Mutating Mice and Other Genetics News

Researchers from the University of Utah and the Howard Hughes Medical Institute have developed a quicker and less expensive way of creating mutant mice--to test the effect of mutations in non-gene DNA.

The new method for mutating large, non-gene stretches of DNA is outlined in this week’s online edition of Nature Genetics. Capecchi and Wu conducted the research with two other University of Utah human geneticists: Guoxin Ying, a postdoctoral fellow, and Qiang Wu, an assistant professor (and no relation to Sen Wu).

In the journal paper, the University of Utah scientists report:

* They found a way to delete or duplicate moderately long to very long pieces of DNA and make those mutations happen much more frequently than other methods can. That makes it easier to find out what defects or diseases arise due to such mutations, and thus what the DNA does normally.

* They devised a much more efficient method for mixing and recombining pieces of two chromosomes, making it easier to breed mice with human cancers. Such mice are needed to develop new treatments.

Read more at the Source

In this study, researchers at the University of Chicago the genetic basis of phenotype differences between chimps and humans. They discovered that much of the difference between gene expression in ten genes in humans and chimps, was due to differences in promoter activity. In other words, even with almost the same genes, differences in gene regulation achieves significant phenotype differences.

Berkeley Lab researchers are discovering more of the importance of "junk DNA" for cell organisation and survival.

Researchers at the University of Virginia Health System discovered yet another interesting determinant of gene expression. It seems that the chromatin packaging of genes (how tightly the genes are wrapped on histones) can determine how quickly, and at what level, the gene will be expressed. This is particularly important in development and cell differentiation.

A collaborative study published in Nature offers more information about the relationship of "junk DNA" and disease causation.

And Yale researchers are using advanced gene sequencing technology to identify HIV strains that are resistant to standard therapy. These particular strains were not detectable using available hospital lab testing.

Gene expression is far more complex than originally thought. The gene regulating effect of "junk DNA" may explain a great deal of disease etiology and progression that has been a mystery up until now. Phenotypic differences between species with similar genomes are becoming easier to explain as the larger picture of gene regulation is elucidated.

We are literally only just beginning to open the book of genetics.

Junk DNA No More?

Since only about 2% of the human genome codes for proteins, about 97% of the human genome has been labeled "junk DNA." But is it really junk?

Gill Bejerano, PhD, assistant professor of developmental biology and of computer science at Stanford, found more than 10,000 nearly identical genetic snippets dotting the human chromosomes. Many of those snippets were located in gene-free chromosomal expanses once described by geneticists as "gene deserts." These sections are, in fact, so clogged with useful DNA bits - including the ones Bejerano and his colleagues describe - that they've been renamed "regulatory jungles."

"It's funny how quickly the field is now evolving," Bejerano said. His work picking out these snippets and describing why they might exist will be published in the April 23 advance online issue of the Proceedings of the National Academy of Sciences.

It turns out that most of the segments described in the research paper cluster near genes that play a carefully orchestrated role during an animal's first few weeks after conception. Bejerano and his colleagues think that these sequences help in the intricate choreography of when and where those genes flip on as the animal lays out its body plan. In particular, the group found the sequences to be especially abundant near genes that help cells stick together. These genes play a crucial role early in an animal's life, helping cells migrate to the correct location or form into organs and tissues of the correct shape.

The 10,402 sequences studied by Bejerano, along with David Haussler, PhD, professor of biomolecular engineering at UC-Santa Cruz, are remnants of unusual DNA pieces called transposons that duplicate themselves and hop around the genome. "We used to think they were mostly messing things up. Here is a case where they are actually useful," Bejerano said.

Source

Junk DNA is very controversial in some quarters. Some people believe much of junk DNA comes from extraterrestrial sources. They claim junk DNA is lying latent, waiting for a special signal to spring to life and transform the human species. Well, it is late . . .

About half of human DNA is made up of transposons, or the jumping genes of Barbara McClintock. Transposons act like viruses in many ways, and may have come from viruses--or a relative of viruses.

Whatever junk DNA is doing, it is likely that its secrets will be discovered in the coming decades--thanks to growing gene databases and increasing sophistication of fast computers and sophisticated gene analysis software.

