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 »

As the cost of sequencing a single human genome drops rapidly, with one company predicting a price of $100 per person in five years, soon the only reason not to look at your “personal genome” will be fear of what bad news lies in your genes.

University of California, Berkeley, scientists, however, have found a welcome reason to delve into your genetic heritage: to find the slight genetic flaws that can be fixed with remedies as simple as vitamin or mineral supplements.

“I’m looking for the good news in the human genome,” said Jasper Rine, UC Berkeley professor of molecular and cell biology.

“Headlines for the last 20 years have really been about the triumph of biomedical research in finding disease genes, which is biologically interesting, genetically important and frightening to people who get this information,” Rine said. “I became obsessed with trying to decide if there is some other class of information that will make people want to look at their genome sequence.”

What Rine and colleagues found and report this week in the online early edition of the journal Proceedings of the National Academy of Sciences (PNAS) is that there are many genetic differences that make people’s enzymes less efficient than normal, and that simple supplementation with vitamins can often restore some of these deficient enzymes to full working order.

First author Nicholas Marini, a UC Berkeley research scientist, noted that physicians prescribe vitamins to “cure” many rare and potentially fatal metabolic defects caused by mutations in critical enzymes. But those affected by these metabolic diseases are people with two bad copies, or alleles, of an essential enzyme. Many others may be walking around with only one bad gene, or two copies of slightly defective genes, throwing their enzyme levels off slightly and causing subtle effects that also could be eliminated with vitamin supplements.

“Our studies have convinced us that there is a lot of variation in the population in these enzymes, and a lot of it affects function, and a lot of it is responsive to vitamins,” Marini said. “I wouldn’t be surprised if everybody is going to require a different optimal dose of vitamins based on their genetic makeup, based upon the kind of variance they are harboring in vitamin-dependent enzymes.”

Though this initial study tested the function of human gene variants by transplanting them into yeast cells, where the function of the variants can be accurately assessed, Rine and Marini are confident the results will hold up in humans. Their research, partially supported by the Defense Advanced Research Projects Agency (DARPA) and the U.S. Army, may enable them to employ U.S. soldiers to test the theory that vitamin supplementation can tune up defective enzymes.

“Our soldiers, like top athletes, operate under extreme conditions that may well be limited by their physiology,” Rine said. “We’re now working with the defense department to identify variants of enzymes that are remediable, and ultimately hope to identify troops that have these variants and test whether performance can be enhanced by appropriate supplementation.”

In the PNAS paper, Rine, Marini and their colleagues report on their initial analysis of variants of a human enzyme called methylenetetrahydrofolate reductase, or MTHFR. The enzyme, which requires the B vitamin folate to work properly, plays a key role in synthesizing molecules that go into the nucleotide building blocks of DNA. Some cancer drugs, such as methotrexate, target MTHFR to shut down DNA synthesis and prevent tumor growth.

Using DNA samples from 564 individuals of many races and ethnicities, colleagues at Applied Biosystems of Foster City, Calif., sequenced for each person the two alleles that code for the MTHFR enzyme. Consistent with earlier studies, they found three common variants of the enzyme, but also 11 uncommon variants, each of the latter accounting for less than one percent of the sample.

They then synthesized the gene for each variant of the enzyme, and Marini, Rine and their UC Berkeley colleagues inserted these genes into separate yeast cells in order to judge the activity of each variant. Yeast use many of the same enzymes and cofactor vitamins and minerals as humans and are an excellent model for human metabolism, Rine said.

The researchers found that four different mutations affected the functioning of the human enzyme in yeast. One of these mutations is well known: Nearly 30 percent of the population has one copy, and nine percent has two copies.

The researchers were able to supplement the diet of the cultured yeast with folate, however, and restore full functionality to the most common variant, and to all but one of the less common variants.

Since this experiment, the researchers have found 30 other variants of the MTHFR enzyme and tested about 15 of them, “and more than half interfere with the function of the enzyme, producing a hundred-fold range of enzyme activity. The majority of these can be either partially or completely restored to normal activity by adding more folate. And that is a surprise,” Rine said.

Most scientists think that harmful mutations are disfavored by evolution, but Rine pointed out that this applies only to mutations that affect reproductive fitness. Mutations that affect our health in later years are not efficiently removed by evolution and may remain in our genome forever.

