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What Is the Human Genome?

The human genome that researchers sequenced at the turn of the century doesn’t really exist as we know it.

The Human Genome project sequenced “the human genome” and is widely credited with setting in motion the most exciting era of fundamental new scientific discovery since Galileo. That’s remarkable, because in important ways “the human genome” that we have labeled as such doesn’t actually exist.

cosmin4000, istockphoto

Plato essentially asserted that things like chairs and dogs, which we observe in this physical world, and even concepts like virtues, are but imperfect representations or instances of some ideal that exists, but not in the material world. Such a Platonic ideal is “the human genome,” a sequence of about 3 billion nucleotides arrayed across a linear scale of position from the start of chromosome 1 to the end of the sex chromosomes. Whether it was obtained from one person or several has so far been shrouded in secrecy for bioethical reasons, but it makes no real difference. What we call the human genome sequence is really just a reference: it cannot account for all the variability that exists in the species, just like no single dog on earth, real or imagined, can fully incorporate all the variability in the characteristics of dogs.

Nor is the human genome we have a “’normal” genome. What would it mean to be “normal” for the nucleotide at position 1,234,547 on chromosome 11?  All we know is that the donor(s) had no identified disease when bled for the cause, but sooner or later some disease will arise. Essentially all available whole genome sequences show potentially disease-producing variants, even including nonfunctional genes, in donors who were unaffected at the time.

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Filed under biology genetics genomics human genome neuroscience psychology science evolution

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Paddlefish’s doubled genome may question theories on limb evolution The American paddlefish — known for its bizarre, protruding snout and eggs harvested for caviar — duplicated its entire genome about 42 million years ago, according to a new study published in the journal Genome Biology and Evolution. This finding may add a new twist to the way scientists study how fins evolved into limbs since the paddlefish is often used as a proxy for a more representative ancestor shared by humans and fishes. “We found that paddlefish have had their own genome duplication,” said Karen Crow, assistant professor of biology at San Francisco State University. “This creates extra genetic material that adds complexity to comparative studies. It may change the way we interpret studies on limb development.” In order to study how human limbs develop, scientists compare the limb-building genes found in mice with fin-building genes found in fishes. Previous research on paddlefish has suggested that fishes possessed the genetic toolkit required to grow limbs long before the evolution of the four-limbed creatures (tetrapods) that developed into reptiles, birds, amphibians and mammals. In the last decade, paddlefish have become a useful benchmark in evolutionary studies because their position on the evolutionary tree makes them a reasonably good proxy for the ancestor of the bony fishes that evolved into tetrapods such as humans. However, the fact that paddlefish underwent a genome duplication could complicate what its genes tell us about the fin-to-limb transition, says Crow.

Paddlefish’s doubled genome may question theories on limb evolution

The American paddlefish — known for its bizarre, protruding snout and eggs harvested for caviar — duplicated its entire genome about 42 million years ago, according to a new study published in the journal Genome Biology and Evolution. This finding may add a new twist to the way scientists study how fins evolved into limbs since the paddlefish is often used as a proxy for a more representative ancestor shared by humans and fishes.

“We found that paddlefish have had their own genome duplication,” said Karen Crow, assistant professor of biology at San Francisco State University. “This creates extra genetic material that adds complexity to comparative studies. It may change the way we interpret studies on limb development.”

In order to study how human limbs develop, scientists compare the limb-building genes found in mice with fin-building genes found in fishes. Previous research on paddlefish has suggested that fishes possessed the genetic toolkit required to grow limbs long before the evolution of the four-limbed creatures (tetrapods) that developed into reptiles, birds, amphibians and mammals.

In the last decade, paddlefish have become a useful benchmark in evolutionary studies because their position on the evolutionary tree makes them a reasonably good proxy for the ancestor of the bony fishes that evolved into tetrapods such as humans. However, the fact that paddlefish underwent a genome duplication could complicate what its genes tell us about the fin-to-limb transition, says Crow.

