Imprinted brain hypothesis

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Imprinted_brain_hypothesis 

 

Imprinted brain hypothesis

Bernard Crespi, the primary originator of the hypothesis, in 2016
Claims	Autism and schizophrenia are genetic opposites via parental genomic imprinting
Related scientific disciplines	Autism, schizophrenia, developmental disability, evolutionary psychology
Year proposed	2008
Original proponents	Bernard Crespi, Christopher Badcock

The imprinted brain hypothesis is an unsubstantiated hypothesis in evolutionary psychology regarding the causes of autism spectrum and schizophrenia spectrum disorders, first presented by Bernard Crespi and Christopher Badcock in 2008. It claims that certain autistic and schizotypal traits are opposites, and that this implies the etiology of the two conditions must be at odds.

The imprinted brain hypothesis is based around genomic imprinting, an epigenetic process through which genes are expressed differently by way of one parent's contribution having more effect than the other. Specifically, proponents of the imprinted brain hypothesis propose that autism spectrum disorders are caused by paternal overimprinting, while schizophrenia spectrum disorders are caused by maternal overimprinting; they point to a number of supposed correlations and anticorrelations seen between the disorders and other traits to support the hypothesis.

While the hypothesis has found some attention in popular science, it lacks scientific backing. It has also been attacked as unfalsifiable, exaggerated, and overly broad. Specific issues for the hypothesis include that the predictions it makes about genetic disorders are falsified, that the effects of the two disorders on empathy and mentalizing are contrary to Crespi and Badcock's model, and that many neuroimaging findings fail to support the hypothesis.

Genomic imprinting

See also: Sexual conflict

Genomic imprinting is an epigenetic process by which certain genes are expressed in a parent-of-origin-specific manner. The imprinted brain theory is a variant of the kinship theory of genomic imprinting, also known as the conflict theory of genomic imprinting. The kinship theory argues that in diploid organisms, such as humans, the maternal and paternal set of genes may have antagonistic reproductive interests since the mother and father may have antagonistic interests regarding the development of the child. The kinship theory is one of multiple competing major hypotheses regarding genomic imprinting and is supported by proponents of the imprinted brain hypothesis, but the precise matter of how genomic imprinting works has not yet been resolved.

Hypothesis and background

Proponents of the imprinted brain hypothesis argue that since it is uncertain if a woman's other and future children have and will have the same father, as well as the father generally having lower parental investment, it may be in the father's reproductive interest for his child to use more of the mother's resources than other children, while it may be in the mother's interest for a child to take fewer resources and free up more for herself and future children. Thus, a genomic imprinting with slight maternal bias would supposedly be associated with factors such as decreased growth, more tractable behavior, and an empathizing and less self-centered personality causing less demands on the mother. The opposite would occur for a slight paternal bias.

However, an extreme genomic imprinting in favor of maternal genes is argued to cause psychosis such as in schizophrenia spectrum disorders, while an extreme genomic imprinting in favor of paternal genes is argued to cause autism spectrum disorders. This claims the symptoms of schizophrenia are caused by overempathizing, resulting in delusions and paranoia, while those of autism are caused by underempathizing. Specifically, autism is considered to be a tendency to under-mentalize and under-empathize in a way that treats people as objects, while schizotypy is considered to be the inverse tendency to over-mentalize and over-empathize until objects are treated as people. Certain neuroimaging findings lend support to the hypothesis, although neuroimaging in schizophrenia is controversial due to the neurological impact of neuroleptic medication, and other neuroimaging findings have results inconsistent with the hypothesis.

Traits such as the ambivalence seen in negative symptoms versus the single-minded focus of autistic special interests are also posited to be distinctions, although the pronounced similarity and overlap between negative symptomatology seen in the two disorders weakens this claim substantially.

The imprinted brain hypothesis was first proposed in 2008 by biologist Bernard Crespi and sociologist Christopher Badcock, neither of who had previous experience with cognitive science or behavioural genetics. Publishing their first presentation of their claims in the influential cognitive science journal Behavioral and Brain Sciences, the hypothesis attracted significant attention, both interested and critical.

