The selective advantage of cystic fibrosis heterozygotes tested by aDNA analysis: A preliminary investigation

Recently a heterozygote advantage was suggested to explain the high incidence (1:25 carrier individuals in Europeans) of the cystic fibrosis gene. This selective advantage was speculated to be due to a high resistance to chloride-secreting diarrhea, including cholera. Up to now the major efforts to test directly this hypothesis have been limited to animal models. We propose to verify the hypothesis directly on a sample of human individuals who died from cholera during the epidemic in the Mediterranean basin at the beginning of the nineteenth century. In this preliminary investigation we have attempted to check for the presence of amplifiable DNA in the human remains simultaneously in terms of genetic fingerprints and for cystic fibrosis mutations.     

Evolutionary meta-analysis of association studies reveals ancient constraints affecting disease marker discovery

Genome-wide disease association studies contrast genetic variation between disease cohorts and healthy populations to discover single nucleotide polymorphisms (SNPs) and other genetic markers revealing underlying genetic architectures of human diseases. Despite scores of efforts over the past decade, many reproducible genetic variants that explain substantial proportions of the heritable risk of common human diseases remain undiscovered. We have conducted a multispecies genomic analysis of 5,831 putative human risk variants for more than 230 disease phenotypes reported in 2,021 studies. We find that the current approaches show a propensity for discovering disease-associated SNPs (dSNPs) at conserved genomic positions because the effect size (odds ratio) and allelic P value of genetic association of an SNP relates strongly to the evolutionary conservation of their genomic position. We propose a new measure for ranking SNPs that integrates evolutionary conservation scores and the P value (E-rank). Using published data from a large case-control study, we demonstrate that E-rank method prioritizes SNPs with a greater likelihood of bona fide and reproducible genetic disease associations, many of which may explain greater proportions of genetic variance. Therefore, long-term evolutionary histories of genomic positions offer key practical utility in reassessing data from existing disease association studies, and in the design and analysis of future studies aimed at revealing the genetic basis of common human diseases.     

A model of the population genetics of cystic fibrosis in the United States

A model of the population genetics of cystic fibrosis is developed. It is shown that in the absence of a selective advantage the cystic fibrosis gene dies out, while in the presence of a reproductive advantage for the heterozygote the gene persists in the population.     

遗传多样性上限假说所揭示的进化历程

作为生物进化的两个主流理论, 中性学说和现代达尔文进化理论相对系统地揭示了进化机理和历程, 但也都有缺陷, 比如对某些重大进化现象如遗传等距离和重叠位点(Overlap sites)的忽视, 对复杂性的视而不见, 对遗传多样性的片面解读, 以及与化石证据相悖等。遗传多样性上限假说(Maximum genetic diversity hypothesis, MGD)通过对遗传等距离现象的重新解读, 给出了复杂性的量化定义和可操作研究手段, 提出了重叠特征和遗传多样性具有上限等结论。它对人猿分类关系和现代人多地区起源的分子解读结论, 与独立的化石证据契合度较高, 重新肯定了中国在人类发展中的关键作用, 点出了流行分子结论的荒谬在于误用了极限距离。该理论同时对复杂性状和复杂疾病的遗传机制研究具有指导意义。文章对多种酵母、鱼类、灵长类的细胞色素c进行序列比对, 独立验证了MGD假说的部分论断, 并解释了重叠位点在遗传距离计算上的重要意义。MGD假说中的上限或最佳平衡概念, 与传统国学和中医阴阳中庸思想对宇宙基本规律的描述是一脉相承的。     

Cilia and centrosomes: a unifying pathogenic concept for cystic kidney disease?

Cystic kidney diseases are among the most frequent lethal genetic diseases. Positional cloning of novel cystic kidney disease genes revealed that their products (cystoproteins) are expressed in sensory organelles called primary cilia, in basal bodies or in centrosomes. Primary cilia link mechanosensory, visual, osmotic, gustatory and other stimuli to mechanisms of cell-cycle control and epithelial cell polarity. The ciliary expression of cystoproteins explains why many other organs might be also affected in patients with cystic kidney disease. Protein-protein interactions among cystoproteins, and their strong evolutionary conservation, provide a basis for a multidisciplinary approach to unravelling the novel signalling mechanisms that are involved in this disease group.     

