Quantitative Epigenetics Through Epigenomic Perturbation of Isogenic Lines [Genetics of complex traits]

Quantitative Epigenetics Through Epigenomic Perturbation of Isogenic Lines Genetics

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Quantitative Epigenetics Through Epigenomic Perturbation of Isogenic Lines Frank Johannes*,1 and Maria Colomé-Tatché,2

*Groningen Bioinformatics Centre, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands and
†Institute for Theoretical Physics, Leibniz Universität Hannover, Appelstr. 2, D-30167, Hannover, Germany 1?Corresponding author: Groningen Bioinformatics Centre, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands. E-mail: f.johannes{at}rug.nl Abstract Interindividual differences in chromatin states at a locus (epialleles) can result in gene expression changes that are sometimes transmitted across generations. In this way, they can contribute to heritable phenotypic variation in natural and experimental populations independent of DNA sequence. Recent molecular evidence shows that epialleles often display high levels of transgenerational instability. This property gives rise to a dynamic dimension in phenotypic inheritance. To be able to incorporate these non-Mendelian features into quantitative genetic models, it is necessary to study the induction and the transgenerational behavior of epialleles in controlled settings. Here we outline a general experimental approach for achieving this using crosses of epigenomically perturbed isogenic lines in mammalian and plant species. We develop a theoretical description of such crosses and model the relationship between epiallelic instability, recombination, parent-of-origin effects, as well as transgressive segregation and their joint impact on phenotypic variation across generations. In the limiting case of fully stable epialleles our approach reduces to the classical theory of experimental line crosses and thus illustrates a fundamental continuity between genetic and epigenetic inheritance. We consider data from a panel of Arabidopsis epigenetic recombinant inbred lines and explore estimates of the number of quantitative trait loci for plant height that resulted from a manipulation of DNA methylation levels in one of the two isogenic founder strains.

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What makes a plant a plant?

Science DailyAlthough scientists have been able to sequence the genomes of many organisms, they still lack a context for associating the proteins encoded in genes with specific biological processes. To better understand the genetics underlying plant physiology and ecology — especially in regard to photosynthesis — a team of researchers including Carnegie’s Arthur Grossman identified a list of proteins encoded in the genomes of plants and green algae, but not in the genomes of organisms that don’t generate energy through photosynthesis.

Their work will be published June 17 in the Journal of Biological Chemistry.

Using advanced computational tools to analyze the genomes of 28 different plants and photosynthetic organisms, Grossman and his colleagues at the University of California in Los Angeles and the Joint Genome Institute of the Department of Energy were able to identify 597 proteins encoded on plant and green algal genomes, but that are not present in non-photosynthetic organisms. They call this suite of proteins the GreenCut.

Interestingly, of the 597 GreenCut proteins, 286 have known functions, while the remaining 311 have not been associated with a specific biological process and are called “unknowns.”

The majority of the GreenCut proteins, 52 percent, have been localized in a cellular organelle called the chloroplast–the compartment where photosynthesis takes place. It is widely accepted that chloroplasts originated from photosynthetic, single-celled bacteria called cyanobacteria, which were engulfed by a more complex, non-photosynthetic cell more than 1.5 billion years ago. While the relationship between the two organisms was originally symbiotic, over evolutionary time the cyanobacterium transferred most of its genetic information to the nucleus of the host organism, losing its ability to live independent of its partner.

“This genetically-reduced cyanobacterium, which is now termed a chloroplast, has maintained its ability to perform photosynthesis and certain other essential metabolic functions, such as the synthesis of amino acids and fats. The processes that take place in the chloroplast must also be tightly integrated with metabolic processes that occur in other parts the cell outside of the chloroplast,” Grossman explained.

While recent evidence suggests that many of the unknowns of the GreenCut are associated with photosynthetic function, not all GreenCut proteins are located in the chloroplast. But since they are unique to photosynthetic organisms and highly conserved throughout plants and other photosynthetic organisms, it is likely that they are critical for other plant-specific processes. Possible functions could be associated with regulation of metabolism, control of DNA transcription, and the functioning of other cellular organelles, including the energy producing mitochondria and the house-cleaning peroxisomes.

Expanding this work, Grossman and his colleagues found that many GreenCut proteins have been maintained in ancient cyanobacteria, red algae, and other single-celled algae called diatoms. Comparison of GreenCut proteins among various organisms is opening windows for discoveries about the roles that these proteins play in photosynthetic cells, the evolution of chloroplasts, and how photosynthetic cells might be tailored for survival under different environmental conditions.