The health effects of tuning up this enzyme in humans are unclear, he said, but folate is already known to protect against birth defects and seems to protect against heart disease and cancer. At least one defect in the MTHFR enzyme produces elevated levels in the blood of the metabolite homocysteine, which is linked to an increased risk of heart disease and stroke, conditions that typically affect people in their post-reproductive years.

“In those people, supplementation of folate in the diet can reduce levels of that metabolite and reduce disease risk,” Marini said.

Marini and Rine estimate that the average person has five rare mutant enzymes, and perhaps other not-so-rare variants, that could be improved with vitamin or mineral supplements.

“There are over 600 human enzymes that use vitamins or minerals as cofactors, and this study reports just what we found by studying one of them,” Rine said. “What this means is that, even if the odds of an individual having a defect in one gene is low, with 600 genes, we are all likely to have some mutations that limit one or more of our enzymes.”

The subtle effects of variation in enzyme activity may well account for conflicting results of some clinical trials, including the confusing data on the effect of vitamin supplements, he noted. In the future, the enzyme profile of research subjects will have to be taken into account in analyzing the outcome of clinical trials.

If one considers not just vitamin-dependent enzymes but all the 30,000 human proteins in the genome, “every individual would harbor approximately 250 deleterious substitutions considering only the low-frequency variants. These numbers suggest that the aggregate incidence of low-frequency variants could have a significant physiological impact,” the researchers wrote in their paper.

All the more reason to poke around in one’s genome, Rine said.

“If you don’t give people a reason to become interested in their genome and to become comfortable with their personal genomic information, then the benefits of much of the biomedical research, which is indexed to particular genetic states, won’t be embraced in a time frame that most people can benefit from,” Rine said. “So, my motivation is partly scientific, partly an education project and, in some ways, a partly political project.”

Marini and Rine credit Bruce Ames, a UC Berkeley professor emeritus of molecular and cell biology now on the research staff at Children’s Hospital Oakland Research Institute, with the research that motivated them to look at enzyme variation. Ames found in the 1970s that many bacteria that could not produce a specific amino acid could do so if given more vitamin B6, and in recent years he has continued exploring the link between micronutrients and health.

“Looked at in one way, Bruce found that you can cure a genetic disease in bacteria by treating it with vitamins,” Rine said. Because the human genome contains about 6 billion DNA base pairs, each one subject to mutation, there could be between 3 and 6 million DNA sequence differences between any two people. Given those numbers, he reasoned that, as in bacteria, “there should be people who are genetically different in terms of the amount of vitamin needed for optimal performance of their enzymes.”

This touches on what Rine considers one of the key biomedical questions today. “Now that we have the complete genome sequences of all the common model organisms, including humans, it’s obvious that the defining challenge of biology in the 21st century is not what the genes are, but what the variation in the genes does,” he said.

Rine, Marini and their colleagues are continuing to study variation in the human MTHFR gene as well as other folate utilizing enzymes, particularly with respect to how defects in these enzymes may lead to birth defects. Rine also is taking advantage of the 1,500 students in his Biology 1A lab course to investigate variants of a second vitamin B6-dependent enzyme, cystathionine beta-synthase.

He also is investigating how enzyme cofactors like vitamins and minerals fix defective enzymes. He suspects that supplements work by acting as chaperones to stabilize the proper folding of the enzyme, which is critical to its catalytic activity. “That is a new principle that may be applicable to drug design,” Rine said.

Source: University of California - Berkeley

Nicholas J. Marini, Jennifer Gin, Janet Ziegle, Kathryn Hunkapiller Keho, David Ginzinger, Dennis A. Gilbert, and Jasper Rine. The prevalence of folate-remedial MTHFR enzyme variants in humans. PNAS published June 3, 2008, 10.1073/pnas.0802813105

Josh says:

The chaperone idea that’s mentioned at the end is intriguing. However, doctors have been treating these types of genetic deficiencies for a while. Most of them are in the pentose phosphate pathway, with the most common being glucose-6-phosphate dehydrogenase (G6PD). A “byproduct” of the pentose phosphate pathway is NADPH, which is also used as a cofactor by methylenetetrahydrofolate reductase (MTHFR).

Certainly, there are little mutations in some of our enzymes that will affect their efficiency. I’m not sure how much it will help to target these minor ones, though it definitely won’t hurt. In the meantime, I’m going to continue to just take my daily multi-vitamin.