Arguments of proponents

The imprinted brain hypothesis has some similarities with the extreme male brain theory of autism, but they come apart significantly. Proponents of the imprinted brain hypothesis state that the hypothesized imprinting mechanism may have detrimental interactions when extreme genomic imprinting occurs in the opposite sex, which they claim provides an explanation for something that would be a 'problem' for the extreme male brain claims—specifically, that female autism tends to be particularly severe. This is also used as an explanation for the relative severity of schizophrenia in males. However, proponents of the extreme male brain theory believe sexual dimorphism in autism severity is already explained by diagnostic discrepancy.

In both autism and schizophrenia, the theory of mind is impaired, which the imprinted brain hypothesis posits occurs via different mechanisms and is not generalizable to the broader underlying neurotypes. Proponents of the hypothesis claim people with schizotypal personality have an enhanced theory of mind, increased emphatic ability, and an improved ability to recognize the emotions of others, but this is not supported by research on the schizotypal personality disorder population or on measures of 'healthy' schizotypy in the general population. Rather, theory of mind appears to be impaired in all schizophrenia-spectrum conditions even in the absence of frank psychosis.

Factors such as nutrition during pregnancy are believed to affect imprinting. Proponents note that schizophrenia is associated with maternal starvation during pregnancy while autism has increased in diagnostic prevalence in affluent societies, although the general scientific consensus is that rising rates of autism diagnosis in wealthy societies are related to awareness rather than prevalence.

Autism and schizophrenia appear to be related to birth weight in opposite ways, with autism being associated with high birth weight and schizophrenia with low birth weight. Supporters of the hypothesis point towards this association as evidence.

Proponents of the hypothesis also point towards genetic disorders with an elevated risk of one disorder and not the other, especially imprinting disorders, to support their claims. For instance, Beckwith-Wiedemann syndrome is caused by increased effects of paternally imprinted genes and has an increased incidence of autism. Contrary to the overall claim here, the majority of disorders that raise the risk of one of autism and schizophrenia also do so for the other, including in ways that directly contradict the imprinted brain hypothesis such as for imprinting disorders. For instance, velocardiofacial syndrome is associated with significant increases (10- to 40-fold above the general population) in the risk for both autism and schizophrenia.

Data from copy number variation and genome-wide association studies support shared genetic mechanisms causing schizophrenia and autism, although this only lends circumstantial support to the imprinted brain hypothesis and can also be used to support many competing hypotheses.

The role of oxytocin in autism and schizophrenia has also been researched, and some findings and characterizations of the research have been used in favour of the hypothesis. Oxytocin appears to have treatment potential in both autism and schizophrenia, likely including schizotypal personality disorder. Crespi proposes that, contrary to this suggestion, high oxytocin is a contributing factor in population schizotypy and creates "hyper-developed" social understanding that induces psychosis. Supporters of the hypothesis point towards associations between higher oxytocin levels and personality traits that are also associated with schizotypy, such as creativity and divergent thinking. However, both schizotypal personality disorder and schizotypy in the general population appear associated with the same oxytocin deficits as observed in schizophrenia, and the degree to which positive symptoms of schizophrenia and schizotypy are associated with high oxytocin—as argued by proponents—appears unclear and contradicted.

Issues

The broad claim that autism and schizophrenia are in opposition on the biological level is not supported by research. In samples of autistic adults, schizophrenia and other non-affective psychotic disorders occur at far higher rates than the general population, occurring in about 8-10% of the broad ASD population and as high as one-third in PDD-NOS. The same association occurs in childhood onset schizophrenia, which is considered a more homogenous form of the disorder that hews closest to the hypothetical neurodevelopmental disorder underlying schizophrenia-spectrum conditions; approximately one-quarter of children with schizophrenia fit the criteria for an autism spectrum disorder prior to the onset of psychosis, and the majority have clinical or subclinical disturbances of social, motor, or language skills similar to those seen in autistic children. Adults with schizophrenia and related psychotic disorders also have higher rates of autistic symptomatology than healthy controls.

