Despite advances in treatments over the last decades, a uniformly reliable and free of side effects therapy of human cancers remains to be achieved. During chromosome replication, a premature halt of two converging DNA replication forks would cause incomplete replication and a cytotoxic chromosome nondisjunction during mitosis. In contrast to normal cells, most cancer cells bear numerous DNA deletions. A homozygous deletion permanently marks a cell and its descendants. Here, we propose an approach to cancer therapy in which a (...) pair of sequence‐specific roadblocks is placed solely at two cancer‐confined deletion sites that are located ahead of two converging replication forks. We describe this method, termed “replication blocks specific for deletions” (RBSD), and another deletions‐based approach as well. RBSD can be expanded by placing pairs of replication roadblocks on several different chromosomes. The resulting simultaneous nondisjunctions of these chromosomes in cancer cells would further increase the cancer‐specific toxicity of RBSD. (shrink)

This paper is an attempt to reconstruct the history of genetic and evolutionary theories of same-sex sexual behavior using Imre Lakatos’ methodology of scientific research programs . Although distinct, those two programs are complementary. Whereas the genetic program maintains that homosexuality is genetically inherited, the evolutionary program attempts to explain how such a gene, which apparently reduces the reproductive fitness of its homozygous carrier, is maintained in the population. This appraisal reveals that the two research programs have not been (...) empirically progressive in the Lakatosian sense. I argue that this situation has arisen precisely because of inappropriate over-commitment to the respective hard cores of the two research programs. As adherence to such cores is essential for success in research programs, according to Lakatos, I argue that Lakatos’ account of science may be descriptively adequate but is normatively inadequate. I provide grounds for generalizing this case as follows: the MSRP may successfully capture the logic of axiomised sciences, such as physics, but applies poorly to most sciences, including biological and social sciences, which do not lend themselves to axiomatic organization. (shrink)

Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR and SPINK1 variants were associated with pancreatitis risk. We now report two associations at genome-wide significance identified and replicated at PRSS1-PRSS2 and X-linked CLDN2 through a two-stage genome-wide study. The PRSS1 variant likely affects disease susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is (...) associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men. © 2012 Nature America, Inc. All rights reserved. (shrink)

The crucial phase of speciation is argued to be the evolution of mating cross-incompatibility (prezygotic incompatibility) between the genotypes distinguishing the prospective species populations. Based on this idea, a single-locus model of speciation is presented, which is shown to be biologically plausible and may help to settle the controversy as to the biological significance of single-locus modes of speciation. The model involves three alleles, two of which characterize in homozygous state the prospective species populations and in heterozygous state their (...) hybrids. The third allele represents a mutant which is equivalent to one of the first two alleles with the exception that it inhibits mating with carriers of the third allele. This third allele is fixed in one population and immigrates into a second population which contains the mutant inhibiting matings with members of the former population. Migration in the reverse direction does not occur. Proceeding from a widely applicable concept of fitness and mating preference it is shown that postzygotic incompatibility (hybrid or heterozygote disadvantage) alone suffices to trigger evolutionary replacement of the extant mating relations in the population receiving immigrants by any arbitrary degree of prezygotic incompatibility. This corroborates Wallace's hypothesis and emphasizes the potential biological relevance of speciation by reinforcement (parapatric speciation) at single gene loci. (shrink)

Almost every human disease has both a genetic and an environmental component. Even a classical inherited condition such as hemophilia can be influenced by external factors—in fact, most of the pathogenic effects of the mutation can be avoided by judicious injections of clotting factor, leading to a nearly normal life expectancy. For infectious diseases, often considered as essentially environmental, there are well-documented inherited differences in susceptibility, one of the most striking being the resistance to HIV infection of homozygous carriers (...) of the delta-32 mutation in the CCR5 gene (Dragic et al. 1996). Nevertheless, a number of conditions are “mostly genetic,” others “mostly environmental,” while many .. (shrink)

The genetic communication system includes the following components: the parent, which represents the information source and which emits messages; the gametes, which are the messenger carriers; and the offspring, which results from the decoding of two of these messages and can, in turn, become an information source.In a diploid species, a pair of heterozygous homologous loci may emit two equally probable messages, the quantity of genetic information (Q) produced being equivalent to: Q=log2 2=1 bit. For n independent pairs of heterozygous (...) homologous loci, Q=n.log2 2=n bits. The evolution of Q is examined whenever the parent is used in inbreeding or crossbreeding. In the case of inbreeding, the initial Q is depleted as the loci become homozygous; for hybridization the evolution of Q is unpredictable. (shrink)

