Category Archives: Genome

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Diving deep into the dolphin genome could benefit human health ... Science Daily A new database of bottlenose dolphin DNA and associated proteins just completed could possibly aid in dolphin care and research of human medical problems ... and more »

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Diving deep into the dolphin genome could benefit human health ... - Science Daily

The Women in Science video series on UMassMedNow highlights the many areas of research conducted by women at UMass Medical School.

Zhiping Weng, PhD, professor of biochemistry & molecular pharmacology and director of the Bioinformatics and Integrative Biology Program, has received a $7.2 million grant from the National Institutes of Health to continue an international effort to catalog all the genes and regulatory elements in the human genome.

Dr. Weng heads the data analysis center of the National Human Genome Research Institute Encyclopedia of DNA Elements (ENCODE) project, part of the NIH, which is now in its fourth phase known as ENCODE 4. Approximately $126 million in grants will be disbursed to various teams throughout the world over the next four years to support ENCODE 4.

The goal of the ENCODE project is to delineate all functional elements in the human genome, Weng said. The rich data and annotations generated by the ENCODE project has had far-reaching impacts on the biomedical and clinical communities. ENCODE 4 will intensify these efforts with greater breadth and depth and accelerate our understanding of genome regulation.

At the data analysis center, Weng orchestrates the integrative analysis of ENCODE data and the synthesis of an encyclopedia of regulatory elements, a resource for the scientific community in the study of mammalian biology and the investigation of human health and disease.

In addition, she is part of the PsychENCODE project, an international research consortium that focuses on disease-related research of epigenomes of psychiatric disorders, such as bipolar, autism and schizophrenia.

In her lab at UMass Medical School, students and postdocs use computational methods to solve biological problems in the field of bioinformatics, studying the human genome by using mathematical computer algorithms.

The human body is an elaborate device. My general approach to research is to use sophisticated computational and/or statistical approaches to understand how the human body and related model organism bodies work, Weng said.

Weng said she is focused on projects such as evaluating regulatory proteins and their interactions, including transcription factors and their target DNAs; RNA- binding proteins and their target RNAs; small silencing RNAs and their target RNAs; and proteinprotein interactions.

Were interested in how genes are regulated. Different people may have different versions of the same gene and it will lead to differences in phenotypes and also susceptibility to diseases. If we could analyze population data, different individuals and their genotype, and differences in epigenomes, maybe we could relate these signals to the different phenotypes and susceptibility to diseases, she said.

Weng said if researchers could figure out which genes are causal for a disease or identify elements that could regulate genes that ultimately could cause diseases, then that would help them to modulate the disease.

For example, if you could use gene therapy to alter the regulatory regions and to correct or alleviate disease symptoms, even if you cant eliminate the cause of the disease, you could help people with the disease, she said.

Women in Science videos: MD/PhD student Miriam Madsen strives to improve communication for those in need Katherine Fitzgerald focuses on novel discoveries in innate immunity Molly Waring focused on helping mothers manage their weight Shlomit Schaal develops methods for early detection of diabetic retinopathy Jill Zitzewitz is unraveling protein misfolding to understand disease

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Zhiping Weng works to accelerate understanding of genome regulation with ENCODE 4 project - News from the University of Massachusetts

Bioengineers at the University of California San Diego have developed a new tool to identify interactions between RNA and DNA molecules. The tool, called MARGI (Mapping RNA Genome Interactions), is the first technology that's capable of providing a full account of all the RNA molecules that interact with a segment of DNA, as well as the locations of all these interactions -- in just a single experiment.

RNA molecules can attach to particular DNA sequences to help control how much protein these particular genes produce within a given time, and within a given cell. And by knowing what genes produce these regulatory RNAs, researchers can start to identify new functions and instructions encoded in the genome.

"Most of the human genome sequence is now known, but we still don't know what most of these sequences mean," said Sheng Zhong, bioengineering professor at the UC San Diego Jacobs School of Engineering and the study's lead author. "To better understand the functions of the genome, it would be useful to have the entire catalog of all the RNA molecules that interact with DNA, and what sequences they interact with. We've developed a tool that can give us that information."

Zhong and his team published their findings in the February issue of Current Biology.

Existing methods to study RNA-DNA interactions are only capable of analyzing one RNA molecule at a time, making it impossible to analyze an entire set of RNA-DNA interactions involving hundreds of RNA molecules.

"It could take years to analyze all these interactions," said Tri Nguyen, a bioengineering Ph.D. student at UC San Diego and a co-first author of the study.

Using MARGI, an entire set of RNA-DNA interactions could be analyzed in a single experiment that takes one to two weeks.

The MARGI technique starts out with a mixture containing DNA that's been cut into short pieces and RNA. In this mixture, a subset of RNA molecules are interacting with particular DNA pieces. A specially designed linker is then added to connect the interacting RNA-DNA pairs. Linked RNA-DNA pairs are selectively fished out, then converted into chimeric sequences that can all be read at once using high-throughput sequencing.

Zhong and his team tested the method's accuracy by seeing if it produced false positive results. First, the researchers mixed RNA and DNA from both fruit fly and human cells, creating both "true" RNA-DNA pairs, meaning they're either fully human or fully fruit fly, and "false" RNA-DNA pairs, meaning they're half human and half fruit fly -- these are the ones that shouldn't be detected. The team then screened the entire mixture using MARGI. The method detected a large set of true RNA-DNA interactions, but it also detected approximately 2 percent of the false ones.

"This method is not perfect, but it's an important step toward creating a full functional annotation of the genome," said co-first author Bharat Sridhar, a visiting bioengineering researcher in Zhong's group.

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Decoding the Genome's Cryptic Language - Bioscience Technology

Guy Billout

In July 2015, 100 geneticists met at the New York Genome Center to discuss yeast. At 12 million base pairs long, it's the largest genome scientists have tried to produce synthetically.

Andrew Hessel, a researcher with the Bio/Nano research group at software company Autodesk, was invited to speak at the event. The audience asked him which organism should be synthesised next. "I said, 'Look around the room. You've got hardly anyone here and you're doing the most sophisticated genetic engineering in the world," Hessel recalls. "Why don't you take a page out of history and set the bar high? Do the human genome."

