Josh: While this is certainly an important genetic variation to find, I’m wondering if doctors would be able to use this information if they tested their patients. What could be done differently in treating high levels of triglycerides? This would be much more useful if a drug existed to treat this specific cause of elevated plasma TG levels.

A genetic variant found almost exclusively in individuals of Asian descent increases the risk of elevated triglycerides over four-fold, reports a comprehensive study in the August Journal of Lipid Research. In fact, all 11 subjects who carried both copies of this rare variant for apolipoprotein A-V had extremely high and dangerous triglyceride levels in their blood.

Apolipoprotein A-V is a recently discovered lipid-binding protein that likely plays an important role in metabolizing triglycerides. Some population studies with groups in China and Taiwan indicate that a polymorphism in the APOA5 gene (553 G>T shift) is associated with elevated plasma TG levels, which like cholesterol, increase the risk of heart disease. … Continue Reading »

Josh: This opens the doors for doctors provide genetic testing to new borns and babies still in the womb to diagnose mitochondrial diseases. Already, in this study, they found one mutation that is a cause of complex I disease.

Imagine trying to figure out how your car’s power train works from just a few of its myriad components: It would be nearly impossible. Scientists have long faced a similar challenge in understanding cells’ tiny powerhouses — called “mitochondria” — from scant knowledge of their molecular parts.

Now, an international team of researchers has created the most comprehensive “parts list” to date for mitochondria, a compendium that includes nearly 1,100 proteins. By mining this critical resource, the researchers have already gained deep insights into the biological roles and evolutionary histories of several key proteins. In addition, this careful cataloging has identified a mutation in a novel protein-coding gene as the cause behind one devastating mitochondrial disease. A full description of the work appears in the July 11 print edition of the journal Cell. … Continue Reading »

A group of researchers from the University of Copenhagen and the Biocentre at the Technical University of Denmark have managed to decipher the final part of the immune system’s key codes.

The same researchers already broke the first part of the codes last autumn, and have now put together a comprehensive picture of how the immune system checks for dangers both in and outside our cells.

According to the researchers this new information, produced with the aid of artificial neural networks, means that it should be possible to predict all the immune system’s known, and also as yet unknown codes. This should in turn lead to the development of new targeted treatments, for e.g. cancer and infectious diseases.

Professor Søren Buus from the Faculty of Health Sciences at the University of Copenhagen has been at the forefront of this research project.

The body’s natural defences uses these key codes in such a way that microorganisms cannot spy on and discover its functions. It this unique protection that has so far made it difficult for scientists to decode the entire human immune system and thus develop precise immunological tools and carry out organ transplants.

Source: University of Copenhagen

In the late 19th century Gregor Mendel used peas to show that one copy of a gene (allele) is inherited from the mother and one from the father. In the progeny, the inherited genes are expressed at the right time and in the right place, but until recently, it was thought that although gene products could be modified during the life of the organism, the genes themselves were unchanged, except for random mutation. Now it appears that one copy of some genes can alter the expression of the other copy, and those changes are passed down to the next generation. These epigenetic alterations, called paramutations may be important in introducing changes when plants and other organisms are environmentally stressed. The exact mechanisms of how genes talk to other genes and change their behavior are being investigated, and recent results suggest that these processes could be important in engineering plants responsive to a variety of environmental conditions.

Dr. Vicki Chandler and her colleagues have studied paramutations in maize and other plants and have identified some of the genes and mechanisms that operate in this epigenetic process. Dr. Chandler, of the Department of Plant Sciences at the University of Arizona, Tucson, will be presenting this work at a symposium on Maize Biology at the annual meeting of the American Society of Plant Biologists in Mérida, Mexico (June 28, 9:10 AM).

The sequencing of genes, proteins, and, ultimately, whole genomes has revealed that genomes are not simply strings of genes, but rather complex, communicating, and interacting regions of information that could be compared to DNA computers controlling growth, development, and metabolism in each organism. The physical architecture of the genome is also highly complex. The nucleus, where the genome resides, is not full of strings of DNA like a pot of spaghetti. Rather, the strands of DNA are wrapped around proteins called histones and the whole is organized into an elegant and highly controlled structure called chromatin. When it is time for genes to be expressed, a section of chromatin is unwound and the DNA for that particular gene is made available to the machinery that transcribes DNA to RNA. Once the process is finished, the DNA is neatly folded back into the chromatin structure until needed again. Different parts of the genome can interact by direct contact or through intermediaries that can be proteins or RNA sequences. The exact mechanisms of how paramutagenic alleles communicate with their homologous partners are still unknown, but the work of Chandler and others suggests that both direct contact of homologous regions and changes induced by intermediary RNA molecules may be involved.