Story Source:
The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Carnegie Institution.

Journal Reference:
S. J. Karpowicz, S. E. Prochnik, A. R. Grossman, S. S. Merchant. The GreenCut2 Resource: A phylogenomically-derived inventory of proteins specific to the plant lineage. Journal of Biological Chemistry, 2011; DOI: 10.1074/jbc.M111.233734

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Parental conflict in plants: Maternal factors silence paternal genes

Science DailyIn flowering plants, the beginning of embryogenesis is almost exclusively governed by maternal gene activity. Maternal factors regulate the development of the embryo and silence paternal genes during early stages of development. This finding — obtained using next generation sequencing technology — was reported by an international team of researchers including plant geneticists from the University of Zurich. This newly uncovered mechanism may be involved in the maintenance of species boundaries and could play an important role in the development of novel crop varieties.

Mother and father each contribute one half of the genetic information to their offspring. Thus, it was thought that both parents contribute equally to the development of the next generation. Indeed, this holds true for late stages of embryo development in plants, but early on, things are quite different: during the earliest phase of embryo development — from the fertilized egg to the globular stage — predominantly the maternal genes are active. This phase of development is controlled largely by maternal factors, which actively repress or silence the genes inherited from the father.

This surprising finding was recently published in the American journal Cell, by an international team of scientists led by plant geneticists from the Universities of Zurich and Montpellier.

Silenced Paternal Genes

For their analysis, the Zürich scientists crossed two genetically distinguishable races of the model plant Arabidopsis thaliana (tale cress) and analyzed the relative contributions of the parental genomes shortly after the first division of the fertilized egg. Such molecular genetic analyses of plant embryos at very early stages are technically challenging, which explains why up to now researchers resorted to studying embryos at later stages. But Ueli Grossniklaus, Professor for Plant Developmental Genetics at University of Zurich, has a marked preference for tackling experimentally challenging problems, including the study of gametes and very young embryos that are hard to obtain.

Using “Next Generation Sequencing,” a novel and powerful technology, Grossniklaus and colleagues were able to show that in an early phase of plant embryo development, predominantly maternal genes are active. Via small ribonucleic acid molecules (siRNAs), the maternal genome controls paternal genes to ensure that, initially, most remain inactive. In the course of development, paternal genes are sucessively activated, which also requires the activity of maternal factors. This finding is surprising because it contradicts earlier findings, which suggested that these siRNAs have a specifc role in preventing “jumping genes” (transposons) to move within the genome.

According to Grossniklaus, the transient silencing of the paternal contribution during early development of the offspring is in the mother plant’s best interest: the mother invests considerable resources into the formation of seeds. Before making this investment, the mother verifies the paternal contribution to the progeny for compatibility with her own genome. If the father’s genome is too divergent from her own, e.g., originating from a different species, the embryo will die. In fact, the two parental plants have opposing interests with regard to their offspring. The pollen-donating father is interested in maximizing transfer of resources from the mother to the offspring. By contrast, the mother plant aims at optimizing the match with the fathers genome in order to prevent a waste of resources. „We are dealing with a classical parental conflict,” Ueli Grossniklaus summarizes the opposing interests.

Maternal Control May Ensure the Maintenance of Species Boundaries

Maternally active genes direct and control early embryogenesis. Genetic incompatibility will cause embryos to abort, such that fertilization with pollen from other plant species is not successful. Therefore, the mechanism unraveled by Grossniklaus and colleagues may play an important role in the maintenance of species barriers. This may also explain why attempts to cross crop plants with their wild relatives, e.g., to transfer disease-resistance genes present in wild relatives to crops, often fail early in embryogenesis. A genetic divergence between the parents that is too large may be recognized by this novel mechanism, leading to embryo abortion. Commercial crop breeders will thus be interested in finding out how the maternal control of early plant embryo development can be circumvented in their breeding programs.

Story Source:
The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by University of Zurich.

