Huntington's disease and Increased Fecundity
Huntington's disease (HD) is a rare, autosomal dominant neurodegenerative disorder in which symptoms typically manifest at an age that is post-reproductive, in the range of 30-45 years of age . Affected individuals often experience chorea, uncontrolled and involuntary movements, in addition to a much shorter life-expectancy. Onset of Huntington's disease is attributed to the presence of a high number of CAG trinucleotide repeat lengths within the Huntingtin (HTT) gene [12, 13]; in particular, when the number of CAG repeats exceeds 37, onset of Huntington's disease symptoms was much more likely to occur .
Huntington's patients show a notable increase in fecundity when compared to the unaffected individuals however, and may also experience lower rates of cancer. In a study of the relative fitness of affected and unaffected individuals in Canada via a comparison of the fitness values of 157 Huntington's patients with 170 related wild-type individuals, the mean number of offspring for the patients was 39% higher than their unaffected siblings and 18% higher than a set of unrelated control individuals matched for age and sex . That investigation went on to predict that if such fitness values as he observed were genuine and were to persist, the disease-associate polymorphisms may double in frequency in as short as 150 years (roughly six generations).
An additional benefit that may be conferred by these antagonistically pleiotropic polymorphisms is a reduced risk of cancer . Sorenson et al  reported that a higher number of CAG repeats within the HTT allele is associated with increased p53 activity. P53 is a tumor suppressor protein that has a role in inducing apoptosis and although apoptosis of neuronal cells may be the major cause of the neuro-degeneration seen in Huntington's patients, a higher level of p53 may also protect from tumor growth and cancer development in general. The increased CAG repeat length of HD individuals may therefore be an explanation for the reduced incidence of cancer seen in a large registry of Huntington's patients .
Variation in the CAG repeat length within the HTT gene therefore seems to exhibit a form of antagonistic pleiotropy that perfectly illustrates that proposed by . Presence of more than 37 CAG trinucleotide repeats in the HTT gene is associated with an increased risk for Huntington's disease, but is also associated with a substantial rise in fertility and perhaps reduced cancer risk.
Cystic fibrosis and fertility
Cystic fibrosis (CF) is an autosomal recessive trait that is often lethal, though life expectancy has increased over time from early infancy to late-30s due to better medication, therapies and more access to medical care . The mutation that causes CF is a codon deletion in the CFTR gene that results in the loss of phenylalanine from the protein product . Loss of phenylalanine results in a non-functional trans-membrane chloride channel, a channel responsible for the movement of bodily fluids throughout many different organs and organ systems in the body. The presence of this defective channel in the body leads to diverse symptoms involving many organ systems and tissues, mainly due to the buildup of fluids throughout the body. The backup of fluid contributes to other serious ailments including increased susceptibility to infections and various breathing problems .
Alleles associated with cystic fibrosis may confer certain benefits via overdominance (i.e., heterozygotes have higher fitness) or epistatic effects however. Data shows that individuals in families with members identified as suffering from CF have more offspring than individuals from control families . Even though the offspring from CF family members experienced higher mortality rates than the offspring of the non-CF family individuals, CF family individuals still out-reproduced non-CF family individuals by roughly 22% (p < 0.001).
Additionally, using a mouse model, an investigation conducted by Gabriel and colleagues  showed that heterozygotes for non-functioning CFTR alleles were resistant to cholera toxin which suggests that increased resistance to cholera may also explain the persistence of CF. These mouse results were similar to results obtained from human tissue cultures , however that study did not explicitly demonstrate a fitness benefit to CF heterozygotes in humans. Finally, an advantage arising from decreased levels of sialic acid on cell membrane surfaces in CF heterozygotes was proposed . This decrease could potentially provide increased resistance to influenza and other myxo- and paramyxoviruses, although as above, cell tissue culture data instead of direct comparisons of fitness differences between CF heterozygotes and other individuals were used to support this hypothesis .
The allele with the deleted CFTR codon therefore seems to exhibit antagonistic pleiotropy. The deletion leads to serious health issues in homozygotes, but individuals likely to be carrying the allele (I.E., families of CF sufferers) appear to have more offspring and may experience increased resistance to cholera and other infectious diseases.