This triggered a panel discussion that stuck in Hessel's mind for weeks. Soon afterwards, he contacted George Church, a prominent geneticist at Harvard University, to gauge his interest in launching what would effectively be the Human Genome Project 2.0. "To me it was obvious," Hessel recalls. "If we could read and analyse a human genome, we should also write one."

A year later, his provocation had become reality. 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.

Leading the Harvard event was Church, whose lab is synthesising the 4.5-million-base-pair E. coli genome, and Jef Boeke 1, the NYU School of Medicine geneticist behind the yeast synthesis project. "I think we realised the two of us were getting good enough at those two genomes that we should be discussing larger ones," says Church.

A Science paper published after the meeting formally laid out the group's proposal: to dramatically advance DNA-synthesis technologies so that the artificial production of genomes becomes easier, faster, and cheaper. Currently, we can synthesise short strands of DNA, up to about 200 base pairs long, but the average gene has several thousand base pairs. Even this limited process is inefficient, costly and slow. But it's vital: in biological sciences, synthesised DNA is the foundation of experiments that drive everything from cancer research to vaccine development. For scientists, it's like working with a blunt yet necessary instrument.

The immense three-billion-base-pair human genome is seen as the project's ultimate goal, dangling like a carrot to drive innovation. Scientists intend to have fully synthesised it in a living cell - which would make the material functional - within ten years, at a projected cost of $1 billion. The fruits of HGP-Write could have wide-ranging, real-world impacts. But in its current form, say the scientists, it's primarily a call for technological advancement in synthetic biology. The May announcement received a frosty reception from some, however. A handful of scientists invited to the event declined to attend, due to organisers' decision not to include the press. Church says they were excluded because of an embargo on the forthcoming paper.

There are bigger concerns: artificial production of genomes raises the ethically unsettling question of gene patenting. Other worries, echoing those that first surrounded the gene-editing technology CRISPR, are of designer humans and parentless babies. "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".

Applications beyond the lab are a distant reality: synthesising a human genome may even prove unworkable. In any case, none of the project's deliverables will be "as exciting or as evocative as a baby", Hessel 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."

HGP-Write's central goal is to improve synthesis technologies so it's easier to write longer strands of genetic material. DNA is made using software that designs the layout of a strand, followed by machines in a laboratory that use this template to synthesise and assemble it. It's a clunky process that limits production to short stretches of DNA. But Hessel sees the potential for enhanced software allowing more precise genome design and printing tools that, for instance, harness enzymes to build DNA the way it happens in our cells. "If we can achieve this, it should be possible to write large genomes in hours," he says.

Smaller plant and animal genomes could also be synthesised along the way. One major scientific benefit could be the creation of living cell lines for pharmaceutical testing. Whole-genome synthesis would also bring down the cost of gene editing. CRISPR allows individual edits to DNA, but producing a full genome would allow thousands of edits in one go. Church sees the potential of genomes being edited to have multiple-virus resistance, for example.

But these are the "byproducts" of HGP-Write, in Hessel's view: the project's true purpose is to create the impetus for technological advances that will lead to these long-term benefits. "Since all these [synthesis] technologies are exponentially improving, we should keep pushing that improvement rather than just turning the crank blindly and expensively," Church says. In 20 years, this could cut the cost of synthesising a human genome to $100,000, compared to the $12 billion estimated a decade ago.

In coming months, scientists will try to take HGP-Write from proposal to project. That depends on funding. Autodesk has pledged $250,000, but organisers want to secure $10 million by the end of 2017. In the meantime, they'll be expanding the HGP-Write conversation. "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."

1. Boeke, JD, et al (2016) The Genome Project-Write, Science, 10:1126/science.aaf6850.

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Humans 2.0: these geneticists want to create an artificial genome by synthesising our DNA - Wired.co.uk

Diana Kennedy, an intrepid chronicler of Mexican cuisine, describes cuatomates as very small cherry tomatoes with an intense flavor and enormous amount of tiny seeds. A potently flavored, tiny green tomatillo variety grows wild in [Mexican] cornfields.[1]

Wild, obscure tomatoesones youve never seen nor tastedrepresent the tomatos intellectual property asset future, in the form of valuable plant patents, closely held trade secrets and memorable trademarks. Their genomic structures tell a fascinating, if indirect story of conquest and domestication.

Successful plant breeding demands genetic variability. While the tomatoes we know appear to come in all kinds of fancy heirloom shapes and colors, their decoded genomes speak of genetic bottlenecks, of roadblocks to tomato plant improvements.

Of course, the best bred tomato falls flat without economic demand. The halting reception this novel fruit qua vegetable received during the Age of Exploration ironically mimics the marketing fate GMO tomatoes face today. Remember Calgenes FlavrSavr tomatothe epic commercial dud of the 1990s?

This post examines the prospects for inventing and branding new tomato cultivars in light of a depleted, domesticated genome.

Tomato Domestication Syndrome

The domesticated tomatos precursor still grows wild in coastal deserts and Andean foothills of Ecuador and northern Peru. Inauspicious and easily overlooked, S. pimpinellifolium fruits are the size of large garden peas.[2] How did such tiny wild tomatoes (just 1 cm in diameter) balloon into the beefsteak tomatoes we relish in a Caprese salad?

Domestication of plants triggers a range of traits that distinguish them from their wild ancestors.[3] Generally speaking, domesticated plants differ in three basic ways:

Collectively, these traits are known the domestication syndrome.[4] Studies reveal that the traits that distinguish crop plants from their wild relatives are often controlled by a relatively small number of [genetic] loci with effects of unequal magnitude.[5]

Classic Arc of Novel Food Acceptance

During the (often horrifying) Age of Conquest, Spanish explorers observed the Amerindians wouldeasily forego meat and most content themselves with some tortillas spread with a chili sauce to which they usually add the fruit of a certain species of solanum called tomamo.[6]

Although Spanish conquistadores brought this strange fruit back to Europe in the early 1500s, they shunned it. They feared consuming New World foods would turn them into emasculated, phlegmatic, beardless Amerindians.[7] They much preferred a steady Iberian diet of meat, wine, olive oil and bread.

