Category Archives: Genome

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Woolly mammoths experienced a genomic meltdown just before extinction Science Daily Dwindling populations created a "mutational meltdown" in the genomes of the last wooly mammoths, which had survived on an isolated island until a few thousand years ago. Rebekah Rogers and Montgomery Slatkin of the University of California, Berkeley, ... Mammoth Genome Analysis Points to Pre-Extinction Genome DeclinesGenomeWeb The last, lonely woolly mammoths faced a 'genomic meltdown'Science Magazine DNA clues to why woolly mammoth died outBBC News Nature.com -Sci-News.com -UPI.com -PLOS all 51 news articles »

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Woolly mammoths experienced a genomic meltdown just before extinction - Science Daily

Scientists at the University of Illinois,led by associate professor of chemistry Douglas Mitchell, Ph.D., report the development of a tool that searches through microbial genomes, identifying clusters of genes that indicate an organism's ability to synthesize therapeutically promising molecules.

In aNature Chemical Biologyarticle ("A New Genome-Mining Tool Redefines the Lasso Peptide Biosynthetic Landscape"), lead authors Jonathan Tietz, Ph.D., and Christopher Schwalen and their colleagues in Mitchell's laboratory describe how their custom software learns to recognize predictive genomic features.

"With genome sequencing going at the pace it has...there's a dearth of functional information about what these genes are doing," Dr. Mitchell said. "It becomes increasingly important to make sense of and interpret metabolic pathways, especially biosynthetic gene clusters encoded by microbes."

His group is particularly interested in a class of molecules commonly referred to as RiPPs (ribosomally synthesized and post-translationally modified peptides). RIPPsmay seem unfamiliar, but they are already present in the average consumer's daily life. A bacterially produced RiPP called nisin, for example, has been used as a pathogen-fighting additive in dairy products, meats, and beverages such as beer since the 1960s.

"RiPPs have some particular advantages compared to other, more traditional, classes of natural products. They're usually larger and more structurally complex," which allows them to interact with cellular machinery in ways a smaller molecule cannot, Dr. Tietz explained. More points of contact with their cellular targets means RiPPs can hang on better and perform more complicated tasks. "At the same time, despite their complexity, RiPP biosynthesis...makes for greater potential for genetic re-engineering of natural products to tailor physical and pharmacological properties," he noted.

For all their advantages, RiPPs present a challenge; it is hard to discover new ones. Traditionally, researchers found potentially useful natural products by screening microbes based on their biological activity. After decades of such efforts, which revealed a range of products including some RiPPs, searches turn up the same common compounds over and over again.

Dr. Mitchell and colleagues are members of a multilaboratory research group at the Carl R. Woese Institute for Genomic Biology (IGB) that has found a way to uncover novel natural productsgenome mining.The Mining Microbial Genomes research theme at the IGB aims to speed drug discovery by searching through the genomes of microbes, essentially skimming through cells' recipe books to see what they might be able to produce, before actually persuading them to do so in a laboratory setting. In this way, researchers can greatly increase the odds that they will isolate a compound that has never been seen before. However, this method relies on the ability to predict what a group of genes might be capable of producing.

"In a practical sense the question became, is there a better way to harness available genomes for augmenting these discovery pipelines," said Schwalen. "That's where we started."

Dr. Mitchell's group faced a tough challenge: creating software that could recognize the groups of genes whose products work together to synthesize a RiPP. They decided to make it even tougher by focusing on a class of RiPPs called lasso peptides, named for their looping structure. The clusters of genes that produce lasso peptides are small and generic-looking, making them difficult to identify even in a manual search.

"If you want to show that you have a useful tool, you pick the hardest example," Dr. Mitchell said. "But also, as a chemist, lasso peptides are extremely interesting. Peptides that are used as drugs cannot be given orally" because they would be digested, he explained. "Lasso peptides are different. You can actually boil these, you can throw proteases at them, you can autoclave them and they don't lose their activity; they are basically a little peptide knot that is extremely resistant to such assaults."