Journal Reference:
Daphné Autran, Célia Baroux, Michael T. Raissig, Thomas Lenormand, Michael Wittig, Stefan Grob, Andrea Steimer, Matthias Barann, Ulrich C. Klostermeier, Olivier Leblanc, Jean-Philippe Vielle-Calzada, Philip Rosenstiel,, Daniel Grimanelli und Ueli Grossniklaus. Maternal Epigenetic Pathways Control Parental Contributions to Arabidopsis Early Embryogenesis. Cell, 2011 DOI: 10.1016/j.cell.2011.04014

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Genetic Traits of Indigenous Mayan People

The Indigenous Maya Genetic Traits: Physical Attributes and Other Characteristics

The genetic traits of the indigenous Mayan people are very distinctive and these characteristics can be observed in almost all of population. Therefore, the indigenous Maya genetic traits are of great interest to clinical researchers and genetic engineers.

The Mayan People

The Mayan people are the large group of early Native Americans living in regions of northern Central America to Mexico. Based on recent surveys, there is an estimated 7 million descendants of Mayan people living in Guatemala, Belize, Honduras, El Salvador and the Mexican states of Yucatan, Campeche, Chiapas, Tabasco, and Quintana Roo. However, there remain very few groups of indigenous Mayan people.

The Mayan people are known for their well-developed written language, the only one of its kind in the pre-Columbian Americas. This Mesoamerican civilization is also recognized for its astronomical systems, unique architecture, arts and mathematical systems.

Aside from these accomplishments, the indigenous Mayan people have also a distinctive set of genetic traits, so it can be deduced that these people came from an isolated origin with a minimal number of individuals. This is clearly shown with nearly 100 percent of the indigenous Mayan population having blood type O. Even up to the modern times, the genetic traits of indigenous Mayan people are distinct enough to allow the easy identification of their descendants.

Traits and Physical Attributes

Without necessarily stereotyping the Maya people and the rest of the Native Americans, there are certain physical attributes that are expressions of the distinct indigenous Maya genetic traits.

One of the distinct physical attributes of the Maya is the presence of melanin on the retina, near the back of the eye. This pigmentation is also coupled with peculiarly heavy eyelids. The extra fold in the eyelids is the distinctive look that makes the Maya appear to have lazy eyes.

This group of people has a set of teeth that have a ledge on the backside, making them look like the shape of a shovel. They also have large front teeth with slight gap. Interestingly, the majority of pure native Maya do not have the Carrabelli cusp on the maxillary first molars.

Other Features
There are many distinctive features of a typical Maya native. One of these features is the inverted breastbone that can make an indentation in one’s chest. Crooked fingers, specifically the pinky, and an extra ridge of bone along the outside of the foot can also be quite common. Large and heavy earlobes are also characteristic features of a Maya.

Native Diseases
Aside from the physical attributes that serve as the expressions of genes, there are also distinct genetic diseases common in indigenous Mayan people. Based on studies, there are five major diseases that can be associated with the genetic makeup common to the indigenous Maya. On the top of the list are fibromyalgia and arthritis. The genes also make the indiginous Maya people prone to diabetes, heart disease and kidney stones. Thyroid problems are also a concern with both hypothyroidism and hyperthyroidism.

Alcoholism is another complex disease that occurs in Mayan people. In the majority of ethnic Native American populations, including the indigenous Maya, very high rates of alcoholism can be observed. This can be attributed to the lack of the enzyme responsible for alcohol metabolism in the bloodstream. Based on linkage analysis, the specific regions on chromosomes 4 and 11 may harbor genes linked to the absence of the alcohol dehydrogenase enzyme. In the case of susceptibility to alcoholism, however, both genetic and environmental factors have been implicated as causes. Hence, the occurrence of such health ailments and conditions cannot be exclusively attributed to the unique features of the Mayan gene pool.

Other Complex Diseases Under Study

There are other conditions with possible genetic causes that are highly researched by clinicians and medical experts. These diseases are highly prevalent among Mayan people. They include congenital hip dysplasia, familial Navajo arthropathy and congenital adrenal hyperplasia.

From the same blood type for the whole population to peculiar physical features, the Maya is an isolated group that retained their own genetic makeup almost unaltered. This makes it a homogenous population with little influences from other cultures. This is the main reason why researchers proclaim interes in studying this group of people.

Restall, Matthew (1997). The Maya World. Yucatecan Culture and Society, 1550-1850. Stanford: Stanford University Press
Sunflower, Cones Kupwah (1996). Let’s Get Physical.
T.L. & M. Genealogy. Talbot Library and Museum P. O. Box 349 Colcord, Oklahoma 74338.

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Did Life arise from RNA?

Is RNA World the Progenitor of Life on our Planet?

The world as we don’t know it. This article explores the role that RNA could have played in the origin of life on this planet.