European herbalists soon classified tomatoes in the Solanaceae or nightshade family of fruits and vegetables that include eggplants, potatoes and chili peppers. At first, tomatoes were considered a decorative fruitnot to be eaten. The tomatos physical likeness with its poisonous bittersweet nightshade relative, Solanum dulcamara,[8] cautioned against its ingestion. One British herbalist described tomato plants to be of ranke and stinking savour.[9]

The first tomato described by an Italian botanist in 1544 is a yellow-fruited variety he called mala aurea, or golden apples.[10] The name stuck in Italy. The first documented tomato recipe, spaghetti con salsa di pomodoro, appears in a 1692 cookbook published in Naples. Translated, pomodoro means apple of gold. The symbolic imagery suggests a medieval conundrum: eating tomatoes could lead to tragic death and metaphorical expulsion from an Edenic garden.

The Doctrine of Signatures offered the wary European consumer with a countervailing, positive tomato association. This ancient notion contends that a plants medicinal qualities can be ascertained by its external appearance. Hence, a walnut becomes the brain food it resembles. A sliced-opened beefsteak tomato looks vaguely like the four chambers of the heart.

Distilled, novel food acceptancelike that of the tomatotends to occur in the following stages:

New foods are at first warily shunned and scorned as impure or unhealthy; this natural reaction may be explained by moral foundations psychology and our innate, Darwinian need for assurances of food safety and sanctity.

Budding entrepreneurs stage public tomato eating demonstrations to defuse concerns that it is poisonous.

Promoters offer free samples, celebrity testimonials, extravagant health claims and favorite recipes.

Hucksters promote medicinal tomato cure-alls; 19th century statesmen endorse tomato farming and consumption; immigrant tomato recipes become ingrained in American food culture.

New 19th century canning technologies transform tomatoes into a Civil War staple food and favorite among returning veterans; tomatoes grow in disparate climates.

Time passes and no one gets demonstrably ill.

Economic adulteration, however, continues to defraud consumers who cannot ascertain the quality of canned foods.

A nostalgic feedback loop ensues. Past consumption experiences are romanticized and pleasing images portray the novel foodstuff. (As the mouth is the portal to the self, consumers seek emotional bonding with the foods they ingest.)

Phenotype = Genotype + Environment

To understand the tomatos intellectual property prospects, some basic plant breeding terminology is helpful.

A phenotype is the composite of observable characteristics or traits in a plant. In the basic plant breeding equation, a plants phenotype is the result of the organisms expression of its genetic codeits genotypein conjunction with the influence of environmental factors.

Historical evidence shows that Mesoamerican farmers domesticated the earliest forms of tomatoes that, in turn, had originated somewhere in the Andean region of South America. They exercised a form of plant breeding summed up as crossing the best with best and hoping for the best.[13] The tremendous increase in the tomato size arose from this trial and error technique.[14]

In this process, yet another form of tomato emerged. Landrace varieties are cultivated plants that have adapted to specific, local environmental conditions, perhaps hundreds or even thousands of years ago.

An Evolving Tomato Genome

While plant patenting laws operate at the observational, phenotype levelrequiring new, distinct and stable varieties of plants for patentability purposestrait inheritance evolves genomically:

Genomes evolve by duplication of genes, chromosomes or whole genomes, by various rearrangements, insertions of organellar, bacterial or viral DNA that are part of horizontal gene transfer (HGT), (micro)satellite expansions, transposable element insertions and other processes.

A major part of the nuclear genome of most plants is represented by repetitive DNA elements; these elements contribute to the higher evolutionary dynamics of genomes, while genes represent slowly evolving (conservative) genetic units.

Perhaps, the most distinctive feature of angiosperm [flowering plants] is the large amount of genome duplication, i.e., polyploidization [containing more than two homologous sets of chromosomes].

Higher repetitive DNA turnover, repeated polyploidizations and subsequent gene losses lead to a much more rapid structural changes of plant genomes when compared to vertebrates, where gene order conservation is evident event after hundreds of millions of years of divergence.[15]

The sheer geographic distance between the original wild tomatoes in South America and their domesticated counterparts in Mexico (and later in Europe and North America) means that tomato genomes diverged a long time ago.

Compared with the rich reservoir in wild species, the cultivated tomato is genetically poor. It is estimated that the genomes of tomato cultivars contain [less than] 5% of the genetic variation of their wild relatives.

Tomato domestication experienced a severe genetic bottleneck as the crop was carried from the Andes to Central America and from there to Europe. The initial domestication process was, in part, reached by selecting preferred genotypes in the existing germplasm.[16]

Reinventing the 21st Century Tomato

During the 20th century, Charles Rick would become the tomatos most important scientist and plant breeder. Described as a cross between a Charles Darwin and an Indiana Jones, Rick traveled through the Andean region of South America collecting wild relatives of the domesticated tomatoes. As early as 1953, Rick showed that crosses between wild species and their cultivated relatives could reveal novel genetic variations of potential use in agriculture.[17]

Ricks astonishingly valuable collection of tomato germplasm is now maintained at the C.M. Rick Genetic Resource Center of the University of California, at Davis:

The Rick Center acts like a lending library, nurturing and preserving its 3,600-specimen collection but also making it readily available to scholars and plant breeders worldwide who want to check out seeds for their own experiments. Today, those seeds are kept in a vault that resembles a restaurants walk-in refrigerator. * * * *

But the Rick collection is not really about taste. Domestic tomatoes had virtually no innate resistance to common tomato diseases and pests until breeders [like Rick] began crossing them with wild species in the 1940s. . . . . Wild tomatoes, on the other hand, are more robust. We know of at least forty-four pathogens for which resistance has been found in wild species.

The possibilities of using wild traits to improve cultivated tomatoes seem almost limitless. Some wild species grow at chilly altitudes thirty-five hundred meters up the in the Andes, tolerating low temperatures that would cause other tomatoes to shrivel and die. Others thrive in humid rainforests. A few can eke out an existence in the desert.[18]

Crosses between wild and cultivated species of tomatoes can generate an array of novel genetic variation in their offspring. Breeding from wild species via interspecific crosses followed by many backcrosses to cultivated tomatoes can lead to the transfer of favorable attributes in the resulting tomato variety.[19] This is known as wild introgression plant breeding.

Genome Editing and Plant Breeding Bandwagons

In one way or another, all plant breeding techniques hearken back to Experiments in Plant Breeding, Gregor Mendels 1866 groundbreaking article (ignored at first and rediscovered 34 years later).

