Last week, I wrote about a disease-causing nematode that infects the roots of soybean plants and a mutation in one strain of soybeans that makes them resistant to these nematodes. In the post I mused,
what if an already existing gene variant with a desired trait from one organism is genetically engineered into another organism of the same species? Would this make GMOs a little bit more palatable to their detractors?
While intended to be more of a thought experiment, a commenter alerted me to a very similar scenario playing out in Ireland, where potato crops are still affected by blight–yes, as in the blight responsible for the Great Famine of the mid-1840s. Blight makes potatoes rot and is caused by infestation of a fungus-like organism (oomycetes) called Phytophthora infestans.
In recent years, scientists have developed blight-resistant GMO strains of potato plants by introducing a blight-resistance gene called RB into the potato’s genome. This gene was identified in Solanum bulbocastanum, a wild potato plant native to Mexico that is closely-related to potatoes. Resistance to blight most likely developed as a result of coevolving with P. infestans, which is considered to be native to Mexico as well.
The scenario facing GMO potatoes, however, is a little bit different from the question I posed earlier since the RB gene isn’t found in cultivated potato plants. Furthermore, traditional breeding methods have been unsuccessful in making hybrids between cultivated potatoes and S. bulbocastanum, therefore necessitating genetic engineering. There are, however, other blight-resistant wild Solanum plants, such as Solanum venturii, that can be hybridized with cultivated potatoes. But using the RB gene from S. bulbocastanum remains the most attractive option because S. bulbocastanum is resistant to the most number of blight-causing P. infestans strains.
The response from one anti-GM campaigner to using genetic engineering in this case?
It is just there to make GM more palatable to the general public. The fact that it comes from a related plant doesn’t make it any different. The real danger is the process.
In hindsight, shoving my hand into a narrow drinking glass wasn’t such a good idea. I learned this the hard way a few years ago while vigorously scrubbing the inside of a glass with a sponge. When the glass shattered in my hands, one of the shards cut the base of my index finger–right by the the knuckle–and required a trip to the local urgent care center. After being stitched up, I was sent home with some antibiotic ointment, extra gauze, and instructions to keep the wound clean. And that’s when things got worse.
Several days later, my finger became red, inflamed, and tender to the touch. There was also stomach-turning pus oozing out of the wound. Fearing that it was infected, I went back to the the urgent care center where the doctor took one look at my wound and then stated the obvious, “That looks infected.” A swab sample was taken from my wound to start a bacterial culture, which would be used to identify the nature of the infection. Since it would take a few days for the results to come back from the lab, she preemptively started me on a course of antibiotics. At the end of the week, there was a message left on my voicemail. The culture was positive for methicillin-resistant Staphylococcus aureus (MRSA).
This was cause for concern because MRSA is a bacterial pathogen that, once it enters the bloodstream, can cause severe to life-threatening infections. MRSA is also notoriously difficult to treat because it is resistant to β-lactams, a class of antibiotics generally prescribed as the first line of defense against normal staph infections. β-lactams, which include drugs like penicillin, oxacillin, and methicillin, kill bacteria by preventing the synthesis of bacterial cell walls–without which bacteria cannot survive. These drugs accomplish this by glomming onto and inactivating penicillin-binding protein (PBP), an enzyme that makes an essential component of bacterial cell walls. MRSA strains, however, are resistant to β-lactam drugs because they carry a gene called mecA. The mecA gene encodes a different form of penicillin-binding protein, PBP2a, which β-lactam drugs cannot inactivate, thus allowing normal cell wall synthesis to occur even in the presence of these drugs.
MRSA infections have long been associated with health care settings such as hospitals and nursing homes. These settings, characterized by a sick general population coupled with high antibiotic usage which selects for drug-resistance, are a perfect environment for MRSA strains to gain a foothold. Given that I had my stitches done at an urgent care center I just assumed that’s where I came into contact with MRSA.
