A study published online in Cellreports the latest investigation of de novo germline mutation by whole genome sequencing in autism patients. This study provides a global view of the landscape of mutability and its influence on genetic diversity and susceptibility in autism, and its implications on other human diseases. The work was a collaborative effort led by international teams comprised of the University of California, San Diego, BGI, and other institutes. The results are expected to shed new light on a deeper understanding of the mechanisms underlying genome evolution and human diseases.
Mutation plays an important role in human diseases, such as Autism Spectrum Disorders (ASDs). Many cases for ASDs are caused by de novo mutations that are not inherited, but arise spontaneously in the ovum, sperm or fertilized egg. Epidemiologists have reported a higher risk of autism in children with older fathers, but so far there has been few biological evidence to support this theory. To comprehensively explore the genetics of ASDs, it is vital to understand the mutational process and how the de novo germline mutation impacts ASDs.
In this study, researchers applied whole genome sequencing (WGS) approach to characterize patterns of de novo germline mutations (DNMs). A total of 581 DNMs were identified from ten monozygotic twins that suffered from ASDs by comparing with their unaffected parents. To better understand the paternal age effects on mutation rate, the twins were separated into two groups, one with younger fathers (40 years old). The results showed that paternal age accounted for a substantial portion of variability in mutation that happened in offspring, while maternal age has no significant effect.
Mutation is a random process. However, researchers in this study found DNMs displayed a remarkably non-random positioning in the genome and spaced more closely than their expectation. More importantly, the distribution of de novo germline mutation can be explained by characteristics of the genome. Clusters of new mutations could be explained by allelic gene conversion or compound mutation. Clustering on larger scales could be explained by mutation-rate variation. The regional mutation rates are subject to a combination of influences, including DNase hypersensitivity, GC content, nucleosome occupancy, recombination rate, simple repeats, the trinucleotide sequence surrounding the site, among others.
Researchers further examined the landscape of mutability throughout the genome, including hotspots with highly elevated mutability, and warm spots with moderately increased mutability. They found some strong evidences to support that hypermutability is a characteristic of disease genes. Intriguingly, they found the mostly highly mutable sequences in the genome are the most highly conserved. This finding has not been reported in the previous studies.
Another interesting result was that the genes impacted by DNMs in twins demonstrated a significant association with autism in other independent projects. These findings suggest that regional hypermutability is a significant factor shaping patterns in genetic variation and disease risk in humans.
Yujian Shi, Project Manager of BGI, said, "The study opens a new way for pedigree studies on neurological diseases and rare diseases. The novel approach and results here will help to massively analyze lineage or sporadic autism population. We found there was a significant relationship between human diseases and individual genetic variation model shaped by DNMs derived regional hypermutability. Furthermore, the discovery of a large number of novel autism susceptibility genes will lay a solid foundation for the early diagnosis and treatment of autism."
BGI Shenzhen: http://www.genomics.org.cn
This press release was posted to serve as a topic for discussion. Please comment below. We try our best to only post press releases that are associated with peer reviewed scientific literature. Critical discussions of the research are appreciated. If you need help finding a link to the original article, please contact us on twitter or via e-mail.
Translucent lab animals could be used for biological and medical research
An exciting new study lays out in detail how our fine feathered friends evolved from the same ancestors as the T. Rex and velociraptors over the course of millions of years, and how they managed to avoid the same doomed fate as their dinosaur cousins
Researchers are trying to figure out how "jackass" penguins—nicknamed for their braying vocalizations—communicate
The rind of good cheese is a thriving microbial community. A single gram—a tiny crumb—contains 10 billion microbial cells, a mix of bacteria and fungi that contribute delicious and sometimes funky flavors.
The world's largest amphipod has been caught on film for the first time – and even if you love shrimp, this critter may give you nightmares
If someone were to create an award for "mother of the year" in the animal kingdom, a remarkably dedicated eight-limbed mom from the dark and frigid depths of the Pacific Ocean might be a strong contender.
Why the lionfish is here to stay
Juhan Sonin is donating his DNA to the hunt for medical breakthroughs. He explains why he decided to share his genome, and why you might want to do the same
The sperm of one nematode species harms the females of other species, perhaps explaining why the species remain distinct
Once-endangered gray seal population is rebounding; Cape Cod fishermen say there are now too many -- and they're taking all the fish