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Because genes are selfish and want to maximise their transmission from generation to generation, if they can distort a population's sex ratio, isn't it always in their interest to cause a biased sex ratio? Or are there cases when distorting the sex ratio isn't in their interest because they decrease the overall fitness at the higher level, i.e., incur too much damage in the individual/population? Their main priority is still to subsist in a population before spreading, right?
Thanks in advance :)
Well first if a gene is not on a a sex chromosome there is little advantage in changing the sex ratio. This is why most of the ultra-selfish genes we know about are on sex chromosomes. A gene is not helping itself spread if makes more Male offspring unless one of two things is true, it is on the Y chromosome or there is already a bias making male offspring more successful. the latter actually helps keep populations rex ratios stable since if there are more of one sex generally having offspring of the other sex is an advantage.
The most impactful sex ratio altering genes we know about result in selfish sweeps where populations can collapse as they take over and eventually prevent mating entirely. but up until that final generations with no mates the gene in question has an advantage, evolution does not care about the survival of the species or population, if a gene can improve its own ability to spread at the cost of the population then so be it. fitness at higher levels is basically irrelevant. A gene is perfectly capable of spreading by favoring itself and driving the species/population extinct. In many ways run away sexual selection is this in a nut shell, detrimental to the individual and population but beneficial to the gene.
First of all, we have to define what is meant by distorting the sex-ratio.
1) Changes to the sex-ratio as defined by the principles of the underlying Sex-determination system, can be seen as extremely unlikely:
In most species, sex is determined by inheritance of sex chromosomes, which based on meiosis results in a 50:50 sex-ratio. In this system, sex is determined by the presence or exact count of the sex-chromosomes (dependent on the species). Once this sex-system is established, I would personally see it as "frozen" and very unlikely to ever change. Other sex-determination systems are based on temperature and other environmental factors, and you can safely assume that evolution of their sex-ratios is based on advantages in the spread of the responsible genes. (Either through higher transmission rates within each population, or through a higher survival of the populations as a whole.)
2) Distortion of the perceived sex-ratio within the XY sex-determination system via TRD:
Transmission ratio distortion (TRD) occurs when one of the two alleles from either parent is preferentially transmitted to the offspring. This leads to a statistical departure from the Mendelian law of inheritance, which states that each of the two parental alleles is transmitted to offspring with a probability of 0.5. A number of mechanisms are thought to induce TRD such as meiotic drive, embryo lethality, and gametic competition. Importantly, such mechanisms only affect the sex-ratio, if the corresponding selfish gene sits on a sex-chromosome.
In this context, it is important to distinguish between true meiotic drives and killer meiotic drivers, as can be read in this review-paper. Killer meiotic drives often use complex [poison|antidote] systems, in which a tightly joined pair of a killer and an antidote gene together cause lethality in (haploid) gametes lacking the antidote containing chromosome after meiosis, while the poison is still present.
In general, drive alleles are predicted to be transient and evolutionarily labile. The transmission advantage enjoyed by drivers can allow them to become fixed in a population. After fixation, all individuals will be homozygous for the driver and exhibit no drive phenotype. However, if it affects a sex-chromosome, it could cause a bizarre state: On the x-chromosome, the mechanism would create a disadvantage in propagation due to the lack of male off-springs. On the y-chromosome, it might theoretically eradicate the whole population. By the way, such systems are considered for mosquito control.
Importantly, I would also like to address the gene R2D2 is an example of the true meiotic (see original publication), which is a “selfish” genetic element that exploits asymmetric female meiotic cell division to promote its preferential inclusion in ova (while the other female haploid cells die). However, against the suggestion of a commenter, this gene is NOT able to cause a distortion of sex ratio in mice, as females are homologous in X chromosomes; the ova always contains an x-chromosome.
So I will answer your question regarding selfish-genes, if it "isn't always in their interest to cause a biased sex ratio" with a clear NO! Distortion of the sex-ratio is an extremely rare event that can result in strong disadvantages for the responsible gene, causing its own distinction.