Sickle Cell Anemia and malaria resistance
Sickle cell disease is an autosomal recessive hemoglobinopathy commonly found in individuals endemic to tropical and Mediterranean regions, especially Africa . Sickle cell disease is attributed to a single missense point mutation in the Hemoglobin (Hb) gene, termed the Hb-S allele. The mutation leads to the replacement of glutamine by valine at position 6 and to the development of the characteristic abnormal sickle shaped erythrocytes that are associated with sickle cell anemia. The sickle shape compromises the elasticity of the red blood cell and causes these cells to obstruct blood flow through narrow vessels, resulting in ischemia and other serious problems. Although life-expectancy of individuals with the homozygous Hb-S genotype has increased in recent years in developed nations (median lifespan of 42-48 in the US) , for most of human history (and even now in undeveloped nations) homozygous individuals had very short expected life expectancies (I.E., high juvenile mortality). In contrast, individuals who are heterozygous for the Hb-S allele do not present with full symptoms and suffer minimal hemoglobinopathies.
The Hb-S allele provides an advantage in individuals heterozygous for the Hb-S allele via increased resistance to malaria, most notably during the ages of 2 to 16 months . The presence of such a benefit early in life is thought to account for the relatively higher frequency of the sickle cell allele in geographic regions that experience high rates of malaria. Malaria is estimated to infect approximately 400 million individuals and kill over one million each year . Although the high rate of malaria is a relatively recent phenomenon, it has been a major health factor for a large proportion of humanity for over 500 generations and therefore has had sufficient time to change the frequencies of alleles associated with resistance .
The Hb-S allele is perhaps the best known and most widely used example of antagonistic pleiotropy in discussions of the topic in human disease due to the clear deleterious effect in homozygotes combined with a clear advantage in heterozygotes. In contrast to the previous examples the advantages and disadvantages of this allele are not experienced by the same individuals, but the overall selective forces acting on the allele remain very similar. Over mankind's evolutionary history (and in the present) selection both favors and acts against the Hb-S allele simultaneously, resulting in an equilibrium at a frequency much higher than that expected for a purely deleterious allele.
Beta-Thalassemia and malaria resistance
Another example of antagonistic pleiotropy in a hemoglobinopathy is the blood disorder Beta-Thalassemia which is caused by a mutation in the beta chains of hemoglobin . Beta-Thalassemia is an autosomal, incompletely recessive, mutation in which individuals that are homozygous for the mutation often present with full disease symptoms (known as Beta-Thalassemia Major). Beta-Thalassemia Major symptoms include anemia, some heart/vascular problems in adults, and infants and newborns that are often underweight and smaller in size than average children (experiencing the condition termed «failure to thrive») . Although heterozygotes for the mutation often present with mild symptoms of this disorders, they seem to suffer no difference in life expectancy relative to the general population .
A study reported that the possession of the Beta-Thalassemia mutation is associated with increased resistance to malaria and that the basis for malarial protection may be due to early childhood exposure to P. vivax resulting in resistance to Plasmodium falciparum . The protection from malaria increases the relative fitness of these individuals greatly and is thought to account for the relatively higher frequency of the Beta-Thalassemia mutation in geographic regions that experience high rates of malaria.
The Beta-Thalassemia anemia variant of hemoglobin B mirrors the case of sickle cell anemia described above due to the clear advantage for heterozygotes and the clear deleterious effects in homozygotes. Interestingly, while the sickle cell and malaria example is more widely known and taught in biology courses, the argument for the role of malaria in the maintenance of the Beta-Thalassemia mutation via an overdominance based antagonistic pleiotropy mechanism predates it [31, 32].
