Monthly Archives: April 2017

April 4, 2017 A salt water marsh, where F. heteroclitus naturally occur. Individuals used in the study were collected in marshes in Mantoloking, NJ. Inset: a male F. heteroclitus. Credit: Douglas Crawford

In a new study, researchers at the University of Miami (UM) Rosenstiel School of Marine and Atmospheric Science examined how the interaction of two genomes in animal cellsthe mitochondrial and nuclear genomesinteract to affect adaptation of the Atlantic killifish to different temperatures. They showed that although these genomes are separate physical entities, the mitochondrial genome affects the evolution of the nuclear genome, the genetic material responsible for variations in most traits such as hair color and height.

Interactions between these two genomes, which affect everything from health and physiology to fitness, have important consequences for human health and medical interventions such as mitochondrial replacement therapy in embryos.

All animal cells are made up of two genomes, the nuclear genome with 10,000s of protein coding genes and the mitochondrial genome with 13 protein-encoding genes. All 13 genes from the mitochondrial genome interact with approximately 76 nuclear genes in a single metabolic pathwaycalled the oxidative phosphorylation pathwaythat produces nearly all the metabolic energy needed for animal cells. This study found that the interaction between these genomes and the implications on energy production is strong enough that the mitochondrial genome can alter which version of a gene is present in the nuclear genome.

Using Atlantic killifish (Fundulus heteroclitus), the researchers examined whether mitochondrial-nuclear interactions alter the frequency of alternative forms of a gene that arise by mutation, called alleles, for over 11,000 nuclear DNA sequence variations within a population of the fish with mixed ancestry. Among individuals with two divergent mitochondrial haplotypes (mt-haplotypes), the genome-wide analyses revealed significant differences in nuclear allele frequencies.

"Our results suggest that metabolic fitness is not simply a function of the mitochondria but instead is reliant on mitochondrial-nuclear interactions and therefore important for our understanding of physiology, human health and evolution," said Doug Crawford, professor of marine biology and ecology at the UM Rosenstiel School.

The study, titled "Evolved genetic and phenotypic differences due to mitochondrial-nuclear interactions," was published in the March 31, 2017 issue of the journal PLoS Genetics.

Explore further: New species concept based on mitochondrial & nuclear DNA coadaptation

More information: Tara Z. Baris et al, Evolved genetic and phenotypic differences due to mitochondrial-nuclear interactions, PLOS Genetics (2017). DOI: 10.1371/journal.pgen.1006517

Journal reference: PLoS Genetics

Provided by: University of Miami

What is a species? Biologistsand ornithologists in particularhave been debating the best definition for a very long time. A new commentary published in The Auk: Ornithological Advances proposes a novel concept: that ...

Mitochondrial replacement therapy (MRT) has now been used in humans to conceive a "three-parent baby" to prevent inherited mitochondrial disorders, but there remain questions about the effectiveness of the process.

The way we age might be determined long before the aging process starts and the first signs appear. Scientists at the Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), in partnership with groups at the ...

(Medical Xpress) -- Researchers have discovered the first real evidence of the 'mother's curse' and its connection to male infertility due to genetic mutations in mitochondria. Led by Dr. Damian Dowling from Monash University ...

(Phys.org)Plantandanimal cells contain two genomes: one in the nucleus and one in the mitochondria. When mutations occur in each, they can become incompatible, leading to disease. To increase understanding of such ...

Diseases caused by genetic mutations in the mitochondria the powerhouses of the cell can be disabling, or even deadly. That is why mitochondrial replacement therapy (MRT), otherwise also known as three-person IVF ...

What's brightly colored, lives on shipwrecks, filter-feeds like a whale, and shoots webs like Spiderman? If you can't readily come up with an answer, that's okay: until now, such animals weren't known to science. But as of ...

When whiteflies take off, they don't just spread their wings and fly. Just .03 of an inch long, these tiny insects possess a variety of sophisticated techniques that provide them with exceptional stability in the air. Tel ...

Great apes help a person access an object when that person thinks they knowswhere it is but is mistaken, according to a study published April 5, 2017 in theopen-access journal PLOS ONE by David Buttelmann from Max Planck ...