The informatics tool that Mitchell's laboratory designed, named RODEO (Rapid Open reading frame Description and Evaluation Online), dealt with the lasso challenge in part through a machine learning approach. They trained the software on known examples of lasso-producing gene clusters, allowing the program to hone in on key features. The resulting software identified promising gene clusters in a broad array of microbial genomes, and could be customized to search for the gene clusters of other classes of RiPPs as well.

RODEO identified 1300 novel lasso peptides, including several with particularly unusual structures that make them promising as potential therapeutics; the researchers confirmed that the empirically determined structures matched those predicted by the software.

"We can now use genomic prioritization to find molecules that without any doubt are structurally novel," said Dr. Mitchell. "The challenge is, is that a useful molecule or not? But the more molecules you can connect to genes, the better informed we're going to get. So that's the next 10 years of discovery."

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Genome Mining of Natural Products Could Lead to Novel Therapeutics - Genetic Engineering & Biotechnology News

In May 2016, scientists, lawyers and government representatives converged at Harvard to discuss the Human Genome Project-Write (HGP-Write), a plan to build whole genomes out of chemically synthesised DNA. It will build on the $3 billion (2.3bn) Human Genome Project, which mapped each letter in the human genome.

Moving beyond reading DNA to writing DNA is a natural next step, concedes Francis Collins, director of the US National Institutes of Health. He warns, however, that any project with real-world implications would require extensive discussion from different perspectives, most especially including the general public.

[N]one of the projects deliverables will be as exciting or as evocative as a baby, [Andrew Hessel, a researcher with the Bio/Nano research group at software company Autodesk] says. Some of the things that were said [after the meeting] were so ludicrous that it allowed us to get through that bubble of misinformation and misinterpretation quickly.

I want it to be as open and transparent as possible, says Hessel, and to keep up as much interest in this powerful universal technology, which will enable us to bring our intention into the machinery we call life. And boy, do we need to get good at it.

The GLP aggregated and excerpted this blog/article to reflect the diversity of news, opinion, and analysis. Read full, original post:Humans 2.0: these geneticists want to create an artificial genome by synthesising our DNA

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Human Genome Project 2: Should scientists synthesize our entire genetic blueprint? - Genetic Literacy Project

BUFFALO, N.Y. Four hundred 8th-graders will take a first step toward understanding personalized medicine when they attend the third annual Genome Day on the Buffalo Niagara Medical Campus on March 9.

The University at Buffalo and Roswell Park Cancer Institute have teamed up to engage these budding scientists and researchers as part of a series of STEM events designed to raise awareness and pique student interest in pursuing careers in the science, technology, engineering and mathematics fields.

Buses arrive at 9:30 a.m. at Roswell Park, located at the corner of Elm and Carlton streets. A pep rally kicks off the event at 9:45 a.m. in the Hohn Auditorium with brief remarks to follow by Buffalo Mayor Byron Brown, Buffalo Public Schools (BPS) Superintendent Kriner Cash and leaders from Roswell and UBs New York State Center of Excellence in Bioinformatics and Life Sciences (CBLS).

Additionally, the Niagara Frontier Transportation Authority and Lamar Transit will recognize Desanay Nalls, a 10th grader at the Buffalo Academy of Visual and Performing Arts, who is this years winning designer of the STEM poster hanging in 10 NFTA bus shelters.

Following these remarks, graduate students and postdoctoral associates will lead small groups of students in DNA extraction and other hands-on learning activities. These include karyotyping for chromosomal differences, origami to model DNA structures and identifying genetic mutations by interpreting sequences from healthy cells and tumor cells.

Genome Day is a partnership of UBs CBLS; UBs Genome, the Environment and the Microbiome (GEM) Community of Excellence; the State University of New York; and Roswell Park; with the City of Buffalo and Buffalo Public Schools.

News media are welcome to attend Genome Day and the following additional events.

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Making it personal at the UB and Roswell Park-hosted Genome Day - UB News Center

Genome sequencing has taken off in recent years, and large-scale projects are leading the way. This review looks at efforts around the world.