Crespi and Badcock make a number of claims about genetic disorders and their relationship to the hypothesis; for instance, that the relationship between those disorders and sex chromosome aneuploidy supports the hypothesis, with trisomy X and Klinefelter syndrome (extra X chromosomes) increasing schizophrenia risk and Turner syndrome (one X chromosome) increasing autism risk. However, polysomy X conditions are associated with increased autism as well as schizophrenia risk, and Turner syndrome is approximately three times as common in schizophrenic women as the general female population. Genetic syndromes in general lend credence to the suggestion that autism and schizophrenia are related rather than contraindicated, with conditions that sharply increase one risk tending to also increase the other. For instance, velocardiofacial syndrome, which is associated with a 20- to 30-fold increase in schizophrenia risk, also significantly increases the risk of autism. Other chromosomal disorders notable for significantly increasing the risk of both autism and schizophrenia include 15q11.2 microdeletions and 17q12 microdeletion syndrome.

Imprinting disorders such as Prader-Willi syndrome tend to have phenotypes that contradict the hypothesis

Moreover, the specific predictions the imprinted brain hypothesis makes about imprinting disorders are for the most part falsified. The imprinted brain hypothesis predicts that Prader-Willi syndrome, a disorder of maternal overimprinting, should have decreased autism and increased psychosis, while Angelman syndrome, a disorder of paternal overimprinting, should have the opposite. However, autism rates are substantially above those of the general population in PWS and similar to or below it in AS, while non-affective psychosis appears to occur at rates comparable to the general population in PWS. Indeed, it has been suggested that maternally imprinted cases of Prader-Willi syndrome have an elevated autism prevalence compared to all etiologies of the disorder, the exact opposite of the imprinted brain hypothesis. Despite being contradicted by other research, Crespi nonetheless claims that imprinting disorders as a rule fit his hypothesis.

While Crespi and Badcock have claimed neuroimaging studies lend support to the imprinted brain hypothesis, other neuroimaging studies have found contradictory results. Several neurological findings are common to both autism and schizophrenia. The brain regions that distinguish schizophrenia from autism are also those at the centre of the controversy regarding neuroleptic medication, reducing the degree to which they can be used to distinguish the disorders; autistic subjects taking psychotropic medication share some of the altered neuroconnectivity that Crespi and Badcock ascribe to schizophrenia.

The imprinting brain hypothesis has also been criticized for inaccurately presenting the schizophrenia spectrum and making claims about schizophrenic disorders that are at odds with their clinical profiles. The claim that milder schizophrenia-spectrum disorders are associated with intensified empathy and strong theory of mind is imperiled by research showing the opposite. The specific pattern of empathy deficits also appears to be consistent between autism and schizophrenia, with both demonstrating impaired cognitive empathy and relatively preserved affective empathy. Crespi and Badcock's attempt to conceptualize schizophrenia as a relatively homogenous disorder that slots neatly into one end of a spectrum has been criticized due to the clinical heterogeneity in even individual cases of schizophrenia, due to the different presentation and course of positive and negative symptoms.

Crespi and Badcock have also been criticized for avoiding falsifiable claims, in addition to the falsification of those claims they do make. Responses to Crespi's major publications on the topic have noted the broad range of evidence it attempts to 'tie up' and explain, without considering the consequences such a sweeping conjecture would have for known traits and comorbidities that contradict the claims, and for avoiding the matter of what would constitute a falsification or disconfirmation.

One of the most significant components of the hypothesis is that it predicts autism should be associated with "hypo-mentalizing" and schizophrenia with "hyper-mentalizing"; that is, that people in each group should have radically different impairments in mentalizing. This is a core component of the imprinted brain hypothesis, and one of the fundamental assumptions involved. However, meta-analysis of mentalizing skills in autism and schizophrenia does not support this claim. Rather, both conditions appear to be associated with similar mentalizing impairments that share common processing deficits.