Evolutionary and developmental dynamics of sex-biased gene expression in common frogs with proto-Y chromosomes
The patterns of gene expression on highly differentiated sex chromosomes differ drastically from those on autosomes, due to sex-specific patterns of selection and inheritance. As a result, X chromosomes are often enriched in female-biased genes (feminization) and Z chromosomes in male-biased genes (masculinization). However, it is not known how quickly sexualization of gene expression and transcriptional degeneration evolve after sex-chromosome formation. Furthermore, little is known about how sex-biased gene expression varies throughout development.
We sample a population of common frogs (Rana temporaria) with limited sex-chromosome differentiation (proto-sex chromosome), leaky genetic sex determination evidenced by the occurrence of XX males, and delayed gonadal development, meaning that XY individuals may first develop ovaries before switching to testes. Using high-throughput RNA sequencing, we investigate the dynamics of gene expression throughout development, spanning from early embryo to froglet stages. Our results show that sex-biased expression affects different genes at different developmental stages and increases during development, reaching highest levels in XX female froglets. Additionally, sex-biased gene expression depends on phenotypic, rather than genotypic sex, with similar expression in XX and XY males correlates with gene evolutionary rates and is not localized to the proto-sex chromosome nor near the candidate sex-determining gene Dmrt1.
The proto-sex chromosome of common frogs does not show evidence of sexualization of gene expression, nor evidence for a faster rate of evolution. This challenges the notion that sexually antagonistic genes play a central role in the initial stages of sex-chromosome evolution.
Sexual dimorphism, or phenotypic differences between males and females of the same species, is one of the most common sources of phenotypic variation in nature [1, 2]. Understanding how this process is regulated in a sex-specific manner at the genomic level still poses an important challenge . Differences in gene expression have emerged as a common mechanism to explain phenotypic differences among individuals sharing almost the same genome [4, 5]. In the last decade, a large number of studies have characterized genes with sex-biased expression in a variety of species, leading to an emerging framework attempting to link sex-biased gene expression to phenotypic divergence of the sexes [4,5,6]. Other mechanisms that may explain the evolution of sexual dimorphism have also been documented, including analyses of signature of selection in coding sequence [7, 8]. Elevated rates of sequence evolution, when detected in the set of genes that are sex-biased, are often interpreted as a sign of adaptive evolution caused by sexual selection and, in some cases, the correlation with sexual dimorphism is particularly appealing [9, 10]. The development of whole genome sequencing techniques also made it possible to assess the genomic distribution of genes associated with sexual dimorphism. Recent studies have notably shown that sex-biased or sex-specific genes tend to be unevenly distributed between chromosomes (e.g., X chromosome versus autosomes), sometimes even forming gene clusters within chromosomes, highlighting a possible role of sexual selection in driving genome evolution [11, 12].
Among the countless examples of sexual dimorphism, some species have evolved extreme characters whereby males, generally, develop such drastic phenotypes that they appear exaggerated compared to homologous traits in the other sex or to other body parts [13,14,15,16]. These growth-related secondary sexual traits have received considerable attention in developmental genetics, but we still lack a general understanding of the genomic regulation underlying their development [13, 17,18,19,20,21,22,23,24,25,26,27]. In addition, studies of sexual dimorphism tend to focus on adult gonads or whole-body transcriptomic datasets, which are unsuited for understanding how secondary sexual characters are built during development and their possible consequences on genome evolution [4, 5, 28,29,30,31,32,33]. Conversely, while some studies in flies examined sex-biased gene expression underlying sex differences in bristle patterns , most studies across tissues and developmental stages lack comparisons between the sexes [35, 36]. We, therefore, know little about which sets of developmental genes are associated with trait exaggeration, whether they present a pattern of sequence evolution or whether they tend to be arranged in any specific genomic organization. Developmental genes are often known to be highly pleiotropic, which may in turn influence the genomic architecture associated with trait exaggeration due to developmental constraints [37,38,39].