Gene sequencing has proved its usefulness as adiagnostic and prognostic tool. Its use in the identification of BRCA1 mutations is already a gold standard in cancer research. Thanks to personalized medicine trends and collaborations between the industry and regulatory authorities, we could see whole genome sequencing (WGS) turning into a common practice faster than one could have originally expected.

The next generation sequencing (NGS) market, including but not limited to WGS, was valued at 4.6Bn in 2015 and is expected to reach 19Bn by 2020. Many private companies, such as Illumina, Roche, Life Technologies and Pacific Biosciences, are rushing into NGS to answer the rising sequencing needs.

Thanks to this competition, the technology has quickly improved in the past years. Nowadays, you can easily order a gene screening test from afew hundredto a few thousand dollars, dependingon the provider and what you are looking for.

The genomic sequence of a cytogenetically aberrant human cancer cell line

Back in 2003, the International Human Genome Sequencing Consortium kicked-off the genome analysis race by sequencing a complete human genome after years of worldwide collaboration and billions of investment. A few years later, the price of WGS reached $1,000.

According to Illumina, it is expected one day that whole genome sequencing will cost less than $100. On one hand, pocket NGS is not yet practical or economical. On theother hand, most available equipment is still quite expensive. For example, Illuminas NovaSeq 5000 costs around800,000and a NovaSeq 6000 reaches almost 1M.

New partnerships, like the one between23andMeandRochesGenentechin 2015, are trying to capitalize on the wealth of data: this partnership aims toobtainwhole genome sequencing data from 3,000 peoplewithParkinsons disease. (Fun Fact:Googleinvested in 23andMe and its co-founder married 23andMes CEO.)

However, sequencing genomes to generate data is only part of the job. Quality check, preprocessing of sequenced reads and mapping to a reference genome still require powerful computing facilities, efficient algorithms and obviously experienced staff. It is a time-consuming process.

Everybody talks about the $1,000 genome, but they dont talk about the $2,000 mapping problem behind the $1,000 genome, says Peter Tonellato, Professor of Biostatistics at the University of Wisconsin.

Moreover, WGS generates huge amounts of data, which poses a challenge fordata storage.

The Broad Institute in Cambridge, Massachusetts, said that during the month of October, it decoded the equivalent of one human genome every 32 minutes. That translated to about 200 terabytes of raw data. Even if that quantity is smaller than what is handled daily by internet companies, it exceeds anything biologists and hospitalshave ever dealt with.

Amazon and Google understand this need and already offer to keep a copy of any genome for 24 ($25) a year, which translates to roughly 0.02/GB per month, since a file is commonly between 100 and 400GB. In 2014, The National Cancer Institute said that it would pay18M ($19M)to move copies of the 2.6 petabyte Cancer Genome Atlas into the cloud.

Our birds eye view is that if I were to get lung cancer in the future, doctors are going to sequence my genome and my tumors genome, and then query them against a database of 50 million other genomes,said Deniz Kural, whose company, Seven Bridges, stores genome data using Amazons cloud system.

The UK was the first to launch a dedicated program to whole genome sequencing in Europe. Genomics England aims to sequence up to 100,000 whole genomes from patients with rare diseases, their families, and cancer patients from 11 Genomic Medicine Centres. Ten companies including GSK, AstraZeneca and Rochehave signed up to be part of the GENE Consortium, giving them access to 5,000 sequenced genomes.

Genomics England

These collaborations can raise concern regarding access to private health data, but there is no doubt that such a massive project could not be possible without private funding. Genomics Englands community management is impressive, with frequent updatesand campaigns to raise public awareness.According to a monthly updated counter, almost 20,000genomes have been sequenced so far!

On a similar framework, Australia is currently working on the 290M (AU$400M), 4-year100,000 Genomes Project (100KGP), sequencing patients with rare diseases and cancer to create a massive database for R&D.

Estoniaproposed an ambitious personalized medicine program in June 2000 and thus became an unexpected pioneer. The Estonian Genome Project Foundation aimed at collecting 100,000 randomly selected samplesbefore 2007. As of February 2014, the project had collected data from 52,000 adult donors including only a few hundred WGS.

