Mendel's experiments: A reinterpretation

Conclusion My conclusion is that Mendel deliberately, though without any real falsification, tried to suggest to his audience and readers an unlikely and substantially wrong reconstruction of the first and most important phase of his research. In my book I offer many reasons for this strange and surprising behavior,⁵³ but the main argument rests on the fact of linkage. Mendelian genetics cannot account for linkage because it was based on the idea of applying probability theory to the problem of species evolution. Central to the theory is the law of probability according to which the chance occurrence of a combination of independent events is the product of their separate probabilities. This is the common basis of Mendel's first and second laws, but this is why Mendel's second law on independent assortment is enunciated in too general a way. From Morgan's work we now know that characters may not always be independent if their genes are located very close one to the other on the same chromosome. And this was also the basis of Mendel's personal drama: he surely observed the effects of linkage, but he had no theoretical tools with which to explain it. So he presented his results in a logical structure consistent with the central idea of his theory. Had he described the real course of his experiments he would have had to admit that his law worked for only a few of the hundreds of Pisum characters — and it would thus have been considered more of an exception than a rule. This is why he insisted on the necessity of testing the law on other plants, and this is why in his second letter to Carl Nägeli he admits that the publication of his data was untimely and dangerous.⁵⁴.We can argue that already in 1866 Mendel was less confident that his so-called second law had the same general validity as the first — and that later he lost his confidence altogether. Contemporary testimony indicates that in the end he became as skeptical as all his contemporaries as to the scientific relevance of his theory.⁵⁵ But he was wrong. His research is in no way the fruit of methodological mistakes or forgery, and it remains a landmark in the history of science. He was only the victim of a strange destiny in which the use of probability theory was responsible, at the same time, for the strength and for the weakness of his theory. We must still consider him the father and founder of genetics.     

Role of de Vries in the rediscovery of Mendel's paper. II. Did de Vries really understand Mendel's paper?

In this paper, we discuss briefly three of the several lines of evidence that we believe demonstrate de Vries's lack of understanding of Mendel's paper. In our view, at least part of de Vries's failure of understanding derives from the fact that he appears to have viewed Mendel's paper as being mainly about the inheritance of characters that was his own interest. Therefore, he looked at it to see whether Mendel had found any laws of inheritance. Mendel had done his research for another purpose, to find the laws describing the formation of hybrids and the development of their offspring. Thus, de Vries started his examination of Mendel's paper with a very fundamental misunderstanding of what it was about.     

L. H. Bailey's citations to Gregor Mendel

L. H. Bailey cited Mendel's 1865 and 1869 papers in the bibliography that accompanied his 1892 paper, Cross-Breeding and Hybridizing, and Mendel is mentioned once in the 1895 edition of Bailey's "Plant-Breeding." Bailey claimed to have copied his 1892 references to Mendel from Focke. It seems, however, that while he may have first encountered references to Mendel's work in Focke, he actually copied them from the Royal Society "Catalogue of Scientific Papers." Bailey also saw a reference to Mendel's 1865 paper in Jackson's "Guide to the Literature of Botany." Bailey's 1895 mention of Mendel occurs in a passage he translated from Focke's "Die Pflanzen-Mischlinge."     

Mendel, the empiricist

In contemporary texts in biology and genetics, Mendel is frequently portrayed as a theorist who was the father of classical genetics. According to some authors, he created his theory of inheritance to explain the results of his experimental hybridizations of peas. Others have proposed that he designed and carried out his experiments to demonstrate the correctness of a theory of inheritance he had already developed. We disagree strongly with these views of Mendel. Instead, we have come to regard him as an empirical investigator trying to discover the empirical natural laws describing the formation of hybrid peas and the development of their offspring over several generations. We have supported our view with an analysis of portions of Mendel's paper and his letters to Carl N ageli.     

Phenotype of apoptotic lymphocytes in children with Down syndrome

Background  

Down syndrome (DS) is the most common and best-known chromosomal disorder and is associated with several other pathologic conditions including immunodeficiency which makes a significant contribution to morbidity and mortality. Various immunological theories and observations to explain the predisposition of individuals with DS to various infections have been published, one of which is increased apoptotic cells.     