DNA Surprises: Gene Research Goes into High Gear

Thanks to Snowcrash for pointing to this CIT newsrelease that details new discoveries in "gene interaction."

The difficulty lies in the fact that two genes can pair up in a gigantic number of ways. If an organism has a genome of 20,000 genes, for example, the total number of pairwise combinations is a staggering total of 200 million possible interactions.

Researchers can indeed perform experiments to see what happens when the two genes interact, but 200 million is an enormous number of experiments, says Weiwei Zhong, a postdoctoral scholar at the California Institute of Technology. "The question is whether we can prioritize which experiments we should do in order to save a lot of time."

....a genetic-interaction network provides a faster and better way at determining how certain genes interact. Such a network also provides information about whether anyone has ever done an experiment to determine the interaction of two particular genes in one of several species.

"This process works like a matchmaking service for the genes," says Zhong. "It provides you with candidate matches that most likely will be interacting genes, based upon a number of specified features."

The benefit, she adds, is that biologists do not need to do a huge number of random experiments to verify if two genes indeed interact. Therefore, instead of the experimenter having to run 20,000 experiments to see if two genes randomly chosen from the genome of a 20,000-gene organism interact, they might get by with 10 to 50 experiments.

"The beneft is that you can be through in a month instead of years," says Sternberg Read the entire report here. Hat tip Biosingularity Blog.

The next story deals with advances in developing transgenic plants--getting plants to make proteins from other species--in this instance getting tobacco plants to make human albumin. This is from a Bio.com newsrelease:

Agricultural engineer, Alicia Fernández San Millán, has developed a novel technique in Spain - plastidial transformation, in order to produce, in a recombinant form, human albumin from tobacco plants. According to her PhD thesis, plastidial transformation is an economically viable alternative, as it enables increasing the levels of HSA by between 10 and a 100 times, compared to levels obtained by nuclear transformation. Read the entire newfeature for more information.

The following story deals with "junk DNA", the 98% of all human DNA that does not code for protein. Buried within the junk DNA is hidden treasure--epigenetic control sequences that influence the gene expression of the 2% of coding DNA.

The notion that mutations in enhancers play a role in human disease progression has been difficult to confirm because usually enhancers are located in the 98 percent of the human genome that does not code for protein, termed non-coding DNA. Unlike DNA sequences that code for protein, non-coding DNA, sometimes referred to as "junk" DNA, follows few rules for organization and sequence patterns and therefore is more difficult to study.

"The difficulty with human genetic approaches to common disease is that we lack the power to precisely localize DNA sequences that are associated with disease, often leaving us immense stretches of DNA to look at," says one of the study's corresponding authors, Andy McCallion, Ph.D., an assistant professor in the McKusick-Nathans Institute. Most often one is limited to looking in the most obvious places, which may not yield the best results. "Until now," he says, "we've only been able to look under the lamplights for the car keys."

....The system is a significant advance over current methods in this model species, allowing researchers to study more sequences in a shorter period of time. Read the entire news report here.

This report discusses a discovery of a gene variant--always think "hapmap" when hearing the term "gene variant"--that affects the onset of cancer.

Normally our genes have to be divided into two perfectly identical copies when a cell divides. The unfortunate variant causes a defect in the division of the genetic material (mitosis), which means that a daughter cell may get too few or too many genes.

If a daughter cell does not receive a gene that prevents cancer, a so-called tumour suppressor gene, then a cancer can grow. One defence mechanism against cancer is for a cell that gets faulty genes to commit suicide (apoptosis).

The defect caused by the unfortunate variant when it divides the genes is so tiny that the suicide mechanism does not detect the fault, which allows the cell to continue its growth into a cancer. Read the rest here.

Finally, here is a glimpse into the distant past, toward the possible origin of life on earth. This Eurekalert newsrelease discusses experiments attempting to delve into possible origins of the DNA-RNA encoding system that supports all known life.

This "evolutionary conversion" provides a modern-day snapshot of how life as we understand it may have first evolved out of the earliest primordial mix of RNA-like molecules-sometimes referred to as the "pre-RNA world"-into a more complex form of RNA-based life (or the "RNA world") and eventually to cellular life based on DNA and proteins. Nucleic acids are large complex molecules that store and convey genetic information, but can also function as enzymes.

