Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New mathematical model explains variability in mutation rates across the human genome

22.02.2016

Fresh approach identifies genetic risk factors that influence complex human diseases

It turns out that the type, how frequent, and where new mutations occur in the human genome depends on which DNA building blocks are nearby, found researchers from the Perelman School of Medicine at the University of Pennsylvania in an advanced online study published this week in Nature Genetics.


This is Mu, the Greek symbol commonly used to symbolize mutation rate.

Image courtesy of Stacie Bumgarner (2016)

"We developed a mathematical model to estimate the rates of mutation as a function of the nearby sequences of DNA 'letters' -- called nucleotides -- in the human genome," said senior author Benjamin F. Voight, PhD, an assistant professor in the department of Systems Pharmacology and Translational Therapeutics and the department of Genetics.

"This new model not only provides clues into the process of mutation, but also helps discover possible genetic risk factors that influence complex human diseases, such as autism spectrum disorder."

This study focuses on the probability that any given nucleotide in the human genome -- one of the four letters (A, C, G or T for adenine, cytosine, guanine or thymine) of the DNA alphabet -- is changed. Voight focused on the simplest type of mutation, a "point" mutation in which a single letter is changed in a given sequence.

Most of these changes -- often called single nucleotide polymorphisms (SNPs), or "snips" -- are usually not harmful to the functioning of the human body. Nevertheless, Voight examined why some sequences are more prone to mutate, whereas others are not.

"The crux of the paper examines the dependency of mutation rate on which nucleotides are one, two, or three bases away from either side of a SNP," Voight said. "We already know about one situation in which this placement matters: DNA sequences in the genome where methyl groups are attached to the cytosine nucleotide, also known as CpG sites, are hotspots for mutation. But are there other types of local sequences that matter beyond these?"

To address this question, Voight and graduate student Varun Aggarwala, a doctoral candidate from the Genomics and Computational Biology graduate group, devised a mathematical model applicable to SNP data found in humans. Their approach took advantage of publicly available data from thousands of human subjects sampled from across the globe, namely from the 1000 Genomes Project. These individuals were sequenced as part of an international initiative to characterize the genetic variation that naturally occurs in human populations.

What they found was surprising: Knowing the three nucleotides flanking either side of a given SNP, for a total of seven nucleotides, predicted up to 93 percent of the variability in the chance of finding a SNP in a given sequence in individuals whose genome sequences are in the 1000 Genomes Project database. In addition, their model uncovered several distinctive sequences of local nucleotides that were not previously known to be prone to mutation.

"It turns out there are indeed DNA sequences beyond CpG sites that are also prone to mutation," Voight said. "What is not immediately obvious is why. The initial rates and our model need to be investigated more deeply to decipher the basic mechanisms that induce mutation in human genomes."

Another finding questioned the assumption that methylated CpG sites always have the same rate of mutation. "I think it is commonly assumed that all CpG sequences mutate at the same rate, though our results indicate far more variability that we expected," Voight said. Using another publicly available database that measured the methylation states at CpG sites across several individuals, Voight and Aggarwala found that the frequency in which different sequence contexts were methylated could not fully explain differences in mutation rates at these sites. "This certainly indicates the possibility of additional genetic mutation phenomenon at CpG hotspots that change how prone these sites are to mutate, for example how well DNA-repair machinery can correct new mutations that might arise," Voight said.

Beyond gleaning clues for different ways mutations occur, Voight and Aggarwala also examined applications of their model to human disease, providing ways to rank which newly discovered mutations identified from clinical genetics studies are the most likely to result in disease. Computational predictive measurements such as these are used to help prioritize rare or new gene variants discovered from these studies for follow-up investigation. Voight and Aggarwala focused on a set of autism sequencing studies by looking for genes with an excess of new mutations in children with autism not otherwise found in parents. When they applied their model to these data, they found an improvement over existing methods for predicting which rare or new mutations were associated with human disease.

"We were able to refine the focus somewhat on likely pathogenic variants for follow-up work, though we'll need quite a bit more work to correctly pinpoint the right variants and genes for autism or even Alzheimer's disease where sequencing data is readily available," Voight said.

He credits not only the large amount of publicly available data, but careful and dedicated efforts over an extended period as major contributing factors to be able to evaluate and refine their proposed mathematical model. "The exciting part of this work is not just what we've found, but the spectrum of new questions that we will be able to systematically address in the next few years. While building solid foundations takes time, the next set of scientific 'skyscrapers' built on these foundations will absolutely persist longer and reach higher as a result."

###

This study was funded by the Alfred P. Sloan Foundation (BR2012-087), the American Heart Association (13SDG14330006), the W.W. Smith Charitable Trust (H1201), and the NIH/NIDDK (R01DK101478).

Karen Kreeger | EurekAlert!

Further reports about: DNA SNP across human genome mathematical model mutations nucleotides sequence sequences

More articles from Health and Medicine:

nachricht 'Living bandages': NUST MISIS scientists develop biocompatible anti-burn nanofibers
16.02.2018 | National University of Science and Technology MISIS

nachricht New process allows tailor-made malaria research
16.02.2018 | Eberhard Karls Universität Tübingen

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: In best circles: First integrated circuit from self-assembled polymer

For the first time, a team of researchers at the Max-Planck Institute (MPI) for Polymer Research in Mainz, Germany, has succeeded in making an integrated circuit (IC) from just a monolayer of a semiconducting polymer via a bottom-up, self-assembly approach.

In the self-assembly process, the semiconducting polymer arranges itself into an ordered monolayer in a transistor. The transistors are binary switches used...

Im Focus: Demonstration of a single molecule piezoelectric effect

Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale

Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...

Im Focus: Hybrid optics bring color imaging using ultrathin metalenses into focus

For photographers and scientists, lenses are lifesavers. They reflect and refract light, making possible the imaging systems that drive discovery through the microscope and preserve history through cameras.

But today's glass-based lenses are bulky and resist miniaturization. Next-generation technologies, such as ultrathin cameras or tiny microscopes, require...

Im Focus: Stem cell divisions in the adult brain seen for the first time

Scientists from the University of Zurich have succeeded for the first time in tracking individual stem cells and their neuronal progeny over months within the intact adult brain. This study sheds light on how new neurons are produced throughout life.

The generation of new nerve cells was once thought to taper off at the end of embryonic development. However, recent research has shown that the adult brain...

Im Focus: Interference as a new method for cooling quantum devices

Theoretical physicists propose to use negative interference to control heat flow in quantum devices. Study published in Physical Review Letters

Quantum computer parts are sensitive and need to be cooled to very low temperatures. Their tiny size makes them particularly susceptible to a temperature...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

2nd International Conference on High Temperature Shape Memory Alloys (HTSMAs)

15.02.2018 | Event News

Aachen DC Grid Summit 2018

13.02.2018 | Event News

How Global Climate Policy Can Learn from the Energy Transition

12.02.2018 | Event News

 
Latest News

'Lipid asymmetry' plays key role in activating immune cells

20.02.2018 | Life Sciences

MRI technique differentiates benign breast lesions from malignancies

20.02.2018 | Medical Engineering

Major discovery in controlling quantum states of single atoms

20.02.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>