Biogenesis – Formation of Life

One of the most argued about topics of science and philosophy is the question of the origin of life on planet Earth. There are several competing hypotheses such as the theory of spontaneous generation and the cosmozoic theory which states that life has an extra-terrestrial origin. And there are those who believe that DNA – the molecule of life – was responsible for getting the whole show on the road. However, there is another candidate, the cellular messenger boy that is RNA.

Origin of Life

DNA is transcribed to RNA which is then translated to protein, and proteins build and maintain living organisms. However, if you consider DNA to be the molecule that originated life then there is a problem. Namely that DNA requires proteins to be actively replicated and this leads us to the conundrum of which came first – DNA or protein? It is a classic chicken and egg scenario.

For a molecule to take on the weighty responsibility of the one that started life, it has to be able to do two things. One is to replicate and the other is to catalyze reactions to enable this to happen.

When RNA was first proposed as the originator molecule there really wasn’t much evidence to back the idea. Proponents of RNA argued that it could be formed more easily than DNA, that it could withstand harsher environments than DNA (such that would be found in the early Earth) and finally, that it could evolve into DNA.

However, this idea did not gain much traction until the 1980s when Sidney Altman & Thomas Cech discovered a reaction where RNA could cleave itself or act on itself without the participation of enzymes (proteins). Prior to this, these biochemical reactions were thought to be a function of protein enzymes only. These RNA enzymes were given the name ribozymes and earned their discoverers the Nobel Prize.

RNA as the founding molecule for Life

The term “RNA World” was proposed by Walter Gilbert in 1986. He promoted the idea that the initial molecule that gave life could have been RNA because it can catalyze its own reactions without the need for other entities (proteins). He also argued that it could give rise to proteins and have the ability to store genetic information – an important trait for the molecule that promoted life. During the course of evolutionary time these proteins would help to synthesize DNA from RNA by a process known as reverse transcription.

RNA and DNA are very similar molecules – they are both nucleic acids – and for this reason RNA cannot easily be ruled out as the one that gave rise to life. As RNA can effectively be replicated, store information and transmit the information when required, it is a worthy competitor to DNA. Furthermore, the ability to catalyze its own reactions without the requirement of proteins makes the case of the RNA World a strong one.

However, the idea of RNA World has not enjoyed full scientific support. There are several compelling reasons that argue against it. First of all, storing complex information in RNA molecules is not an easy task. And secondly, the larger the RNA molecule the more fragile it becomes. Given the harsh environmental conditions billions of years ago, it may not have been able to promote life.

Present State of RNA World

Although many scientists have provided great insights into the possibility of RNA as the origin of life, there is still no unified opinion about RNA World theory. Some argue that it was an intermediate molecule, between the first molecule and DNA. Research continues of course, as it is a tantalizing dilemma, a challenge for scientists to solve, keen to find out once and for all where we came from.

Nature, http://www.nature.com/nature/journal/v319/n6055/abs/319618a0.html
Science, http://www.sciencemag.org/content/292/5520/1319.abstract
Proceedings of the National Academy of Science, http://www.pnas.org/content/95/14/7933.abstract

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Genetic ‘wiring’ of seeds revealed

www.diversidadgenetica.comThe genetic ‘wiring’ that helps a seed to decide on the perfect time to germinate has been revealed by scientists for the first time. Plant biologists at The University of Nottingham have also discovered that the same mechanism that controls germination is responsible for another important decision in the life cycle of plants — when to start flowering.

Their discovery throws light on the genetic mechanisms that plants use to detect and respond to vital environmental cues and could be a significant step towards the development of new crop species that are resistant to climate change and would help secure future food supplies.

Seeds in the soil sense a whole range of environmental signals including temperature, light, moisture and nutrients, when deciding whether to germinate or to remain dormant.

To ensure that the decision for a seed to germinate is made at the perfect moment to ensure survival, evolution has genetically ‘wired’ seeds in a very complex way to avoid making potentially deadly mistakes.

The breakthrough has been made by scientists at Nottingham’s Division of Crop and Plant Sciences who collaborate within one of the University’s Research Priority Groups, Global Food Security. The team compiled publicly available gene expression data and used a systematic statistical analysis to untangle the complex web of genetic interactions in a model plant called Arabidopsis thaliana or thale cress. The plant is commonly used for studying plant biology as changes in the plant are easily observed and it was the first plant to have its entire genome sequenced.

