Adam Siepel's team at Cold Spring Harbor Laboratory (CSHL) has created a computer program that can trace the history of harmful mutations in the human genome over time. Through their research, they discovered that certain regions of the genome are more susceptible to mutations, which could potentially have serious or even fatal consequences.
These findings which were published in Nature Communication could be useful for clinicians in identifying the causes of genetic diseases. In general, mutations can have both positive and negative effects on an organism. While some mutations can improve survival and adaptability, others can be so damaging that they prevent an organism from reproducing or surviving.
Siepel's program, called ExtRaINSIGHT, can search for harmful mutations by looking for their absence. Every region of the human genome should, by random chance, contain some mutations. However, certain regions may have none. Siepel refers to these areas as "ultraselected." The mutations that do occur in these regions can be deadly or significantly reduce the likelihood of reproduction.
Harmful History Mutation
Siepel explains that, if the program looks at a panel of 100,000 humans and never sees a mutation at a particular gene, it suggests that any mutation that did occur was so harmful that anyone carrying it died out and was not passed onto future generations. This indicates that the region is "ultraselected" and highly susceptible to harmful mutations.
This repository includes a model for estimating the proportion of genomic regions that are under strong negative selection by observing a lack of rare variants concerning a neutral mutation model. The pipeline for extracting and fitting the data, as well as the main extraINSIGHT model, is included in the repository.
The scientists used ExtRaINSIGHT to analyze over 70,000 human genomes and found that three parts of the genome are particularly vulnerable to mutations over time. The most sensitive of these is the splice site, which helps produce correct instructions for making proteins. Mutations in this region can have a significant impact on the likelihood of genes being passed on, also known as fitness. Splice site mutations have been linked to several diseases, including spinal muscular atrophy, the leading genetic cause of mortality in newborns and toddlers.
Detecting Genetic Disease
Siepel says that if a mutation is found in a splice site, it should be taken seriously because it could significantly reduce an individual's fitness. He explains that the mutation alone would lessen one's fitness by 1 or 2%. That might sound like a lot, but that's a huge fitness effect. And if one had multiple of those, pretty soon the chance of passing on to one gene might be close to zero.
As stated by CSHL, in addition to splice sites, the scientists also found that molecules called miRNA and central nervous system genes are sensitive to mutations. Siepel says that if one will find a mutation in miRNA there's a good chance it's responsible for a genetic disease. He also notes that the nervous system is particularly sensitive to mutations because of its complex and interconnected nature.
The causes of many genetic diseases and conditions are still unknown. Siepel hopes that technology like ExtRaINSIGHT will help uncover their origins and guide diagnoses and future treatments. He also hopes that his work will shed light on how mutations continue to shape the evolution of the human genome.
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