(Phys.org)A team of researchers from several institutions in Germany has found that middle-age killifish fed the gut contents of younger killifish lived longer than normal. In their paper uploaded to the bioRxiv preprint ...

An American who fell in love with both the Great Barrier Reef and his wife via The University of Queensland has led a breakthrough discovery that could protect one of the Seven Natural Wonders. Husband-and-wife Professor ...

A detailed analysis of 39 U.S. fisheries by Duke University economists offers strong new evidence that catch shares curb the "race to fish" that compresses fishing seasons.

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Fish study shows important genome interactions in animal cells - Phys.Org

April 3, 2017 by Ken Kingery Charles Gersbach, the Rooney Family Associate Professor of Biomedical Engineering at Duke University. Credit: Duke University

Researchers have developed a method to swiftly screen the non-coding DNA of the human genome for links to diseases that are driven by changes in gene regulation. The technique could revolutionize modern medicine's understanding of the genetically inherited risks of developing heart disease, diabetes, cancer, neurological disorders and others, and lead to new treatments.

The study appeared online in Nature Biotechnology on April 3, 2017.

"Identifying single mutations that cause rare, devastating diseases like muscular dystrophy has become relatively straightforward," said Charles Gersbach, the Rooney Family Associate Professor of Biomedical Engineering at Duke University. "But more common diseases that run in families often involve lots of genes as well as genetic reactions to environmental factors. It's a much more complicated story, and we've been wanting a way to better understand it. Now we've found a way."

The new technique relies on the gene-hacking system called CRISPR/Cas9. Originally discovered as a natural antiviral defense mechanism in bacteria, the system recognizes and homes in on the genetic code of previous intruders and then chops up their DNA. In the past several years, researchers have harnessed this biologic system to precisely cut and paste DNA sequences in living organisms.

In the current study, researchers added molecular machinery that can control gene activity by manipulating the web of biomolecules that determines which genes each cell activates and to what degree.

With the new tool, Gersbach and his colleagues are exploring the 98 percent of our genetic code often referred to as the "dark matter of the genome."

"Only a small fraction of our genome encodes instructions to make proteins that guide cellular activity," said Tyler Klann, the biomedical engineering graduate student who led the work in Gersbach's lab. "But more than 90 percent of the genetic variation in the human population that is associated with common disease falls outside of those genes. We set out to develop a technology to map this part of the genome and understand what it is doing."

The answer, says Klann, lies with promoters and enhancers. Promoters sit directly next to the genes they control. Enhancers, however, which modulate promoters, can be just about anywhere due to the genome's complex 3D geometry, making it difficult to discern what they're actually doing.

"If an enhancer is dialing a promoter up or down by 10 or 20 percent, that could logically explain a small genetic contribution to cardiovascular disease, for example," said Gersbach. "With this CRISPR-based system, we can more strongly turn these enhancers on and off to see exactly what effect they're having on the cell. By developing therapies that more dramatically affect these targets in the right direction, we could have a significant effect on the corresponding disease."

That's all well and good for exploring the regions of the genome that researchers have already identified as being linked to diseases, but there are potentially millions of sites in the genome with unknown functions. To dive down the dark genome rabbit hole, Gersbach turned to colleagues Greg Crawford, associate professor of pediatrics and medical genetics, and Tim Reddy, assistant professor of bioinformatics and biostatistics. All three professors work together in the Duke Center for Genomic and Computational Biology.

Crawford developed a way of determining which sections of DNA are open for business. That is, which sections are not tightly packed away, providing access for interactions with biomachinery such as RNA and proteins. These sites, the researchers reason, are the most likely to be contributing to a cell's activity in some way. Reddy has been developing computational tools for interpreting these large genomic data sets.

Over the past decade, Crawford has scanned hundreds of types of cells and tissues affected by various diseases and drugs and come up with a list of more than 2 million potentially important sites in the dark genomeclearly far too many to investigate one at a time. In the new study, Crawford, Reddy and Gersbach demonstrate a high-throughput screening method to investigate many of these potentially important genetic sequences in short order. While these initial studies screened hundreds of these sites across millions of base pairs of the genome, the researchers are now working to scale this up 100- to 1000-fold.