Peas also played an important role in the discovery of paramutations, as the first mutants of this type were observed in peas in 1915. Then, in the 1950s, Alexander Brink identified these types of mutations as interactions between alleles. He recognized that these interactions resulted in heritable changes to the expression of those genes. Since then, paramutations have been found in humans and other animals, as well as other plant species including tomato, tobacco, petunia, and maize. In animals, paramutations may be important in mediating the occurrence of diseases like diabetes. Chandler and her co-workers have been investigating paramutations in maize at the b1 gene, which regulates the distribution of the purple pigment anthocyanin in plant tissues.

At the b1 locus, the paramutagenic allele, which causes light or stippled pigmentation arises spontaneously from the wild-type allele, which causes dark purple pigmentation. If a plant with the paramutagenic allele is crossed with a wild-type allele, the progeny get both alleles. However, the paramutagenic allele silences the wild-type allele and produces a plant with stippled rather than purple pigmentation. The silent state is then passed on in subsequent crosses.

Several different components may be involved in paramutation, although they may differ among species. One important player is an array of repeated non-coding DNA sequences that lies upstream of the gene sequence of the paramutagenic allele. Seven of these tandem repeats are required for b1 paramutation. If only three tandem repeats are present, there is only partial paramutagenic activity. One possibility is that these tandem repeats are involved in direct interactions of chromatin regions, which results in paramutation changes. However, RNA also appears to be part of the process. The gene mediator of paramutation1 (mop1), an RNA dependent RNA polymerase is absolutely required for paramutation silencing at the b1 locus as well as for several other maize genes. In Arabidopsis, this RNA polymerase is associated with the production of small, interfering RNAs (siRNA) that function in gene silencing in other contexts. The siRNA could thus act as an intermediary molecule, being sent to silence the homologous allele. A third component is the placement of methyl groups on the control sequence (promoter) of the wild-type gene. Gene methylation has been known for some time as a cell defense mechanism for silencing foreign DNA but is also functional in other cellular processes. In several species, such methylation is also directed by RNA molecules. None of these processes is likely to be sufficient by themselves to effect paramutation, but rather all of them may interact, although to varying degrees in different species.

The molecular components of paramutation probably arose as cell defense mechanisms against viral or bacterial DNA. They have evolved to serve the needs of plants that grow in complex and changing environments from which they cannot escape, but to which they may be able to adapt through mechanisms like paramutation. Indeed, two instances of paramutation are known to be influenced by temperature. This work has implications for engineering crops that may be able to adapt to higher temperatures or drought conditions, as well as for applications in human and veterinary medicine.

Source: American Society of Plant Biologists

A collaboration of scientists from Iceland and the United States has used Iceland’s genealogical database (by deCODE genetics) to trace the ancestors of patients suffering from hereditary cystatin C amyloid angiopathy (HCCAA). Analysis shows that the deadly mutation in the cystatin C gene, L68Q, derives from a common ancestor born roughly 18 generations ago, around 1550AD. Details are published June 20th in the open-access journal PLoS Genetics.

This dominantly inherited disease, which is due to a mutation in cystatin C (L68Q), strikes young adults with healthy blood pressure. The disease results in death from repeated brain haemorrhages, on average by the age of 30. The origin of the mutation causing HCCAA was previously unknown, but using DNA haplotype analysis the scientists have shed light on the history of this autosomal dominant disease that has high penetrance in contemporary Icelanders.

The scientists found that 200 years ago, obligate carriers of the mutation lived a normal life span compared to the control population (their spouses). In carriers born around 1820, however, a trend of shortening life span began, resulting in an average life span of only 30 years in people born around 1900. This 30-year lifespan has stayed constant since then in both men and women.

At the same time, a matrilinear effect appeared whereby those who inherited the mutation from the mother died earlier. For carriers born after 1900, the difference is a loss of 9.4 years for those who inherited the mutation from their mothers rather than their fathers. Based on this information, the authors propose that the traditional diet of the nation (which in the past consisted largely of whey-preserved offal as well as meat, dried fish, and butter) “protected” the mutation carriers for almost 300 years until the Icelandic diet changed early in the early 19th century, exemplified by drastic increases in imported carbohydrates and salt.