We aimed here to assess how ontogenetic sexual dimorphism is associated with sex-specific regulation of gene expression and genome architecture in the water strider Microvelia longipes (Heteroptera, Gerromorpha, Veliidae), an emerging model in the field of sexual selection and trait exaggeration [40, 41]. M. longipes is a hemimetabolous insect that displays a striking case of male-specific exaggerated trait where some males develop extremely long third legs compared to females (Fig. 1a). The length of the third legs in males is under strong directional sexual selection and these legs are used as weapons to kick opponents away from the sites where females mate and lay eggs . Such directional selection is associated with the evolution of disproportionate growth (i.e., hyperallometry) in male third legs. Here we study the genomic regulation underlying the elaboration of this exaggerated phenotype in order to shed light on the role of sexual dimorphism in shaping genome evolution. We generated a high-quality genome of M. longipes, with chromosome-scale resolution, and compared the expression, molecular evolution, and genomic location of sex-biased genes in the three pairs of legs at a developmental stage where the legs diverge between the sexes . Combined, our approach first identified signatures of trait exaggeration in terms of sex-biased gene expression patterns and sequence evolution. Second, it characterized chromosomes and genomic regions that are enriched in sex-biased genes associated with the directional sexual selection applying to male exaggerated legs in M. longipes.
a Microvelia longipes in the wild. b Sexual dimorphism in the legs, showing differences in length and male-specific sex combs in the first-legs (Inset). c, d Principal component analysis (PCA) on measurements of male and female leg length from the long-leg and short-leg selected inbred populations, also used for the transcriptomic analyses . c The first principal component (Dim1) explains primarily differences between legs of the same sex while the second PCA (Dim 2) explains differences between inbred populations, specifically in males. d The third PCA (Dim 3) explains the differences between the sexes. e, f Principal Component Analysis on the whole transcriptomic dataset. e The three first PCAs (Dim1, 2, 3) recapitulate the variance between the Big (blue) and Small (green) lines. f Within-class analysis after correcting for line effects. Dimension 1 separates sexes while Dimension 3 separates legs. The inset represents the within-class correction for the line effects
Genetic study takes research on sex differences to new heights
Throughout the animal kingdom, males and females frequently exhibit sexual dimorphism: differences in characteristic traits that often make it easy to tell them apart. In mammals, one of the most common sex-biased traits is size, with males typically being larger than females. This is true in humans: Men are, on average, taller than women. However, biological differences among males and females aren’t limited to physical traits like height. They’re also common in disease. For example, women are much more likely to develop autoimmune diseases, while men are more likely to develop cardiovascular diseases.
In spite of the widespread nature of these sex biases, and their significant implications for medical research and treatment, little is known about the underlying biology that causes sex differences in characteristic traits or disease. In order to address this gap in understanding, Whitehead Institute Director David Page has transformed the focus of his lab in recent years from studying the X and Y sex chromosomes to working to understand the broader biology of sex differences throughout the body. In a paper published in Science, Page, a professor of biology at MIT and a Howard Hughes Medical Institute investigator Sahin Naqvi, first author and former MIT graduate student (now a postdoc at Stanford University) and colleagues present the results of a wide-ranging investigation into sex biases in gene expression, revealing differences in the levels at which particular genes are expressed in males versus females.
The researchers’ findings span 12 tissue types in five species of mammals, including humans, and led to the discovery that a combination of sex-biased genes accounts for approximately 12 percent of the average height difference between men and women. This finding demonstrates a functional role for sex-biased gene expression in contributing to sex differences. The researchers also found that the majority of sex biases in gene expression are not shared between mammalian species, suggesting that — in some cases — sex-biased gene expression that can contribute to disease may differ between humans and the animals used as models in medical research.
Having the same gene expressed at different levels in each sex is one way to perpetuate sex differences in traits in spite of the genetic similarity of males and females within a species — since with the exception of the 46th chromosome (the Y in males or the second X in females), the sexes share the same pool of genes. For example, if a tall parent passes on a gene associated with an increase in height to both a son and a daughter, but the gene has male-biased expression, then that gene will be more highly expressed in the son, and so may contribute more height to the son than the daughter.
