-causing mutations in humans? Previous efforts to estimate their number have relied on studies of disease in children born to related parents. With this method, increased rates of childhood mortality and disease are assumed to be due to recessive mutations. But this method mixes genetics with socioeconomics.

For example, in some places, marriage between close relatives correlates with poverty. In those cases, children with related parents can have higher disease and death rates simply because their families suffer from poor nutrition or lack of access to medical care. "There are many different — but non-genetic — factors that can bias this kind of approach," said Gao. However, the new method elegantly sidesteps this problem. It relies on facts collected by the Hutterite community.

The Hutterites are a religious group that settled in North America in the 1870s and keeps meticulous genealogical records. They live a communal life ensuring uniform access to healthcare and food.

Co-author Carole Ober of the University of Chicago has worked closely with a group of Hutterites from South Dakota for two decades, studying genetic contributions to disease using a large 13-generation family tree tracing the ancestry of more than 1,500 living people.

Molly Przeworski, a population geneticist at Columbia University, realized that this ancestry tree could be used to estimate the number of recessive disease mutations carried by the group’s founders in the 18th and 19th century. This was possible because Ober’s team along with other medical researchers had compiled comprehensive records on the frequency of disorders that cause sterility or childhood death in the Hutterites. Using this information, the team estimated that there were around three mutations of this type for every five people among the original founders. But that only accounted for mutations that allow children carrying two copies to survive at least until birth.

Based on estimates of the proportion of recessive mutations that cause death during fetal growth, the team concluded each founder carried approximately one to two recessive mutations causing sterility or death before adolescence.

Gao: "This number is probably lower than the real average for most populations, but is in the right ballpark. More importantly unlike previous estimates, it is unaffected by socioeconomics."

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