By the latter 20th century, plant breeders applied increasingly sophisticated biotechnology tools to improve the tomato. Goals included breeding for yield in the 1970s, for shelf life in the 1980s, for taste in the 1990s, and for nutritional quality currently.[20]

The first transgenic tomato, Calgenes Flavr Savr tomato, relied on recombinant DNA techniques to extend the shelf life of tomatoes by inhibiting an enzyme involved in fruit softening. The Flavr Savr tomato had some initial market success in the mid-1990s, then flopped. Its developers chose a tomato intended for the food processing market as it target cultivar, rather than a tomato grown for fresh food markets. Apparently, the resulting GMO tomato had very little flavor worth saving. It found its best use in the tomato processing market, but consumers rebelled against its GMO provenance.[21]

In contrast to recombinant DNA technologyin which foreign genes are inserted into a target hosta new wave of plant breeding relies on genomic editing tools, such as the CRISPR/Cas system. In broad terms:

Genome editing focuses on the G component of P = G +E [i.e., that phenotype value (P) is the sum of genetic (G) and environmental effects (E)], and it represents an infinitely more precise form of mutation breeding. Genome editing allows changes in targeted DNA sequences, with the edits involving the deletion, substitution, or addition of one or more bases.

[G]enome editing requires prior information on gene identity and function and leads only to targeted mutations. In practice, however, the plant regeneration process after genome editing may lead to unwanted somaclonal variation in the target cultivar. Genome editing may be particularly valuable in plant species for which backcrossing (to introgress favorable alleles) is impractical due to a long generation interval or infeasible to a heterozygous recurrent parent.

[G]enome editing will be most useful in the same situations where linkage mapping of QTL [quantitative trait loci] is most useful: for traits that have major QTL or major genes. For such traits, such as disease resistance or flowering date, changes in the known underlying genes can be directly made via genome editing. These changes will involve loss-of-function mutations or gain-of-function mutations equivalent to naturally occurring mutations with known effects, or novel mutations that need to be characterized via phenotypic screening.

The many genes affecting a trait such as yield in elite germplasm remain largely unknown even after whole genomes have been sequenced.[22]

While this description of genome editing may read somewhat like Greek, the most important finding is that most quantitative [plant] traits are controlled by a large number of small effect genes locked away in low-recombinant regions, presenting challenges in (even) sequenced and highly genotyped association mapping panels.[23]

In other words, even though genomic editing is the latest and greatest biotech bandwagon, its technical shortcomings will also confound the plant breeding industry.

Wild Tomatoes are Not Patentable

U.S. plant patenting laws, 35 U.S.C. 161-164, protect new and distinct varieties of asexually reproduced plants other than those found in an uncultivated state. More generally, U.S. utility patents, among other things, cover new and useful compositions of matter, or any new and useful improvement thereof. 35 U.S.C. 101. In addition, the Plant Variety Protection Act offers patent-like protections for new, distinct, uniform and stable sexually reproduced plant varieties. 7 U.S.C. 2321-2582.

Plant explorers will find no solace in U.S. plant patent lawssince plants discovered in the wild are not patentable. A recent Federal Circuit decision discussing plant patenting, In re Beineke(2012), stands for the proposition that:

[T]wo things [are] necessary for an applicant to obtain plant patent protection: (1) the plant must have been created in its inception by human activity, i.e., it must be the result of plant breeding or other agricultural or horticultural efforts; and (2) the plant must have been created by the inventor, i.e., the person seeking the patent must have contributed to the creation of the plant in addition to having appreciated its uniqueness and asexually reproduced it.[24]

Although plants found in the wild are not patentable, their progeny may be. These plant patenting activities appear relatively immune from a line of attack generated by the recent Myriad/Mayo Supreme Court casesi.e., that naturally occurring DNA segments constitute unpatentable products of nature. [25] The Plant Patent Act of 1930 altered former law rejecting plant inventions as unpatentable laws of nature. The same can be said for the Plant Variety Protection Act.

Standard utility patent applications, however, may present separate patenting difficulties. If the utility patent claims seek to cover naturally occurring genomic sequences, new plant variety patents may be subject to Mayo/Myriad-based rejections.

In this regard, an analysis of patent claims in human biomedicine vs. crop-based agriculture reveals a substantive overlap in claimed genome sequences. Such practice could, in principle, raise infringement concernsfor example, if an agribusiness and a medical diagnostic company use the same DNA primers for polymerase chain reaction-based genetic testing.[26]

If the Mayo/Myriad case holdings operate as a brake on plant patent activities at the genomic level, one can anticipate that agribusinesses and other plant patent inventors will guard their plant-based innovations under a reinvigorated trade secret law, now federalized per the Defend Trade Secrets Act of 2016.[27]

Genome Edited Plants Evade Regulatory Scrutiny

Genetically engineered (GE) plants are presumptively subject to a convoluted array of federal regulatory oversight by the Food and Drug Administration, the Environmental Protection Agency, and the United States Department of Agriculture. Generally speaking, the FDA established a voluntary structure for GE plant producers to consult with the FDA before marketing these products.

Much of this regulatory structuredeveloped in the mid-1980sis premised on theoretical plant pests and recombinant DNA techniques involving foreign gene insertion.

The USDA regulatory process for GE crops is triggered by the use of plant pests in any portion of the modification process or the derived potential of the GE crop to behave as plant pests. In practice, the routine use of pest-derived genetic components triggers a de facto process-based regulatory regime by the USDAs inspection service, APHIS [Animal and Plant Health Inspection Service].[28]

This regulatory framework focuses on transgenic biotechnology toolsnow a fading, late 20th century bandwagon. Genome editing tools tend not to trigger this GE food regulatory regime. When requested to opine on genome editing tools, APHIS determined that genome editing technologies create two potential classes of products:

(i) those in which endogenous genetic material is removed (targeted deletions); and (ii) those in which precise sequence changes are introduced by using specific template oligonucleotides (targeted substitutions and insertions).