Filed under science neuroscience genomics biology genetics psychology evolution

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The human microbiome: Me, myself, us Looking at human beings as ecosystems that contain many collaborating and competing species could change the practice of medicine. A human being is an individual who has grown from a fertilised egg which contained genes from both father and mother. A growing band of biologists, however, think this definition incomplete. They see people not just as individuals, but also as ecosystems. In their view, the descendant of the fertilised egg is merely one component of the system. The others are trillions of bacteria, each equally an individual, which are found in a person’s gut, his mouth, his scalp, his skin and all of the crevices and orifices that subtend from his body’s surface. A healthy adult human harbours some 100 trillion bacteria in his gut alone. That is ten times as many bacterial cells as he has cells descended from the sperm and egg of his parents. These bugs, moreover, are diverse. Egg and sperm provide about 23,000 different genes. The microbiome, as the body’s commensal bacteria are collectively known, is reckoned to have around 3m. Admittedly, many of those millions are variations on common themes, but equally many are not, and even the number of those that are adds something to the body’s genetic mix.

The human microbiome: Me, myself, us

Looking at human beings as ecosystems that contain many collaborating and competing species could change the practice of medicine.

A human being is an individual who has grown from a fertilised egg which contained genes from both father and mother. A growing band of biologists, however, think this definition incomplete. They see people not just as individuals, but also as ecosystems. In their view, the descendant of the fertilised egg is merely one component of the system. The others are trillions of bacteria, each equally an individual, which are found in a person’s gut, his mouth, his scalp, his skin and all of the crevices and orifices that subtend from his body’s surface.

A healthy adult human harbours some 100 trillion bacteria in his gut alone. That is ten times as many bacterial cells as he has cells descended from the sperm and egg of his parents. These bugs, moreover, are diverse. Egg and sperm provide about 23,000 different genes. The microbiome, as the body’s commensal bacteria are collectively known, is reckoned to have around 3m. Admittedly, many of those millions are variations on common themes, but equally many are not, and even the number of those that are adds something to the body’s genetic mix.

Filed under science neuroscience biology biochemistry psychology bacteria diseases disorders

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DNA: The Ultimate Hard Drive When it comes to storing information, hard drives don’t hold a candle to DNA. Our genetic code packs billions of gigabytes into a single gram. A mere milligram of the molecule could encode the complete text of every book in the Library of Congress and have plenty of room to spare. All of this has been mostly theoretical—until now. In a new study, researchers stored an entire genetics textbook in less than a picogram of DNA—one trillionth of a gram—an advance that could revolutionize our ability to save data. A few teams have tried to write data into the genomes of living cells. But the approach has a couple of disadvantages. First, cells die—not a good way to lose your term paper. They also replicate, introducing new mutations over time that can change the data. To get around these problems, a team led by George Church, a synthetic biologist at Harvard Medical School in Boston, created a DNA information-archiving system that uses no cells at all. Instead, an inkjet printer embeds short fragments of chemically synthesized DNA onto the surface of a tiny glass chip. To encode a digital file, researchers divide it into tiny blocks of data and convert these data not into the 1s and 0s of typical digital storage media, but rather into DNA’s four-letter alphabet of As, Cs, Gs, and Ts. Each DNA fragment also contains a digital “barcode” that records its location in the original file. Reading the data requires a DNA sequencer and a computer to reassemble all of the fragments in order and convert them back into digital format. The computer also corrects for errors; each block of data is replicated thousands of times so that any chance glitch can be identified and fixed by comparing it to the other copies. To demonstrate its system in action, the team used the DNA chips to encode a genetics book co-authored by Church. It worked. After converting the book into DNA and translating it back into digital form, the team’s system had a raw error rate of only two errors per million bits, amounting to a few single-letter typos. That is on par with DVDs and far better than magnetic hard drives. And because of their tiny size, DNA chips are now the storage medium with the highest known information density, the researchers report online today in Science. Don’t replace your flash drive with genetic material just yet, however. The cost of the DNA sequencer and other instruments “currently makes this impractical for general use,” says Daniel Gibson, a synthetic biologist at the J. Craig Venter Institute in Rockville, Maryland, “but the field is moving fast and the technology will soon be cheaper, faster, and smaller.” Gibson led the team that created the first completely synthetic genome, which included a “watermark” of extra data encoded into the DNA. The researchers used a three-letter coding system that is less efficient than the Church team’s but has built-in safeguards to prevent living cells from translating the DNA into proteins. “If DNA is going to be used for this purpose, and outside a laboratory setting, then you would want to use DNA sequence that is least likely to be expressed in the environment,” he says. Church disagrees. Unless someone deliberately “subverts” his DNA data-archiving system, he sees little danger.