Relating the Disease Mutation Spectrum to the Evolution of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)

Cystic fibrosis (CF) is the most common genetic disease among Caucasians, and accordingly the cystic fibrosis transmembrane conductance regulator (CFTR) protein has perhaps the best characterized disease mutation spectrum with more than 1,500 causative mutations having been identified. In this study, we took advantage of that wealth of mutational information in an effort to relate site-specific evolutionary parameters with the propensity and severity of CFTR disease-causing mutations. To do this, we devised a scoring scheme for known CFTR disease-causing mutations based on the Grantham amino acid chemical difference matrix. CFTR site-specific evolutionary constraint values were then computed for seven different evolutionary metrics across a range of increasing evolutionary depths. The CFTR mutational scores and the various site-specific evolutionary constraint values were compared in order to evaluate which evolutionary measures best reflect the disease-causing mutation spectrum. Site-specific evolutionary constraint values from the widely used comparative method PolyPhen2 show the best correlation with the CFTR mutation score spectrum, whereas more straightforward conservation based measures (ConSurf and ScoreCons) show the greatest ability to predict individual CFTR disease-causing mutations. While far greater than could be expected by chance alone, the fraction of the variability in mutation scores explained by the PolyPhen2 metric (3.6%), along with the best set of paired sensitivity (58%) and specificity (60%) values for the prediction of disease-causing residues, were marginal. These data indicate that evolutionary constraint levels are informative but far from determinant with respect to disease-causing mutations in CFTR. Nevertheless, this work shows that, when combined with additional lines of evidence, information on site-specific evolutionary conservation can and should be used to guide site-directed mutagenesis experiments by more narrowly defining the set of target residues, resulting in a potential savings of both time and money.     

Cystic fibrosis allele frequency,sex ratio anomalies and fertility: a new theory for the dissemination of mutant alleles

Summary The observation that mothers of cystic fibrosis patients come from sibships that are larger than those of the fathers is explained by a decrease in sex ratio with increasing size of parental sibships. This feature also provides the basis for a new theory for the dissemination of the major mutant allele, deduced to have arisen 2700–5000 years ago, in accordance with an overall heterozygote advantage of around 3%. In heterozygous women with heterozygous partners, sex-related selection probably occurs after fertilization.     

The relationship between legal abortion and marriage

Abstract

Tay‐Sachs disease is a recessively inherited, invariably lethal, degenerative neurological disorder caused by a lack of hexoaminidase‐A. It is a hundred times more prevalent among the American‐born descendants of the East European Ashkenazim Jews than among any other people in the world. The present retrospective study demonstrates that the currently observed increased gene frequency among these formerly endogamous, highly fecund people is most probably a result of genetic drift. Unique and drastic population contractive and expansion phases are documented to deduce the formation of numerous founder populations which were scattered throughout Eastern Europe by the nineteenth century. The subsequent mass familial migrations to the United States, coupled with the cultural practices of the immigrant generation, greatly enhanced the chances for heterozygote carriers to marry each other. Even if some form of selection were operative in the past, the concatenation of unique cultural events provides convincing evidence for the acceptance of drift as the primary cause for the differential gene frequency.     

Experimental studies on ploidy evolution in yeast

Variation in the prominence of haploidy and diploidy is a striking feature of eukaryote life cycles that has not been explained from an evolutionary point of view. the ease with which ploidy and other variables of population genetics may be manipulated in yeast make Saccharomyces cerevisiae an excellent subject for experiments on the fitness effects of ploidy. Several hypotheses have been advanced to explain the emphasis on diploidy in plants and animals, and yeast experiments have been particularly informative for a few. Evidence suggests that diploids may enjoy an immediate advantage over haploids in masking harmful mutations, avoiding the fitness cost such mutations impose on haploids. A convincing longer-term advantage for diploidy has proven elusive, and different evolutionary explanations for the origin and for the subsequent maintenance of diploidy may be required.     

Ethnic variation in genetic disease: possible roles of hitchhiking and epistasis.

The high incidence of some genetic diseases in certain ethnic groups is important in planning of medical genetic programs. Simple interaction models predict that at least some lethal recessive alleles will have "hitchhiked" to increased frequencies because of linkage to genes whose alleles have been favored by selection for other reasons in certain populations. In the absence of linkage or epistasis with a gene favored by selection, heterozygote advantage for a recessive lethal may produce the same phenomenon. In the hitchhiking model (linkage), the increase in the gene frequency is temporary, but the length of time that the increased gene frequency is at least double the base frequency may be quite long. Changes in gene frequency for the unlinked epistatic model result in a new equilibrium with a possibly higher gene frequency. The most likely chromosomal regions in which hitchhiked lethal recessives would be found are in the vicinity of genes whose allelic frequencies vary substantially among human racial groups (e.g., Gm, Rh, Duffy, lactose tolerance, or HL-A). There will be a hitchhiking effect if recombination distance is less than the selective advantage. The closer the linkage of two loci, the easier hitchhiking effects will be to detect. Hitchhiking is suggested by nonrandom association of the recessive disease and one of the selected markers, as in the case of Gm and cystic fibrosis. However, there is so far insufficient evidence of linkage between them. More pedigree information is necessary than is now available.     