The real objective of Mendel's paper: A response to Monaghan and Corcos

Mendel's work in hybridization is ipso facto a study in inheritance. He is explicit in his interest to formulate universal generalizations, and at least in the case of the independent segregation of traits, he formulated his conclusions in the form of a law. Mendel did not discern, however, the inheritance of traits from that of the potential for traits. Choosing to study discrete non-overlapping traits, this did not hamper his efforts.     

On the origins of the Mendelian laws

The two laws usually attributed to Mendel were not considered as laws by him. The first law, the law of independent segregation occurs in Mendel's paper as an assumption or hypothesis. Hugo de Vries refers to this as a law discovered by Mendel. This appears to be the first use of an expression equivalent to Mendel's law. In his paper de Vries did not associate the observable characters with structures having a causitive role. That was done by Correns, who transformed the law of segregation of characters into a law of the segregation of anlagen. The second law, the law of independent assortment, is present in embryonic form in Mendel's paper. Here the independent assortment of characters appears as a secondary conclusion to a series of experiments involving several pairs of traits. Mendel repeats the primary conclusion later in the paper but not the secondary one. This leads us to believe that he considered the secondary conclusion as of lesser importance. We note in this context that the 9:3:3:1 ratio commonly associated with the idea of independent assortment, and attributed to Mendel, also does not occur in his paper. A careful reading of the papers of his discoverers shows it was Correns who first drew attention to this ratio. However, he did not formulate the second Mendelian law even though it was clearly implied. Neither was it stated by de Vries. Indeed, the first clear separation of the two laws and the naming of the second law was by T. H. Morgan some 13 years later.     

Choreoathetosis – an unusual adverse effect of dihydroartemisinin-piperaquine: a case report

Background

Dihydroartemisinin-piperaquine is a combination of dihydroartemisinin and piperaquine which is highly effective in the treatment of uncomplicated falciparum malaria. Its adverse effects are generally tolerable and temporary. Choreoathetosis, an involuntary movement disorder characterized by continuous irregular twisting of the body, is not a documented adverse effect of this medication.

Case presentation

A 41-year-old Cameroonian man of black African ethnicity was brought to our primary care hospital because over the previous 6 hours he had been experiencing involuntary twisting movements of his body and he no longer had control of his limbs. Earlier that day, he had been prescribed an appropriate dose of dihydroartemisinin-piperaquine in our hospital. The abnormal movements started approximately 3 hours after ingesting the first dose of the drug. The review of systems and his past history were unremarkable. On clinical examination, he was conscious and oriented but was unsteady and displayed continuous generalized irregular twisting movements combined with abrupt low amplitude flinging of his limbs. Dihydroartemisinin-piperaquine-induced generalized choreoathetosis was diagnosed. He was sedated with diazepam and dihydroartemisinin-piperaquine was discontinued. The antimalarial drug was substituted with artemether-lumefantrine combination. The clinical progress was good and he was discharged home after 72 hours. No further abnormalities were noted during 7 months of follow-up.

Conclusion

Although dihydroartemisinin-piperaquine is increasingly popular as a well-tolerated/efficacious antimalarial drug, clinicians must note the rare possibility of choreoathetosis as an adverse effect of this medication and educate patients accordingly.

     

Internet-based profiler system as integrative framework to support translational research

Background  

Translational research requires taking basic science observations and developing them into clinically useful tests and therapeutics. We have developed a process to develop molecular biomarkers for diagnosis and prognosis by integrating tissue microarray (TMA) technology and an internet-database tool, Profiler. TMA technology allows investigators to study hundreds of patient samples on a single glass slide resulting in the conservation of tissue and the reduction in inter-experimental variability. The Profiler system allows investigator to reliably track, store, and evaluate TMA experiments. Here within we describe the process that has evolved through an empirical basis over the past 5 years at two academic institutions.     