In theUSA, the Precision Medicine Initiative (PMI), with its 1-million-volunteer health study, will gather a large database of health data including genetics and lifestyle factors. To make a long story short, the Mayo Clinic will analyze and store onemillion blood and DNA samples.

As in theUK, some of the anonymized data will be probably made available to researchers and industries in order to stimulate the project, which started in 2016 with 52M ($55M) from the NIH to build the foundational partnerships and infrastructure needed to launch theprogram.

In 2016, France announced the France Medecine Genomique 2025 program, aiming to open 12 sequencing centers and ensure235,000 WGS a year. TheFrench government is planning to inject 670Min this program, whose mainaim is to use WGS as a diagnostics tool.

Many other western countries such as Ireland and Iceland have launched their own programs. However, when, but when it comes to personalized medicine, take into account genetic variability between populations is a prerequisite. Western medicine has historically targeted western populations but, nowadays, western medicine is a worldwide practice.

There is a massive bias in medical research;Europeans have been developing drugs for Europeans without asking how compatible these pharmaceuticals are for the rest of the world. Stephan Schuster, Chair of the Genome Asia consortium.

Based on this observation, the non-profit consortiumGenomeAsia 100Kdecided to generate genomic data for Asian populations. Supporters of the initiative include genomics companies Macrogen inKorea and MedGenome inIndia, as well as Illumina. According to thePHGFoundation, at least 50,000 DNAsamples havealready been collected, and initial work will focus on creating suitable reference genome sequences for key populations in Malaysia, India, Japan or Thailand.

With the same purpose, the Qatar Genome Program aims to establish the Qatari Reference Genome Map by sequencing 3,000 whole genomes, which accounts for around 1% of the Qatari population.

Last but not least, China has been an unbeatable leader in genome sequencing for years now. In 2010, the BGIgenomics institutein Shenzhen was probably hosting a higher sequencing capacity than that of the entire United States. Chinas sequencing program is not just aiming for thousands but ratherone million human genomes and will include subgroups of 50,000 people, each with specific conditions such as cancer or metabolic disease. There will also be cohorts fromdifferent regions of China to look at the different genetic backgrounds of subpopulations.

It is difficult to anticipate the impact of WGS in modern medicine, but ethical issues regarding privacy of health data have already emerged. It is obvious that no one would like to see GAFA (Google, Apple, Facebook, Amazon) selling genome data as they are probablyalready doing with personal data from their users.

A key challenge is that ethical, legal, and social concerns raised by the most innovative technologies, including celland gene therapy as well as sequencing, significantly differ between regions. This definitely gives a certain advantage to countries with less restrictive laws, which areusually not western countries. For example, in Europe, transparency about the purpose of sample collection and protocols aremandatory before any research is conducted.

Although it is easier said than done, regulators should be proactive and set up an appropriate framework for these promising but challenging approaches while ensuring it does not hinder R&D.

Images via whiteMocca /Shutterstock; Clark MJ et al. (2010),PLoS Genet 6(1): e1000832; GenomicsEngland;National Institutes of Health

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The Past, Present and Future of Genome Sequencing - Labiotech.eu (blog)

Integrated DNA Technologies (IDT) is the first genomics company to develop and bring to market a complete ribonucleoprotein-based Cpf1 CRISPR system. The Alt-R A.s. Cpf1 CRISPR System inherits the optimised, efficient, and cost-effective traits of IDTs innovative Cas9-based system while taking advantage of Cpf1s natural AT-rich target sequence preference and ability to make staggered cuts. In addition, IDT is launching an associated range of CRISPR support tools to expand experimental options and capabilities for molecular biology researchers. The new tools extend the ease-of-use and performance of IDTs Alt-R system through options for fluorescent visualisation, enhanced nuclease transfection, and genome editing detection. Together, the new expanded Alt-R range breaks barriers to wider target spaces not addressable by Cas9 systems alone, and provides a level of flexibility in experimental design not previously possible.