Evolutionary psychiatry: foundations,progress and challenges

Evolutionary biology provides a crucial foundation for medicine and behavioral science that has been missing from psychiatry. Its absence helps to explain slow progress; its advent promises major advances. Instead of offering a new kind of treatment, evolutionary psychiatry provides a scientific foundation useful for all kinds of treatment. It expands the search for causes from mechanistic explanations for disease in some individuals to evolutionary explanations for traits that make all members of a species vulnerable to disease. For instance, capacities for symptoms such as pain, cough, anxiety and low mood are universal because they are useful in certain situations. Failing to recognize the utility of anxiety and low mood is at the root of many problems in psychiatry. Determining if an emotion is normal and if it is useful requires understanding an individual's life situation. Conducting a review of social systems, parallel to the review of systems in the rest of medicine, can help achieve that understanding. Coping with substance abuse is advanced by acknowledging how substances available in modern environments hijack chemically mediated learning mechanisms. Understanding why eating spirals out of control in modern environments is aided by recognizing the motivations for caloric restriction and how it arouses famine protection mechanisms that induce binge eating. Finally, explaining the persistence of alleles that cause serious mental disorders requires evolutionary explanations of why some systems are intrinsically vulnerable to failure. The thrill of finding functions for apparent diseases is evolutionary psychiatry's greatest strength and weakness. Recognizing bad feelings as evolved adaptations corrects psychiatry's pervasive mistake of viewing all symptoms as if they were disease manifestations. However, viewing diseases such as panic disorder, melancholia and schizophrenia as if they are adaptations is an equally serious mistake in evolutionary psychiatry. Progress will come from framing and testing specific hypotheses about why natural selection left us vulnerable to mental disorders. The efforts of many people over many years will be needed before we will know if evolutionary biology can provide a new paradigm for understanding and treating mental disorders.     

Molecular pathways for intracellular cholesterol accumulation: common pathogenic mechanisms in Niemann-Pick disease Type C and cystic fibrosis

It has been less than two decades since the underlying genetic defects in Niemann-Pick disease Type C were first identified. These defects impair function of two proteins with a direct role in lipid trafficking, resulting in deposition of free cholesterol within late endosomal compartments and a multitude of effects on cell function and clinical manifestations. The rapid pace of research in this area has vastly improved our overall understanding of intracellular cholesterol homeostasis. Excessive cholesterol buildup has also been implicated in clinical manifestations associated with a number of genetically unrelated diseases including cystic fibrosis. Applying knowledge about anomalous cell signaling behavior in cystic fibrosis opens prospects for identifying similar previously unrecognized disease pathways in Niemann-Pick disease Type C. Recognition that Niemann-Pick disease Type C and cystic fibrosis both impair cholesterol regulatory pathways also provides a rationale for identifying common therapeutic targets.     

A two-locus selection hypothesis for Duchenne Muscular Dystrophy

Three hypotheses to explain the incidence and familial structure of Duchenne Muscular Dystrophy are examined. The classical explanations of a high rate of mutation and heterozygote advantage are shown to be inconsistent with the data. The third hypothesis of two closely linked loci on the X chromosome is developed and shown to be compatible with a set of Utah families including many large Mormon families. The application of the results to other X-linked and autosomal diseases is discussed.     

Viral evolution and the emergence of SARS coronavirus

The recent appearance of severe acute respiratory syndrome coronavirus (SARS-CoV) highlights the continual threat to human health posed by emerging viruses. However, the central processes in the evolution of emerging viruses are unclear, particularly the selection pressures faced by viruses in new host species. We outline some of the key evolutionary genetic aspects of viral emergence. We emphasize that, although the high mutation rates of RNA viruses provide them with great adaptability and explain why they are the main cause of emerging diseases, their limited genome size means that they are also subject to major evolutionary constraints. Understanding the mechanistic basis of these constraints, particularly the roles played by epistasis and pleiotropy, is likely to be central in explaining why some RNA viruses are more able than others to cross species boundaries. Viral genetic factors have also been implicated in the emergence of SARS-CoV, with the suggestion that this virus is a recombinant between mammalian and avian coronaviruses. We show, however, that the phylogenetic patterns cited as evidence for recombination are more probably caused by a variation in substitution rate among lineages and that recombination is unlikely to explain the appearance of SARS in humans.     