In recent years, however, community-acquired MRSA (CA-MRSA) infections have been on the rise. These are infections contracted from settings like schools, childcare centers, gyms, and prisons. Infections caused by CA-MRSA strains are a particular concern because they are more virulent, spread more rapidly, and can cause more severe infections than its healthcare-acquired MRSA (HA-MRSA) counterparts. What’s worse is the line between the two are blurring as HA-MRSA strains move out into the community and CA-MRSA moves into the hospitals. Because of the increased virulence of CA-MRSA strains there are fears that these strains will eventually replace HA-MRSA strains in healthcare settings–although a recent model published in PLOS Pathogens suggests otherwise.
How MRSA developed β-lactam resistance is still unclear. While there are quite a few different strains of MRSA (some of which have also developed resistance to other classes of drugs) they all carry the mecA gene. The mecA gene, in turn, is part of a larger piece of foreign DNA known as the SCCmec element, which is not normally found in S. aureus. Since bacteria are quite adept at exchanging DNA with each other, scientists speculate that the SCCmec element found its way into a normal staph strain from an as-of-yet identified trading partner. This process of swapping and transferring DNA is known as horizontal gene transfer.
Interestingly, MRSA has a finely-tuned, “on-demand system” that turns mecA expression on in the presence of β-lactam drugs, while keeping expression turned off in the absence of these drugs. This regulation is carried out by proteins whose genes are also found on the SCCmec element. In the absence of β-lactams–when the bacteria doesn’t need the drug-resistant PBP2a protein around– the expression of mecA is kept in check by the protein MecI. MecI binds to the DNA promoter region of mecAand prevents gene transcription. However, in the presence of β-lactam drugs the bacteria needs PBP2a around in order to survive. In this case, expression of mecA is turned on through the action of the cell surface protein MecR1 whose job is to keep an eye out for β-lactams. When MecR1 detects the presence of β-lactams, it instructs the bacterial cell to break down the MecI inhibitor. This allows expression ofthe mecA gene that is essential for the bacteria’s survival to occur.
Recently, researchers from Portugal have identified and characterized another gene on the SCC element called mecR2. As it turns out the MecR2 protein is another component of the finely-tuned, “on-demand system”that regulates mecA expression. When MRSA bacteria encounter β-lactam drugs it starts ramping up the production of MecR2 protein. MecR2, in turn, knocks the MecI inhibitor protein off of the mecA gene promoter, thereby increasing mecA expression. The researchers speculate that the dislodged MecI protein becomes unstable and is then degraded inside the bacterial cell.
Importantly, the researchers demonstrated that in order to get the optimal expression of mecA that would confer resistance to β-lactam drugs, the bacteria needed MecR2 protein around. When they removed the mecR2 gene, the bacteria once again became sensitive to the β-lactam drug oxacillin, which coincided with a decrease in mecA expression. This research not only helps further our understanding of drug resistance in MRSA but also highlights new targets for therapeutics. For instance, drugs could be designed that either short circuit the ability of MecR1 to alert the bacterial cell to the presence of β-lactam drugs or prevent MecR2 from dislodging the MecI inhibitor from the mecA promoter, thereby keeping mecAexpression in check.
As for my finger and me, we made it out of the MRSA scare relatively unscathed–other than a barely noticeable scar at the base of my index finger. Once the lab results came back positive for MRSA, the doctor switched my prescription to Bactrim. Luckily for me, I wasn’t dealing with one of the multi-drug resistant varieties of the bug so the infection cleared in a few days.