IDTs Alt-R System already overcomes the limitations of using sgRNAs in the ribonucleoprotein (RNP) complex by enhancing editing efficiency and lowering toxicity. Now, in developing a complementary Cpf1-based system, IDT has opened up options for targeting AT-rich sequences. The new system includes the Alt-R A.s. Cpf1 nuclease, containing two integrated nuclear localisation sites, which complexes as an RNP with a minimal 41-44 nucleotide Alt-R CRISPR-Cpf1 crRNA. The system requires no tracrRNA, reducing potential reagent costs and experimental complexity.

The expanded range of Alt-R support tools now includes the Alt-R CRISPR-Cas9 tracrRNA5 ATTO 550, and Alt-R Electroporation Enhancers for Cas9 and Cpf1. The former allows in vivo fluorescent visualisation of the RNP complex and FACS enrichment of transfected cells without affecting RNP functionality, while the enhancers improve the efficiency of transfection using the Nucleofector (Lonza) and Neon (Thermo) electroporation systems. These new tools enable researchers to improve the overall efficiency of their genome editing over traditional methods. In addition, the new Alt-R Genome Editing Detection Kit provides a fast, easy, and low-cost method for confirming editing events with a T7 Endonuclease I (T7EI)-based mismatch detection system.

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Complete Cpf1-Based CRISPR Genome Editing System Available - Labmate Online

The National Academies of Science and Medicine (NASEM) released a report on Feb. 14 exploring the implications of new technologies that can alter the genome of living organisms, including humans.

Although scientists have been able to edit genes for several decades, new genome editing technologies are more efficient, more precise and far less expensive than previous ones. One of these techniques, known as CRISPR-Cas9, could allow for new applications ranging from editing viruses and bacteria to animals, plants and human beings.

For example, scientists could design pest-resistant plants. They could modify the genome of animals, bacteria and viruses to help fight diseases and plagues.

CRISPR could potentially be used by almost anybody willing to tinker with the genome. This, and the fact that it can be used either for beneficial or harmful purposes, have raised fears that CRISPR could become a weapon of mass destruction.

CRISPR could also be used to modify the human genome. The big question scientists are wrestling with is whether these technologies should be used to make modifications in human reproductive cells. Changes made in these cells are heritable from one generation to the next, and are called germline modifications.

Some scientists working with these techniques called for a moratorium for editing that could result in germline modifications. Others thought that a prudent path for using these technologies was needed.

The NASEM report did not endorse a moratorium. But it recommended that at least 10 stringent conditions should be met before authorizing this use. The report also said that more discussion with wide public participation was needed before proceeding with human germline modification.

I explore the ethical and policy questions raised by emerging technologies such as CRISPR at the Duke Initiative for Science and Society. I am particularly interested in how different countries regulate these technologies.

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Safe And Ethical Ways To Edit The Human Genome - IFLScience

FDA addresses modern genome editing technologies in animals American Veterinary Medical Association 18 post in the FDA Voice blog, When animals are produced using genome editing, FDA has determined that, unless otherwise excluded, the portion of an animal's genome that has been intentionally altered, whether mediated by rDNA or modern genome ... Genome Editing Market Witness a Pronounce Growth During 2017 2025 -Persistence Market ResearchSatellite PR News (press release) all 2 news articles »

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FDA addresses modern genome editing technologies in animals - American Veterinary Medical Association

The National Heart Lung and Blood Institutes (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program has named the Human Genome Sequencing Center (HGSC) at Baylor College of Medicine as a participant in a groundbreaking half-billion dollar program to bring whole genome sequencing and other omic technologies that monitor the expression of the genome in response to the environment, to the forefront of clinical research.

Through its TOPMed program, NHLBI is expanding its dedication to advancing the understanding of the underpinnings of complex diseases and how they develop. Previously, the HGSC was awarded funding by NHLBI to sequence whole genomes for TOPMed studies such as sickle cell disease, and venous thromboembolism and will continue to expand this effort in the next phase of the program. The new contract will span five years. In addition to the whole genome sequencing component, the TOPMed program will also provide analysis of other datatypes over the course of the contract period, including RNA transcription sequencing, DNA methylation, metabolomics profiles, and other omics, including analysis of the microbiome. The initial award from NHLBI supports the whole genome sequencing of 20,000 samples at the HGSC in the first year of the program.