The researchers searched for sex-biased genes in tissues across the body in humans, macaques, mice, rats, and dogs, and they found hundreds of examples in every tissue. They used height for their first demonstration of the contribution of sex-biased gene expression to sex differences in traits because height is an easy-to-measure and heavily studied trait in quantitative genetics.
“Discovering contributions of sex-biased gene expression to height is exciting because identifying the determinants of height is a classic, century-old problem, and yet by looking at sex differences in this new way we were able to provide new insights,” Page says. “My hope is that we and other researchers can repeat this model to similarly gain new insights into diseases that show sex bias."
Because height is so well studied, the researchers had access to public data on the identity of hundreds of genes that affect height. Naqvi decided to see how many of those height genes appeared in the researchers’ new dataset of sex-biased genes, and whether the genes’ sex biases corresponded to the expected effects on height. He found that sex-biased gene expression contributed approximately 1.6 centimeters to the average height difference between men and women, or 12 percent of the overall observed difference.
The scope of the researchers’ findings goes beyond height, however. Their database contains thousands of sex-biased genes. Slightly less than a quarter of the sex-biased genes that they catalogued appear to have evolved that sex bias in an early mammalian ancestor, and to have maintained that sex bias today in at least four of the five species studied. The majority of the genes appear to have evolved their sex biases more recently, and are specific to either one species or a certain lineage, such as rodents or primates.
Whether or not a sex-biased gene is shared across species is a particularly important consideration for medical and pharmaceutical research using animal models. For example, previous research identified certain genetic variants that increase the risk of Type 2 diabetes specifically in women however, the same variants increase the risk of Type 2 diabetes indiscriminately in male and female mice. Therefore, mice would not be a good model to study the genetic basis of this sex difference in humans. Even when the animal appears to have the same sex difference in disease as humans, the specific sex-biased genes involved might be different. Based on their finding that most sex bias is not shared between species, Page and colleagues urge researchers to use caution when picking an animal model to study sex differences at the level of gene expression.
“We’re not saying to avoid animal models in sex-differences research, only not to take for granted that the sex-biased gene expression behind a trait or disease observed in an animal will be the same as that in humans. Now that researchers have species and tissue-specific data available to them, we hope they will use it to inform their interpretation of results from animal models,” Naqvi says.
The researchers have also begun to explore what exactly causes sex-biased expression of genes not found on the sex chromosomes. Naqvi discovered a mechanism by which sex-biased expression may be enabled: through sex-biased transcription factors, proteins that help to regulate gene expression. Transcription factors bind to specific DNA sequences called motifs, and he found that certain sex-biased genes had the motif for a sex-biased transcription factor in their promoter regions, the sections of DNA that turn on gene expression. This means that, for example, a male-biased transcription factor was selectively binding to the promoter region for, and so increasing the expression of, male-biased genes — and likewise for female-biased transcription factors and female-biased genes. The question of what regulates the transcription factors remains for further study — but all sex differences are ultimately controlled by either the sex chromosomes or sex hormones.
The researchers see the collective findings of this paper as a foundation for future sex-differences research.
“We’re beginning to build the infrastructure for a systematic understanding of sex biases throughout the body,” Page says. “We hope these datasets are used for further research, and we hope this work gives people a greater appreciation of the need for, and value of, research into the molecular differences in male and female biology.”
This work was supported by Biogen, Whitehead Institute, National Institutes of Health, Howard Hughes Medical Institute, and generous gifts from Brit and Alexander d’Arbeloff and Arthur W. and Carol Tobin Brill.
Population and evolutionary theory has long relied on the hypothesis of ASR stability, and thereby kept the issue of ASR dynamics largely out of the spotlight (2, 12-14). Our results demonstrate that ASR dynamics can have profound consequences for individual behavior and ultimately for population dynamics. Contrary to the common expectation that behavioral responses to ASR variation should stabilize the sex structure of animal populations, our experimental manipulation of lizard populations and the numerical simulations of their long-term dynamics showed that sexual aggression by males can rapidly amplify male bias and cause population collapse. Thus, the male behavior described here is harmful to females and severely threatens population viability.
