Humans carry one to two lethal recessive mutations on average, study estimates

April 9, 2015

Humans carry on average one to two mutations that, if inherited from both parents, can cause severe genetic disorders or death before reaching reproductive age, report scientists from the University of Chicago and Columbia University. The estimate is based on an analysis of the genealogy of an isolated founder population with more than 1,500 living descendants. The results, reported in GENETICS on April 9, also reveal surprising similarities in average number of recessive lethal mutations between humans and other organisms.

"The trust and partnership between the Hutterite community and researchers greatly facilitated diagnosis and identification of genetic diseases in this population, which made our method possible," said study author Ziyue Gao, graduate student in the Genetics, Genomics and Systems Biology program at the University of Chicago. "Their records offered a fantastic opportunity to estimate the burden of recessive lethal mutations in a new way that disentangles the effects of genetic and socioeconomic factors."

Every person carries two copies of all their autosomal genes, inheriting one copy from their mother and one from their father. A large number of genetic diseases are caused by recessive mutations, which are harmless when present in one copy of a gene but can lead to severe or lethal disorders if present in both. Recessive disease mutations are much more common than mutations that cause disease when present on only one copy of a gene, but the rate at which they appear in a general population has been unclear.

To investigate how many recessive lethal mutations are carried by humans on average, Gao and her colleagues worked closely with a group of Hutterites, a religious community that settled in North America in the 1870s. Co-author Carole Ober, PhD, chair of the Department of Human Genetics at the University of Chicago, has worked closely this community for two decades, studying genetic contributions to disease using a large 13-generation family tree that traces the ancestry of the more than 1,500 living people in her studies. Ober and colleagues compiled comprehensive records on the frequency of disorders that caused sterility or childhood death in this population.

With a detailed family tree and comprehensive disease information, the researchers simulated the transition of recessive lethal mutations from generation to generation and estimated the total number carried by the original founders. This allowed them to then calculate the average number of recessive mutations for each individual

The team found roughly three lethal recessive mutations in every five people among the original founders, but this only accounted for mutations that allowed children carrying two copies to survive at least until birth. Based on estimates of the proportion of recessive mutations that cause death during fetal development, the team concluded that each founder carried approximately one to two recessive mutations that cause sterility or death before adolescence.

"This number is probably lower than the real average for most populations, but it is in the same ballpark," Gao said. "Most importantly, unlike previous estimates in other populations, it is unaffected by socioeconomic factors."

Small, isolated founder populations such as those in the study are expected to carry fewer harmful recessive mutations than the general population, because lethal mutations are more effectively selected against by natural selection in small populations. This number also excludes recessive mutations carried on the sex chromosomes.

Gao cautions that the number of recessive disease mutations will vary from person to person, and the new number doesn't necessarily help predict a specific couple's risk for passing on a genetic disorder. She also points out that most infant mortality worldwide is caused by non-genetic factors such as poor nutrition and infectious disease, rather than inherited disorders.

Surprisingly, the recessive disease mutation estimate for humans is similar to those from fruit fly and fish species, even though these organisms have very different total genome sizes. "We don't yet understand why the number of recessive lethal mutations might be relatively constant across distantly related organisms," said Gao. "It's an interesting evolutionary question for further research."

The study, "An Estimate of the Average Number of Recessive Lethal Mutations Carried by Humans," was supported by the National Institutes of Health. Additional authors include Darrel Waggoner, Matthew Stephens and Molly Przeworski.