There is a significant need for large sample sizes; a need that goes beyond the research setting and into the clinic, said Dr. Richard Gibbs, director of the HGSC and professor of molecular and human genetics at Baylor. We are grateful to be a part of the TOPMed program which will allow us to access this large sample number and obtain valuable insights into adult heart disease, sickle cell disease, atrial fibrillation and other heart, lung and hematologic disorders.

To support this trans-omic approach, the HGSC will continue its ongoing collaboration with the Alkek Center for Metagenomics and Microbiome Research (CMMR) at Baylor and The University of Texas Health Science Center at Houston (UTHealth) School of Public Health, which would aid in executing the methylation and metabolomics tasks. The team was deemed eligible to perform all elements of these additional analyses.

The TOPMed program and resulting data will allow us to better understand the link between pediatric and adult disease genes, thereby creating enhanced diagnostics for adult diseases and disorders. There are direct clinical applications to improve and individualize care for these adult diseases within the Texas Medical Center, said Dr. Eric Boerwinkle, dean of UTHealth School of Public Health and associate director of the HGSC.

The HGSC has been operational for more than 20 years, gaining international recognition as a large-scale DNA sequencing and analysis center, and is currently a Center for Complex Disease Genomics supported by the National Institutes of Health and the National Human Genome Research Institute. A key mission of the HGSC is to use genetic approaches to guide discovery and diagnosis of human disease, which offers insight into new therapeutic strategies, echoing the bench-to-bedside framework that is the foundation of the national Precision Medicine Initiative. This mission has been greatly enhanced and facilitated by a collaboration with Boerwinkle, who leads a group of population and data scientists at UTHealth with expertise in analyzing genomic information to discover new disease genes and improve diagnosis. The TOPMed project will better enable the HGSC and UTHealth to pursue this mission to move adult whole genome sequencing into the clinical setting, supporting the advance of precision medicine.

The whole genome and other data made available by TOPMed has the capability to be analyzed to provide a more comprehensive picture of what factors may lead to, or protect against, common disease development. The UTHealth team is one of four analysis centers in the country catalyzing new discoveries using this data.

The TOPMed program encourages data sharing and collaboration among institutions across the United States and will encourage an integrative analysis approach, which will be crucial to understanding the mechanisms that contribute to development of these common adult diseases, said Ginger Metcalf, director of project development at the HGSC. The resources available to us at Baylor and in the Texas Medical Center make us uniquely poised to facilitate multi-omic approaches for the study of complex disease.

The flow of data will begin with the HGSC, which will receive samples from NHLBI investigators. The HGSC will perform the whole genome sequencing, and is eligible for RNA sequencing, operably distributing the samples to UTHealth for methylation and metabolomics profiling, and to Baylors CMMR for metagenomic analysis as program needs dictate. The data from all three sources would then be funneled into a data sharing portal and relayed back to TOPMed.

Introducing novel -omics data sources into this phase of the TOPMed program will accelerate the discovery of diagnostics and treatments in ways that are not possible with single dataset approaches. Programs such as TOPMed are paving the way for precision medicine innovations that will shape clinical practice in the near future, said Dr. Joseph Petrosino, founding director of the Baylor CMMR.

The HGSC has increased its number of Illumina sequencing machines to accommodate the large sample size of the TOPMed program. This represents a 30 percent increase in our whole genome sequencing capacity, allowing us to support NHLBI and other programs which seek to use genomics to better understand disease development and identify potential therapeutic targets, said Donna Muzny, Director of Operations at the HGSC. The HGSC is prepared to leverage the framework made possible by the TOPMed program to execute other multi-omic studies.

The NHLBI contract is a huge contribution to the research community here at Baylor, and for the Texas Medical Center as a whole. The scope of whole genome research it will allow us to execute and apply to the clinical setting is groundbreaking, and I look forward to seeing what we are able to discover in the realm of adult hematological disorders as a result, said Dr. Adam Kuspa, senior vice president and dean of research at Baylor.