Genomic imprinting

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Genomic_imprinting 

Genomic imprinting is an epigenetic phenomenon that causes genes to be expressed or not, depending on whether they are inherited from the mother or the father. Genes can also be partially imprinted. Partial imprinting occurs when alleles from both parents are differently expressed rather than complete expression and complete suppression of one parent's allele. Forms of genomic imprinting have been demonstrated in fungi, plants and animals. In 2014, there were about 150 imprinted genes known in mice and about half that in humans. As of 2019, 260 imprinted genes have been reported in mice and 228 in humans.

Genomic imprinting is an inheritance process independent of the classical Mendelian inheritance. It is an epigenetic process that involves DNA methylation and histone methylation without altering the genetic sequence. These epigenetic marks are established ("imprinted") in the germline (sperm or egg cells) of the parents and are maintained through mitotic cell divisions in the somatic cells of an organism.

Appropriate imprinting of certain genes is important for normal development. Human diseases involving genomic imprinting include Angelman, Prader–Willi, and Beckwith-Wiedemann syndromes. Methylation defects have also been associated with male infertility.

Overview

In diploid organisms (like humans), the somatic cells possess two copies of the genome, one inherited from the father and one from the mother. Each autosomal gene is therefore represented by two copies, or alleles, with one copy inherited from each parent at fertilization. The expressed allele is dependent upon its parental origin. For example, the gene encoding insulin-like growth factor 2 (IGF2/Igf2) is only expressed from the allele inherited from the father. Although imprinting accounts for a small proportion of mammalian genes they play an important role in embryogenesis particularly in the formation of visceral structures and the nervous system.

The term "imprinting" was first used to describe events in the insect Pseudococcus nipae. In Pseudococcids (mealybugs) (Hemiptera, Coccoidea) both the male and female develop from a fertilised egg. In females, all chromosomes remain euchromatic and functional. In embryos destined to become males, one haploid set of chromosomes becomes heterochromatinised after the sixth cleavage division and remains so in most tissues; males are thus functionally haploid.

Imprinted genes in mammals

That imprinting might be a feature of mammalian development was suggested in breeding experiments in mice carrying reciprocal chromosomal translocations. Nucleus transplantation experiments in mouse zygotes in the early 1980s confirmed that normal development requires the contribution of both the maternal and paternal genomes. The vast majority of mouse embryos derived from parthenogenesis (called parthenogenones, with two maternal or egg genomes) and androgenesis (called androgenones, with two paternal or sperm genomes) die at or before the blastocyst/implantation stage. In the rare instances that they develop to postimplantation stages, gynogenetic embryos show better embryonic development relative to placental development, while for androgenones, the reverse is true. Nevertheless, for the latter, only a few have been described (in a 1984 paper).

No naturally occurring cases of parthenogenesis exist in mammals because of imprinted genes. However, in 2004, experimental manipulation by Japanese researchers of a paternal methylation imprint controlling the Igf2 gene led to the birth of a mouse (named Kaguya) with two maternal sets of chromosomes, though it is not a true parthenogenone since cells from two different female mice were used. The researchers were able to succeed by using one egg from an immature parent, thus reducing maternal imprinting, and modifying it to express the gene Igf2, which is normally only expressed by the paternal copy of the gene.

Parthenogenetic/gynogenetic embryos have twice the normal expression level of maternally derived genes, and lack expression of paternally expressed genes, while the reverse is true for androgenetic embryos. It is now known that there are at least 80 imprinted genes in humans and mice, many of which are involved in embryonic and placental growth and development. Hybrid offspring of two species may exhibit unusual growth due to the novel combination of imprinted genes.

Various methods have been used to identify imprinted genes. In swine, Bischoff et al. compared transcriptional profiles using DNA microarrays to survey differentially expressed genes between parthenotes (2 maternal genomes) and control fetuses (1 maternal, 1 paternal genome). An intriguing study surveying the transcriptome of murine brain tissues revealed over 1300 imprinted gene loci (approximately 10-fold more than previously reported) by RNA-sequencing from F1 hybrids resulting from reciprocal crosses. The result however has been challenged by others who claimed that this is an overestimation by an order of magnitude due to flawed statistical analysis.