"Small molecules can target proteins and RNA interference targets RNA, but we needed something to go in and modulate the non-coding part of the genome," said Crawford. "Up until now, we didn't have that."

The method starts by delivering millions of CRISPR systems loaded into viruses, each targeting a different genetic point of interest, to millions of cells in a single dish. After ensuring each cell receives only one virus, the team screens them for changes in their gene expression or cellular functions.

For example, someone researching diabetes could do this with pancreatic cells and watch for changes in insulin production. Those cells that show interesting alterations are then isolated and sequenced to determine which stretch of DNA the CRISPR affected, revealing a new genetic piece of the diabetes puzzle.

The technique is already producing results, identifying previously known genetic regulatory elements while also spotting a few new ones. The results also showed it can be used to turn genes either on or off, which is superior to other tools for studying biology which only turn genes off. Different cell types also produced differentbut partially overlappingresults, highlighting the biological complexity in gene regulation and disease that can be interrogated with this technology.

"Now that we have this tool, we can go in and annotate the functions of these previously unknown but important stretches of our genome," said Gersbach. "With so many places to look, and the ability to do it quickly and robustly, we'll undoubtedly find new segments that are important for disease, which will provide new avenues for developing therapeutics."

Explore further: Controlling genes using CRISPR shows high degree of specificity

More information: CRISPRCas9 epigenome editing enables high-throughput screening for functional regulatory elements in the human genome, Nature Biotechnology, nature.com/articles/doi:10.1038/nbt.3853

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Screening the dark genome for disease - Medical Xpress - Medical Xpress

Bionano Genomics has announced the immediate availability of its entirely new suite of tools for genome assembly, structural variation (SV) detection, and visualization of the genomes true structure. The Bionano Access 1.0 and Bionano Solve 3.0 software tools are released as a free download, and will be introduced during two live webinars on Wednesday, April 5.

Mark Borodkin, Bionanos Vice President, Systems Development, commented, With Bionano Access and our updated Bionano Solve analysis pipeline, we are making it easier than ever for scientists to get more value from Bionano genome maps related to their genome research. Following feedback from our customers, we have designed Bionano Access to be feature-rich, fast and intuitive. Bionano Access is also a browser-based application, allowing it to be run on an enterprise server or a lightweight laptop; Linux, Windows, macOS supported. Coupled with Bionano Solve, Bionano Access provides a powerful set of new tools for identifying structural variants or performing hybrid scaffolding, and this will benefit any scientist studying the true structure of the genome.

Bionano Access centralizes all software tools required to generate, edit, analyze and visualize Bionano maps. For Irys users, it replaces the IrysView software. It enables visualization of Bionano results in a web browser, providing instantaneous interaction with Bionano maps used for the scaffolding and SV applications.

Bionano Access also comes with a powerful variant annotation pipeline that can filter out common variants based on a database of controls, analyze trios or two samples to identify inherited and de novo SVs, and visualize and export in a dbVar-compliant VCF file for downstream analysis.

Hybrid scaffolding is enhanced with map editing, improved two-enzyme scaffolding and NCBI-compliant data exporting.

When connected with the Saphyr System it allows users to set-up experiments, start runs, monitor data quality metrics in real-time and automatically start de novo assemblies and SV discovery analysis when enough data is collected.

The Bionano Solve 3.0 assembly pipeline within Bionano Access allows users to run SV analysis or hybrid scaffolding. Bionano Solve 3.0 automatically calls SVs with unprecedented sensitivity. Insertions and deletions larger than 1 kilobasepair (kbp) are detected with more than 90% sensitivity and translocations with 98% sensitivity. Significant improvements to translocation calling and masking of common variants significantly reduces the false positive translocation calls.

The pipeline also significantly improves the hybrid scaffolding application by integrating two genome maps created separately with different nicking enzymes. Compared to the prior version, the new two-enzyme hybrid scaffolding incorporates up to 50% more NGS contigs in the assembly, improves contiguity significantly and allows for improved resolving of conflicts and correction of chimeric sequence contigs. This application continues to support any NGS data of suitable quality.

Bionano has validated these tools across a variety of patient samples, including those with undiagnosed disorders and leukemia.