APHIS [states] that products resulting from targeted deletions would, in most cases, not be regulated because no new genetic material is integrated into the recipient genome, and the engineered nucleases did not originate from plant pests. The second class of products (targeted substitutions and insertions) would need to be reviewed on a case-to-case basis to assess the inserted trait and determine regulatory status.[29]

Based on this dichotomy, genome editing appears to sidestep US regulatory oversight. While this may be a policy loophole, there may be little impetus to expand bureaucratic review of genome edited plant food products when a sufficiently large body of scientific literature on GE traits already shows that DNA modification per se is not inherently unsafe or a threat to the environment.[30]

Guacamole Con Tomate Verde

You need not be a wild plant explorer to experience unusual tomato flavors. Green tomatillos are more widely available in American grocery store shelves nowadays. Their paper husks and sticky skin may be off-putting, but these are small bothers in a quest for sublime taste.

To mix up your standard guacamole recipe, try Diana Kennedys recipe for guacamole con tomate verde.[31] After youve ground white onions, serrano chilies, cilantro and broiled tomatillos (preferably with a mortar and pestle), you mashnever machine blend!avocadoes into this mixture. Voil, your taste buds will be transported to the state of Mexico bordering on Morelos, where this recipe originated perhaps eons ago.

_______________________________

* The opening photograph of tomatoes included in the Earth & Table version of this article is licensed under the GNU Free Documentation License, Version 1.2. For photographer information, see https://commons.wikimedia.org/wiki/User:Berrucomons.

[1] D. Kennedy, The Essential Cuisines of Mexico (2000), at 490-91.

[2] B. Estabrook. Tomatoland: How Modern Industrial Agriculture Destroyed Our Most Alluring Fruit (2011), at 3.

[3] Y. Bau and P. Lindhout, Domestication and Breeding of Tomatoes: What Have We Gained and What Can We Gain in the Future, 100 Annals of Botany 1085, 1086 (August 2008).

[4] Id.

[5] Id.

[6] R. Earle, The Body of the Conquistador: Food, Race and the Colonial Experience in Spanish America, 1492-1700 (2012), at 42.

[7] Id. at 52

[8] Photograph in the Earth & Tableblog post version by Guido Gerding, https://commons.wikimedia.org/w/index.php?curid=1037325.

[9] A.F. Smith, The Tomato in America: Early History, Culture, and Cookery (1994), at 17.

[10] C. Wright, A Mediterranean Feast: The Story of the Birth of the Celebrated Cuisines of the Mediterranean, from the Merchants of Venice to the Barbary Corsairs (1999), at 32.

[11] See, e.g., http://herbs.lovetoknow.com/doctrine-signatures.

[12] See http://www.whfoods.com/genpage.php?tname=foodspice&dbid=44 (Worlds Healthiest Food website page devoted to tomatoes).

[13] G. Acquaah, Principles of Plant Genetics and Breeding (2d ed. 2012), at 7.

[14] See n.2, at 4.

[15] P. Smykal, et al., From Mendels discovery on pea to todays plant genetics and breeding, 129 Theoretical and Applied Genetics, 2267, 2271-72 (2016) (citations omitted and text formatting altered for readability).

[16] See n. 3, at 1086.

[17] S. Tanksley and G. Khush, Charles Madera Rick 1915-2002, Biographical Memoirs, Vol. 84 (2003), at 10, available online at https://www.nap.edu/read/10992/chapter/17.

[18] Id. at 13-16.

[19] See n. 13, at 56.

[20] See n. 3, at 1088.

[21] See n. 13, at 256.

[22] R. Bernardo, Bandwagons I, too have known, 129 Theoretical and Applied Genetics 2323 (2016), at 2329-30 (text formatting altered for readability). The reference to elite germplasm in the quoted material refers to germplasm that is adapted (selectively bred) and optimized to new surroundings (i.e., environment).

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Wild Introgressions: The Tomato Genome's Impact on Plant Patenting and Trademark Branding Prospects - JD Supra (press release)

When the National Academy of Sciences (NAS) released its Human Genome Editing Report last week, a wave of questions arose regarding the reports scientific and clinical implications. The report, which outlines criteria that should be met before allowing clinical trials involving germline editing to go forward, was issued in response to the promising research and clinical opportunities associated with powerful genome-editing tools such as CRISPR/Cas9.

Richard O. Hynes is a Daniel K. Ludwig Professor for Cancer Research at MIT, a member of MIT's Koch Institute for Integrative Cancer Research, and a former director of the Koch Institute's predecessor, the MIT Center for Cancer Research. Hynes, a co-chair of the NAS study committee that created the report, sat down to shed additional light on the reports recommendations and its impact on the future of genome editing.

Q: Why is a report like this needed now?

A: We are in the midst of an explosion of new research and clinical opportunities that can be enabled by genome-editing tools. Genome editing is now much easier, faster, cheaper, and more versatile than ever. Because this field is advancing so rapidly, the issues and concerns that genome editing raises needed to be seriously reviewed and addressed, alongside the development of the technology itself.

There are, of course, many technical questions such as what risks exist, how to reduce them, and how to regulate the different ongoing applications which need to be explored further, but there are plenty of societal questions as well. For example, should one allow enhancement or going beyond treatment and prevention of disease and disability? Should heritable germline editing be allowed, if and when it might become sufficiently reproducible, accurate, and safe? And if so, how would that affect societal attitudes toward disability, issues of equity and fairness, and concerns around creating a slippery slope that could lead to inappropriate applications?

The reports committee represented four continents and included scientists, clinicians, ethicists, lawyers, and public engagement experts, among others. Each member offered a unique perspective on how oversight guidelines should be crafted and regulated and how to further public discussion. We believe the resulting recommendations will have universal applicability across multiple countries and cultures, and we recommend a set of principles that could be incorporated into the regulation and oversight in any country pursuing human genome editing.

Q: What are the reports primary take-home points?

A: First, human genome editing in the contexts of basic laboratory research, and somatic gene therapy for the treatment and prevention of disease and disability are valuable and well-regulated. They should proceed under the existing oversight and regulatory norms.

Second, editing for purposes other than treatment or prevention of disease and disability should not be approved at this time. Public engagement and discussion on this topic should be actively promoted before advancing past these purposes, and specific funding should be allotted to support this.