In domesticated livestock, single-nucleotide polymorphisms in imprinted genes influencing foetal growth and development have been shown to be associated with economically important production traits in cattle, sheep and pigs.

Genetic mapping of imprinted genes

At the same time as the generation of the gynogenetic and androgenetic embryos discussed above, mouse embryos were also being generated that contained only small regions that were derived from either a paternal or maternal source. The generation of a series of such uniparental disomies, which together span the entire genome, allowed the creation of an imprinting map. Those regions which when inherited from a single parent result in a discernible phenotype contain imprinted gene(s). Further research showed that within these regions there were often numerous imprinted genes. Around 80% of imprinted genes are found in clusters such as these, called imprinted domains, suggesting a level of co-ordinated control. More recently, genome-wide screens to identify imprinted genes have used differential expression of mRNAs from control fetuses and parthenogenetic or androgenetic fetuses hybridized to gene expression profiling microarrays, allele-specific gene expression using SNP genotyping microarrays, transcriptome sequencing, and in silico prediction pipelines.

Imprinting mechanisms

Imprinting is a dynamic process. It must be possible to erase and re-establish imprints through each generation so that genes that are imprinted in an adult may still be expressed in that adult's offspring. (For example, the maternal genes that control insulin production will be imprinted in a male but will be expressed in any of the male's offspring that inherit these genes.) The nature of imprinting must therefore be epigenetic rather than DNA sequence dependent. In germline cells the imprint is erased and then re-established according to the sex of the individual, i.e. in the developing sperm (during spermatogenesis), a paternal imprint is established, whereas in developing oocytes (oogenesis), a maternal imprint is established. This process of erasure and reprogramming is necessary such that the germ cell imprinting status is relevant to the sex of the individual. In both plants and mammals there are two major mechanisms that are involved in establishing the imprint; these are DNA methylation and histone modifications.

Recently, a new study has suggested a novel inheritable imprinting mechanism in humans that would be specific of placental tissue and that is independent of DNA methylation (the main and classical mechanism for genomic imprinting). This was observed in humans, but not in mice, suggesting development after the evolutionary divergence of humans and mice, ~80 Mya. Among the hypothetical explanations for this novel phenomenon, two possible mechanisms have been proposed: either a histone modification that confers imprinting at novel placental-specific imprinted loci or, alternatively, a recruitment of DNMTs to these loci by a specific and unknown transcription factor that would be expressed during early trophoblast differentiation.

Regulation

The grouping of imprinted genes within clusters allows them to share common regulatory elements, such as non-coding RNAs and differentially methylated regions (DMRs). When these regulatory elements control the imprinting of one or more genes, they are known as imprinting control regions (ICR). The expression of non-coding RNAs, such as antisense Igf2r RNA (Air) on mouse chromosome 17 and KCNQ1OT1 on human chromosome 11p15.5, have been shown to be essential for the imprinting of genes in their corresponding regions.

Differentially methylated regions are generally segments of DNA rich in cytosine and guanine nucleotides, with the cytosine nucleotides methylated on one copy but not on the other. Contrary to expectation, methylation does not necessarily mean silencing; instead, the effect of methylation depends upon the default state of the region.

Functions of imprinted genes

The control of expression of specific genes by genomic imprinting is unique to therian mammals (placental mammals and marsupials) and flowering plants. Imprinting of whole chromosomes has been reported in mealybugs (Genus: Pseudococcus) and a fungus gnat (Sciara). It has also been established that X-chromosome inactivation occurs in an imprinted manner in the extra-embryonic tissues of mice and all tissues in marsupials, where it is always the paternal X-chromosome which is silenced.

The majority of imprinted genes in mammals have been found to have roles in the control of embryonic growth and development, including development of the placenta. Other imprinted genes are involved in post-natal development, with roles affecting suckling and metabolism.