The resulting gene network — or SeedNet as it was dubbed — highlighted what little scientists already know about the regulation of seed germination while being able to predict novel regulators of this process with remarkable accuracy.

The work was led by Dr George Bassel who joined The University of Nottingham on an NSERC PDF fellowship from the Canadian government to work with Professor Mike Holdsworth on research into seed germination.

Dr Bassel said: “To our surprise, the seed network demonstrated that genetic factors controlling seed germination were the same as those controlling the other irreversible decision in the life cycle of plants: the decision to start flowering. The induction of flowering, like germination, is highly responsive to cues from the environment.”

Another key finding from SeedNet was that the same genes that leaves and roots use to respond to stress are used by seeds to stop their germination. Given that seeds were evolved long after plants developed their ability to withstand environmental stress, this indicated that plants have adapted existed genes to fulfil a different role. The work could lead to identifying important factors controlling stress response in seeds and the plant itself, contributing towards the development of new crops producing increased yields under extreme environmental conditions such as drought or floods.

The work is being published in the Proceedings of the National Academy of Sciences.

Story Source:
The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by University of Nottingham.

Journal Reference:
George W. Bassel, Hui Lan, Enrico Glaab, Daniel J. Gibbs, Tanja Gerjets, Natalio Krasnogor, Anthony J. Bonner, Michael J. Holdsworth, and Nicholas J. Provart. Genome-wide network model capturing seed germination reveals coordinated regulation of plant cellular phase transitions. Proceedings of the National Academy of Sciences, 2011; DOI: 10.1073/pnas.1100958108

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Non-independent mutations present new path to evolutionary success

Science DailyMutations of DNA that lead to one base being replaced by another don’t have to happen as single, independent events in humans and other eukaryotes, a group of Indiana University Bloomington biologists has learned after surveying several creatures’ genomes.

And, the scientists argue, if “point mutations” can happen in twos, threes — even nines — large evolutionary jumps are possible, especially when problems caused by a single point mutation are immediately compensated for by a second or third. The work appears in the latest issue of Current Biology.

“A similar phenomenon had been observed in bacteria,” said Matthew Hahn, the project’s principal investigator. “And the idea that this might be happening in eukaryotes has been around for a while. We are the first ones to use exhaustive genomic studies to show it’s actually happening, and happening in a big way.”

Hahn and two members of his lab, Ph.D. student Daniel Schrider and undergraduate Jonathan Hourmozdi, surveyed the disparate genomes of yeast (Saccharomyces cerevisiae), roundworm (Caenorhabditis elegans), fruit fly (Drosophila melanogaster), the model plant Arabidopsis thaliania and humans, and found that across the board, about three percent of new mutations are “multi-nucleotide mutations,” or MNMs, perhaps the result of a single, error-prone DNA polymerase making two or more mistakes as it made its way down the chromosome. The group also studied human trios of parent-parent-offspring DNA, as well as the complete genomes of a Yan Chinese (YH01) and J. Craig Venter, cofounder of (and donor to) the Human Genome Project. The researchers found tens of thousands of likely MNMs.

MNMs were essentially defined by the proximity of two or more point mutations. Since mutations are rare, the statistical likelihood of finding two mutations within 20 or 100 bases of each other after a few generations (or a few replication events in the germ line) is low enough to assume two nearby mutations have a near-100 percent likelihood of being caused by the same mutational event.

Three percent of new mutations may not sound like a lot, but even rare genetic phenomena can be very powerful if they impact a creature’s fitness, the measure of an individual’s ability to survive and reproduce.

“There are cases where an organism could improve its fitness if it acquired multiple mutations that would each reduce fitness if they occurred individually,” Schrider said. “In cases like this, the organism would not be able to reach the improved fitness state, as the less-fit intermediate states would be eliminated by natural selection. Cases like this are referred to as ‘fitness valleys.’”

The exchange of a single base within a gene can have drastic consequences for the behavior of the protein that gene encodes. Sickle cell anemia, for example, which causes red blood cells to become rigid, sharp-edged, and resistant to oxygen absorption — and is the cause of listlessness and excruciating pain in the humans who have it — is caused by a point mutation.

The idea, Hahn and Schrider say, is that whatever problems a point mutation causes could be ameliorated by a second, with one point mutation compensating for the other in between generations. The scientists admit they expect this would be a very rare event. But possible.