While the transfer of sequence information between two different classes of nucleic acid-like molecules-between RNA and DNA, for example-is straightforward because it relies on the one-to-one correspondence of the double helix pairing, transferring catalytic function is significantly more difficult because function cannot be conveyed sequentially. The present study demonstrates that the "evolutionary conversion" of an RNA enzyme to a DNA enzyme with the same function is possible, however, through the acquisition of a few critical mutations.

The study was released in an advance online version of the journal Chemistry & Biology. Read more here.

This posting covers only a small cross section of ongoing genetic research. Al Fin has covered several of these topics previously. All of those past postings are available via the archives on the sidebar. Most people would feel overwhelmed if they had attempted to look deeply into any of these reports. No one is expected to know everything about everything, after all.

Genes are only 2% of Human DNA: What About the Rest?

Humans have a lot of "extra" DNA beyond what is contained in the 30,000 or so genes in the genome. Scientists expected humans to have 100,000 or more genes, given the complexity of the human organism. What is all that extra DNA doing? According to this report from news-medical.net, the worldwide race is on to locate the small DNA sequences that participate in the control of the "turning on" and "turning off" of genes.

Growing knowledge of how regulatory sequences control gene behavior has the potential to create new classes of treatment for nerve disorders and heart failure. Such sequences may also help to explain why humans are so complex, despite having one-fifth as much genetic material as wheat for instance. Medical center researchers are working on just one of more than 100 regulatory sequences identified so far, each the subject of intense study.

"Most people don't realize that genes make up a very small percentage of the human DNA code," said Joseph M. Miano, Ph.D., senior author of the journal paper and associate professor within the Cardiovascular Research Institute at the medical center. "Genes are relatively straightforward compared to what lies ahead. We believe that the real genetic gymnastics, the real intelligence of our system, is controlled by tiny bits of genetic material that tell genes what to do."

....Researchers also concluded that genes, specific batches of code that direct protein construction, comprise just about 2 percent of all human DNA. A central question in genetics has become: what does the remaining 98 percent of human genetic material do?

Regulatory sequences are emerging as an important part of the non-gene majority of human genetic material, once thought of as "junk DNA." A new frontier in genetic research is the defining of the regulome, the complete set of DNA sequences that regulate the behavior of genes. DNA segments that code for proteins average 200 base pairs in length, whereas regulatory sequences typically include just six to 10 base pairs, making them hard to find.

....In Miano's study, the regulatory sequence under examination was the CArG box. The nucleotide building blocks of DNA chains may contain any one of four nucleobases: adenine (A), thymine (T), guanine (G) and cytosine (C). Any sequence of code starting with 2 Cs, followed by any combination of 6 As or Ts, and ending in 2 Gs is a CArG box.

According to Miano, there are 1,216 variations of CArG box that together occur approximately three million times throughout the human DNA blueprint.

....When a piece of genetic material, gene or regulatory segment, is conserved by evolution from mice to humans it suggests that the segment has a valuable function. Miano's screen required that CArG boxes shared by humans and mice be included in his expanded version of the CarGome. CArG boxes identified by the computer screen were then tested to see if they indeed interacted with SRF and changed the behavior of genes as predicted.

This approach resulted in the disclosure of more than 100 hypothetical CArG boxes and the same number of genes previously unknown to be targeted by CArG-SRF. Of those, 60 CArG boxes have been validated as exerting influence over a gene.

....In the larger picture, regulatory sequences may help to explain why humans have just 25,000 genes when, given the degree of human complexity, researchers had expected to find more than 100,000. Regulatory sequences may be part of the answer because they enable a single gene to produce the same protein at different times, places and concentrations with subtly different roles.

"Humans share about one quarter of their genes with fish," Miano said. "Something must be at work to explain why we are so many times more complex. Regulatory sequences offer one of several emerging explanations for how we do more with fewer genes."

Go here for the full story.

Mapping the genome was only the start of the solving of the puzzle. Now we have to learn how the whole Rube-Goldberg device really works.