Disease genes are unable to adapt as the rest of the genome, says research

Researchers recently discovered a novel detrimental effect of genes that induce inherited diseases. The observations are published in the journal eLife.

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The research indicates that these genes hinder adaptation (or the evolution of beneficial genes) from occurring around them in the genome. This permits them to persist for a long time in human populations by prohibiting their removal by selective sweeps.

The observations provide a new understanding of evolutionary processes in the last 50,000 years that permitted certain disease-causing genes to remain in human populations, in spite of their harmful effects.

Advanced genome sequencing is allowing scientists to learn more about the evolution of diseases and more beneficial traits in humans. But limited research on disease genes focuses on evolutionary processes occurring in the last 50,000 years. Our understanding of the relationship between disease and adaptation in the human genome has been hampered by this gap in more recent information.”

Chenlu Di, Study First Author and PhD Student, Department of Ecology & Evolutionary Biology, University of Arizona

Chenlu Di is a student at the Enard Laboratory.

To bridge the gap, Di and coworkers compared the rates of recent genetic adaptation in disease-associated genes and non-disease genes in 26 distinct human populations worldwide included in the 1000 Genomes Project. The researchers also included inherited diseases resultant from mutations in a single gene—known as Mendelian diseases.

They have a simple pattern of inheritance where a child inherits the disease if they acquire a copy of a dominant disease-causing gene from one of their parents. The disease also occurs if the child acquires two copies of a recessive disease-causing gene—one from each parent.

The researchers wanted to identify whether the genes that induce human Mendelian diseases have undergone more or less positive selection than non-disease-causing genes in the human genome.

The researchers discovered that recessive Mendelian disease-causing genes are impossible to be swept out of a population. The patterns indicate that a process named genetic interference would have hindered these genes from adapting to changing environments.

Recessive disease-causing gene variants that prevent adaptation from occurring in the genome can dodge gene sweeps that would normally wipe them out in a population.”

Chenlu Di, Study First Author and PhD Student, Department of Ecology & Evolutionary Biology, University of Arizona

The researchers also found certain regional variations in patterns of gene adaptation while comparing various parts of the genome of the same population. When compared to the rest of their genomes, African populations had a higher deficit of gene sweeps at disease genes. In European and East Asian populations, a weaker sweep deficit at disease genes was noticed compared to other parts of the genome.

The researchers state that this might be due to severe population bottlenecks that took place in human populations that migrated out of Africa and eventually settled in Asia and Europe. A small number of individuals migrating is sufficient to cause the loss of a substantial amount of recessive gene variants found at low frequencies in the genome.

We also see a clearer sweep deficit at disease genes in African populations because they have overall clearer genome-wide sweep signals. This provides a better contrast for us to distinguish between disease genes and the rest of the genome.”

David Enard, Study Senior Author and Assistant Professor, Department of Ecology & Evolutionary Biology, University of Arizona

Even though the research gives interesting information, Enard alerts the need for further research to substantiate the findings and to assure that biases in the data utilized by them did not distort the results. For instance, he remarks that most of the Mendelian diseases in the research were identified in Europe.

Enard adds, “Our work improves on previous studies trying to address this important question by using larger gene datasets and carefully controlling for confounding factors that could result in disease-causing genes and non-disease genes showing different patterns. But there is more work to do to better understand recent genetic adaptation in humans.”