Glucose-6-Phosphate Dehydrogenase Deficiency and malaria resistance
Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency is a genetic disorder that often results in hemolytic anemia because G6PD is essential for the prevention of hemolysis due to reactive oxygen species accumulating in red blood cells during regular cellular metabolism and from exposure to certain environmental stimuli. A number of observed mutations to the G6PD gene cause a truncated dehydrogenase enzyme that is severely compromised in function and with an estimated 400 million affected individuals this disorder is one of the most common among enzyme deficiencies . Homozygous (females) and hemizygous (males) individuals manifest the effects of the recessive mutation which often results in fetal mortality and, later in life, causes hemolytic anemia if red blood cell production cannot be increased enough to offset the rate of destruction from hemolysis. Current studies show that the life expectancy of affected individuals can be normal with adequate and frequent treatment [33, 34], although this treatment is not available in much of the world and was not available throughout most of medical history.
As is the case for the hemoglobinopathies described above, G6PD deficiency is associated with protection from malaria. Various alleles that cause G6PD deficiency have been associated with improved resistance to malaria, especially to the most life-threatening cerebral malaria, in hemizygous males and heterozygous females [35, 36].
Although they cause hemolytic anemia, the resistance to such a widespread and serious disease conferred by G6PD mutations may cause the net fitness effect of these alleles to be comparable to wildtype fully functional G6PD alleles. The high prevalence and serious health consequences of malaria infection may explain the extremely high number of cases of G6PD estimated to exist.
ALOX15 gene and Bone Mineral Density
Osteoporosis is a condition in which the bones weaken, making sufferers more prone to fractures in accidents and falls, and poses a serious global health risk. For example, in the US in 2005 there were an estimated 300,000 hip and 550,000 vertebral fractures  and in a Canadian cohort study these fractures were associated with 419% and 253% increases in mortality over the next year respectively . Clinical definition of osteoporosis typically includes low bone mineral density (BMD) measurements. In a study of SNP frequencies the presence of a guanine instead of the more common adenine within intron 12 of the 12/15-lipoxygenase (ALOX15) gene was associated with a reduced risk of low BMD at the femoral neck in pre-menopausal women (OR = 0.442, p = 0.007) but an increased risk in postmenopausal women (OR = 1.727, p = 0.042) . The guanine allele therefore either reduces or increases osteoporosis risk depending on which stage of life one is considering; if we consider the actions of ALOX15 during different life stages to be different functions then this allele is a clear case of an antagonistically pleiotropy.
Cancers and reproductive traits
Cancer is a primary cause of genetically caused mortality worldwide, with estimates of up to 569,490 deaths in 2010 in the US alone . A number of allelic variants for certain genes have been discovered in which the genotypes of individuals seem to correlate with risk of developing cancer . One of these genes is the androgen receptor (AR) gene. The AR gene contains a repeated CAG trinucleotide sequence and the CAG repeat length influences gene expression, which determines the density of androgen receptors in human epithelial tissue, mainly of the reproductive system.
In females, a shorter CAG repeat length in the AR gene is associated with ovarian cancer. Shorter repeats of the CAG segment have been associated with an increased expression of the AR gene in ovarian tissue [42, 43] and another study presented a Western Blot analysis of tissue cultures as evidence that increased expression of AR gene is associated with ovarian tumor formation . Consistent with this process, women who inherited a shorter repeat of the CAG segment of the androgen receptor allele presented with an earlier age of incidence of ovarian cancer, roughly about 7.2 years earlier compared to a control group .
In males, a shorter CAG repeat length in the AR gene is associated with prostate cancer. As in ovarian tissue, a shorter CAG repeat length is associated with increased expression of the AR gene in prostate tissue . Higher density of AR in prostate tissue seems to amplify androgen activity, which is expected to increase cell proliferation and prostate tissue growth rates . Increased cell proliferation, via hormonal stimulation for example, is associated with an increase in frequency and malignancy of prostate cancer [43, 47]. Consistent with this process, Ingles and colleagues reported that males with a shorter repeat length experienced a two-fold increase in prostate cancer risk . Similarly, another investigation reported an association between shorter CAG repeats and prostate cancer in 587 prostate cancer patients and 588 control individuals and that the association was driven by the most severe cases .
In contrast, shorter repeat CAG lengths within the AR gene may provide benefits to females and males.
