Epistatic Genetic Effects among Alzheimer’s Candidate Genes

Background

Novel risk variants for late-onset Alzheimer’s disease (AD) have been identified and replicated in genome-wide association studies. Recent work has begun to address the relationship between these risk variants and biomarkers of AD, though results have been mixed. The aim of the current study was to characterize single marker and epistatic genetic effects between the top candidate Single Nucleotide Polymorphisms (SNPs) in relation to amyloid deposition.

Methods

We used a combined dataset across ADNI-1 and ADNI-2, and looked within each dataset separately to validate identified genetic effects. Amyloid was quantified using data acquired by Positron Emission Tomography (PET) with ¹⁸F-AV-45.

Results

Two SNP-SNP interactions reached significance when correcting for multiple comparisons, BIN1 (rs7561528, rs744373) x PICALM (rs7851179). Carrying the minor allele in BIN1 was related to higher levels of amyloid deposition, however only in non-carriers of the protective PICALM minor allele.

Conclusions

Our results support previous research suggesting these candidate SNPs do not show single marker associations with amyloid pathology. However, we provide evidence for a novel interaction between PICALM and BIN1 in relation to amyloid deposition. Risk related to the BIN1 minor allele appears to be mitigated in the presence of the PICALM protective variant. In that way, variance in amyloid plaque burden can be better classified within the context of a complex genetic background. Efforts to model cumulative risk for AD should explicitly account for this epistatic effect, and future studies should explicitly test for such effects whenever statistically feasible.     

Host–Pathogen Coevolution: The Selective Advantage of Bacillus thuringiensis Virulence and Its Cry Toxin Genes

Reciprocal coevolution between host and pathogen is widely seen as a major driver of evolution and biological innovation. Yet, to date, the underlying genetic mechanisms and associated trait functions that are unique to rapid coevolutionary change are generally unknown. We here combined experimental evolution of the bacterial biocontrol agent Bacillus thuringiensis and its nematode host Caenorhabditis elegans with large-scale phenotyping, whole genome analysis, and functional genetics to demonstrate the selective benefit of pathogen virulence and the underlying toxin genes during the adaptation process. We show that: (i) high virulence was specifically favoured during pathogen–host coevolution rather than pathogen one-sided adaptation to a nonchanging host or to an environment without host; (ii) the pathogen genotype BT-679 with known nematocidal toxin genes and high virulence specifically swept to fixation in all of the independent replicate populations under coevolution but only some under one-sided adaptation; (iii) high virulence in the BT-679-dominated populations correlated with elevated copy numbers of the plasmid containing the nematocidal toxin genes; (iv) loss of virulence in a toxin-plasmid lacking BT-679 isolate was reconstituted by genetic reintroduction or external addition of the toxins. We conclude that sustained coevolution is distinct from unidirectional selection in shaping the pathogen''s genome and life history characteristics. To our knowledge, this study is the first to characterize the pathogen genes involved in coevolutionary adaptation in an animal host–pathogen interaction system.     

Accepting Adoption’s Uncertainty: The Limited Ethics of Pre-Adoption Genetic Testing

An increasing number of children are adopted in the United States from countries where both medical care and environmental conditions are extremely poor. In response to worries about the accuracy of medical histories, prospective adoptive parents increasingly request genetic testing of children prior to adoption. Though a general consensus on the ethics of pre-adoption genetic testing (PAGT) argues against permitting genetic testing on children available for adoption that is not also permitted for children in general, a view gaining traction argues for expanding the tests permitted. The reasoning behind this view is that the State has a duty to provide a child with parents who are the best “match,” and thus all information that advances this end should be obtained. While the matching argument aims to promote the best interests of children, I show how it rests on the claim that what is in the best interests of children available for adoption is for prospective adoptive parents to have their genetic preferences satisfied such that the “genetics” of the children they end up adopting accurately reflects those preferences. Instead of protecting a vulnerable population, I conclude, PAGT contributes to the risks of harm such children face as it encourages people with strong genetic preferences to adopt children whose genetic backgrounds will always be uncertain.     