In many sexually reproducing species, individuals of one sex (typically males) compete for access to mating partners, whereas individuals of the other sex (typically females) choose between partners of the opposite sex and compete for food resources (8). Fluctuations in the ASR are central to predicting the intensity of competition for mates and resources (3, 4). However, there is little information available on how ASR-mediated changes in social behavior can influence reproductive effort and demographic performances in males and females (27). According to the prevailing theory of intrasexual competition (8), we expected higher reproductive effort and poorer demographic performances in the sex of experimentally increased frequency. In contrast, demographic performances (measured by survival) of male lizards were not affected by the ASR manipulation. Rather, male excess resulted in increased levels of sexual aggression against females, whose survival, birth, and emigration rates dropped. A previous study in natural populations of the common lizard demonstrated intrasexual competition for food among females (15). Thus, the results of the present manipulation indicate that effects of males on females in response to the ASR perturbation were disproportionate compared to competition among females for food.
The behavior of males toward female conspecifics demonstrated by this experiment is a likely evolutionary outcome of a sexual conflict over mating and reproduction tactics, which has led to adaptations which benefit males (in the short term) but not females (28, 29). Sexual coercion (e.g., forced copulation, sexual harassment, and punishment), as it has been termed, has been recognized as one of the key forces of sexual selection along with mate choice and mate competition (23). Sexual coercion seems to be widespread in insects and other invertebrates, where it involves sexual harassment by males and causes survival and lifetime reproductive costs to females (30). For example, in seed-eating true bugs, harassment can reduce fecundity by up to 50%, and females are seen to leave prime oviposition sites when males are abundant (31). Although less is known about the fitness costs of such behaviors in vertebrates, several observations suggest that harassment by males may be common, with potentially substantial fitness consequences for females (23, 32). In fish, females can be harassed by males and suffer reduced foraging time at male-biased ASRs (22). In the Australian quacking frog (Crinia georgiana), females that are amplexed by several males risk asphyxia, and struggles between males reduce fertilization success (33).
Despite these dramatic empirical observations, population theory remains strongly female-focused and the role of males in the population dynamics of animal species has chronically been underestimated (34). In fact, males and females often differ in their vital rates, density dependence, and sensitivity to the environment (9). Nonmanipulative studies have identified possible consequences of sex structure on population dynamics (9, 11), including reproductive collapse after male rarity (13). By experimental manipulation, long-term monitoring, and mathematical projections of populations of common lizards, we demonstrate rigorously that male-biased ASRs exacerbate male aggression and become deleterious to females, which amplifies further the sex ratio biases toward males and leads to a positive feedback of population decline, that is, an extinction vortex. For example, it is suspected that attacks by adult males on females, occurring under a male-biased ASR, are a major threat to population persistence of the Hawaiian monk seal (Monachus schauinslandi) (35). In other species, social dominance, reproductive suppression, and infanticide are behaviors of adult males that similarly erode female fitness (21, 36) these effects should be aggravated by male-biased ASRs.
We thank Monique Borgerhoff Mulder, Caroline Uggla, Rebecca Sear and the Early Life Conditions Research group (Michael Hollingshaus, Alla Chernenko, Kelli Rasmussen and Heidi Hanson), for their helpful comments and suggestions. We also thank Zhe (David) Yu, Alison Fraser and Diana Lane Reed for invaluable assistance in managing and preparing the data. We are also grateful to Wissenschaftskolleg zu Berlin for funding a platform for us to present and receive valuable feedback on our work. Lastly, we wish to thank Douglas Tharp for his SAS guidance.
Sex ratio (SR) manipulation theory is one of the founding pillars of sociobiology and modern evolutionary theory –. Early work on frequency-dependent selection on gender and resulting population dynamics (notably Fisher ) is celebrated for showing that advantages to individual parents will lead to equal investment, and stabilize the birth population sex ratio at 50∶50. Sex allocation theory, first proposed by Hamilton , builds on and also challenges this work. If offspring sex can be manipulated, and a grandparent can predict the likely success of their offspring, then a grandparent can obtain a fitness advantage (in terms of grandchildren produced) by biasing its birth sex ratio (SR) in favor of the sex with the greatest potential to disproportionately outperform peers, disproportionately contribute to inclusive fitness, or fail to compete the least . The physiology of mammalian sex determination is supposedly stochastic, producing equal numbers of sons and daughters. Nevertheless if functional consequences of SR manipulation were to be found in mammals, then it would suggest that mammals (either in individual species, or in general), possess unknown physiological mechanisms to control birth SR. Such a bridge between evolutionary and basic molecular biology would be one of the most exciting implications of SR manipulation (e.g. ).