Finally, while human heritable germline editing is not yet practicable and much further research is necessary before it could be considered for clinical trials, there are arguments for limited applications to prevent heritable disease should that become feasible. At the same time, there are technical, practical, societal, and ethical concerns that need to be addressed. The report lays out a set of stringent criteria that would need to be met for approval of any trial of heritable germline editing, and it recommends extensive public engagement in discussionsabout how to assess its implications before any such trials.

Q: Are there any misconceptions about the report that you would like to address?

A: Of course, there is always the potential for concern around these topics when they enter the public sphere, but this report is firmly grounded in existing ethical, scientific, and regulatory practices and in consultation with the individuals and communities who will be directly affected by this technology. I would say that the committee is not opening the door to human genome editing, but we are, so to speak, removing the padlock pending possible new applications. Furthermore, the report is recommending human applications only for purposes of treatment and prevention of disease or disability and not for any applications that go beyond that, such as enhancements.

We limited our recommendations to this because of concerns about making unnecessary, potentially risky edits aimed toenhance human capacities beyond what is necessary to treat a life-threatening or debilitating condition. Enhancement is a topic that needs more discussion and public engagement to assess societal attitudes. At this time, we say no to any germline enhancements. If technology moves forward to enable the possibility, our current recommendation would be that it should be used to enable healthy babies, notdesigner babies. We also have confidence in the current systems of regulation and decision-making based on risk/benefit analysis but believe it should incorporate more engagement with public opinion.

Overall, we have been pleased with the coverage of the report so far, and the public seems to be excited about the major acceleration of our understanding of human biology. There is real potential to combat many diseases, such as cancer and thousands of genetically inherited diseases, which affect a significant number of people in the global population. Somatic editing is already in clinical trials, and many more are yet to come that we will learn a great deal from particularly about efficacy, risks, and the impact of this modern form of gene therapy. Germline editing is not possible yet probably not for several years but it is time to think carefully about the implications while the technical aspectsare still being explored, rather than waiting until the decisions as to whether or not to proceed are imminent.

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3Q: Behind the scenes of the National Academy of Sciences' report on human genome editing - The MIT Tech

Science Daily

New tool to map RNA-DNA interactions could help researchers translate gene sequences into functions Science Daily The tool, called MARGI (Mapping RNA Genome Interactions), is the first technology that's capable of providing a full account of all the RNA molecules that interact with a segment of DNA, as well as the locations of all these interactions -- in just a ... and more »

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New tool to map RNA-DNA interactions could help researchers translate gene sequences into functions - Science Daily

Would you want to know if you were at a higher risk of getting dementia later in life? Would you want to know that you could die under general anaesthesia, or might die suddenly of heart failure? Would you want to know if you had a higher-than-normal chance of getting cancer? You could learn these things by looking at your genome. But would you want to be faced with the answers?

Your genome is the complete set of genetic information in the cells of your body. It is like a recipe book that provides the instructions for who you are, and the recipes are your genes. Each gene provides a set of instructions for the protein molecules that make up your body. Much like how your cake recipe might differ from your neighbours, these genetic recipes can differ slightly from person to person. However, if there is a significant error in the recipe for example, if baking powder were left out this can have a damaging effect on the final product. So, if there is a harmful variant in a gene, this can affect the protein produced, which can cause genetic disease.

When a doctor suspects that you have a genetic disease, they can now read your genome from cover to cover. After nearly 13 years of international collaboration, the first complete sequence of the human genome was unveiled in 2003. Since then, the cost of genome sequencing has dropped from 1 billion to less than 1,000 allowing genome sequencing to enter routine clinical care, and transforming the way we diagnose and treat disease.

NHS England is currently sequencing 100,000 genomes, and the US has plans to sequence 1m genomes. A 2015 study predicted that up to two billion people worldwide could have their genomes sequenced within the next decade comparable to the reach of the internet. With so many genomes getting sequenced, and increasing opportunities to get genetic information outside of the healthcare system, you could be next.

Genetic variants help shape who we are and can tell us a lot about ourselves. This ranges from rather harmless characteristics such as eye colour to potentially serious conditions. These include findings for which there is no treatment, such as genetic changes associated with an increased risk of Alzheimers, as well as medically actionable findings, such as genetic predispositions to breast cancer where screening and treatment is available. One to two per cent of people who undergo genome sequencing could have genetic changes that point to these serious but medically actionable conditions.

Sometimes, in genetic testing for one condition, we can find variants that point to other serious diseases. For example, genome sequencing of a patient with a heart condition could flag up an additional genetic variant associated with cancer. However, much of our understanding of these genetic variants comes from patients who have the associated disease, so we can safely assume that the genetic variant is at fault. But with more and more data, we are learning that more people have disease-causing variants than we expect to have the disease which means that simply carrying a variant doesnt necessarily mean disease will follow. So for this patient with a heart condition, interpreting variants that point to any other disease, such as cancer, is challenging.

There are other issues to consider. How would you feel if you were told you had a 90% increased risk of breast cancer or that you might die suddenly from a problem with your heart like some young athletes in the news? Even if our ability to understand these variants were stronger, would the benefit of knowing this information outweigh the potential anxiety it could cause?

Genetic variants arent the full picture the environment plays a role, too. There are also concerns around storage, security, privacy and discrimination. Further complicating all of this is the shared nature of genetic information. We share half of our genome with our parents, children and siblings, one quarter with our grandparents, aunts, uncles, nieces and nephews. Unlike a typical medical test, genetic results not only affect us, but our family members.

In the coming years, as these large genome sequencing projects are completed, our understanding of these variants will improve and policy will catch up with the technology. In the meantime, genome sequencing programmes including our own are offering these results to participants, generating the data needed to inform our understanding of these variants. These results, however, are optional: it is your choice whether or not you want them. So, before you provide a saliva sample to have your own genetic recipe book read, its important to know which results are worth knowing about.

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Do you really want to know what's lurking in your genome? - The Conversation UK

Can biologists sequence the genomes of all the plants and the animals in the world, including this greater bird of paradise in Indonesia?

TIM LAMAN/National Geographic Creative

By Elizabeth PennisiFeb. 24, 2017 , 1:15 PM

WASHINGTON, D.C.When it comes to genome sequencing, visionaries like to throw around big numbers: Theres the UK Biobank, for example, which promises to decipher the genomes of 500,000 individuals, or Icelands effort to study the genomes of its entire human population. Yesterday, at a meeting here organized by the Smithsonian Initiative onBiodiversity Genomics and the Shenzhen, Chinabased sequencing powerhouse BGI, a small group of researchers upped the ante even more, announcing their intent to, eventually, sequence all life on Earth.