The Genetic Code: What Is It Good For? An Analysis of the Effects of Selection Pressures on Genetic Codes

How did the ``universal' genetic code arise? Several hypotheses have been put forward, and the code has been analyzed extensively by authors looking for clues to selection pressures that might have acted during its evolution. But this approach has been ineffective. Although an impressive number of properties has been attributed to the universal code, it has been impossible to determine whether selection on any of these properties was important in the code's evolution or whether the observed properties arose as a consequence of selection on some other characteristic. Therefore we turned the question around and asked, what would a genetic code look like if it had evolved in response to various different selection pressures? To address this question, we constructed a genetic algorithm. We found first that selecting on a particular measure yields codes that are similar to each other. Second, we found that the universal code is far from minimized with respect to the effects of mutations (or translation errors) on the amino acid compositions of proteins. Finally, we found that the codes that most closely resembled real codes were those generated by selecting on aspects of the code's structure, not those generated by selecting to minimize the effects of amino acid substitutions on proteins. This suggests that the universal genetic code has been selected for a particular structure—a structure that confers an important flexibility on the evolution of genes and proteins—and that the particular assignments of amino acids to codons are secondary. Received: 29 December 1998 / Accepted: 8 July 1999     

The Genetic Correlation between Height and IQ: Shared Genes or Assortative Mating?

Traits that are attractive to the opposite sex are often positively correlated when scaled such that scores increase with attractiveness, and this correlation typically has a genetic component. Such traits can be genetically correlated due to genes that affect both traits (“pleiotropy”) and/or because assortative mating causes statistical correlations to develop between selected alleles across the traits (“gametic phase disequilibrium”). In this study, we modeled the covariation between monozygotic and dizygotic twins, their siblings, and their parents (total N = 7,905) to elucidate the nature of the correlation between two potentially sexually selected traits in humans: height and IQ. Unlike previous designs used to investigate the nature of the height–IQ correlation, the present design accounts for the effects of assortative mating and provides much less biased estimates of additive genetic, non-additive genetic, and shared environmental influences. Both traits were highly heritable, although there was greater evidence for non-additive genetic effects in males. After accounting for assortative mating, the correlation between height and IQ was found to be almost entirely genetic in nature. Model fits indicate that both pleiotropy and assortative mating contribute significantly and about equally to this genetic correlation.     

The Patient’s View: Issues of Theory and Practice

Almost all the knowledge now produced about psychiatry includes what is called “the patient’s or client’s perspective.” This paper analyzes how this notion has been framed in the discourses on mental health over the last two decades, particularly in mental health research and in anthropology. The very concept of the “patient’s perspective” is a social and historical construct. Despite its remarkable prevalence, the notion remains vague. Mental health research pictures it as a stable attribute of the individual. Anthropologists integrate the contextual nature of the patient view; but they still largely envision the psychiatric patient as a rational actor producing narratives based on common sense. However, in psychiatric practice, the client’s perspective is not something the patient individually produces; it is rather shaped by and in a context. To explore this process, my research investigated interactions between staff and patients in a French community mental health center, and showed that the client’s perspective is the result of a collective process. Further analysis demonstrates that eliciting or producing the patient’s view is sometimes considered a therapeutic goal in itself, since being granted the status of a rational and narrative actor gives access to the most valued model of care, one that is based on partnership. Being an outcome that is negotiated between patients and care providers, the “patient’s view” then becomes a new resource in mental health settings.

The N’s and O’s of Drosophila glycoprotein glycobiology

The past 25 years have seen significant advances in understanding the diversity and functions of glycoprotein glycans in Drosophila melanogaster. Genetic screens have captured mutations that reveal important biological activities modulated by glycans, including protein folding and trafficking, as well as cell signaling, tissue morphogenesis, fertility, and viability. Many of these glycan functions have parallels in vertebrate development and disease, providing increasing opportunities to dissect pathologic mechanisms using Drosophila genetics. Advances in the sensitivity of structural analytic techniques have allowed the glycan profiles of wild-type and mutant tissues to be assessed, revealing novel glycan structures that may be functionally analogous to vertebrate glycans. This review describes a selected set of recent advances in understanding the functions of N-linked and O-linked (non-glycosaminoglycan) glycoprotein glycans in Drosophila with emphasis on their relatedness to vertebrate organisms.     

Genetic improvement of brewer’s yeast: current state, perspectives and limits

Brewer’s yeast strain optimisation may lead to a more efficient beer production process, better final quality or healthier beer. However, brewer’s yeast genetic improvement is very challenging, especially true when it comes to lager brewer’s yeast (Saccharomyces pastorianus) which contributes to 90% of the total beer market. This yeast is a genetic hybrid and allopolyploid. While early studies applying traditional genetic approaches encountered many problems, the development of rational metabolic engineering strategies successfully introduced many desired properties into brewer’s yeast. Recently, the first genome sequence of a lager brewer’s strain became available. This has opened the door for applying advanced omics technologies and facilitating inverse metabolic engineering strategies. The latter approach takes advantage of natural diversity and aims at identifying and transferring the crucial genetic information for an interesting phenotype. In this way, strains can be optimised by introducing “natural” mutations. However, even when it comes to self-cloned strains, severe concerns about genetically modified organisms used in the food and beverage industry are still a major hurdle for any commercialisation. Therefore, research efforts will aim at developing new sophisticated screening methods for the isolation of natural mutants with the desired properties which are based on the knowledge of genotype–phenotype linkage.     