The myf5 and myoD genes are implicated in the specification of vertebrate skeletal muscle. These genes have been thought to be functionally redundant because neonatal mice bearing homozygous null mutations in either gene show grossly normal muscle development. By analyzing the early embryonic development of the mutants, Michael Rudnicki and coworkers show that trunk muscle development is retarded in embryos bearing myf5 null mutations, while early limb and branchial arch muscle development is retarded by myoD null mutations.1 These results (...) indicate that the myoD and myf5 genes are not redundant but that each controls the early specification of distinct muscle cell lineages. BioEssays 20:357–362, 1998.© 1998 John Wiley & Sons Inc. (shrink)

The Human Fertilisation and Embryology Authority have recently granted a licence to perform preimplanation genetic diagnosis (PGD) for the homozygous form of familial hypercholesterolaemia (FH), explicitly excluding its use for the heterozygous form. The grounds for such decisions centre on how serious a condition is thought to be as well as on the availability of effective treatment, and decisions are made on a case-by-case basis. The case for licensing homozygous FH is discussed and compared with other cases, and (...) the case for making a distinction between PGD for homozygous and heterozygous FH is also examined. Testing for homozygous FH raises difficult issues of non-disclosure of results for heterozygous FH. Fears that this decision may represent a ‘slippery slope’ to more widespread testing are argued to be overstated. (shrink)

Two recent reports of mice homozygously deleted for cyclin D1 provide unequivocal evidence that the critical G1 cyclin, cyclin D1, is by itself rate‐limiting for growth in some mammalian tissues(1,2). Cyclin D1 knockout mice are small and exhibit behavioral abnormalities. Specific hypoplasias of retinal and mammary tissues suggest an unusual dependence on cyclin D1 function for tissue growth in those organs. The odd coincidences that cyclin D1 functions as the retinoblastoma gene kinase, together with associations between increased cyclin D1 expression (...) and breast cancer, suggest, but do not prove, a special function of cyclin D1 in those tissues. (shrink)

A variety of studies show that parental absence early in life leads to deleterious effects on the developing CNS. This is thought to be largely because evolutionary-dependent stimuli are necessary for the appropriate postnatal development of the young brain, an effect sometimes termed the “experience-expectant brain,” with parents providing the necessary input for normative synaptic connections to develop and appropriate neuronal survival to occur. Principal among CNS systems affected by parental input are the monoamine systems. In the present study,N= 434 (...) rhesus monkeys (233 males, 201 females) were reared in one of two conditions: as mother-reared controls (MR;n= 269) or without adults with 24-h access to same-aged peers (PR;n= 165). When subjects were six-months-old, they underwent a separation paradigm involving 4, sequential, four-day social separations from their mothers or peers, with each separation followed by three-day reunions with their mothers or their peers. Prior to the separation paradigm, baseline cisternal CSF samples were obtained, as well as at the end of each the four social separations, and after final separation, during a recovery period. CSF was assayed for concentrations of monoamine metabolites and a blood sample was genotyped for the serotonin transporter (5-HTT) genotype. Replicating earlier landmark findings, PR subjects with thesallele exhibited lower baseline concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), when compared to PR subjects homozygous for theLallele. MR subjects were undifferentiated by genotype. PR subjects exhibited lower CSF 5-HIAA concentrations during baseline, but higher CSF 5-HIAA during social separations, when compared to MR subjects. There were rearing effects for the dopamine metabolite homovanillic acid (HVA) and for the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG), with PR subjects showing higher HVA and lower MHPG when compared to MR subjects. These findings indicate that there are long-term deficits in the response of monoamines following early maternal absence. The results of this study confirm and extend earlier findings that early parental absence has deleterious consequences for the development of the monoamine systems, and that these consequences are modulated by the 5-HTT genotype. (shrink)

Six essential genes located near the mouse albino locus have been identified as required during specific periods of development. Amongst these six, each is required either during the preimplantation stages of development, at specific times during gastrulation, within 12 hrs after birth or during juvenile development. These genes were identified as a result of extensive genetic complementation analysis using embryos homozygous for the albino deletions. Although, in principal, the associated developmental abnormalities could result from loss of multiple genes, the (...) deletion phenotype in one case is identical to that induced by chemical mutagenesis. These results indicate that the abnormalities observed in deletion homozygotes may result from single gene loss. The deletions have proven useful not only as genetic tools to localize the position of the genes, but also as molecular entry points to the regions containing these genes. The current methodology being used to isolate candidate genes from the albino region is also reviewed here. (shrink)