We have applied Bionano genome mapping technology to a variety of cancer cell lines and primary patient leukemia samples and compared our results to those obtained by other genome mapping techniques, such as cytological karyotyping and whole genome sequencing, said James Broach, chair of Biochemistry and Molecular Biology, Pennsylvania State College of Medicine. In all cases, using the Bionano technology, we were able to detect all the translocations identified by these other techniques but were also able to detect many more translocations that had not been identified by those techniques. Moreover, we also detected hundreds of deletions and insertions that could not be seen by these other methodologies and therefore whose role in cancer onset and progression have not been evaluated. Given increased speed, lower cost, higher sensitivity and greater reliability of the Bionano technology, we surmise that it may supplant classical cytology as the primary method for clinical detection of genomic structural variation.

Bionano is introducing key new features in Bionano Access and Bionano Solve during two webinars on Wednesday April 5th, at 9 am and at 6 pm PDT / 12 pm and 9 pm EDT. They can be found online here Webinar 1: April 5th, 9am PDT and Webinar 2: April 5th, 6pm PDT and will be available shortly thereafter for replay on the Bionano website on new support pages dedicated to Bionano Access and Bionano Solve.

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Bionano Genomics Announces Immediate Availability of New Suite of Genomic Analysis Tools - Technology Networks

Imagine reading a blueprint thats 3.2 billion pages long.

Thats how many strands of DNA make up the human genome, the set of instructions that makes each of us who we are. Geneticists like UConn professor Rachel ONeill of the Department of Molecular & Cell Biology are deciphering that expansive blueprint to help us better understand the building blocks of life.

We now know the order and structure of between 80 to 90 percent of the human genome, ONeill said. Today, the field of genomics and the accompanying technology thats been developed has expanded to examining how DNA interacts within a single cell and how different genes are active in different tissues and even single cells across complex tissues, such as the brain.

ONeill noted that genomes can morphwhich presents the next challenges in genomic research. She focuses her research on understanding this instability: why in some cases its detrimental, such as with cancer, or how, in other cases, it provides opportunities for new species to evolve or adapt to their environment.

The focus of this effort is on the DNA in our genome that is considered selfish and recently evolved. Retroviruses are an example of that kind of DNA that our genomes all have, ONeill said. More specifically, I work on trying to understand why our genomes remain stable most of the time, while every so often a genome can fall into relative chaos or instability.

While most of us dont think about our genome every day, this type of research can have a significant impact on our lives.

It is tightly tied to our perception of ourselves in so many respects, ONeill said. For example, when we go into a doctors office and fill in the family history form, we are providing some genetic information that will guide the diagnosis and treatment of patients. Another relevance is that genomic information is a future diary in some respects as to what may happen to us as we age. Because of this, genetic information has to be handled very differently than other medical tests. For example, a cholesterol screening says something about your metabolism; but it can be altered with diet and exercise, so its not a permanent record.

ONeill oversees UConns Center for Genome Innovation, which supports faculty and student research with state-of-the-art technology, technical support, and grant project assistance. Additionally, the Center supports more than 100 labs across UConn Health and the Storrs and Avery Point campuses, so ONeill stays busy researching and mentoring students.

One of my recent memorable moments is when a student came running into my office having experienced the same discovery excitement I had as a grad student, this time on her own research, she said. She found that the retrovirus we were working on was a primary component of the chromosome we were studying. That was a gold moment!

As she continues her work on the human genome, one of her priorities as a scientist is to relate her research back to the public.

One of my goals is to promote the idea that the study of genetics is important, ONeill said. Understanding genomes can tell us so much about ourselves and our world. The study of genomics is increasingly intersecting with individuals at the most personal level, with a potential to shape the future of healthcare.

Take a tour of the Center for Genome Innovation: cgi.uconn.edu.

This article was first posted in the UConn Foundations online newsletter, Inside UConn Nation.

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Morphing Genomes Can Harm and Help - UConn Today

Unique genome architectures after fertilization in single-cell embryos Science Daily After fertilization, maternal and paternal genomes erase some of the epigenetic memory of the previously differentiated states in order to facilitate the beginning of new life as the zygote. In the first cell cycle after fertilization the maternal ...

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Unique genome architectures after fertilization in single-cell embryos - Science Daily