Hypotheses on the origins of imprinting

A widely accepted hypothesis for the evolution of genomic imprinting is the "parental conflict hypothesis". Also known as the kinship theory of genomic imprinting, this hypothesis states that the inequality between parental genomes due to imprinting is a result of the differing interests of each parent in terms of the evolutionary fitness of their genes. The father's genes that encode for imprinting gain greater fitness through the success of the offspring, at the expense of the mother. The mother's evolutionary imperative is often to conserve resources for her own survival while providing sufficient nourishment to current and subsequent litters. Accordingly, paternally expressed genes tend to be growth-promoting whereas maternally expressed genes tend to be growth-limiting. In support of this hypothesis, genomic imprinting has been found in all placental mammals, where post-fertilisation offspring resource consumption at the expense of the mother is high; although it has also been found in oviparous birds where there is relatively little post-fertilisation resource transfer and therefore less parental conflict. A small number of imprinted genes are fast evolving under positive Darwinian selection possibly due to antagonistic co-evolution. The majority of imprinted genes display high levels of micro-synteny conservation and have undergone very few duplications in placental mammalian lineages.

However, our understanding of the molecular mechanisms behind genomic imprinting show that it is the maternal genome that controls much of the imprinting of both its own and the paternally-derived genes in the zygote, making it difficult to explain why the maternal genes would willingly relinquish their dominance to that of the paternally-derived genes in light of the conflict hypothesis.

Another hypothesis proposed is that some imprinted genes act coadaptively to improve both fetal development and maternal provisioning for nutrition and care. In it, a subset of paternally expressed genes are co-expressed in both the placenta and the mother's hypothalamus. This would come about through selective pressure from parent-infant coadaptation to improve infant survival. Paternally expressed 3 (PEG3) is a gene for which this hypothesis may apply.

Others have approached their study of the origins of genomic imprinting from a different side, arguing that natural selection is operating on the role of epigenetic marks as machinery for homologous chromosome recognition during meiosis, rather than on their role in differential expression. This argument centers on the existence of epigenetic effects on chromosomes that do not directly affect gene expression, but do depend on which parent the chromosome originated from. This group of epigenetic changes that depend on the chromosome's parent of origin (including both those that affect gene expression and those that do not) are called parental origin effects, and include phenomena such as paternal X inactivation in the marsupials, nonrandom parental chromatid distribution in the ferns, and even mating type switching in yeast. This diversity in organisms that show parental origin effects has prompted theorists to place the evolutionary origin of genomic imprinting before the last common ancestor of plants and animals, over a billion years ago.

Natural selection for genomic imprinting requires genetic variation in a population. A hypothesis for the origin of this genetic variation states that the host-defense system responsible for silencing foreign DNA elements, such as genes of viral origin, mistakenly silenced genes whose silencing turned out to be beneficial for the organism. There appears to be an over-representation of retrotransposed genes, that is to say genes that are inserted into the genome by viruses, among imprinted genes. It has also been postulated that if the retrotransposed gene is inserted close to another imprinted gene, it may just acquire this imprint.

Imprinted Loci Phenotypic Signatures

Unfortunately, the relationship between the phenotype and genotype of imprinted genes is solely conceptual. The idea is frameworked using two alleles on a single locus and hosts three different possible classes of genotypes. The reciprocal heterozygotes genotype class contributes to understanding how imprinting will impact genotype to phenotype relationship. Reciprocal heterozygotes have a genetically equivalent, but they are phenotypically nonequivalent. Their phenotype may not be dependent on the equivalence of the genotype. This can ultimately increase diversity in genetic classes, expanding flexibility of imprinted genes. This increase will also force a higher degree in testing capabilities and assortment of tests to determine the presences of imprinting.

