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Research News |

Recent research from HudsonAlpha scientists:

 

How the cat got his blotches

As any cat lover knows, distinct patterns of dark and light hair color are apparent not only in house cats but also in their wild relatives, from cheetahs to tigers to snow leopards. Researchers at the HudsonAlpha Institute for Biotechnology and Stanford University, along with colleagues around the world, today reported new genetic findings that help to understand the molecular basis of these patterns in all felines.

A so-called “mackerel tabby” cat has dark tiger stripes, which coalesce into swirls and blotches in a “classic tabby” cat. Like other periodic natural patterns such as stripes on a zebra or spinal bones and vertebra, the origin of these repetitive structures is an unsolved mystery. “Until now, there’s been no obvious biological explanation for cheetah spots or the stripes on tigers, zebras or even the ordinary house cat,” said Gregory Barsh, M.D., Ph.D., faculty investigator at HudsonAlpha and emeritus professor of genetics at Stanford University, one of the senior authors of the study.

 

When comparing sequence differences between striped and blotched domestic cats, the researchers saw the evidence pointed to a gene that they named Taqpep. Blotched cats had specific mutations in both copies of this gene, while striped cats did not. Remarkably, the rare “king cheetah,” once thought to be a unique species because of an unusual striped pattern rather than regular spots, also carried a mutation in Taqpep.

 

The team then went on to ask how spots, stripes or blotches form in the first place. “Somehow, cells in the black stripes know they are in a black stripe and remember that fact throughout the organism’s life,” said Barsh. “We were curious about what’s happening at the boundary between light and dark stripes and spots. How do these spots know to grow with an animal?”

 

Their examination of genes expressed in dark versus light hair cells revealed that patterned markings are due to variations in another gene, Edn3, being expressed at high levels in the darkly colored hair cells. The researchers thus suggest that the Taqpep gene helps to establish either a periodic pattern for stripes or a spotted or blotched pattern, by determining the level of Edn3 expressed in each skin area at an early stage of the cat’s development.

According to Barsh, discovery of new genetic pathways and mechanisms is the foundation for understanding the blueprint encoded in any genome, including humans. Studies with fruit flies and roundworms have revealed principles that govern how cancer cells live and die, he noted. “Uncovering new biologic principles in animals that are more closely related to humans, like cats, dogs and laboratory mice, may reveal unexpected insights with far-reaching implications for human biology and disease.”

Next up for the group: figuring out the exact mechanism by which Taqpep and Edn3 function, and looking at why some animals like lions, cougars, and the Abyssinian breed of domestic cat, don’t have noticeable patterns regardless of their Taqpep status. “We know there’s a mutation that suppresses pattern formation in some cats,” said Barsh. “We’d like to investigate that mechanism as well.”

The research, funded by the NIH and HudsonAlpha, is described in the paper “Specifying and sustaining pigmentation patterns in domestic and wild cats, published in the 21 September issue of Science.

 

 

Shining a light on human variation

One of the most interesting things about people is how different we are from each other. Work published Sunday by a large international consortium, including Lindsay Waite at the HudsonAlpha Institute for Biotechnology, reports that sequence variants in one specific gene influence the amount of variation in a group of people’s body mass index, or BMI.

The science of genetics has long focused on measuring the components of our genome versus our environment in determining how we look, how big or tall we are, and many other medical and physical traits. In order to find genomic contributors to BMI, scientists in 14 countries pooled together their previous studies on nearly 170,000 individuals. They reexamined data looking at many genetic variants across the entire genome, and statistically determined which variants were truly associated with variation in the BMI value between people.

One gene, called FTO and located on chromosome 16, stood out as the single genomic location where this massive study could show significant association with variation in BMI. Other variants in FTO have previously been reported to be associated with obesity levels within an individual. The new study shows that FTO is also the single detectable gene associated with between-individual variation, or how humans vary as a population in their BMI. In other words, the group of people with one variant at FTO will have a larger range of BMI than the group of people with the other observed variant in the gene.

A popular analogy about this type of study is that we are looking for the keys to certain human traits, and genome-wide association studies like this one shine streetlights on the parts of the genome where we will probably find the keys. We don’t yet know how the function of the FTO gene controls BMI, but now we have an industrial-strength spotlight shining on FTO for further mechanistic studies.

The paper, FTO genotype is associated with phenotypic variability of body mass index,” was published online by Nature on 16 September 2012.