DNA: The Ultimate Hard Drive

When it comes to storing information, hard drives don’t hold a candle to DNA. Our genetic code packs billions of gigabytes into a single gram. A mere milligram of the molecule could encode the complete text of every book in the Library of Congress and have plenty of room to spare. All of this has been mostly theoretical—until now. In a new study, researchers stored an entire genetics textbook in less than a picogram of DNA—one trillionth of a gram—an advance that could revolutionize our ability to save data.

A few teams have tried to write data into the genomes of living cells. But the approach has a couple of disadvantages. First, cells die—not a good way to lose your term paper. They also replicate, introducing new mutations over time that can change the data.

To get around these problems, a team led by George Church, a synthetic biologist at Harvard Medical School in Boston, created a DNA information-archiving system that uses no cells at all. Instead, an inkjet printer embeds short fragments of chemically synthesized DNA onto the surface of a tiny glass chip. To encode a digital file, researchers divide it into tiny blocks of data and convert these data not into the 1s and 0s of typical digital storage media, but rather into DNA’s four-letter alphabet of As, Cs, Gs, and Ts. Each DNA fragment also contains a digital “barcode” that records its location in the original file. Reading the data requires a DNA sequencer and a computer to reassemble all of the fragments in order and convert them back into digital format. The computer also corrects for errors; each block of data is replicated thousands of times so that any chance glitch can be identified and fixed by comparing it to the other copies.

To demonstrate its system in action, the team used the DNA chips to encode a genetics book co-authored by Church. It worked. After converting the book into DNA and translating it back into digital form, the team’s system had a raw error rate of only two errors per million bits, amounting to a few single-letter typos. That is on par with DVDs and far better than magnetic hard drives. And because of their tiny size, DNA chips are now the storage medium with the highest known information density, the researchers report online today in Science.

Don’t replace your flash drive with genetic material just yet, however. The cost of the DNA sequencer and other instruments “currently makes this impractical for general use,” says Daniel Gibson, a synthetic biologist at the J. Craig Venter Institute in Rockville, Maryland, “but the field is moving fast and the technology will soon be cheaper, faster, and smaller.” Gibson led the team that created the first completely synthetic genome, which included a “watermark” of extra data encoded into the DNA. The researchers used a three-letter coding system that is less efficient than the Church team’s but has built-in safeguards to prevent living cells from translating the DNA into proteins. “If DNA is going to be used for this purpose, and outside a laboratory setting, then you would want to use DNA sequence that is least likely to be expressed in the environment,” he says. Church disagrees. Unless someone deliberately “subverts” his DNA data-archiving system, he sees little danger.