Note: for biochemistry, wikipedia is a surprisingly thorough resource. It doesn’t have as much when it comes to specific proteins for developmental biology or some aspects of molecular biology, but the biochemistry is exceptional.

A team of scientists has provided, for the first time, a detailed map of how the building blocks of chromosomes, the cellular structures that contain genes, are organized in the fruit fly Drosophila melanogaster. The work identifies a critical stop sign for transcription, the first step in gene expression, and has implications for understanding how the AIDS virus regulates its genes. The findings will be published in the 15 May 2008 issue of the journal Nature.

The scientists found that nucleosomes–chromosomal building blocks made up of proteins around which DNA is coiled–occur at precise locations along genes that are actively undergoing transcription. They also showed that RNA polymerase–the enzyme that reads genes as the first step in making proteins–is stopped at the first nucleosome, where it remains idle until it is directed to continue moving forward. “This discovery is important because nucleosomes are barriers to transcription and we now are seeing the impact of nucleosome organization on RNA polymerase,” said lead investigator B. Franklin Pugh, professor and Willaman Chair in Molecular Biology at Penn State University. … Continue Reading »

Researchers at the OU Cancer Institute have identified a new gene that causes cancer. The ground-breaking research appears in Nature’s cancer journal Oncogene.

The gene and its protein, both called RBM3, are vital for cell division in normal cells. In cancers, low oxygen levels in the tumors cause the amount of this protein to go up dramatically. This causes cancer cells to divide uncontrollably, leading to increased tumor formation.

Researchers used new powerful technology to genetically “silence” the protein and reduce the level of RBM3 in cancerous cells. The approach stopped cancer from growing and led to cell death. The new technique has been tested successfully on several types of cancers – breast, pancreas, colon, lung, ovarian and prostate. … Continue Reading »

Genetic variation in the DNA of mitochondria – the “power plants” of cells – contributes to a person’s risk of developing age-related macular degeneration (AMD), Vanderbilt investigators report May 7 in the journal PLoS ONE.

The study is the first to examine the mitochondrial genome for changes associated with AMD, the leading cause of blindness in Caucasians over age 50.

“Most people don’t realize that we have two genomes,” said lead author Jeff Canter, M.D., M.P.H., an investigator in the Center for Human Genetics Research. “We have the nuclear genome – the “human genome” – that makes the cover of all the magazines, and then we also have this tiny genome in mitochondria in every cell.” … Continue Reading »

Much work has been done to identify genetic variations that predispose women to breast cancer. Previous work showed that variants in the gene called fibroblast growth factor receptor 2 (FGFR2) were associated with increased risk of the disease, but how these variants translated into increased risk was unknown. A new paper by Kerstin Meyer and colleagues, published this week in the open-access journal PLoS Biology, shows how specific changes in the FGFR2 gene alter the way regulatory molecules bind to it, leading to increased gene expression, which, in turn, increases the risk of developing breast cancer.

By comparing all of the tiny differences in the genomes of people with breast cancer to those in a control population, FGFR2 had been flagged up as a region of the genome that is consistently different between the two groups. FGFR2 encodes a protein that sits in the membrane of cells and works in a signalling pathway important for cell growth.

This study, conducted in the Cancer Research UK Cambridge Research Institute, has identified just what these slight genetic changes mean at the molecular level. FGFR2 genes altered at two specific points have a greater affinity for binding certain transcription factors—regulatory proteins that influence gene expression patterns. Because of this additional binding, more FGFR2 protein is produced in cells carrying the mutation and this seems to be enough to increase the risk of cancer a small but significant amount.

Interestingly, the mutation occurs not in the coding regions of the genes (the bits translated into protein by cellular machinery), but rather, in an intron (a region of DNA found amongst the coding bits). The two alterations therefore affect the regulation of the gene, but the proteins produced are normal; there is too much of it for the cells to develop as normal, instead becoming cancerous.

Meyer KB, Maia A-T, O’Reilly M, Teschendorff AE, Chin S-F, et al. (2008) Allele-specific up-regulation of FGFR2 increases susceptibility to breast cancer. PLoS Biol 6(5):e108. doi:10.1371/journal.pbio.0060108

Source: Public Library of Science