 

 

The beads and string of DNA

You may have heard the analogy “beads on a string” to describe genetic code. Two new papers from the HudsonAlpha Institute for Biotechnology report that both the beads and string contribute to how genetic code relates to human health.

Envision DNA as a very long string, wrapped around millions of beads made of proteins. To regulate genes, cells use thousands of different proteins. Imagine the beads are made of thousands of combinations of different colors and designs. The technique used in these papers, chromatin immunoprecipitation or ChIP-seq, allows researchers to go in and pick out the specific protein-DNA complexes, or individual beads from this huge jumble, that they want to study.

Writing in the journal Nature Methods, Yiwen Chen and colleagues from multiple institutions, including HudsonAlpha, reported in April 2012 on the best methods to perform ChiP-seq. Since this technique is used in laboratories worldwide, the group investigated the factors most influencing accuracy of ChIP-seq, meaning they pull out the correct beads more frequently. This paper should serve as a guide for standardizing results throughout the field, allowing for easier comparisons between large datasets.

Separately, Timothy Reddy, Ph.D. and other scientists in the laboratory of Rick Myers, Ph.D., at HudsonAlpha, along with colleagues at Duke University and the California Institute of Technology, used ChIP-seq to examine the effects of protein binding on gene expression. We all should have two copies of each gene in our genome: one from our maternal chromosome, and one from our paternal. These genes are often expressed due to the binding of specific proteins called transcription factors at the start of the gene.

Using cells from one person, the scientists were able to compare the expression of each parent’s given copy of a number of different genes in the person, and then use ChIP-seq to tell which transcription factors were bound to the genome at each copy of the gene. They saw that in 5.5 percent of genes, the levels of binding and expression were not equal between the two copies of the genes. This would mean that the individual would express more of either the paternal or maternal gene, potentially influencing many traits or risk for disease.

In particular, these sites that were differentially bound and expressed were more often associated with risk for autoimmune disease. These findings suggest an individual’s genotype, or set of genomic variants, alone, might not be enough to determine phenotype, or collection of expressed traits and disease risk.

Together, these two papers demonstrate the most accurate methods for investigating regulation of our genomic code through ChIP-seq, and the importance of understanding protein binding to DNA for proper interpretation of DNA’s influence on human health.

The paper by Yiwen Chen et al. was published online by the journal Nature Methods on 22 April 2012, and can be found here:
http://www.nature.com/nmeth/journal/vaop/ncurrent/full/nmeth.1985.html

The paper by Timothy Reddy et al. was published in the journal Genome Research on 2 February 2012, and can be found here:
http://genome.cshlp.org/content/early/2012/03/07/gr.131201.111.abstract

 

 

Why we have plenty of fish in the sea

HUNTSVILLE, Ala. — New work from the HudsonAlpha Institute for Biotechnology, with collaborators at Stanford University and five other groups, has pinpointed evolution in action.
By determining genomic sequence from many groups of stickleback fish, the scientists were able to show specific genomic changes leading to the ability of different fish populations to adapt to new environments. “We were pleased with the ability of genomics to show us what molecular changes are important in evolutionary processes,” said Richard Myers, Ph.D., president and director of HudsonAlpha.
At the end of the last ice age, marine stickleback fish were present in many waters, and then became separated into different populations in lakes and streams worldwide. These populations evolved separate traits, such as number of spines, body length or eye size, which allowed them to thrive in their specific habitat.
To tie these traits to specific DNA changes, the scientists generated a reference of the threespine stickleback fish genome at high quality. “With our reference genome and genetic map for stickleback, we will now be able to use it as a model organism for future studies of adaptation and environmental selection,” said HudsonAlpha faculty investigator Jeremy Schmutz.
They then sequenced 21 pairs of fish that varied at different traits and compared them to each other and to the reference fish genome. Small regions of the fish genome stood out due to changes in the genomic DNA, and many of these could be related to how the fish look and behave.
Two interesting findings stood out. First, the changes between fish populations often happened not by mutations in single DNA bases, but by inversions of very large chunks of DNA on fish chromosomes. When these large inversions of DNA occur, fish can no longer breed with each other effectively and start to become separate species.
Second, the scientists saw that when evolution allowing fish to adapt to their environment seemed to come from single DNA base changes, these were most often in regions of the genome that regulate genes and proteins instead of in the genes themselves. In contrast, previous work has shown that in laboratory or domesticated animals, changes in genes and proteins are found more often.
Jane Grimwood, Ph.D., also a faculty investigator at HudsonAlpha, explained, “The predominance of regulatory changes in the evolution of sticklebacks suggests that natural populations may behave differently than domesticated animals, and our genetic mapping of many species will advance similar studies in natural and wild organisms.”