In females, shorter repeats may increase reproductive ability and reduced breast cancer risk. Shorter CAG repeat lengths within the AR gene are associated with a potential increase in reproductive fitness via the link between AR gene expression and follicular development during the uterine cycle. Serum androgen activity is mediated by the androgen receptor and the effects appear additive, implying that a high density of the receptor (such as that caused by increased expression due to shorter repeat lengths) would amplify androgen activity. Androgen activity is associated with follicular growth and maturation and increases the viability of oocytes, which increases fertility . Consistent with this process is evidence provided by Chaterjee and colleagues in which shorter CAG repeat lengths were associated with a reduced degree of pre-mature ovarian failure . Shorter repeat lengths may also provide an advantage via reduced cancer risk; in a study of women with the BRCA1 allele, shorter CAG repeat lengths within the AR gene were associated with reduced risk of breast cancer .
In males, shorter CAG repeat lengths within the AR gene are associated with a potential increase in reproductive ability, reduced risk of Kennedy's disease and perhaps greater sexual attractiveness. There is evidence of an inverse relation between CAG repeat lengths in the AR gene and the level of reproductive fitness; on average, males with a shorter CAG repeat length presented with fewer non-viable, defective sperm . The level of severity and the associated amount of defective sperm were directly correlated to longer repeat lengths and individuals with shorter repeats experienced reduced rates of infertility. There is also evidence that a shorter repeat length is associated with increased counts of viable sperm in adolescent males . Shorter repeat lengths may provide an advantage via reduced risk of Kennedy's disease, a neuromuscular disease similar to ALS that only affects males. In a study of 35 unrelated men with Kennedy's disease and 75 controls  all the affected males had longer CAG repeat lengths. It appears that a decreased repeat length is associated with higher expressions of a range of male- specific traits that may have had (or indeed, still have) roles in mate acquisition and attraction.
Variation in the CAG repeat length within the AR gene therefore seems to exhibit antagonistic pleiotropy in both females and males. In females, shorter CAG repeat lengths correlate with increased risk of ovarian cancer, the second leading cause of gynecological cancer deaths , yet shorter repeats are also associated with increased reproductive fitness via increased viability of oocytes and reduced pre-mature ovarian failure as well as reduced breast cancer risk. In males, shorter CAG repeat length is associated with decreased survivorship (mostly in older age) due to higher risk of prostate carcinogenesis, but shorter repeats are associated with increased reproductive fitness (manifested mainly in youth) via increased viability of sperm, reduced risk of Kennedy's disease and perhaps increased reproductive opportunities due to phenotypic traits that are more attractive to females.
Other putative antagonistically pleiotropic alleles
The examples of antagonistic pleiotropy cited above demonstrate the widespread nature of this phenomenon in terms of physiological systems and tissues as well as mechanisms of action. The previous examples are based on specifically characterized genes; other possible occurrences of antagonistic pleiotropy in humans have been suggested, based upon correlations and less comprehensive data. Further investigation of the proposed cases of antagonistically pleiotropic alleles below seems warranted in order to round out our understanding of the pervasiveness of this phenomenon.
Recent evidence suggests that there may be a link between Triose Phosphate Isomerase (TPI) deficiency, a disease that causes a number of severe symptoms (chronic hemolytic anemia, cardiomyopathy, susceptibility to infection and severe neurological dysfunction), but may also confer oxidative stress resistance. TPI deficiency in yeast confers a protective benefit by reducing oxidative stress during cellular metabolism , which suggests that humans who are heterozygous for the mutant TPI allele may also experience this benefit. However, more definitive evidence involving vertebrate models, if not human models, are necessary to further validate this hypothesis.
Tay Sachs disease, a severe neurodegenrative disease due to a number of different mutations described in the HEXA gene which encodes the alpha-subunit of the lysosomal enzyme beta-N-acetylhexosaminidase, has been proposed to owe its surprisingly high frequency to the benefit provided by protection from tuberculosis during the historical process of urbanization [57, 58].