This finding has implications for studies of Alzheimer’s disease as cerebral amyloid angiopathy (CAA) is almost universally found in Alzheimer’s patients and normal cystatin C protein is one of the proteins found in amyloid in brains of Alzheimer’s patients. Studies are underway to try to elucidate the risk factors with the hope of providing a preventive stategy for cystatin L68Q carriers.

Source: Public Library of Science

Palsdottir A, Helgason A, Palsson S, Bjornsson HT, Bragason BT, et al. (2008) A Drastic Reduction in the Life Span of Cystatin C L68Q Carriers Due to Life-Style Changes during the Last Two Centuries. PLoS Genet 4(6): e1000099. doi:10.1371/journal.pgen.1000099

Josh says:

This is amazing. It almost makes me wish that the United States and other countries had a database like Iceland does, except I don’t really trust the US government. Regardless, as the costs for sequencing decrease, we should start to see more discoveries like this.

Reporting in this week’s PLoS ONE, an Italian research team, consisting of Andrea Camperio Ciani and Giovanni Zanzotto at the University of Padova and Paolo Cermelli at the University of Torino, found that the evolutionary origin and maintenance of male homosexuality in human populations could be explained by a model based around the idea of sexually antagonistic selection, in which genetic factors spread in the population by giving a reproductive advantage to one sex while disadvantaging the other.

Male homosexuality is thought to be influenced by psycho-social factors, as well as having a genetic component. This is suggested by the high concordance of sexual orientation in identical twins and the fact that homosexuality is more common in males belonging to the maternal line of male homosexuals. These effects have not been shown for female homosexuality, indicating that these two phenomena may have very different origins and dynamics.

Male homosexuality is difficult to explain under Darwinian evolutionary models, because carriers of genes predisposing towards male homosexuality would be likely to reproduce less than average, suggesting that alleles influencing homosexuality should progressively disappear from a population. This changed when previous work by Camperio Ciani and collaborators, published in 2004, showed that females in the maternal line of male homosexuals were more fertile than average.

Challenged by all these empirical data, the authors of the new study published in PLoS ONE considered a range of different hypotheses for the genetic diffusion of male homosexuality. These included: the genetic maternal effects on sons, the heterozygote advantage (as is found in malaria resistance), and “sexually antagonistic selection.” The latter is a particular aspect of Darwinian evolution, in which genetic factors spread in the population by giving a reproductive advantage to one sex while disadvantaging the other. This type of evolution has been previously found in insects, birds, and some mammals, but never in humans.

To discover and clarify the dynamics of the genetic factors for homosexuality, the researchers had to screen a large set of models and exclude them one by one. They concluded that the only possible model was that of sexually antagonistic selection. The other models did not fit the empirical data, either implying that the alleles would become extinct too easily or invade the population, or failing to describe the distribution patterns of male homosexuality and female fecundity observed in the families of homosexuals. Only the model of sexually antagonistic selection involving at least two genes – at least one of which must be on the X chromosome (inherited in males only through their mother) – accounted for all the known data.

The results of this model show the interaction of male homosexuality with increased female fecundity within human populations, in a complex dynamic, resulting in the maintenance of male homosexuality at stable and relatively low frequencies, and highlighting the effects of heredity through the maternal line.

These findings provide new insights into male homosexuality in humans. In particular, they promote a focus shift in which homosexuality should not be viewed as a detrimental trait (due to the reduced male fecundity it entails), but, rather, should be considered within the wider evolutionary framework of a characteristic with gender-specific benefits, and which promotes female fecundity. This may well be the evolutionary origin of this genetic trait in human beings.

The possible widespread occurrence of sexually antagonistic characteristics in evolutionary processes, which play their evolutionary game by giving a fecundity benefit to one sex while disadvantaging the other, has only recently begun to be appreciated. This is understood as a key mechanism through which high levels of genetic variation are maintained in biological populations. Male homosexuality is just the first example of an unknown number of sexually antagonistic traits, which contribute to the maintenance of the natural genetic variability of humans. The new perspectives opened by the models developed for sexually antagonistic selection may also contribute to a better understanding of most genetically-based sexual conflicts, which are, at present, poorly understood in humans.