Filed under science biology genetics DNA neuroscience genomics

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The PLOS ONE Synthetic Biology Collection: Six Years and Counting Since it was launched in 2006, PLOS ONE has published over fifty articles illustrating the many facets of the emerging field of synthetic biology. This article reviews these publications by organizing them into broad categories focused on DNA synthesis and assembly techniques, the development of libraries of biological parts, the use of synthetic biology in protein engineering applications, and the engineering of gene regulatory networks and metabolic pathways. Finally, we review articles that describe enabling technologies such as software and modeling, along with new instrumentation. In order to increase the visibility of this body of work, the papers have been assembled into the PLOS ONE Synthetic Biology Collection (www.ploscollections.org/synbio). Many of the innovative features of the PLOS ONE web site will help make this collection a resource that will support a lively dialogue between readers and authors of PLOS ONE synthetic biology papers. The content of the collection will be updated periodically by including relevant articles as they are published by the journal. Thus, we hope that this collection will continue to meet the publishing needs of the synthetic biology community.

The PLOS ONE Synthetic Biology Collection: Six Years and Counting

Since it was launched in 2006, PLOS ONE has published over fifty articles illustrating the many facets of the emerging field of synthetic biology. This article reviews these publications by organizing them into broad categories focused on DNA synthesis and assembly techniques, the development of libraries of biological parts, the use of synthetic biology in protein engineering applications, and the engineering of gene regulatory networks and metabolic pathways. Finally, we review articles that describe enabling technologies such as software and modeling, along with new instrumentation. In order to increase the visibility of this body of work, the papers have been assembled into the PLOS ONE Synthetic Biology Collection (www.ploscollections.org/synbio). Many of the innovative features of the PLOS ONE web site will help make this collection a resource that will support a lively dialogue between readers and authors of PLOS ONE synthetic biology papers. The content of the collection will be updated periodically by including relevant articles as they are published by the journal. Thus, we hope that this collection will continue to meet the publishing needs of the synthetic biology community.

Filed under science biology synthetic biology articles plos one

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Palaeontologists from the University of Zurich have “rediscovered” a skull bone that was thought to have been lost during the course of evolution for many mammals. Mammals’ skulls are composed of around 20 bones — fewer than those of fish, reptiles and birds. This is because when mammals evolved from reptile-like vertebrates 320 million years ago, the skull structure simplified. Some bones were lost in the process, particularly some of the skull roof bones. The interparietal is one such bone, but it has perplexed researchers since it had survived in some mammals, such as horses and cats (and 2.8 percent of humans) but not in others. The interparietal is clearly discernible in the embryo, but fuses with other bones beyond recognition shortly afterwards. As a result it’s often been missed. However, new imaging techniques have been able to detect its presence in all mammals.

Palaeontologists from the University of Zurich have “rediscovered” a skull bone that was thought to have been lost during the course of evolution for many mammals.

Mammals’ skulls are composed of around 20 bones — fewer than those of fish, reptiles and birds. This is because when mammals evolved from reptile-like vertebrates 320 million years ago, the skull structure simplified. Some bones were lost in the process, particularly some of the skull roof bones. The interparietal is one such bone, but it has perplexed researchers since it had survived in some mammals, such as horses and cats (and 2.8 percent of humans) but not in others.

The interparietal is clearly discernible in the embryo, but fuses with other bones beyond recognition shortly afterwards. As a result it’s often been missed. However, new imaging techniques have been able to detect its presence in all mammals.

Filed under science neuroscience brain psychology biology evolution mammals

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The UT Dallas “tag and track” method not only sheds light on how DNA loops form, but also might be adapted to screen drugs for effectiveness against certain viruses that shuffle genetic material, such as HIV. Until now, scientists primarily had “snapshots” of the initial and final stages of DNA loop formation, with only limited information about what happens during the intermediate steps. "Scientists have known for more than 30 years that DNA looping is an important part of molecular biology and gene regulation, but until our work, there have been few serious attempts to understand the basic biophysics of the process, … We estimate that using fluorescence-based methods such as this for drug screening could be as much as 10,000 times more efficient than methods that are currently used," -Dr. Stephen Levene, professor of bioengineering, molecular and cell biology, and phyiscs at UT Dallas.

The UT Dallas “tag and track” method not only sheds light on how DNA loops form, but also might be adapted to screen drugs for effectiveness against certain viruses that shuffle genetic material, such as HIV.