Expression of Novel Alzheimer’s Disease Risk Genes in Control and Alzheimer’s Disease Brains

Late onset Alzheimer’s disease (LOAD) etiology is influenced by complex interactions between genetic and environmental risk factors. Large-scale genome wide association studies (GWAS) for LOAD have identified 10 novel risk genes: ABCA7, BIN1, CD2AP, CD33, CLU, CR1, EPHA1, MS4A6A, MS4A6E, and PICALM. We sought to measure the influence of GWAS single nucleotide polymorphisms (SNPs) and gene expression levels on clinical and pathological measures of AD in brain tissue from the parietal lobe of AD cases and age-matched, cognitively normal controls. We found that ABCA7, CD33, and CR1 expression levels were associated with clinical dementia rating (CDR), with higher expression being associated with more advanced cognitive decline. BIN1 expression levels were associated with disease progression, where higher expression was associated with a delayed age at onset. CD33, CLU, and CR1 expression levels were associated with disease status, where elevated expression levels were associated with AD. Additionally, MS4A6A expression levels were associated with Braak tangle and Braak plaque scores, with elevated expression levels being associated with more advanced brain pathology. We failed to detect an association between GWAS SNPs and gene expression levels in our brain series. The minor allele of rs3764650 in ABCA7 is associated with age at onset and disease duration, and the minor allele of rs670139 in MS4A6E was associated with Braak tangle and Braak plaque score. These findings suggest that expression of some GWAS genes, namely ABCA7, BIN1, CD33, CLU, CR1 and the MS4A family, are altered in AD brains.     

Barbieri’s Organic Codes Enable Error Correction of Genomes

Barbieri introduced and developed the concept of organic codes. The most basic of them is the genetic code, a set of correspondence rules between otherwise unrelated sequences: strings of nucleotides on the one hand, polypeptidic chains on the other hand. Barbieri noticed that it implies ‘coding by convention’ as arbitrary as the semantic relations a language establishes between words and outer objects. Moreover, the major transitions in life evolution originated in new organic codes similarly involving conventional rules. Independently, dealing with heredity as communication over time and relying on information theory, we asserted that the conservation of genomes over the ages demands that error-correcting codes make them resilient to casual errors. Moreover, the better conservation of very old parts of the genome demands that they result from combining successively established nested codes such that the older an information, the more numerous component codes protect it. Barbieri’s concept of organic code and that of genomic error-correcting code may seem unrelated. We show however that organic codes actually entail error-correcting properties. Error-correcting, in general, results from constraints being imposed on a set of sequences. Mathematical equalities are conveniently used in communication engineering for expressing constraints but error correction only needs that constraints exist. Biological sequences are similarly endowed with error-correcting ability by physical-chemical or linguistic constraints, thus defining ‘soft codes’. These constraints are moreover presumably efficient for correcting errors. Insofar as biological sequences are subjected to constraints, organic codes necessarily involve soft codes, and their successive onset results in the nested structure we hypothesized. Organic codes are generated and maintained by means of molecular ‘semantic feedback loops’. Each of these loops involves genes which code for proteins, the enzymatic action of which controls a function needed for the protein assembly. Taken together, thus, they control the assembly of their own structure as instructed by the genome and, once closed, these loops ensure their own conservation. However, the semantic feedback loops do not prevent the genome lengthening. It increases both the redundancy of the genome (as an error-correcting code) and the information quantity it bears, thus improving the genome reliability and the specificity of the enzymes, which enables further evolution.     