Their plan, which does not yet have funding dedicated to it specifically but could cost at least several billions of dollars, has been dubbed the Earth BioGenome Project (EBP). Harris Lewin, an evolutionary genomicist at the University of California, Davis, who is part of the group that came up with this vision 2 years ago, says the EBP would take a first step toward its audacious goal by focusing on eukaryotesthe group of organisms that includes all plants, animals, and single-celled organisms such as amoebas.

That strategy, and the EBPs overall concept, found a receptive audience at BioGenomics2017, a gathering this week of conservationists, evolutionary biologists, systematists, and other biologists interested in applying genomics to their work. This is a grand idea, says Oliver Ryder, a conservation biologist at the San Diego Zoo Institute for Conservation Research in California. If we really want to understand how life evolved, genome biology is going to be part of that.

Ryder and others drew parallels between the EBP and the Human Genome Project, which began as an ambitious, controversial, and, at the time, technically impossible proposal more than 30 years ago.That earlier effort eventually led not only to the sequencing of the first human genome, but also to entirely new DNA technologies that are at the center of many medical frontiers and the basis for a $20 billion industry. People have learned from the human genome experience that [sequencing] is a tremendous advance in biology, Lewin says.

Many details about the EBP are still being worked out. But as currently proposed, the first step would be to sequence in great detail the DNA of a member of each eukaryotic family (about 9000 in all) to create reference genomes on par or better than the reference human genome. Next would come sequencing to a lesser degree a species from each of the 150,000 to 200,000 genera. Finally, EBP participants would get rough genomes of the 1.5 million remaining known eukaryotic species. These lower resolution genomes could be improved as needed by comparing them with the family references or by doing more sequencing, says EBP co-organizer Gene Robinson, a behavioral genomics researcher and director of the Carl R. Woese Institute for Genomic Biology at the University of Illinois in Urbana.

In this representation of the tree of life, there are very few completed genomes (red lines in inner rim) among named eukaryotes (green), but many more among bacteria (blue) and archaea (purple). Among the millions of eukaryotic species, there are even relatively few lower resolution genome sequences (blue, light and dark gray).

Keith A. Crandall, David B. Stern, and Jimmy Bernot of The George Washington Universitys Computational Biology Institute

The entire eukaryotic effort would likely cost about the same as it did to sequence that first human genome, estimate Lewin, Robinson, and EBP co-organizer John Kress, an evolutionary biologist at the Smithsonian National Museum of Natural History here. It took about $2.7 billion to read and order the 3 billion bases composing the human genome, about $4.8 billion in todays dollars. With a comparable amount of support, the EBPs eukaryotic work might be done in a decade, its organizers suggest.

Such optimism arises from ever-decreasing DNA sequencing costsone meeting presenter fromComplete Genomics, based in Mountain View, California, says his company plans to be able to roughly sequence whole eukaryotic genomes for about $100 within a yearand improvements in sequencing technology that make possible higher quality genomes, at reasonable prices. It became apparent to me that at a certain point, it would be possible to sequence all life on Earth, Lewin says.

Although some may find the multibillion-dollar price tag hard to justify for researchers not studying humans, the fundamentals of matter, or the mysteries of the universe, the EBP has a head start, thanks to the work of several research communities pursuing their own ambitious sequencing projects. These include the Genome 10K Project, which seeks to sequence 10,000 vertebrate genomes, one from each genus; i5K, an effort to decipher 5000 arthropods; and B10K, which expects to generate genomes for all 10,500 bird species. The EBP would help coordinate, compile, and perhaps fund these efforts. The [EBP] concept is a community of communities, Lewin says.

There are also sequencing commitments from giants in the genomics field, such as Chinas BGI, and the Wellcome Trust Sanger Institute in the United Kingdom. But at a planning meeting this week, it became clear that significant challenges await the EBP, even beyond funding. Although researchers from Brazil, China, and the United Kingdom said their nations are eager to participate in some way, the 20 people in attendance emphasized the need for the effort to be more international, with developing countries, particularly those with high biodiversity, helping shape the projects final form. They proposed that the EBP could help develop sequencing and other technological experts and capabilities in those regions. The Global Genome Biodiversity Network, which is compiling lists and images of specimens at museums and other biorepositories around the world, could supply much of the DNA needed, but even broader participation is important, says Thomas Gilbert, an evolutionary biologist at the Natural History Museum of Denmark in Copenhagen.

The planning group also stressed the need to develop standards to ensure high-quality genome sequences and to preserve associated information for each organism sequenced, such as where it was collected and what it looked like. Getting DNA samples from the wild may ultimately be the biggest challengeand the biggest cost, several people noted. Not all museum specimens yield DNA preserved well enough for high-quality genomes. Even recently collected and frozen plant and animal specimens are not always handled correctly for preserving their DNA, says Guojie Zhang, an evolutionary biologist at BGI and the University of Copenhagen. And the lack of standards could undermine the projects ultimate utility, notes Erich Jarvis, a neurobiologist at The Rockefeller University in New York City: We could spend money on an effort for all species on the planet, but we could generate a lot of crap.

But Lewin is optimistic that wont happen. After he outlined the EBP in the closing talk at BioGenomics2017, he was surrounded by researchers eager to know what they could do to help. Its good to try to bring together the tribes, says Jose Lopez, a biologist from Nova Southeastern University in Fort Lauderdale, Florida, whose tribe has mounted GIGA, a project to sequence 7000 marine invertebrates. Its a big endeavor. We need lots of expertise and lots of people who can contribute.

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Biologists propose to sequence the DNA of all life on Earth - Science Magazine

After the 2003 completion of the Human Genome Project which sequenced all 3 billionletters,or base pairs, in the human genome many thought that our DNA would become an open book. But a perplexing problem quickly emerged: although scientists could transcribe the book, they could only interpret a small percentage of it.

The mysterious majority as much as 98 percent of our DNA do not code for proteins. Much of this dark matter genome is thought to be nonfunctional evolutionary leftovers that are just along for the ride. However, hidden among this noncoding DNA are many crucial regulatory elements that control the activity of thousands of genes. What is more, these elements play a major role in diseases such as cancer, heart disease, and autism, and they could hold the key to possible cures.