Featured image: Scanning electron micrograph of methicillin-resistant Staphylococcus aureus (MRSA, yellow) surrounded by cellular debris. Credit: NIAID
1. Kouyos R, Klein E, & Grenfell B (2013). Hospital-Community Interactions Foster Coexistence between Methicillin-Resistant Strains of Staphylococcus aureus. PLoS Pathogens, 9 (2) PMID: 23468619 doi:10.1371/journal.ppat.1003134
2. Arêde P, Milheiriço C, de Lencastre H, & Oliveira DC (2012). The anti-repressor MecR2 promotes the proteolysis of the mecA repressor and enables optimal expression of β-lactam resistance in MRSA. PLoS Pathogens, 8 (7) PMID: 22911052 doi:10.1371/journal.ppat.1002816
Wrapping up Glaucoma Awareness Month over at PLOS Public Health Perspectives blog with a post on the ethnic disparities in the risk of developing glaucoma as well as current research in identifying the genetic basis for glaucoma in Asians:
Glaucoma isn’t exactly an equal opportunity thief, either. While it is estimated that over 4 million Americans have glaucoma, the prevalence of glaucoma in African Americans and Latino (particularly Mexican) Americans is significantly greater than in Caucasian Americans. African Americans are also more likely to develop glaucoma at a younger age and suffer blindness from the disease. While roughly 90% of all glaucoma cases in the US are what is known as primary open angle glaucoma (POAG), Asian Americans are at the greatest risk of all ethnicities to develop a different form of glaucoma called primary angle closure glaucoma (PACG)(1). The genetic causes underlying glaucoma remain unclear, but these ethnic disparities in the risk of developing glaucoma suggest a genetic basis that is ethnicity-specific. Read more…
Barr bodies used to bar men from competing as women
Last week, I discussed the inadequacies of genetic-based gender verification. What I failed to mention was that at the 1968 Olympic games in Mexico,
“Barr body detection was introduced and was widely proclaimed to be the solution to gender misrepresentation in sport. This reportedly ‘simpler, objective and more dignified’ test involved the cytological analysis of a buccal smear. The Barr body was first detected by Murray Barr in 1948 during research on the nervous system of cats – cells were analysed following electrical stimulation and a dark staining body was found in the nucleus of some animals and not others. The distinction was found to be related to sex and a similar finding was noted in human autopsies. The findings were published in Nature in 1949 and the nuclear marking became known as the Barr Body.“1
As it turns out the Barr body is actually an inactivated X chromosome found only in the cells of females. The genetic imbalance of having two X chromosomes in females and only one X chromosome in males means that the expression of X-linked genes in females can potentially be twice as high as that in males. A process called X-inactivation ensures that expression of X-linked genes are equal between sexes by “silencing” the gene expression from one copy of the X chromosome in every cell of the female body. As a result of this silencing, the inactivated X chromosome appears as a clump attached to the edge of cell nucleus.
In marsupials (kangaroos and other weirdo mammals) it’s always the paternal X chromosome that is silenced, whereas in placental mammals (us and most other normal mammals) the X chromosome that gets inactivated is selected randomly. This random inactivation means that not every cell in the female body is genetically equivalent–some cells are expressing genes from only the paternal X chromosome, while others are expressing genes from only the maternal X chromosome. A visual consequence of this random inactivation can be seen intortoiseshell and calico catssince one of the genes responsible for coat color is found on the X chromosome.
Using Barr body detection to verify female gender in athletes, however, raised more issues than it solved. Barr bodies, although normally present in only female cells, can also be found in males with Klinefelter’s syndrome, who have an XXY sex karyotype. Using Barr body detection, alone, would have qualified these males to compete as females in the Olympics.
The combination of Twitter, sports, and race generally makes for some cringe-worthy moments. Take for example, comments about Jeremy Lin made by Floyd Mayweather or the racist aftermath of Joel Ward’s winning goal that eliminated (my beloved) Boston Bruins. Unfortunately, this year’s Olympics was no exception:
One particular episode of Twitteracism during the Olympics that caught my attention was when some really observant people tweeted about how all the women on the North Korean National Soccer team had “the same face.” The old “you all look alike” stereotype is familiar to many Asians, and this made me consider if there were an ounce of truth to it. Maybe Asians are more homogeneous with respect to their physical features than other races/ethnicities. Admittedly, when I saw the North Korean team photo, even to my discriminating Asian eyes, I thought they all looked uncannily alike (you know, except for the one in orange). But, then again, so did the women on the Swedish team:
The inability to distinguish, or discriminate, individuals of another race/ethnicity is a well-documented phenomenon called the “cross-race” or “other-race” effect. Current explanations for why the cross-race effect exists lie largely outside of my specialty and in the realm of sociology and evolutionary psychology. It’s often related to a concept known as in-group advantage or bias, where individuals within a group (in this case race or ethnicity) are viewed favorably over individuals from outside the group.