“The most exciting implication of our work is that it raises the possibility that organisms could leap across fitness valleys and reach a higher-fitness state by acquiring multiple mutations simultaneously,” Schrider said.

Hahn says he does not yet know of examples of genes in which valley leaping might have occurred, but that he and other researchers are eager to investigate.

“Our work provides evidence for a possible new mechanism of adaptation,” Hahn said. “It also raises questions about whether thousands of supposedly independent mutations others have observed in important genes are truly independent. Some of these genes will need to be reanalyzed, because the recognition that some of these mutations are actually MNMs could have an impact on many analyses of DNA sequences.”

But first, Hahn’s group will try to see whether the MNMs they’ve found in humans conform to the mechanism geneticists have observed in humans’ faultier DNA polymerases.

“It’s satisfying to be able to be able to show that this is real,” Hahn said. “I talked about this at a recent conference, and no matter who we talked to, they said the same sorts of things: ‘Oh yeah I’ve seen those before, but I just thought it was a statistical anomaly.’ People have seen the phenomenon but they just didn’t know it was meaningful. We hope this gets people excited to go back and look at their old sequence data.”

This work was supported by grants from the Sloan Foundation, the National Science Foundation, and the Indiana University Cox Scholarship Program.

Story Source:
The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Indiana University, via EurekAlert!, a service of AAAS.

Journal Reference:
Daniel R. Schrider, Jonathan N. Hourmozdi, Matthew W. Hahn. Pervasive Multinucleotide Mutational Events in Eukaryotes. Current Biology, June 2, 2011 DOI: 10.1016/j.cub.2011.05.013

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Genetics of Sex Determination

How Sex is Determined by Genetics

The human organism contains threadlike, gene-bearing chromosomes, twenty three pairs of them. These chromosomes contain the complete heredity, including characteristics such as the color of the eyes, the hair and skin. One specific pair of chromosomes determines the sex or gender of the individual.Chromosomal sex determination.

Of the 46 chromosomes in each human cell except sperm and egg cells (which have only half that number), 44 are non-sex chromosomes or “autosomes.” The other two are the sex chromosomes. Sex chromosomes come in only two varieties: an X and a Y. If one of the two chromosomes is an X and the other is a Y, the individual is male. If both chromosomes are X, the individual is female. In addition to its sex-determining role, the X chromosome includes a great deal of other information. This is because the X chromosome contains several times the number of genes contained in the Y chromosome.

X and Y Sex ChromosomesX and Y Chromosomes – NASA

Of course, this was not always known. The first indication of a chromosomal mechanism for sex determination is traceable to experiments carried out by Thomas Hunt Morgan and his students in the early Twentieth Century. In researching a batch of fruit flies, Drosophila melanogaster, which typically have red eyes but in which there were some with white eyes, he noticed that all of the white-eyed flies present were male.

He already knew female flies have two X chromosomes, while males have only one. He correctly concluded from this that the white-eye color trait is on the X chromosome. Female flies rarely have white eyes because a white-eye trait on one X chromosome is likely to be cancelled out by a much more prevalent red version on the second X chromosome. Males, on the other hand, only have one X chromosome, and if contains the white trait, the eyes of the fly must be white.

This work demonstrates that the X chromosome is an important factor in sex determination. It also was the basis for further use of the fruit fly by later genetics researchers. For his work, Morgan was awarded the Nobel Prize in physiology in 1933.

Boys, Girls and King Henry VIII

A child can only inherit an X chromosome from its mother, but it can inherit either an X or a Y chromosome from its father. This comes about because of the fertilization of the female egg (with its 23 chromosomes, one of which is an X) with a sperm from the male (with its 23 chromosomes, one of which is either an X or a Y).

Interestingly, King Henry VIII, who desired a male child for an heir to the throne, was angered by his first two wives who failed to provide him such an heir. Since gender is determined by the father and not the mother, the “failure” to produce a male child was actually Henry’s failure.

References and Resources
Biology Reference, http://www.biologyreference.com/Re-Se/Sex-Determination.html
The University of Utah: Genetic Science Learning Center, http://learn.genetics.utah.edu/
Suggested Reading: The Basic Parts of Human Chromosomes, by Paul Arnold.

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New technique sheds light on the mysterious process of cell division

Science DailyUsing a new technique in which models of primitive cells are constructed from the bottom up, scientists have demonstrated that the structure of a cell’s membrane and cytoplasm may be as important to cell division as the specialized machinery — such as enzymes, DNA or RNA — which are found within living cells.