When a locus is identified as imprinted, two different classes express different alleles. Inherited imprinted genes of offspring are believed to be monoallelic expressions. A single locus will entirely produce one's phenotype although two alleles are inherited. This genotype class is called parental imprinting, as well as dominant imprinting. Phenotypic patterns are variant to possible expressions from paternal and maternal genotypes. Different alleles inherited from different parents will host different phenotypic qualities. One allele will have a larger phenotypic value and the other allele will be silenced. Underdominance of the locus is another possibility of phenotypic expression. Both maternal and paternal phenotypes will have a small value rather than one hosting a large value and silencing the other.

Statistical frameworks and mapping models are used to identify imprinting effects on genes and complex traits. Allelic parent-of -origin influences the vary in phenotype that derive from the imprinting of genotype classes. These models of mapping and identifying imprinting effects include using unordered genotypes to build mapping models. These models will show classic quantitative genetics and the effects of dominance of the imprinted genes.

Disorders associated with imprinting

Imprinting may cause problems in cloning, with clones having DNA that is not methylated in the correct positions. It is possible that this is due to a lack of time for reprogramming to be completely achieved. When a nucleus is added to an egg during somatic cell nuclear transfer, the egg starts dividing in minutes, as compared to the days or months it takes for reprogramming during embryonic development. If time is the responsible factor, it may be possible to delay cell division in clones, giving time for proper reprogramming to occur.

An allele of the "callipyge" (from the Greek for "beautiful buttocks"), or CLPG, gene in sheep produces large buttocks consisting of muscle with very little fat. The large-buttocked phenotype only occurs when the allele is present on the copy of chromosome 18 inherited from a sheep's father and is not on the copy of chromosome 18 inherited from that sheep's mother.

In vitro fertilisation, including ICSI, is associated with an increased risk of imprinting disorders, with an odds ratio of 3.7 (95% confidence interval 1.4 to 9.7).

Male infertility

Epigenetic deregulations at H19 imprinted gene in sperm have been observed associated with male infertility. Indeed, methylation loss at H19 imprinted gene has been observed associated with MTHFR gene promoter hypermethylation in semen samples from infertile males. 

Prader-Willi/Angelman

The first imprinted genetic disorders to be described in humans were the reciprocally inherited Prader-Willi syndrome and Angelman syndrome. Both syndromes are associated with loss of the chromosomal region 15q11-13 (band 11 of the long arm of chromosome 15). This region contains the paternally expressed genes SNRPN and NDN and the maternally expressed gene UBE3A.

• Paternal inheritance of a deletion of this region is associated with Prader-Willi syndrome (characterised by hypotonia, obesity, and hypogonadism).
• Maternal inheritance of the same deletion is associated with Angelman syndrome (characterised by epilepsy, tremors, and a perpetually smiling facial expression).

DIRAS3 (NOEY2 or ARH1)

DIRAS3 is a paternally expressed and maternally imprinted gene located on chromosome 1 in humans. Reduced DIRAS3 expression is linked to an increased risk of ovarian and breast cancers; in 41% of breast and ovarian cancers the protein encoded by DIRAS3 is not expressed, suggesting that it functions as a tumor suppressor gene. Therefore, if uniparental disomy occurs and a person inherits both chromosomes from the mother, the gene will not be expressed and the individual is put at a greater risk for breast and ovarian cancer.

Other

Other conditions involving imprinting include Beckwith-Wiedemann syndrome, Silver-Russell syndrome, and pseudohypoparathyroidism.

Transient neonatal diabetes mellitus can also involve imprinting.

The "imprinted brain hypothesis" argues that unbalanced imprinting may be a cause of autism and psychosis.

Imprinted genes in other animals

In insects, imprinting affects entire chromosomes. In some insects the entire paternal genome is silenced in male offspring, and thus is involved in sex determination. The imprinting produces effects similar to the mechanisms in other insects that eliminate paternally inherited chromosomes in male offspring, including arrhenotoky.

In placental species, parent-offspring conflict can result in the evolution of strategies, such as genomic imprinting, for embryos to subvert maternal nutrient provisioning. Despite several attempts to find it, genomic imprinting has not been found in the platypus, reptiles, birds, or fish. The absence of genomic imprinting in a placental reptile, the Pseudemoia entrecasteauxii, is interesting as genomic imprinting was thought to be associated with the evolution of viviparity and placental nutrient transport.