Hemochromatosis, a well-known blood disease, has a very clear genetic basis in its manifestation and progression  and is often the result of many different potential mutations to different genes with the most common mutation being the C282Y mutation of the HFE gene. Evidence suggests that individuals heterozygous for the C282Y mutation in the HFE gene may experience benefit due to more efficient dietary iron absorption and via increased resistance to typhoid fever and tuberculosis, diseases that became more prevalent with the rise of urbanization .
Phenylketonuria (PKU) may also display evidence of selection by antagonistic pleiotropy. Woolf  presented data which suggests that heterozygote females may experience a lower chance of mold infection induced miscarriages; potentially an important advantage prior to modern methods of food sanitation and storage. Although the PKU causing allele is likely to be purely deleterious today, its historical heterozygote advantage may account for its current prevalence. The sample of PKU individuals referenced in that study was small and included only individuals in Ireland and Scotland where mold problems have have been more severe than elsewhere, alternative explanations may be necessary to explain the global distribution of PKU.
Another putative example involves hepatocellular carcinoma (HCC), a well-known cancer, and the PTNP11 gene. The wild type allele for PTNP11 is proto-oncogenic and produces the shp2 protein. In its wild-type form, PTNP11 aids in the prevention of HCC but may also contribute to the manifestation of leukemia. Chapeau and colleagues showed that mice and human Leukemia cases are associated with a mutation that leads to the overexpression of the PTNP11 gene . They investigated mouse models with the PTNP11 allele knocked out to simulate under-expression of the gene and the mice were less prone to develop leukemia, but many developed HCC . This data suggests an antagonistic relationship between the levels of PTNP11 expression and the development of leukemia and HCC; further studies must be performed to properly ascertain this same relationship in humans.
Even psychological disorders may be subject to selection of antagonistically pleiotropic alleles. Schizophrenia is believed to have a heritable component with alleles implicated for genetic susceptibility reported to be located in chromosomal regions 6p24-p22  and perhaps 11q21-22. Other studies have shown that although schizophrenic individuals themselves have reduced reproductive success, their unaffected relatives often have higher relative fertility , indicating a potential advantage conferred by alleles associated with schizophrenia when those are present as single copies or in different genetic backgrounds (i.e., different epistatic interactions).
Osteoprogesterin (OPG) is a cytokine receptor protein that has a role in malignant tumor progression and modulation of bone density. OPG is encoded by the tumor necrosis factor receptor superfamily member 11B (TNFRSF11B) gene . Overexpression of the TNFRESF11B gene has been associated with several epithelial cancers  and another study has suggested that OPG does, in fact, have a modulatory role in tumor angiogenesis . Furthermore, Ito et al  have suggest that overexpression is positively correlated with the severity of the associated epithelial cancer (i.e., malignancy increases with the concentration of OPG in the blood). A high level of OPG has also been shown to decrease the likelihood of bone disease; Samuelson and colleagues presented a human clinical study in which a higher than normal level of OPG was associated with stronger bones in both men and women . OPG may act as a promoter of osteoblast activity by reducing the number of activated osteoclasts in the blood. Human clinical studies have shown that there is an association in increased Bone Mineral Density (BMD) in individuals who have higher circulating levels of OPG in their blood plasma. Such costs and benefits associated with the TNFRSF11B gene would be an example of antagonistic pleiotropy, but further evidence, including the identification of the specific genetic polymorphism responsible, is needed to support this hypothesis.
For these less characterized cases of antagonistic pleiotropy, and other cases not identified yet, the genetic mechanism providing the advantage may be straightforward or more complex. The most straightforward mechanism is overdominance (heterozygote advantage), but incomplete penetrance of the deleterious aspect of the alleles or epistatic interactions that differ in different genetic backgrounds may also be important for the full fitness ramifications of disease alleles. The latter two mechanisms are more subtle and difficult to recognize or demonstrate statistically and this may contribute to the unresolved nature of the examples described in this section.
Given the number of diseases caused by antagonistically pleiotropic alleles that have been identified to date and the potential complexity of the mechanisms providing the benefits, many more genetic disorders may exist that have yet to be identified as antagonistically pleiotropic.