A.N. Kolmogorov's defence of Mendelism

In 1939 N.I. Ermolaeva published the results of an experiment which repeated parts of Mendel's classical experiments. On the basis of her experiment she concluded that Mendel's principle that self-pollination of hybrid plants gave rise to segregation proportions 3:1 was false. The great probability theorist A.N. Kolmogorov reviewed Ermolaeva's data using a test, now referred to as Kolmogorov's, or Kolmogorov-Smirnov, test, which he had proposed in 1933. He found, contrary to Ermolaeva, that her results clearly confirmed Mendel's principle. This paper shows that there were methodological flaws in Kolmogorov's statistical analysis and presents a substantially adjusted approach, which confirms his conclusions. Some historical commentary on the Lysenko-era background is given, to illuminate the relationship of the disciplines of genetics and statistics in the struggle against the prevailing politically-correct pseudoscience in the Soviet Union. There is a Brazilian connection through the person of Th. Dobzhansky.     

A worldwide correlation of lactase persistence phenotype and genotypes

Background  

The ability of adult humans to digest the milk sugar lactose - lactase persistence - is a dominant Mendelian trait that has been a subject of extensive genetic, medical and evolutionary research. Lactase persistence is common in people of European ancestry as well as some African, Middle Eastern and Southern Asian groups, but is rare or absent elsewhere in the world. The recent identification of independent nucleotide changes that are strongly associated with lactase persistence in different populations worldwide has led to the possibility of genetic tests for the trait. However, it is highly unlikely that all lactase persistence-associated variants are known. Using an extensive database of lactase persistence phenotype frequencies, together with information on how those data were collected and data on the frequencies of lactase persistence variants, we present a global summary of the extent to which current genetic knowledge can explain lactase persistence phenotype frequency.     

A variational Bayes algorithm for fast and accurate multiple locus genome-wide association analysis

Background  

The success achieved by genome-wide association (GWA) studies in the identification of candidate loci for complex diseases has been accompanied by an inability to explain the bulk of heritability. Here, we describe the algorithm V-Bay, a variational Bayes algorithm for multiple locus GWA analysis, which is designed to identify weaker associations that may contribute to this missing heritability.     

Two-part permutation tests for DNA methylation and microarray data

Background  

One important application of microarray experiments is to identify differentially expressed genes. Often, small and negative expression levels were clipped-off to be equal to an arbitrarily chosen cutoff value before a statistical test is carried out. Then, there are two types of data: truncated values and original observations. The truncated values are not just another point on the continuum of possible values and, therefore, it is appropriate to combine two statistical tests in a two-part model rather than using standard statistical methods. A similar situation occurs when DNA methylation data are investigated. In that case, there are null values (undetectable methylation) and observed positive values. For these data, we propose a two-part permutation test.     

Elastic,not plastic species: Frozen plasticity theory and the origin of adaptive evolution in sexually reproducing organisms

Background  

Darwin's evolutionary theory could easily explain the evolution of adaptive traits (organs and behavioral patterns) in asexual but not in sexual organisms. Two models, the selfish gene theory and frozen plasticity theory were suggested to explain evolution of adaptive traits in sexual organisms in past 30 years.     

Commercial nucleic-acid amplification tests for diagnosis of pulmonary tuberculosis in respiratory specimens: meta-analysis and meta-regression

Background

Hundreds of studies have evaluated the diagnostic accuracy of nucleic-acid amplification tests (NAATs) for tuberculosis (TB). Commercial tests have been shown to give more consistent results than in-house assays. Previous meta-analyses have found high specificity but low and highly variable estimates of sensitivity. However, reasons for variability in study results have not been adequately explored. We performed a meta-analysis on the accuracy of commercial NAATs to diagnose pulmonary TB and meta-regression to identify factors that are associated with higher accuracy.

Methodology/Principal Findings

We identified 2948 citations from searching the literature. We found 402 articles that met our eligibility criteria. In the final analysis, 125 separate studies from 105 articles that reported NAAT results from respiratory specimens were included. The pooled sensitivity was 0.85 (range 0.36–1.00) and the pooled specificity was 0.97 (range 0.54–1.00). However, both measures were significantly heterogeneous (p<.001). We performed subgroup and meta-regression analyses to identify sources of heterogeneity. Even after stratifying by type of commercial test, we could not account for the variability. In the meta-regression, the threshold effect was significant (p = .01) and the use of other respiratory specimens besides sputum was associated with higher accuracy.