An unexpected implication of the new models concerns the impact that the sexually antagonistic genetic factors for male homosexuality have on the overall fecundity of a population. The findings suggest that the proportion of male homosexuals may signal a corresponding proportion of females with higher fecundity. Consequently, these factors always contribute, all else being equal, a positive net increase of the fecundity of the whole population, when compared to populations in which such factors are lower or absent. This increase grows as the population baseline fecundity decreases; this means that the genes influencing male homosexuality end up playing the role of a buffer effect on any external factors lowering the overall fecundity of the whole population.

Source: Public Library of Science

Camperio Ciani A, Cermelli P, Zanzotto G (2008) Sexually Antagonistic Selection in Human Male Homosexuality. PLoS ONE 3(6): e2282. doi:10.1371/journal.pone.0002282

Josh says:

Wow. While they did not actually find a gene mutation linked to this, the data fits the model. Certainly it provides an explanation, and I personally like it better than many other explanations. However, whether a male is homosexual or heterosexual cannot be solely genetic, but rather is more likely a genetic predisposition (though I could be wrong). So what about this type of mutation would create such a predisposition?

Note: For those not familiar with the term, fecundity refers to how fertile a female is or how many offspring are produced.

Researchers at the University of Minnesota have discovered a gene that may provide a clue as to why obesity rates increase with age. The research was published today in the Proceedings of the National Academy of Sciences.

Researchers in the lab of Kevin Wickman, Ph.D., associate professor of pharmacology at the University of Minnesota Medical School, removed a single gene from mice as part of an ongoing study to understand how the brain controls heart function. While some cardiac deficiencies were detected in these mice, the researchers unexpectedly found that these mice exhibited a predisposition to adult-onset obesity.
“This was not an outcome we expected, but now we have an animal model that may provide new insight into human obesity,” said Wickman, co-author of the article.

By examining closely where this gene, termed Girk4, is expressed in the body, the researchers found particularly high levels in the hypothalamus, a brain region involved in regulating food intake and energy expenditure. Wickman speculated that disruption of normal function in the hypothalamus may underlie the obesity seen in the mutant mice, but he acknowledges that more research is needed to understand where and how this gene works, and consequently, why mice missing this gene develop obesity.

The age-dependence of the obesity seen in this mouse model mimics human obesity patterns, researchers said. Indeed, the likelihood of people developing obesity more than doubles between the ages of 20 and 60.

“This is a novel finding that may provide important new insight to the underlying cellular mechanisms that influence obesity,” said Catherine Kotz, Ph.D., co-author of the article, scientist at the Minneapolis VA Medical Center and adjunct professor in the Department of Food Science and Nutrition at the University of Minnesota.

Source: University of Minnesota

Cydne A. Perry, Marco Pravetoni, Jennifer A. Teske, Carolina Aguado, Darin J. Erickson, Juan F. Medrano, Rafael Luján, Catherine M. Kotz, and Kevin Wickman. Predisposition to late-onset obesity in GIRK4 knockout mice. PNAS 2008 105: 8148-8153; published online on June 3, 2008, 10.1073/pnas.0803261105

Josh says:

Sometimes, the best discoveries in science are made by accident, though this isn’t exactly Nobel Prize worthy. Regardless, I’m still curious about the affects in humans and what the protein encoded by this gene normally does.

A new approach to treating vision loss caused by Type 1 Usher syndrome (USH1), the most common condition affecting both sight and hearing, will be unveiled by a scientist at the annual conference of the European Society of Human Genetics tomorrow (Tuesday 3 June). Ms Annie Rebibo Sabbah, from the Genetics Department of the Rappaport Faculty of Medicine, Technion, Haifa, Israel, will tell the conference that preliminary results using a class of drugs called aminoglycosides, commonly used as antibiotics, had had promising effects in vitro and in cell culture.

Usher syndrome is a recessively- inherited disease; in order to have it, the child must receive a mutated form of the Usher gene from each parent. Approximately 3 to 6 percent of all children who are deaf and another 3 to 6 percent of children who are hard-of-hearing have it. In developed countries, about four babies in every 100,000 births have Usher syndrome. Children born with USH1 begin to develop visual problems in early childhood, and these develop quickly into an eye disorder called retinitis pigmentosa, which leads to complete blindness. … Continue Reading »