HudsonAlpha researchers have been part of the NHGRI – NIH funded Center for Excellence in Genome Sciences, or CEGS, project for developing stickleback as a model organism since 2002. As part of this effort, they and colleagues at Stanford University have produced genomic resources for several freshwater and marine stickleback fish. Currently, the HudsonAlpha Genome Sequencing Center is building a reference sequence for the Y chromosome for stickleback, as the sequenced fish was a female.
The paper “The genomic basis of adaptive evolution in threespine sticklebacks” was published in the April 4, 2012 issue of the journal Nature.

 

 

Tales from the crypt lead researchers to cancer discovery

HUNTSVILLE, Ala – Tales from the crypt are supposed to be scary, but new research from Vanderbilt University, the HudsonAlpha Institute for Biotechnology, and colleagues shows that crypts can be places of renewal too: intestinal crypts, that is. Intestinal crypts are small areas of the intestine where new cells are formed to continuously renew the digestive tract. By focusing on one protein expressed in our intestines called Lrig1, the researchers have identified a special population of intestinal stem cells that respond to damage and help to prevent cancer.

The research, published in the March 30 issue of Cell, also shows the diversity of stem cells in the intestines is greater than previously thought.

“Identification of these cells and the role they likely play in response to injury or damage will help advance discoveries in cancer,” said Shawn Levy, Ph.D., faculty investigator at the HudsonAlpha Institute and an author on the study.

The intestines and colon are normally lined with a single layer of cells to absorb nutrients from food. There are regular small pockets in the intestines called crypts, where stem cells are gathered. Rapid turnover of the lining cells and replacement by new lining cells made in the crypt, keep the intestines and colon healthy and keep damaged cells from turning into cancerous ones.

The new paper demonstrates that, although the makeup of stem cells in the crypt is still controversial, one protein called Lrig1 can distinguish a group of long-lived cells at the base of the crypt. These Lrig1-positive stem cells do not regularly replace lining cells, but instead are only activated when there is damage or injury to the intestine.

In addition, the researchers show that the Lrig1 protein functions to prevent cancer as a tumor suppressor molecule. When the protein is completely absent from a mouse model, the mice all develop adenomas and then tumors. This suggests that Lrig1 is an important target for understanding and treating intestinal and colon cancer.

Levy added, “RNA sequencing work at HudsonAlpha found that the Lrig1-positive stem cells are molecularly different in multiple ways from previously identified crypt stem cells, in keeping with their role in responding to damage.” Further work on genes expressed or silenced in this population of cells, he added, will increase understanding of both normal and cancer cell progression in the intestines.

The paper, “The Pan-ErbB Negative Regulator Lrig1 Is an Intestinal Stem Cell Marker that Functions as a Tumor Suppressor” was published in Cell on 30 March 2012.

 

Genomic variations play complex role in autism spectrum disorder

HUNTSVILLE, Ala. – Because autism spectrum disorders are so diverse, scientists have only found a few genetic factors that clearly contribute a risk of developing the condition. New work from HudsonAlpha, along with colleagues from Vanderbilt University, the Broad Institute and 11 other groups, has examined genome mutations in autism and concludes that the picture is still complex.

 

Scientists can now use genome sequencing to compare the genetic codes of parents and children, and look for new mutations in the children and not in the parents. These are called de novo mutations. In the case of autism spectrum disorder (ASD), the new study compared 175 children with their parents, and found that de novo mutations only occurred slightly more than by chance.

 

Shawn Levy, Ph.D., a faculty investigator at HudsonAlpha and author in the study, explained, “These results show that new mutations have a limited but possibly important role in autism spectrum disorder, perhaps contributing at most 10-20 percent of the risk we see.”

 

To understand what effects the mutations might be having, the researchers then went on to model the interactions between proteins made by the genes with new mutations and other genes previously identified to be associate with Autism. These proteins form a web of interactions in cells and are quite highly connected. This suggests that when de novo mutations do happen they could disturb the web and have an effect on the entire process of brain development or function.

 

Levy added, “Although the causes and complexities of ASD remain elusive, this study has illustrated that elaborate networks of proteins and contributing factors such as parental age are keys to our understanding of ASD”.

The paper, “Patterns and rates of exonic de novo mutations in autism spectrum disorders” was published in the April 4, 2012 issue of the journal Nature.

 

 

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