The P’s and Q’s of cellular PrP-Aβ interactions

Prion disease research has opened up the “black-box” of neurodegeneration, defining a key role for protein misfolding wherein a predominantly alpha-helical precursor protein, PrP^C, is converted to a disease-associated, β-sheet enriched isoform called PrP^Sc. In Alzheimer disease (AD) the Aβ peptide derived from the β-amyloid precuror protein APP folds in β-sheet amyloid. Early thoughts along the lines of overlap may have been on target,¹ but were eclipsed by a simultaneous (but now anachronistic) controversy over the role of PrP^Sc in prion diseases.^2,3 Nonetheless, as prion diseases such as Creutzfeldt-Jakob Disease (CJD) are themselves rare and can include an overt infectious mode of transmission, and as familial prion diseases and familial AD involve different genes, an observer might reasonably have concluded that prion research could occasionally catalyze ideas in AD, but could never provide concrete overlaps at the mechanistic level. Surprisingly, albeit a decade or three down the road, several prion/AD commonalities can be found within the contemporary literature. One important prion/AD overlap concerns seeded spread of Aβ aggregates by intracerebral inoculation much like prions,⁴ and, with a neuron-to-neuron ‘spreading’ also reported for pathologic forms of other misfolded proteins, Tau^5,6 and α-synuclein in the case of Parkinson Disease.^7,8 The concept of seeded spread has been discussed extensively elsewhere, sometimes under the rubric of “prionoids”⁹, and lies outside the scope of this particular review where we will focus upon PrP^C. From this point the story can now be subdivided into four strands of investigation: (1) pathologic effects of Aβ can be mediated by binding to PrP^C,¹⁰ (2) the positioning of endoproteolytic processing events of APP by pathologic (β-cleavage + γ-cleavage) and non-pathologic (α-cleavage + γ-cleavage) secretase pathways is paralleled by seemingly analogous α- and β-like cleavage of PrP^C (Fig. 1) (3) similar lipid raft environments for PrP^C and APP processing machinery,^11-13 and perhaps in consequence, overlaps in repertoire of the PrP^C and APP protein interactors (“interactomes”),^14,15 and (4) rare kindreds with mixed AD and prion pathologies.¹⁶ Here we discuss confounds, consensus and conflict associated with parameters that apply to these experimental settings.     

The P’s and Q’s of cellular PrP-Aβ interactions

Prion disease research has opened up the “black-box” of neurodegeneration, defining a key role for protein misfolding wherein a predominantly alpha-helical precursor protein, PrP^C, is converted to a disease-associated, β-sheet enriched isoform called PrP^Sc. In Alzheimer disease (AD) the Aβ peptide derived from the β-amyloid precuror protein APP folds in β-sheet amyloid. Early thoughts along the lines of overlap may have been on target,¹ but were eclipsed by a simultaneous (but now anachronistic) controversy over the role of PrP^Sc in prion diseases.^2,3 Nonetheless, as prion diseases such as Creutzfeldt-Jakob Disease (CJD) are themselves rare and can include an overt infectious mode of transmission, and as familial prion diseases and familial AD involve different genes, an observer might reasonably have concluded that prion research could occasionally catalyze ideas in AD, but could never provide concrete overlaps at the mechanistic level. Surprisingly, albeit a decade or three down the road, several prion/AD commonalities can be found within the contemporary literature. One important prion/AD overlap concerns seeded spread of Aβ aggregates by intracerebral inoculation much like prions,⁴ and, with a neuron-to-neuron ‘spreading’ also reported for pathologic forms of other misfolded proteins, Tau^5,6 and α-synuclein in the case of Parkinson Disease.^7,8 The concept of seeded spread has been discussed extensively elsewhere, sometimes under the rubric of “prionoids”⁹, and lies outside the scope of this particular review where we will focus upon PrP^C. From this point the story can now be subdivided into four strands of investigation: (1) pathologic effects of Aβ can be mediated by binding to PrP^C,¹⁰ (2) the positioning of endoproteolytic processing events of APP by pathologic (β-cleavage + γ-cleavage) and non-pathologic (α-cleavage + γ-cleavage) secretase pathways is paralleled by seemingly analogous α- and β-like cleavage of PrP^C (Fig. 1) (3) similar lipid raft environments for PrP^C and APP processing machinery,^11-13 and perhaps in consequence, overlaps in repertoire of the PrP^C and APP protein interactors (“interactomes”),^14,15 and (4) rare kindreds with mixed AD and prion pathologies.¹⁶ Here we discuss confounds, consensus and conflict associated with parameters that apply to these experimental settings.     

The expression of person and number: a typologist’s perspective

The categories of person and number have been analyzed extensively, both from a generative/structural perspective and from a typological/cross-linguistic perspective. The goal of both approaches is to account for the diversity of human languages, but in practice both have a rather different take on the subject. One major difference between these approaches is the relation between language-specific and cross-linguistic analyses. This paper argues that it is crucial to strictly distinguish between the two. However, this plea is at odds with the generative/structural perspective, which attempts to deal with both kinds of analyses at the same time. In contrast, it is of central importance from a typological/cross-linguistic perspective to keep the comparison constant across the wide variation as attested among human languages, thereby often ignoring many language-specific details (for the course of the comparison). The final section of this paper summarizes some major results of recent cross-linguistic comparisons of the person/number categories in the world’s languages.     