Hamilton , focused on scenarios specific to particular insect groups. In Mammals and birds a more general principle applies: the number of offspring a male produces is often limited by how many females he can mate with, while a female is limited by how many offspring she can physiologically produce , .This generates a tendency for males to vary more in first-generation success than females. Thus male offspring are a high-risk-high-reward bet for potential grandparents in the genetic lottery while females are a safe, hedged bet , . However, just like in insects, if a grandparent ‘knows’ that a male offspring is a low-risk-high-reward bet, then they can beat the house, and hit a jackpot (in terms of grandchildren produced) , . Furthermore, grandparents can beat the house in other more subtle ways, leading later authors to propose a variety of advantages to SR manipulation that might apply to vertebrate species (e.g. local resource competition or enhancement ). Each of these different SR manipulation theories proposes different corresponding cues that grandparents might use to predict the success of their offspring, and corresponding selective pressures underlying these benefits (for an excellent review, see ). For example (and most obviously), parents can produce more of the sex most likely to out-reproduce peers  and either grandparent’s quality or social status may be excellent cues for the subsequent reproductive success of their offspring relative to their potential competitors , . Thus high quality granddams may bias towards males. Conversely, a low quality or stressed granddam, may bias towards daughters, not because they will outcompete peers, but because their failure to compete will be less impactful than that of a son. Although this example (the “Trivers-Willard Hypothesis”) is the most famous, other benefits clearly occur through biasing towards the sex which can reduce reproductive costs or competition, or maximize inclusive fitness (for instance via enhanced production of the sex that disperses or the sex that provides care for younger siblings, respectively ). Similarly, simple sexual selection can drive bias – for instance, a granddam should bias towards males if the grandsire excels in a sexually selected heritable trait that will result in ‘sexy sons’, enhanced sperm competition, or other reproductive advantages distinct from the maternal quality emphasized by the Trivers-Willard Hypothesis. In nature, mammalian parents often do bias birth SR in correlation with physiological, behavioral, or environmental cues that are in turn consistent with these ideas (e.g. –). For instance, dominant red deer mothers skew their SRs toward sons, which is tantalizing as red deer stags with greater mating success tend to have mothers of higher dominance .
However, while this and other examples suggest that SR manipulation could be adaptive, and are often taken as evidence of such, they in fact provide only circumstantial evidence . This example, and all other mammalian studies to our knowledge, require a leap of faith – the true test is to demonstrate that grandparents with skewed birth SRs produce more grandchildren than their peers , and that this benefit accrues specifically through the biased individuals in the intermediate generation. In other words, if a grandmother biases towards sons (for example), then those particular sons must outcompete other males in their generation to produce her more grandchildren in total, and more grandchildren per son. Thus all SR manipulation theories (from Trivers-Willard, to sexy sons, to local resource competition or enhancement) all ultimately make the same prediction: that favoring the sex with the greatest potential to disproportionately outperform peers, disproportionately contribute to inclusive fitness, or fail to compete the least, will mean that biased F1 individuals should produce more F2 offspring per capita than their non-biased peers. The power of this prediction is that it is agnostic to the particular theory under test, the particular cues grandparents may be responding to, or the direction of bias and hence should be general across mammals irrespective of mating systems, natural history, or their particular responses to captivity. However, it has an Achilles’ heel – testing it requires a complete three-generation pedigree where every grandchild of every grandparent is known , , which is practically unobtainable in the wild. Thus Clutton-Brock’s seminal work in red deer  could not test whether the females that produced more sons actually gained more grandchildren nor whether the successful sons descended from the particular females who biased (because not all the dominant females did actually bias). Instead they could only show that dominant females produce more sons and that males with more offspring had more dominant mothers. Thus, the most successful males could just as easily have come from the dominant dams who only invest in one ‘super son’ offspring (which would falsify the hypothesis). As a result, the empirical work in SR manipulation has come under increasing criticism in recent years (e.g. , ), not least because other predicted effects have been much more elusive. In particular, SR theory predicts that males should also control birth SR  (and arguably the mechanisms are far more straightforward for them to do so in mammals ), but to date examples have been very rare , .