Conclusions/Significance

The sensitivity and specificity estimates for commercial NAATs in respiratory specimens were highly variable, with sensitivity lower and more inconsistent than specificity. Thus, summary measures of diagnostic accuracy are not clinically meaningful. The use of different cut-off values and the use of specimens other than sputum could explain some of the observed heterogeneity. Based on these observations, commercial NAATs alone cannot be recommended to replace conventional tests for diagnosing pulmonary TB. Improvements in diagnostic accuracy, particularly sensitivity, need to be made in order for this expensive technology to be worthwhile and beneficial in low-resource countries.     

Regional species gains outpace losses across North American continental shelf regions

Aim

Although species richness globally is likely to be declining, patterns in diversity at the regional scale depend on species gains within new habitats and species losses from previously inhabited areas. Our understanding of the processes associated with gains or losses remains poor, including whether these events exhibit immediate or delayed responses to environmental change.

Location

The study focuses on nine temperate marine ecosystems in North America.

Time period

The study period varies by region, but overall encompasses observations from 1970 to 2014.

Major taxa studied

We identified regional gains and losses for 577 marine fish and invertebrate species.

Methods

From a total of 166,213 sampling events from bottom trawls across North America that informed 17,997 independent observations of species gains and losses, we built generalized linear mixed effects models to test whether lagged temperature can explain instances of gains and losses of marine fishes and invertebrates in North American continental shelf habitats.

Results

We found that gains were less likely in years with high seasonality, consistent with seasonal extremes as a strong constraint on species occurrence. Losses were also negatively associated with high seasonality, but the response was delayed by 3 years.

Main conclusions

Environmental conditions play a role in species occupancy across diverse temperate marine ecosystems. Immediate gains paired with delayed losses can drive transient increases in species richness during times of environmental change. Identifying the dynamics behind regional species gains and losses is an important step towards prediction of biodiversity changes across ecosystems.     

Hypodipsic-hypernatremia syndrome in an adult with polycythemia: a case report

Background

Hypernatremia is a very common electrolyte disorder and is frequently encountered in out-patient as well as in-hospital settings. We describe an adult who was found to have unexplained relative polycythemia and episodic hypernatremia. A diagnosis of idiopathic hypodipsic-hypernatremia syndrome was made and the patient was managed with a water-drinking schedule.

Case presentation

A 24-year-old South African-Indian man was found to have polycythemia in association with episodes of hypernatremia. Investigations indicated that he had relative polycythemia. He experienced no thirst at a time when his serum sodium concentration was found to be 151?mmol/L. Further testing indicated that his renal response to arginine vasopressin was intact and magnetic resonance imaging of his brain revealed no hypothalamic lesions. A diagnosis of idiopathic hypodipsic-hypernatremia syndrome was made and he was managed with a water-drinking schedule that corrected his hypernatremia.

Conclusion

Hypodipsia should always be considered when a patient without physical or cognitive disability presents with unexplained episodic hypernatremia or with relative polycythemia.

     

The rediscovery of Mendelism in agricultural context: Erich von Tschermak as plant-breeder

Why was Mendelism rediscovered? One way in which historians have addressed this issue is to look at wider trends in research during the 1890s of which the rediscoverers were part. Quite a lot is known about one such research tradition, namely the attempts to resolve the question of evolutionary mechanism through the use of varietal crosses. But another relevant research tradition is still largely unknown: the work of commercial breeders, several of whom were using hybridisation by the 1890s. In this paper I begin by looking at Tschermak's initial career, the sequence of events by which he came upon Mendel's work, and why he was excited by what he read. Then I place Tschermak's early work in the context of commercial plant-breeding in German-speaking Europe toward the end of the 19th century. Finally I look again at the question of Tschermak's somewhat ambivalent relationship to Mendelism after 1900. I argue that his initial misunderstanding of the concept of segregation was due to the fact that he approached Mendel's work with the perspective of a breeder rather than that of a geneticist.