Let me be clear here, that the cross-race effect exists doesn’t absolve people of the racist crap they pull. Having difficulty distinguishing Asians in a group is one thing, but calling them all shemales is just offensive. And for the record, starting a statement with the “I’m not being racist, but” disclaimer immediately signals that whatever follows the “but” is going to be racist. Denying individuality to people of other races only contributes to racism. Not to mention that cross-race effects introduce bias in eyewitness testimonies that can lead to wrongful incarceration of people like Ronald Cotton, who was convicted of rape but was later exonerated by DNA tests. Lastly, as Bruce Reyes-Chow writes, “Sure, everyone is mistaken for someone at some point in time, but I simply do not think this happens to white folks as much as it does for people of color.” I suppose that explains why there were no tweets about the Swedish women’s soccer team.
The taboo of race and genetics in sports.
Ever wonder why it seems that East African runners dominate long distance races while runners of West African descent are the kings of sprinting? Jon Entine, writer of Taboo, argues that it mainly comes down to the genetic makeup of these two distinct populations that churn out elite, albeit different style, runners. This is not a new idea, in fact his articles in The Daily Beast and Forbes seem to be rehashes of his earlier writing. But this provocative idea, which invariably touches “the third rail of race,” will surely ruffle some feathers (for proof, see the comments section for each article).
At the heart of his argument is that East Africans and West Africans have different physical packages that are favorable for particular styles of running. He then infers that the physical characteristics specific to each population are genetic, heritable traits. In The Daily Beast he writes, “Kenyans simply don’t seem to have the genetic package to make them world-class sprinters. But East Africans do tend to excel at long-distance running, and many suggest that’s due to an increased natural lung capacity and a preponderance of slow-twitch muscles.” That both populations are black, he would argue, are correlative coincidences–their black skin is indicative of shared ancestry but their success in different styles of running represents their genetic divergence. The fact that both populations are black and that they are the focus of his argument, however, cannot be escaped. (Although, later in the article he does discuss the traits that might lend specific athletic advantages to whites and Asians). Understandably, his arguments can appear like justifications for existing stereotypes, such as the stereotype of the naturally superior, black athlete or the slavery-bred black athlete, dressed up in genetics and science. The nuance of his premise is further muddled when he has to rely on racially-charged descriptors such as black and white.
Entine runs into a bit of scientific trouble as well. He cites little genetic evidence in support of his argument and, in fact, concedes the paucity of data. Instead, to bolster his claim, he points to the genetics of skin color–an analogy that is tenuous at best. “Do we yet know the specific genes that contribute to on-the-field success? No, but that’s not an argument against the powerful role of genetics in sports. We do not yet know all the factors that determine skin color, but we know that genetics determines it.” Except, we know a lot about the genetics of skin color, enough to safely conclude that genetics is a main determinant. And while many genes contribute to skin color, the major environmental factor that impacts skin color outcome is sun exposure. When considering athletic ability, however, Entine cites a host of physical characteristics that contribute to success: skeletal structure, muscle fiber types, reflex capabilities, metabolic efficiency, and lung capacity, for each of which it can be assumed is controlled by a whole set of genes. Entine is only able to cite one gene, ACTN3, a variant of which has been dubbed the sprint gene and “is more common in those of West African descent than in Europeans.” But as Dr. Daniel Macarthur, one of the discoverers of ACTN3, explains in his blog, “an excessive emphasis on ACTN3 as a major explanation for Jamaican success does a grave disservice to the complex interplay of genetic and environmental factors required for top-level athletic performance.” This is a notion that is seconded by evolutionary biologist Dr. Joseph Graves in an interview with PBS, “all of those genetic factors have to be tempered in terms of the environment in which individuals train.” So, in the absence of such genetic data, what Entine has is a collection of observations and only a hypothesis to explain them.