Given the power of SR manipulation’s theoretical argument, the compelling but circumstantial field data in the literature, and the implications for basic reproductive physiology our goal was to test the central, yet untested, predictions of SR manipulation theory – that skewing birth SRs enhances parental fitness and that offspring of the favored sex out-reproduce their peers. To do so required overcoming the hurdle of obtaining the three-generation pedigree required. Our solution was to use 90 years of breeding records from San Diego Zoo Global (SDZG) to reconstruct the complete three-generation pedigrees for 198 species of Artiodactyla, Perissodactyla, Carnivora, and Primates. Grandmothers and Grandsires who biased their birth SR gained more grandchildren – specifically via disproportionate success of the individual favored offspring. To our knowledge this is the first demonstration of the key prediction of SR manipulation theory in mammals, vindicating the earlier classic field studies that could not build the three-generation pedigrees required.
Are Male Genes From Mars, Female Genes From Venus? Sex Differences in Health and Disease
Males and females share the vast majority of their genomes. Only a sprinkling of genes, located on the so-called X and Y sex chromosomes, differ between the sexes. Nevertheless, the activities of our genes—their expression in cells and tissues—generate profound distinctions between males and females.
Not only do the sexes differ in outward appearance, their differentially expressed genes strongly affect the risk, incidence, prevalence, severity and age-of-onset of many diseases, including cancer, autoimmune disorders, cardiovascular disease and neurological afflictions.
Researchers have observed sex-associated differences in gene expression across a range of tissues including liver, heart, and brain. Nevertheless, such tissue-specific sex differences remain poorly understood. Most traits that display variance between males and females appear to result from differences in the expression of autosomal genes common to both sexes, rather than through expression of sex chromosome genes or sex hormones.
A better understanding of these sex-associated disparities in the behavior of our genes could lead to improved diagnoses and treatments for a range of human illnesses.
Wilson is a researcher in the Biodesign Center for Mechanisms in Evolution, the Center for Evolution and Medicine, and ASU’s School of Life Sciences. Credit: The Biodesign Institute at Arizona State University
In a new paper in the PERSPECTIVES section of the journal Science, Melissa Wilson reviews current research into patterns of sex differences in gene expression across the genome, and highlights sampling biases in the human populations included in such studies.
“One of the most striking things about this comprehensive study of sex differences,” Wilson said, “is that while aggregate differences span the genome and contribute to biases in human health, each individual gene varies tremendously between people.”
Wilson is a researcher in the Biodesign Center for Mechanisms in Evolution, the Center for Evolution and Medicine, and ASU’s School of Life Sciences.
A decade ago, an ambitious undertaking, known as the Genotype-Tissue Expression (GTEx) consortium began to investigate the effects DNA variation on gene expression across the range of human tissues. Recent findings, appearing in the Science issue under review, indicate that sex-linked disparities in gene expression are far more pervasive than once assumed, with more than a third of all genes displaying sex-biased expression in at least one tissue. (The new research highlighted in Wilson’s PERSPECTIVES piece describes gene regulatory differences between the sexes in every tissue under study.)
Sex-linked differences in gene expression are shared across mammals, though their relative roles in disease susceptibility remain speculative. Natural selection likely guided the development of many of these attributes. For example, the rise of placental mammals some 90 million years ago may have led to differences in immune function between males and females.
Such sex-based distinctions arising in the distant past have left their imprint on current mammals, including humans, expressed in higher rates of autoimmune disorders in females and increased cancer rates in males.