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Baylor's Human Genome Sequencing Center looks to bring adult whole genome sequencing to clinical space with ... - Baylor College of Medicine News...

The second generation of apple trees bred with resistance to blue mold from a wild ancestor are growing in the U.S. Department of Agricultures Appalachian Fruit Research Laboratory in Kearneysville, West Virginia. DNA tests developed through RosBREED and apples genetically engineered to flower early are helping researchers introduce the disease resistance into high-quality cultivars faster. (Courtesy Jay Norelli, USDA Appalachian Fruit Research Laboratory)

Over generations, as breeders have selected apple trees with the best flavor, size and color, resistance to many common diseases was lost.

But genes for resistance are often still lurking in wild apple ancestors, and new DNA tools are giving breeders the power to return those key genes to domestic apple varieties in a matter of years, not decades.

In the case of blue mold the most significant postharvest disorder globally scientists found resistance hiding in the genome of Malus sieversii, the wild Eurasian apple from which the domestic species was derived. Now, researchers with the U.S. Department of Agricultures Appalachian Fruit Research Station in Kearneysville, West Virginia, are breeding that wild resistance back into an elite breeding parent.

New tools are helping them to do it fast: Cultivars are expected to be ready for breeders in just a few more years, said Jay Norelli, the plant pathologist leading the project. We are tapping into the latest advantages that have been made in genomics science to really advance the efficiency of apple breeding, Norelli said.

But while some of the tools used to expedite breeding are the result of genetic engineering, Norelli stressed that the process is not creating genetically modified apples.

The final, blue-mold resistant cultivar will have no genetically modified DNA. Thats very important to growers because some consumers have been wary of genetically modified crops, he said.

All the genomics tools are available thanks to RosBREED a national team of scientists seeking to improve the quality and disease resistance of apple, blackberry, peach, pear, rose, strawberry and sweet and tart cherry crops and to a sister effort in Europe known as FruitBreedomics.

The American project was funded by the U.S. Department of Agriculture first in 2009 with a $14 million grant to look at fruit quality traits, then re-upped in 2015 for a $10 million focus on disease resistance.

From the start, RosBREED has been clear that it was not seeking to genetically engineer better crops, but rather to use DNA analysis tools to inform and improve conventional crossbreeding, said Cameron Peace, RosBREED co-director and horticulture professor at Washington State University.

Every generation, Norelli sends samples from his new seedlings to Peaces lab at WSU, where RosBREEDs DNA-informed breeding programs for apple and cherries are based.

The lab focuses on translating discoveries from genomics research into strategies breeders can use, Peace said.

So far, his lab is developing DNA markers for disease resistance, fruit color, acidity levels and other desirable traits so that breeders can test and select seedlings without waiting for fruit.

That saves breeders the expense and time of growing a nursery full of trees that lack the desired genes in search of the perfect fruit. Eventually, RosBREED aims to help commercial service providers offer the tests it develops to breeders, expanding access to the tools, Peace said.

One-year-old apple trees are fruiting, thanks to an early-flowering gene that accelerates the crossbreeding process. These trees are the second generation of a cross to bring blue mold resistance from a wild apple ancestor into a modern cultivar. This fruit will be exposed to blue mold to verify that the DNA test scientists are using in the breeding program is accurate. (Courtesy Jay Norelli, USDA Appalachian Fruit Research Laboratory)

The challenge for breeders is that the wild ancestors carrying resistance also come with lots of undesirable traits that have been bred out of modern apples.

Keeping only the key resistance gene traditionally required four or five decades of back-crossing with high-quality cultivars to get rid of that wild DNA. Now, DNA-markers and genetically engineered tools have dramatically improved the pace.

Locating the blue mold resistance marker involved developing a genetic map of a cross between the resistant wild apple and a Royal Gala.

Then scientists compared the DNA of all the offspring to find the DNA associated with the resistance trait. In the case of blue mold, there was one clear spot on one of the apples 17 chromosomes associated with resistance.