Until now, scientists primarily had “snapshots” of the initial and final stages of DNA loop formation, with only limited information about what happens during the intermediate steps.

"Scientists have known for more than 30 years that DNA looping is an important part of molecular biology and gene regulation, but until our work, there have been few serious attempts to understand the basic biophysics of the process, … We estimate that using fluorescence-based methods such as this for drug screening could be as much as 10,000 times more efficient than methods that are currently used," -Dr. Stephen Levene, professor of bioengineering, molecular and cell biology, and phyiscs at UT Dallas.

Filed under DNA biology genetics neuroscience science virus DNA looping

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The genetic code of the fruit fly Drosophila has been hacked into, allowing it to make proteins with properties that don’t exist in the natural world. The advance could ultimately lead to the creation of new or “improved” life forms in the burgeoning field of synthetic biology. The four letters of the genetic code, A, C, T and G, are read in triplets, called codons, by the cell’s protein-making machinery. Each codon gives an instruction for the type of amino acid that gets added next in a protein chain, or tells the machinery to stop. Complex proposition As a proof of principle, Chin’s team has engineered fruit flies that incorporated three new amino acids into proteins in the cells of their ovaries. The flies were engineered using bacteria that had been modified to insert the genetic code for the unnatural amino acid into the fly DNA. There was no apparent impact on the flies’ health, and they even produced healthy offspring that also made the new protein chains. Bulletproof flies None of the amino acids were particularly remarkable, but the fact that engineering the flies had no obvious impact on their health suggests that many more useful amino acids could be similarly incorporated. For example, work in bacterial cells has shown that it is possible to incorporate unnatural amino acids that cross-link to each other or turn an enzyme’s activity on or off when a light is shone on them. Doing this in a complex organism like a fly could shed new light on how proteins interact within cells, or how rapidly turning an enzyme on or off affects the cell’s function. The technique could even be used to create animals with new or improved properties, although that is probably some years off.

The genetic code of the fruit fly Drosophila has been hacked into, allowing it to make proteins with properties that don’t exist in the natural world. The advance could ultimately lead to the creation of new or “improved” life forms in the burgeoning field of synthetic biology.

The four letters of the genetic code, A, C, T and G, are read in triplets, called codons, by the cell’s protein-making machinery. Each codon gives an instruction for the type of amino acid that gets added next in a protein chain, or tells the machinery to stop.

Complex proposition

As a proof of principle, Chin’s team has engineered fruit flies that incorporated three new amino acids into proteins in the cells of their ovaries.

The flies were engineered using bacteria that had been modified to insert the genetic code for the unnatural amino acid into the fly DNA. There was no apparent impact on the flies’ health, and they even produced healthy offspring that also made the new protein chains.

Bulletproof flies

None of the amino acids were particularly remarkable, but the fact that engineering the flies had no obvious impact on their health suggests that many more useful amino acids could be similarly incorporated.

For example, work in bacterial cells has shown that it is possible to incorporate unnatural amino acids that cross-link to each other or turn an enzyme’s activity on or off when a light is shone on them. Doing this in a complex organism like a fly could shed new light on how proteins interact within cells, or how rapidly turning an enzyme on or off affects the cell’s function.

The technique could even be used to create animals with new or improved properties, although that is probably some years off.

Filed under memory disease mechanisms science neuroscience fruit flies Drosophila biology proteins

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These days, 3D printing is being used to mock up far more complex systems, says Arthur Olson, who founded the molecular graphics lab at the Scripps Research Institute in La Jolla, California, 30 years ago. These include molecular environments made up of thousands of interacting proteins, which would be onerous-to-impossible to make any other way. With 3D printers, Olson says, “anybody can make a custom model”. But not everybody does: many researchers lack easy access to a printer, aren’t aware of the option or can’t afford the printouts (which can cost $100 or more).

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Filed under 3D printing biology neuroscience research science molecules DNA

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