Biology and potential strategies for the treatment of GM2 gangliosidoses

The G_M2 gangliosidoses are a group of heritable neurodegenerative disorders caused by excessive accumulation of the ganglioside G_M2 owing to deficiency in β-hexosaminidase activity. Tay–Sachs and Sandhoff diseases have similar clinical phenotypes resulting from a deficiency in human hexosaminidase α and β subunits, respectively. The lack of treatment for G_M2 gangliosidoses stimulated interest in developing animal models to understand the molecular mechanisms underlying the various forms of this disease and to test new potential therapies. In this review, we discuss the molecular biology of G_M2 gangliosidoses and the different strategies that have been tested in animal models for the treatment of this genetic disorder, including gene transfer and cell engraftment of neural stem cells engineered to express the hexosaminidase isoenzymes.     

Genetic modifiers in mice: the example of the fragile X mouse model

Modifiers play an important role in most, if not all human diseases, and mouse models. For some disease models, such as the cystic fibrosis knockout mouse model, the effect of genetic factors other than the causative mutation has been well established and a modifier gene has been mapped. For other mouse models, including those of the fragile X syndrome, a common form of inherited mental retardation, controversies between test results obtained in different laboratories have been well recognized. Yet, the possibility that modifiers could at least explain part of the discrepancies is only scarcely mentioned. In this review we compare the test results obtained in different laboratories and provide evidence that modifiers may affect disease severity in the fragile X knockout mouse.     

Heterozygote Advantage and the Evolution of a Dominant Diploid Phase

The life cycle of eukaryotic, sexual species is divided into haploid and diploid phases. In multicellular animals and seed plants, the diploid phase is dominant, and the haploid phase is reduced to one, or a very few cells, which are dependent on the diploid form. In other eukaryotic species, however, the haploid phase may dominate or the phases may be equally developed. Even though an alternation between haploid and diploid forms is fundamental to sexual reproduction in eukaryotes, relatively little is known about the evolutionary forces that influence the dominance of haploidy or diploidy. An obvious genetic factor that might result in selection for a dominant diploid phase is heterozygote advantage, since only the diploid phase can be heterozygous. In this paper, I analyze a model designed to determine whether heterozygote advantage could lead to the evolution of a dominant diploid phase. The main result is that heterozygote advantage can lead to an increase in the dominance of the diploid phase, but only if the diploid phase is already sufficiently dominant. Because the diploid phase is unlikely to be increased in organisms that are primarily haploid, I conclude that heterozygote advantage is not a sufficient explanation of the dominance of the diploid phase in higher plants and animals.     

Multiple mutations in a specific gene in a small population

Hereditary diseases have been reported with relatively high frequency in some small populations. Founder effect and genetic drift, associated or not with selective advantage of heterozygotes in case of recessive diseases, are the main explanations. Therefore, if we consider one population and one particular disease, only one deleterious allele should be observed.Determination of mutations has shown that in most cases the situation is more complex; more than one mutation is found among the patients. This finding can be explained by a multiple founder effect, with genetic drift and new mutations.     

Regulation of offspring and the Roman Catholic Church

Abstract

The 1976 enactment of the National Sickle Cell Anemia, Cooley's Anemia, Tay‐Sachs, and Genetic Disease Act may mark the emergence of a national policy on mass genetic screening. The law includes provisions intended to protect persons who are tested for genetic traits in screening programs operated with government funds. Two key features are (1) guaranteed access to competent genetic counseling and (2) strict confidentiality of test results. Because genetic screening will be conducted through state public health departments, I surveyed the states to determine how they were currently providing access to genetic counseling and protection of genetic data. The responses indicated that (1) there is an extreme heterogeneity of counseling services, and (2) that most states have not developed programs to safeguard genetic data.     

Heterozygote Advantage Probably Maintains Rhesus Factor Blood Group Polymorphism: Ecological Regression Study

Rhesus factor polymorphism has been an evolutionary enigma since its discovery in 1939. Carriers of the rarer allele should be eliminated by selection against Rhesus positive children born to Rhesus negative mothers. Here I used an ecologic regression study to test the hypothesis that Rhesus factor polymorphism is stabilized by heterozygote advantage. The study was performed in 65 countries for which the frequencies of RhD phenotypes and specific disease burden data were available. I performed multiple multivariate covariance analysis with five potential confounding variables: GDP, latitude (distance from the equator), humidity, medical care expenditure per capita and frequencies of smokers. The results showed that the burden associated with many diseases correlated with the frequencies of particular Rhesus genotypes in a country and that the direction of the relation was nearly always the opposite for the frequency of Rhesus negative homozygotes and that of Rhesus positive heterozygotes. On the population level, a Rhesus-negativity-associated burden could be compensated for by the heterozygote advantage, but for Rhesus negative subjects this burden represents a serious problem.