That key finding enabled the research to move forward much more quickly and is much easier to work with than a trait that appears to be associated with multiple genes, Norelli said.

Once that locus a location on a chromosome was identified, WSU researchers built a DNA test to assess which seedlings inherited the resistance gene.

The growing library of DNA tests means that Norellis seedlings can also be screened for about 10 other desirable traits, such as acidity and skin color, Peace said.

In traditional breeding efforts combining two already high-quality cultivars, fewer DNA tests are usually needed, but theres a lot more bad genetics in this material from the wild apple, Peace said. Using all the tests on each generation of seedlings helps to weed out those unwanted wild genes faster.

Before DNA tests, breeders measured disease resistance by purposely infecting new trees. But having access to the genetic markers is a huge advantage, especially for a disease like blue mold, which causes fruit decay during storage rather than damages the tree itself.

For a lot of diseases like scab and fire blight, we can screen seedlings directly with the pathogens, but DNA tests are better. And one of the big advantages of DNA markers for fruit traits is it saves us years versus waiting for apples, Norelli said.

To speed up the breeding process even further, Norelli is using a genetically modified apple that carries a gene from a birch tree that initiates early flowering. By using it as a parent, his trees are blooming and ready to breed at just over a year old, instead of having to wait three years for each generation to flower.

That transgene for early flowering was introduced into the Pinata cultivar by German researchers, who used it in a similar way to breed fire blight resistance into modern cultivars as part of the FruitBreedomics project.

The early flowering trait comes from a single, dominant gene, which means that every generation, half the seedlings produced are early flowering; the other half flower normally because they did not inherit the chromosome with the transgene.

To accelerate this breeding process, Norelli crossed the parents the offspring of the wild apple and the Royal Gala and the Pinata cultivar containing the birch tree gene in the conventional manner and selected offspring with both the resistance gene and the early flowering gene. Now, he is continuing to cross those offspring for several more generations to weed out unwanted wild apple genes.

Once that breeding process creates high-quality, blue mold resistant cultivars, Norelli will no longer need the early flowering gene. So in the final round of the breeding process, he will select offspring that dont carry the transgenic gene from the birch tree and thus are not considered genetically modified to grow into normal apple trees.

The second generation of blue-mold resistant, early flowering apple trees are growing in the U.S. Department of Agriculture greenhouse in West Virginia. Some of the spindly trees are already fruiting. But even high-tech tools need to be proven in the nursery. So, Norelli is preparing to test the DNA-based breeding by exposing the first crop of fruit to the blue mold fungus, so he can evaluate how susceptible they really are.

We are validating whether that test actually predicts resistance. Thats really important because before we at RosBREED release a tool, we test it so breeders can use it with confidence, Norelli said.

If the test proves itself, as scientists suspect, the cultivar should be ready for breeders by 2019. There are a few more crosses to go, Norelli said, to maximize the domestic apple genes and minimize the wild genes. To meet that deadline, the team is employing one more novel genetic tool that helps to select seedlings with the least wild DNA.

Every new generation has a mix of its parents traits typically 50-50 but due to some genetic rearranging that happens as chromosomes are passed on, theres always a little variation.

By the third generation, about 25 percent of the genetics should be M. seversii, but because of crossing over of the chromosomes, some have less and some have more, Norelli said. Were using a DNA test to track how much wild DNA is left.

FruitBreedomics developed the test to track apples lineage by looking at about 20,000 loci. Thats far from sequencing the entire genome, but it provides a significant snapshot of an apples 17 chromosomes.

After the test is run on each parent the wild apple, Royal Gala, and Pinata with the early flowering gene the offspring can be compared to see how much they still resemble the wild apple. With that insight, Norelli can beat the 50-50 odds slightly with each cross and select those seedlings with both the key traits and the least wild DNA to give rise to his next generation.

With the accelerated system, that should be a one- to two-year window to get that next generation, he said. Our first objective is to produce elite breeding parents with resistance alleles and then trying to incorporate other resistance alleles for fire blight and scab.

by Kate Prengaman

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Taming traits from the wild genome - Good Fruit Grower