Despite their critical importance for understanding disease prevalence and severity, sex differences in gene expression have only recently received serious attention in the research community. Wilson and others suggest that much historical genetic research, using primarily white male subjects in mid-life, have yielded an incomplete picture.
Such studies often fail to account for sex differences in the design and analysis of experiments, rendering a distorted view of sex-based disease variance, often leading to one-size-fits-all approaches to diagnosis and treatment. The authors therefore advise researchers to be more careful about generalizations based on existing databases of genetic information, including GTEx.
A more holistic approach is emerging, as researchers investigate the full panoply of effects related to male and female gene expression across a broader range of human variation.
The development of a gene drive capable of collapsing a human malaria vector population to levels that cannot support malaria transmission is a long-sought scientific and technical goal 22 . The gene drive dsxF CRISPRh targeting exon 5 of dsx has several features that make it suitable for future field testing. Specifically, this drive has high inheritance bias, heterozygous individuals are fully fertile, homozygous females are sterile and unable to bite, and we found no evidence for nuclease-resistant functional variants at the drive target site. We note that these proof-of-principle experiments cannot conclude that this drive is resistance proof. This is in contrast to a recent study in Drosophila that targeted the transformer gene, upstream of doublesex. Invasion of the drive in transformer was rapidly compromised by the accumulation of large numbers of functional and nonfunctional resistant alleles 23 .
Our doublesex gene drive now needs to be rigorously evaluated in large confined spaces that more closely mimic native ecological conditions, in accordance with the recommendations of the US National Academy of Sciences 24 . Under such conditions, competition for resources or mating success may disproportionately affect individuals harboring the gene drive, resulting in invasion dynamics substantially different from those observed in insectary cage experiments. Indeed, previous work with other genetically manipulated insects would suggest that in the less ideal conditions present in field cages and natural landscapes (competition for food, presence of predators and environmental stressors), heterozygous female mosquitoes carrying the drive allele might have a further reduction in fitness as result of the combined effect of the genetic background of the laboratory strain and the presence of the drive construct itself (Supplementary Table 1) 25,26,27 . To mimic less ideal conditions, we modeled varying levels of additional reduction in fitness (over the experimentally observed value of reproduction rate) associated with the heterozygous gene drive and evaluated the effects on penetrance of the doublesex gene drive (Supplementary Fig. 10). An additional reduction in fitness (over the experimentally observed value) of up to 40% would still allow the drive to reach 100% frequency and cause population suppression, albeit more slowly. Further reductions in fitness would result in different equilibrium frequencies that might still cause a large reproductive load on the population.
Our results may have implications beyond malaria vector control. The role of doublesex in sex determination in all insect species so far analyzed, and the high degree of doublesex sequence conservation among members of the same species (in gene regions involved in sex-specific splicing), suggests that these sequences might be an Achilles heel present in many insect pests that could be targeted with gene editing approaches.
Rainfall linked to skewed sex ratios in African buffalo
An increased proportion of male African buffalo are born during the rainy season. Researchers writing in the open access journal BMC Evolutionary Biology collected data from over 200 calves and 3000 foetuses, finding that rain likely exerts this effect by interaction with so-called sex ratio (SR) genes, which cause differences in number, quality or function of X- and Y-bearing sperm.
Pim van Hooft, from Wageningen University, The Netherlands, worked with a team of researchers to study animals in the Kruger National Park, the scene of the famous 'Battle at Kruger' wildlife video. He said, "Here we show temporal correlations between information carried on the male Y chromosome and foetal sex ratios in the buffalo population, suggesting the presence of SR genes. Sex ratios were male-biased during wet periods and female-biased during dry periods, both seasonally and annually."
The researchers studied data collected between 1978 and 1998 to investigate the associations between rainfall, birth rates/ratios and genetic information. Ejaculate volume, sperm motility and proportion of normal-shaped sperm decrease significantly during the dry season. This decline in quality is likely due to decreasing availability and quality of food resources.
According to van Hooft, "These observations may point towards a general mechanism in mammals whereby semen-quality related sex-ratio variation is driven by SR genes."
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