BACKGROUND: Serotonin transporter promoter genotype appears to increase risk for depression in the context of stressful life events. However, the effects of this genotype on measures of stress sensitivity are poorly understood. Therefore, this study examined whether 5-HTTLPR genotype was associated with negative information processing biases in early childhood. METHOD: Thirty-nine unselected seven-year-old children completed a negative mood induction procedure and a Self-Referent Encoding Task designed to measure positive and negative schematic processing. Children were also genotyped for the 5-HTTLPR gene. (...) RESULTS: Children who were homozygous for the short allele of the 5-HTTLPR gene showed greater negative schematic processing following a negative mood prime than those with other genotypes. 5-HTTLPR genotype was not significantly associated with positive schematic processing. LIMITATIONS: The sample size for this study was small. We did not analyze more recently reported variants of the 5-HTTLPR long alleles. CONCLUSIONS: 5-HTTLPR genotype is associated with negative information processing styles following a negative mood prime in a non-clinical sample of young children. Such cognitive styles are thought to be activated in response to stressful life events, leading to depressive symptoms; thus, cognitive styles may index the "stress-sensitivity" conferred by this genotype. (shrink)

OBJECTIVES: Early-emerging, temperamental differences in fear-related traits may be a heritable vulnerability factor for anxiety disorders. Previous research indicates that the serotonin transporter promoter region polymorphism is a candidate gene for such traits. METHODS: Associations between 5-HTTLPR genotype and indices of fearful child temperament, derived from maternal report and standardized laboratory observations, were examined in a community sample of 95 preschool-aged children. RESULTS: Children with one or more long alleles of the 5-HTTLPR gene were rated as significantly more nervous during (...) standardized laboratory tasks than children who were homozygous for the short alleles. Children homozygous for the short alleles were also rated as significantly shyer, by maternal report, than those with at least one copy of the long allele of the 5-HTTLPR gene. CONCLUSIONS: This study extends the literature linking the short alleles of the serotonin transporter promoter region polymorphism to fear and anxiety-related traits in early childhood and adulthood, and is one of very few studies to examine the molecular genetics of preschoolers' temperament using multiple measures of traits in a normative sample. (shrink)

Helen Dean King's scientific work focused on inbreeding using experimental data collected from standardized laboratory rats to elucidate problems in human heredity. The meticulous care with which she carried on her inbreeding experiments assured that her results were dependable and her theoretical explanations credible. By using her nearly homozygous rats as desired commodities, she also was granted access to venues and people otherwise unavailable to her as a woman. King's scientific career was made possible through her life experiences. She (...) earned a doctorate from Bryn Mawr College under Thomas Hunt Morgan and spent a productive career at the Wistar Institute of Anatomy and Biology in Philadelphia where she had access to the experimental subjects which made her career possible. In this paper I examine King's work on inbreeding, her participation in the debates over eugenics, her position at the Wistar Institute, her status as a woman working with mostly male scientists, and her involvement with popular science. (shrink)

Helen Dean King's scientific work focused on inbreeding using experimental data collected from standardized laboratory rats to elucidate problems in human heredity. The meticulous care with which she carried on her inbreeding experiments assured that her results were dependable and her theoretical explanations credible. By using her nearly homozygous rats as desired commodities, she also was granted access to venues and people otherwise unavailable to her as a woman. King's scientific career was made possible through her life experiences. She (...) earned a doctorate from Bryn Mawr College under Thomas Hunt Morgan and spent a productive career at the Wistar Institute of Anatomy and Biology in Philadelphia where she had access to the experimental subjects which made her career possible. In this paper I examine King's work on inbreeding, her participation in the debates over eugenics, her position at the Wistar Institute, her status as a woman working with mostly male scientists, and her involvement with popular science. (shrink)

Females and males often exhibit conspicuous morphological, physiological and behavioral differences. Similarly, gene expression profiles indicate that a large portion of the genome is sex‐differentially deployed, particularly in the germ line. Because males and females are so fundamentally different, each sex is likely to have a different optimal gene expression profile that is never fully achieved in either sex because of antagonistic selection in females versus males. Males are hemizygous for the X chromosome, which means that recessive male‐favorable de novo (...) mutations on the X chromosome are subject to immediate selection. In females, a recessive female‐favorable mutation on one of two X chromosomes is not available for selection until it becomes frequent enough in the local population to result in homozygous individuals. Given that most mutations are recessive, one would expect that genes or alleles favoring males should accumulate on the X chromosome. Recent microarray work in Drosophila and C. elegans clearly shows the opposite. Why is the X chromosome a highly disfavored location for genes with male‐biased expression in these animals? BioEssays 26:543–548, 2004. Published 2004 Wiley Periodicals, Inc. (shrink)