Christine Keating, an associate professor of chemistry at Penn State University, and Meghan Andes-Koback, a graduate student in the Penn State Department of Chemistry, generated simple, non-living model “cells” with which they established that asymmetric division — the process by which a cell splits to become two distinct daughter cells — is possible even in the absence of complex cellular components, such as genes. The study, which will be published in the Journal of the American Chemical Society, may provide important clues to how life originated from non-life and how modern cells came to exhibit complex behaviors.

Keating explained that how biological cells split into asymmetrical daughter cells with very different compositions and different “fates” is something of a mystery. Cellular differentiation — the process by which an unspecialized cell, such as a stem cell, becomes a specialized cell — requires that different biological components reorganize themselves into each of the resulting daughter cells. For this apparently complex task to be accomplished, some important mechanism must guide both the reorganization of cellular parts and the maintenance of polarity — the property of a cell to exhibit distinct front and back “sides” with specific placement and distribution of cellular machinery. “Many genes have been implicated in the maintenance of cell polarity and the facilitation of division into nonidentical daughter cells. It’s thanks to changes in the expression of these genes that a skin cell becomes a skin cell and a heart cell becomes a heart cell,” Keating said. “But our research took a different approach. We asked: In addition to the genetic factors that guide asymmetrical cell division and polarity maintenance, what structural, biophysical factors might be at work, and how might these factors have predated the evolution of the complex genetic systems known to exist in modern cells?”

The team began with the hypothesis that because new daughter cells arise by division of existing mother cells, certain inherited material — such as the cell membrane — could serve as a sort of informational “landmark.” This landmark could set in motion and guide a cascade of chemical events related to ordered cell division and polarity maintenance. To test this hypothesis, Keating and Andes-Koback built model cells from the bottom up, allowing water, lipids, and polymers to assemble into mimics of the most basic constituents of real, living cells — such as a membrane and cytoplasm. They then altered the osmotic pressure outside of the “cells” by adding sugar, which forced them to divide in a way that is reminiscent of how living, biological cells split under natural conditions.

“We observed that even model cells can divide in a structured way, which implies a kind of intrinsic order,” Andes-Koback said. She explained that, like a biological cell, the model mother cell was designed to exhibit asymmetry in both its membrane and its cellular interior. The membrane asymmetry was modeled using two distinct lipid domains, while the cellular interior was modeled using two distinct polymers called polyethylene glycol (PEG) and dextran. These polymers form distinct domains, or compartments, on the inside of the model cells, with the dextran-rich compartment containing a higher concentration of a particular protein. The team observed that when the asymmetric mother cell divided, one daughter inherited one lipid domain surrounding the PEG-rich interior, and the other daughter inherited the other membrane domain surrounding the dextran-rich interior, which contained the larger portion of the protein. “Most importantly, we also found that when we varied the relative size of the two lipid domains, one daughter cell got both types of membrane and the other daughter got only one type,” Andes-Koback said. “This was possible since the interior aqueous phases controlled the fission plane, and it is important because it provides a way to achieve a patch of distinct membrane to serve as a landmark for polarity in subsequent ‘generations.’”

The team members note that the new modeling technique seems to suggests that simple chemical and physical interactions within cells — such as self-assembly, phase separation, and partitioning — can result in seemingly complex behaviors — like asymmetric division — even when no additional cellular machinery is present. “Since there were no nucleic acids nor enzymes present, we clearly didn’t have genes governing how our model cells would behave,” Keating said. “So our study supports the hypothesis that structural and organizational ‘cues’ work in concert with genetic signals to achieve and maintain polarity through successive cell-division cycles.”

Keating added that a working model of cellular dynamics requires a good understanding, not just of the role of genes, but also of the role of the structural organization of cells. “Once we have a firm grasp of what guides a cell’s behavior, we might one day be able to design better disease treatments based on targeting errors in intracellular organization,” she said.

Keating also explained that experimentation on non-living model cells that contain no DNA could help point to clues explaining the mysterious process of abiogenesis — the formation of life from non-living matter, an event that happened at least once during our Earth’s history. “Scientists have simulated early-Earth conditions in laboratories and have demonstrated that many amino acids — the biochemical constituents of proteins — can form through natural chemical reactions,” Keating said. “We hope our research helps to fill in another part of the puzzle: how chemical and spatial organization may have contributed to the success of early life forms.”