But would it be surprising if, in the end, geneticists did “link human performance, including sports skills, to our DNA and more specifically to our ancestral roots—populations?” Not to me, and probably not for most geneticists. I might not have put it in such certain terms as Entine did, preferring instead, Steven Ross’s measured, hedging-his-bets quote, “There are…probably genetic as well as environmental reasons why Ethiopians make good marathon runners whereas Nigerians on the whole do not” [emphasis mine]. The problem again is not whether science will find the population genetics that underpin athletic skill, but the blurred line between what is meant by population and race (read the PBS interview of Dr. Graves for a discussion on this topic). At the end of Entine’s piece, he declares, “There’s no need to make consideration of race in sports a taboo.” But what I really think he means is that we shouldn’t let the social construct of race stop us from having a discussion of how the genetics of populations, which are genetically divergent or geographically-confined groups, might give individuals of that population a “leg up” in certain types of athletic competitions. The focus shouldn’t be that East and West Africans are black, but that their geographic separation might point to real genetic differences that account for their differing athletic skill sets. This discussion might be made easier, or be bolstered, if there were also such stark examples in “white” populations or in “Asian” populations.
Lastly, Entine does a fairly inadequate job of framing the taboo of race in sports: ‘every defeat encouraged simplistic, racist beliefs that blacks were an inferior “race,” too frail to handle extreme physical challenges and not smart enough to plan a race strategy. Even winning didn’t shatter the stereotype; racist whites just created a new one… black athletes succeed because of their “natural” athleticism.’ Although he points out the stereotypes that surround black athletes, he does little to explain why it’s taboo. Perhaps that’s because he’s written a book on the topic–which he amusingly plugs several times in the comments section (disclaimer: I have not read it).
Talking about the greatness of African athletes can be fraught in the Western world. Generations of American slavery were justified in part by arguments that Africans were “specialized” for physical labor, and whites for mental work, ideas that have persisted in American paternalism and racism through today. For a white writer like myself (or a white researcher or a white anthropologist) to talk about the physical attributes of black men and women can echo some of the worst moments in modern history. And there is something distasteful about reducing Africans to the prowess of their best athletes. After all, Kenya’s contributions to the world include, for example, great writers,environmentalists, and politicians.
It’s hard to talk about the subject without revealing some bias, or giving the impression of trying to explain away their success, or hitting on some still-fresh cultural wound from centuries of exploitation. This may be why definitive answers seem so hard to find, and why we tend to embrace theories that downplay legitimate biological distinctions and emphasize the idea that Kenyans simply work harder. But this kind of thinking, though clearly well intentioned, is a kind of condescension in itself. We’re so afraid of reducing Africans to their physical attributes that we’ve ended up reducing them to an outdated stereotype: Cool Runnings, the barefoot village boy who overcame.
Without properly discussing why it’s taboo, I imagine that Entine does little to engender his view with black readers. And if he’s unable to do that, then how does he expect to remove the taboo of discussing race from sports?
You could make a case for “looking weird” being an effective survival strategy. Just ask Calvin the lobster whose calico-patterned shell spared it from dining table destiny. Rather than being dunked into a pot of boiling water, Calvin is now on display at the New England Aquarium. Calico-patterned lobsters are extremely rare, occuring about 1 in 30 million. For comparison, the rarest are albino lobsters, which occur at a rate of about 1 in 100 million whereasblue lobsters are more commonly found (~1 in 2 million).
But even stranger looking lobsters are lurking out there in our oceans. Take for instance this two-toned lobster that looks like only one half of it was cooked :
As odd as this lobster looked initially, the more I looked at this picture the more familiar it seemed to me. Where have I seen something like this before? I paced around the lab a bit yesterday and it dawned on me. I’ve seen something like this happen in Drosophila. Every once in a while I’ll find a fruit fly where one half of its body is yellow and other half is brown–split right down the middle. Or more strikingly one eye is white and the other is red. And what’s even more peculiar, one half of the fly will be male with male specific structures like the sex comb and the other half is female. The genitalia of these individuals can vary from having “two complete sets of genitalia, one male, one female. Most of the time, you get weird mish-mashes of tissue that don’t look like male or female genitalia (h/t @DaveMellert).” This bilateral sexual asymmetry is a form of gynandromophy, where an organism abnormally displays both male and female characteristics and is not to be confused with hermaphrodites which are organisms that have both male and female sexual reproductive organs.