As part of a major ongoing effort to fully map and annotate the functional sequences of the human genome,including this silent majority, the National Institutes of Health (NIH)on Feb. 2, 2017, announced new grant funding for a nationwide project to set up five characterization centers, including two at UC San Francisco, to study how theseregulatory elements influence gene expression and, consequently, cell behavior.

The projects aim is for scientists to use the latest technology, such as genome editing, to gain insights into human biology that could one day lead to treatments for complex genetic diseases.

After the shortfalls of the Human Genome Project became clear, the Encyclopedia of DNA Elements (ENCODE) Project was launched in September 2003 by the National Human Genome Research Institute (NHGRI). The goal of ENCODE is to find all the functional regions of the human genome, whether they form genes or not.

The Human Genome Project mapped the letters of the human genome, but it didnt tell us anything about the grammar: where the punctuation is, where the starts and ends are.

Elise Feingold, PhD

NIH Program Director

The Human Genome Project mapped the letters of the human genome, but it didnt tell us anything about the grammar: where the punctuation is, where the starts and ends are, said NIH Program Director Elise Feingold, PhD. Thats what ENCODE is trying to do.

The initiative revealed that millions of these noncoding letter sequences perform essential regulatory actions, like turning genes on or off in different types of cells. However, while scientists have established that these regulatory sequences have important functions, they do not know what function each sequence performs, nor do they know which gene each one affects. That is because the sequences are often located far from their target genes in some cases millions of letters away. Whats more, many of the sequences have different effects in different types of cells.

The new grants from NHGRI will allow the five new centers to work to define the functions and gene targets of these regulatory sequences. At UCSF, two of the centers will be based in the labs of Nadav Ahituv, PhD, and Yin Shen, PhD. The other three characterization centers will be housed at Stanford University, Cornell University, and the Lawrence Berkeley National Laboratory. Additional centers will continue to focus on mapping, computational analysis, data analysis and data coordination.

New technology has made identifying the function and targets of regulatory sequences much easier. Scientists can now manipulate cells to obtain more information about their DNA, and, thanks to high-throughput screening, they can do so in large batches, testing thousands of sequences in one experiment instead of one by one.

It used to be extremely difficult to test for function in the noncoding part of the genome, said Ahituv, a professor in the Department of Bioengineering and Therapeutic Sciences. With a gene, its easier to assess the effect because there is a change in the corresponding protein. But with regulatory sequences, you dont know what a change in DNA can lead to, so its hard to predict the functional output.

Ahituv and Shen are both using innovative techniques to study enhancers, which play a fundamental role in gene expression. Every cell in the human body contains the same DNA. What determines whether a cell is a skin cell or a brain cell or a heart cell is which genes are turned on and off. Enhancers are the secret switches that turn on cell-type specific genes.

During a previous phase of ENCODE, Ahituv and collaborator Jay Shendure, PhD, at the University of Washington, developed a technique called lentivirus-based massive parallel reporter assay to identify enhancers. With the new grant, they will use this technology to test for enhancers among 100,000 regulatory sequences previously identified by ENCODE.

Their approach pairs each regulatory sequence with a unique DNA barcode of 15 randomly generated letters. A reporter gene is stuck in between the sequence and the barcode, and the whole package is inserted into a cell. If the regulatory sequence is an enhancer, the reporter gene will turn on and activate the barcode. The DNA barcode will then code for RNA in the cell.

Once the researchers see that the reporter gene is turned on, they can easily sequence the RNA in the cell to see which barcode is activated. They then match the barcode back to its corresponding regulatory sequence, which the scientists now know is an enhancer.

With previous enhancer assays, you had to test each sequence one by one, Ahituv explained. With our approach, we can clone thousands of sequences along with thousands of barcodes and test them all at once.

Shen, an assistant professor in the Department of Neurology and the Institute for Human Genetics, is taking a different approach to characterize the function of regulatory sequences. In collaboration with her former mentor at the Ludwig Institute for Cancer Research and UC San Diego, Bing Ren, PhD, she developed a high-throughput CRISPR-Cas9 screening method to test the function of noncoding sequences. Now, Shen and Ren are using this approach to identify not only which sequences have regulatory functions, but also which genes they affect.

Shen will use CRISPR to edit tens of thousands of regulatory sequences in a large pool of cells and track the effects of the edits on a set of 60 pairs of genes that commonly co-express.

For this work, each cell will be programmed to reflect two fluorescent colors one for each gene when a pair of genes is turned on. If the light in a cell goes out, the scientists will know that its target gene has been affected by one of the CRISPR-based sequence edits. The final step is to sequence each cells DNA to determine which regulatory sequence edit caused the change in gene expression.

By monitoring the colors of co-expressed genes, Shen will reveal the complex relationship between numerous functional sequences and multiple genes, which was beyond the scope of traditional sequencing techniques.

Until the recent development of CRISPR, it was not possible to genetically manipulate non-coding sequences in a large scale, said Shen. Now, CRISPR can be scaled up so that we can screen thousands of regulatory sequences in one experiment. This approach will tell us not only which sequences are functional in a cell, but also which gene they regulate.

By cataloging the functions of thousands of regulatory sequences, Shen and Ahituv hope to develop rules about how to predict and interpret other sequences functions. This would not only help illuminate the rest of the dark matter genome, it could also reveal new treatment targets for complex genetic diseases.

A lot of human diseases have been found to be associated with regulatory sequences, Ahituv said. For example, in genome-wide association studies for common diseases, such as diabetes, cancer and autism, 90 percent of the disease-associated DNA variants are in the noncoding DNA. So its not a gene thats changed, but what regulates it.

As the price for sequencing a persons genome has dropped significantly, there is talk about using precision medicine to cure many serious diseases. However, the hurdle of how to interpret mutations in noncoding DNA remains.

If we can characterize the function and identify the gene targets of these regulatory sequences, we can start to reveal how their mutations contribute to diseases, Shen said. Eventually, we may even be able to treat complex diseases by correcting regulatory mutations.

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The Mysterious 98%: Scientists Look to Shine Light on Our Dark Genome - ScienceBlog.com (blog)