The work was funded by the Chemistry and Molecular and Cellular Biosciences divisions of the National Science Foundation and by the National Institutes of Health.

Story Source:
The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Penn State.

Journal Reference:
Meghan Andes-Koback, Christine D. Keating. Complete Budding and Asymmetric Division of Primitive Model Cells to Produce Daughter Vesicles with Different Interior and Membrane Compositions. Journal of the American Chemical Society, 2011; 110518124742024 DOI: 10.1021/ja202406v

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New malaria protein structure upends theory of how cells grow and move

ScienceDaily (May 30, 2011) — Researchers from the Walter and Eliza Hall Institute have overturned conventional wisdom on how cell movement across all species is controlled, solving the structure of a protein that cuts power to the cell ‘motor’. The protein could be a potential drug target for future malaria and anti-cancer treatments.

By studying the structure of actin-depolymerising factor 1 (ADF1), a key protein involved in controlling the movement of malaria parasites, the researchers have demonstrated that scientists’ decades-long understanding of the relationship between protein structure and cell movement is flawed.

Dr Jake Baum and Mr Wilson Wong from the institute’s Infection and Immunity division and Dr Jacqui Gulbis from the Structural Biology division, in collaboration with Dr Dave Kovar from the University of Chicago, US, led the research, which appears in the May 31 edition of the Proceedings of the National Academy of Sciences USA.

Dr Baum said actin-depolymerising factors (ADFs) and their genetic regulators have long been known to be involved in controlling cell movement, including the movement of malaria parasites and movement of cancer cells through the body. Anti-cancer treatments that exploit this knowledge are under development.

“ADFs help the cell to recycle actin, a protein which controls critical functions such as cell motility, muscle contraction, and cell division and signaling,” Dr Baum said. “Actin has unusual properties, being able to spontaneously form polymers which are used by cells to engage internal molecular motors — much like a clutch does in the engine of your car. A suite of accessory proteins control how the clutch is engaged, including those that dismantle or ‘cut’ these polymers, such as ADF1.

“For many years research in yeast, plants and humans has suggested that the ability of ADFs to dismantle actin polymers — effectively disengaging the clutch — required a small molecular ‘finger’ to break the actin in two,” Dr Baum said. “However, when we looked at the malaria ADF1 protein, we were surprised to discover that it lacked this molecular ‘finger’, yet remarkably was still able to cut the polymers. We discovered that a previously overlooked part of the protein, effectively the ‘knuckle’ of the finger-like protrusion, was responsible for dismantling the actin; we then discovered this ‘hidden’ domain was present across all ADFs.”

Mr Wong said that the Australian Synchrotron was critical in providing the extraordinary detail that helped the team pinpoint the protein ‘knuckle’. “This is the first time a 3D image of the ADF protein has been captured in such detail from any cell type,” Mr Wong said. “Imaging the protein structure at such high resolution was critical in proving beyond question the segment of the protein responsible for cutting actin polymers. Obtaining that image would have been impossible without the synchrotron facilities.”

Dr Baum said the new knowledge will give researchers a much clearer understanding of one of the fundamental steps governing how cells across all species grow, divide and, importantly, move. “Knowing that this one small segment of the protein is singularly responsible for ADF1 function means that we need to focus on an entirely new target not only for developing anti-malarial treatments, but also other diseases where potential treatments target actin, such as anti-cancer therapeutics,” Dr Baum said. “Malaria researchers are normally used to following insights from other biological systems; this is a case of the exception proving the rule: where the malaria parasite, being so unusual, reveals how all other ADFs across nature work.”

More than 250 million people contract malaria each year, and almost one million people, mostly children, die from the disease. The malaria parasite has developed resistance to most of the therapeutic agents available for treating the disease, so identifying novel ways of targeting the parasite is crucial.

Dr Baum said that the discovery could lead to development of drugs entirely geared toward preventing malaria infection, without adverse effects on human cells. “One of the primary goals of the global fight against malaria is to develop novel drugs that prevent infection and transmission in all hosts, to break the malaria cycle,” Dr Baum said. “There is a very real possibility that, in the future, drugs could be developed that ‘jam’ this molecular ‘clutch’, meaning the malaria parasite cannot move and continue to infect cells in any of its conventional hosts, which would be a huge breakthrough for the field.”

This project was funded by the National Health and Medical Research Council (NHMRC).

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The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Walter and Eliza Hall Institute.

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