In Drosophila, sexis determined using the XX/XY sex-determination system (also used in humans) in which females have 2 X chromosomes and males have 1 X chromosome and 1 Y chromosome. Bilateral gynandromorphy in Drosophila occurs when there is a spontaneous, anomalous loss of an X chromosome during the first mitotic division in a female zygote. This results in one daughter nucleus* containing 2 X chromosomes (denoted as XX) and the other daughter nucleus containing only 1 X chromosome (denoted as XO). In this situation, cells derived from the XX nucleus will give rise to the female body plan in half of the fly while cells derived from the XO nucleus will give rise to the male half despite the lack of a Y chromosome. This is because in Drosophila the most important factor in sex determination is the number of X chromosomes. This phenomena also indicates that by the first mitotic division the left and right side of the Drosophila has been determined since one half will become male and the other female. All of the descendants of one cell will makeup the entire left side of the animal while all the descendants of the other cell will makeup the right side!
Although this explains how bilateral sexual asymmetry occurs, you might be wondering why in the Drosophila gynandromorph above one half of its body is yellow (left) and the other is brown (right) or why one eye is white and the other is red. This is because the genes that determine eye and body color are found on the X chromosome. So in the case of eye color, the original zygote was heterozygous for the gene controlling eye color–it has the recessive allele or gene variant for white eyes (w) on one X chromosome and the wildtype allele for red eyes (w+) on the other X chromosome. During mitosis, one of the w+ -bearing X chromosomes is lost and so cells derived from this XO nucleus will carry only the white eye gene, therefore giving rise to 1 white eye. The other eye is heterozygous for the eye color gene, but since w is recessive the eye will be red by virtue of also carrying the wildtype w+ allele. Of course, loss of the X chromosome can also occur after the first mitotic division, in which case the animal will be a mosaic gynandromorph having patches or regions that are male or female instead of the stark left-right division of male and female body plans.
Gynandromorphy occurs in other animals also, although the specific details depend on the species in question. In butterflies, gynandromorphy is a result of sex chromosome aneuploidy as well but their situation is reversed: XX cells are male and XY or XO cells are female.
In birds, however, gynandromorphy occurs by a different process. Sex determination in birds is different from insects and humans: females have a Z and W chromosome whereas males have 2 Z chromosomes. This chicken is a mosaic of both normal male (ZZ) and female (ZW) cells, with male cells concentrated on 1 side and female cells concentrated on the other.
The exact details of this phenomena in birds is unknown. One hypothesis is that it is due to an error that “occurs in the formation of an egg, which normally carries one chromosome to unite with the single chromosome carried by the sperm. But if an egg accidentally ends up with two chromosomes — a Z and a W — and if this aberrant egg is fertilized by two Z-carrying sperm, the bird that results will have some ZZ cells and some ZW cells, he explained.” Another hypothesis is that the egg is abnormally fertilized by two sperm.
Coming back to lobsters, bilateral gynandromorphs can occur in crustaceans as well. As for humans, however, despite Conrad Lycosthenes’s claims that a bilateral human gynandromorph existed, Natalie Reed explains why this phenomena in all likelihood would not happen, “Back to this not happening in humans: yes, intersexual chimerism can happen in humans. You can even end up with human beings who have one ovary and one testicle. But given that almost all sexual differentiation is a result of hormones, which are more or less evenly distributed throughout the body, you would never see any kind of stark split down the middle of a human with, say, a breast on one side and a flat chest on the other.”
*I say nucleus rather than cells because Drosophila do this strange thing during early embryonic development where the chromosomes duplicate and segregate into separate nuclei without the normal cell division (cytokinesis) that occurs after mitosis. This results in a cell called the syncytial blastoderm that has multiple nuclei without cell membranes separating the nuclei from each other. After 13 rounds of nuclear divisions, cell membranes are finally erected (cellularization) to partition the nuclei into individual cells.
Here is a video of mitosis in the early Drosophila embryo. Note the lack of cell membranes.
The recent buzz surrounding the drinking habits of Drosophila, from dealing with rejection to killing parasites by self-medicating, got me thinking: How might fruit flies be used for research in understanding the cause of alcohol use disorder (AUD)? AUD, which encompasses both alcohol abuse and dependency, affects millions of Americans and is a complex disorder influenced by a myriad of environmental and genetic factors. Not surprisingly, efforts to identify the genes responsible for AUD in human and animal models are fraught with limitations. Human studies comparing the genetic variability between affected and unaffected individuals have identified many potential genes responsible for AUD, but only with weak statistical support, thus leaving scientists to ponder which genes are bona fide candidates. On the other hand, more feasible experiments performed in animals and cell culture have identified genes involved in ethanol response, but whether these genes are relevant to a complex, human disorder such as AUD is unknown.