An innate twist between Crick’s wobble and Watson-Crick base pairs

Non-Watson-Crick pairs like the G·U wobble are frequent in RNA duplexes. Their geometric dissimilarity (nonisostericity) with the Watson-Crick base pairs and among themselves imparts structural variations decisive for biological functions. Through a novel circular representation of base pairs, a simple and general metric scheme for quantification of base-pair nonisostericity, in terms of residual twist and radial difference that can also envisage its mechanistic effect, is proposed. The scheme is exemplified by G·U and U·G wobble pairs, and their predicable local effects on helical twist angle are validated by MD simulations. New insights into a possible rationale for contextual occurrence of G·U and other non-WC pairs, as well as the influence of a G·U pair on other non-Watson-Crick pair neighborhood and RNA-protein interactions are obtained from analysis of crystal structure data. A few instances of RNA-protein interactions along the major groove are documented in addition to the well-recognized interaction of the G·U pair along the minor groove. The nonisostericity-mediated influence of wobble pairs for facilitating helical packing through long-range interactions in ribosomal RNAs is also reviewed.     

The discovery of slowness: Time to deconstruct Gretzky’s and Messi’s predictive brains

Jafari and Smith hypothesized that time during games may pass slower for the world’s best football player, Lionel Messi, from Argentina. This hypothesis leads to two questions: How can we explain such temporal paradox and how could this explain his dominant performances? Remarkably, the Argentinian’s case was preceded by the equally astonishing case of Wayne Gretzky: The Canadian considered ice hockey as a rather slow game and was the best player in the sport’s history. Whether Messi’s and Gretzky’s motor neurons fire faster, (inter)act differently or whether other mechanisms are at (inter)play warrants targeted research. A further explanation for such dominance of football and ice hockey, respectively, could be that both athletes “buy time”: To this end, automized motor skills may allow their predictive brains to make better use of time than other players to read the games and plan ahead. Deconstructing predictive minds of outperforming individuals like Gretzky and Messi could provide unique options to elucidate how differential time perception may make performances in athletes, and beyond, more swift and more efficient.     

The Other Edge of Ockham’s Razor: The A-PR Hypothesis and the Origin of Mind

Charles Darwin’s theory of evolution characterized all life as engaged in a “struggle for existence”. To struggle requires internal data processing to detect and interpret patterns to guide behavior, a mechanism to struggle for existence. The cognitive bootstrapping A-PR cycle (Autonomy | Pattern Recognition) couples the origin of life and mind, enabling their symbiotic co-evolution. Life processes energy to create order. Mind processes data to create meaning. Life and mind co-evolve toward increased functional effectiveness, using A-PR feedback cycles that reflect the two Laws deduced from Ockham’s Razor. The Law of Parsimony is only one of two laws that have emerged from debate about Ockham’s Razor. Less well known is the “other edge of Ockham’s Razor”, the Law of Succinctness which, when viewed through the lens of Charles Darwin’s theory of evolution, enables the A-PR Hypothesis to fulfill the criteria of Ockham’s Razor.     

Parallels Between Major Depressive Disorder and Alzheimer’s Disease: Role of Oxidative Stress and Genetic Vulnerability

The thesis of this review is that oxidative stress is the central factor in major depressive disorder (MDD) and Alzheimer’s disease (AD). The major elements involved are inflammatory cytokines, the hypothalamic–pituitary axis, the hypothalamic–pituitary gonadal, and arginine vasopressin systems, which induce glucocorticoid and “oxidopamatergic” cascades when triggered by psychosocial stress, severe life-threatening events, and mental-affective and somatic diseases. In individuals with a genomic vulnerability to depression, these cascades may result in chronic depression–anxiety–stress spectra, resulting in MDD and other known depressive syndromes. In contrast, in subjects with genomic vulnerability to AD, oxidative stress-induced brain damage triggers specific antioxidant defenses, i.e., increased levels of amyloid-β (Aβ) and aggregation of hyper-phosphorylated tau, resulting in paired helical filaments and impaired functions related to the ApoEε4 isoform, leading to complex pathological cascades culminating in AD. Surprisingly, all the AD-associated molecular pathways mentioned in this review have been shown to be similar or analogous to those found in depression, including structural damage, i.e., hippocampal and frontal cortex atrophy. Other interacting molecular signals, i.e., GSK-3β, convergent survival factors (brain-derived neurotrophic factor and heat shock proteins), and transition redox metals are also mentioned to emphasize the vast array of intermediates that could interact via comparable mechanisms in both MDD and AD.