In a study published last December in G3: Genes, Genomes, Genetics, biologists from UCSD and UCSF used a multispecies approach to work around these obstacles to identify and test potential genes involved in alcohol-induced behavioral responses (Josyln et al., 2011). Behavioral changes in response to ethanol can be indicative of later AUD development. To prune the list of potential genes from the entire genome, the researchers analyzed available mouse genetic data to identify regions of the mouse genome associated with ethanol-induced ataxia (loss of coordination). These genomic regions represent clusters of genes that could influence AUD. Despite differences in overall structure and number of chromosomes, many of these gene clusters have been maintained in the genomes of many organisms–this is known as synteny. The researchers exploited this fact to cross-reference the mouse-identified regions to the corresponding sections in the human chromosomes, allowing them to focus on smaller regions rather than the daunting task of searching across the entire human genome.
Corresponding genomic regions between mouse and human genomes are color-coded.
Next, an alcohol challenge study was performed in human subjects. Study participants were given ethanol to consume and the researchers then measured how much ethanol affected the participants inclination to sway to the left and right (another measure of coordination similar to ataxia). Using DNA collected from participants, a genetic association analysis of the human genome corresponding to the regions of the mouse genome associated with ethanol-induced ataxia was performed to identify genes linked to ethanol-induced body sway. The logic behind genetic association is that differences in DNA sequence (genetic variability) amongst individuals underly the variability in human traits (phenotypes, i.e. hair color, eye color, and in this case disease). Thus the researchers looked for a change in DNA sequence (genetic variant) that was common to individuals with the most pronounced ethanol-induced body sway (phenotype). This analysis revealed glypican 5 (GPC5) as a candidate gene involved in ethanol response in humans. GPC5 belongs to a class of genes that encode cell surface proteins, known as glypicans, that act like cellular antennas to receive protein-encoded messages from other cells (see figure below). These protein messages can induce specific responses in the cell, such as turning on the expression of specific genes or alter cellular metabolism. This form of cellular communication is known as signal transduction and is vital for the proper development of an organism.
To test whether glypicans can affect ethanol response the researchers turned to Drosophila. The researchers found that mutations in the equivalent (homologous) Drosophila glypican genes, dally and dally-like (dlp), affected fruit fly behaviors sensitive to ethanol exposure. Normally, when exposed to ethanol vapor, fruit flies are initially startled and display elevated locomotor activity that becomes increasingly uncoordinated until the flies eventually becomes sedated. Mutations in both dally and dlp affected ethanol-induced locomoter activityand decreased the time it took for the fruit flies to become sedated. Interestingly, wildtype Drosophila become tolerant to ethanol since a second exposure to ethanol vapor takes a longer time to induce sedation. Only the mutation in dally displayed an inability to develop this second exposure tolerance suggesting that dally and dlp have different roles in developing tolerance to alcohol. These results confirmed that glypicans influenced alcohol-induced behaviors in Drosophila.
The authors of the study reasoned that the convergence of data obtained from their mouse, human and fly studies “provides strong support to the hypothesis that GPC5 is involved in cellular and organismal ethanol response and the etiology of alcohol use disorders in humans.” In further support of their hypothesis, they point to other research indicating that the signal transduction pathways regulated by glypicans are also involved in ethanol response. While the role of GPC5 in the etiology of AUD requires further study, this research provides an example of a powerful, combinatorial genetic strategy that may prove useful in identifying causative genes in the context of other complex, multifactorial diseases such as cancer, metabolic syndrome, or heart disease.
Joslyn, G., Wolf, F., Brush, G., Wu, L., Schuckit, M., White, R., & Hall, I. (2011). Glypican Gene GPC5 Participates in the Behavioral Response to Ethanol: Evidence from Humans, Mice, and Fruit Flies G3: Genes|Genomes|Genetics, 1 (7), 627-635 DOI: 10.1534/g3.111.000976