Studies in domestic livestock, such as dairy and beef cattle, have implicated imprinted genes (e.g. IGF2) in a range of economic traits, including dairy performance in Holstein-Friesian cattle.

Mouse foraging behavior

A study published in March, 2022, documents that foraging behavior in mice studied was influenced by a sexually dimorphic allele expression implicating a cross-gender imprinting influence that varies throughout the body and may dominate expression and shape a behavior.

Imprinted genes in plants

A similar imprinting phenomenon has also been described in flowering plants (angiosperms). During fertilization of the egg cell, a second, separate fertilization event gives rise to the endosperm, an extraembryonic structure that nourishes the embryo in a manner analogous to the mammalian placenta. Unlike the embryo, the endosperm is often formed from the fusion of two maternal cells with a male gamete. This results in a triploid genome. The 2:1 ratio of maternal to paternal genomes appears to be critical for seed development. Some genes are found to be expressed from both maternal genomes while others are expressed exclusively from the lone paternal copy. It has been suggested that these imprinted genes are responsible for the triploid block effect in flowering plants that prevents hybridization between diploids and autotetraploids. Several computational methods to detect imprinting genes in plants from reciprocal crosses have been proposed.

Superseded theories in science

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Superseded_theories_in_science 

 

The obsolete geocentric model places Earth at the centre of the Universe.

This list catalogs well-accepted theories in science and pre-scientific natural philosophy and natural history which have since been superseded by scientific theories. Many discarded explanations were once supported by a scientific consensus, but replaced after more empirical information became available that identified flaws and prompted new theories which better explain the available data. Pre-modern explanations originated before the scientific method, with varying degrees of empirical support.

Some theories are discarded in their entirety, such as the replacement of the phlogiston theory by energy and thermodynamics. Some theories known to be incomplete or in some ways incorrect are still used. For example, Newtonian classical mechanics is accurate enough for practical calculations at everyday distances and velocities, and it is still taught in schools. The more complicated relativistic mechanics must be used for long distances and velocities nearing the speed of light, and quantum mechanics for very small distances and objects.

Some aspects of discarded theories are reused in modern explanations. For example, miasma theory proposed that all diseases were transmitted by "bad air". The modern germ theory of disease has found that diseases are caused by microorganisms, which can be transmitted by a variety of routes, including touching a contaminated object, blood, and contaminated water. Malaria was discovered to be a mosquito-borne disease, explaining why avoiding the "bad air" near swamps prevented it. Increasing ventilation of fresh air, one of the remedies proposed by miasma theory, does remain useful in some circumstances to expel germs spread by airborne transmission, such as COVID-19.

Some theories originate in, or are perpetuated by, pseudoscience, which claims to be both scientific and factual, but fails to follow the scientific method. Scientific theories are testable and make falsifiable predictions. Thus, it can be a mark of good science if a discipline has a growing list of superseded theories, and conversely, a lack of superseded theories can indicate problems in following the use of the scientific method. Fringe science includes theories that are not currently supported by a consensus in the mainstream scientific community, either because they never had sufficient empirical support, because they were previously mainstream but later disproven, or because they are preliminary theories also known as protoscience which go on to become mainstream after empirical confirmation. Some theories, such as Lysenkoism, race science or female hysteria have been generated for political rather than empirical reasons and promoted by force.

Discarded theories

Biology

• Spontaneous generation – a principle regarding the spontaneous generation of complex life from inanimate matter, which held that this process was a commonplace and everyday occurrence, as distinguished from univocal generation, or reproduction from parent(s). Falsified by an experiment by Louis Pasteur: where apparently spontaneous generation of microorganisms occurred, it did not happen on repeating the process without access to unfiltered air; on then opening the apparatus to the atmosphere, bacterial growth started.
• Transmutation of species, Lamarckism, inheritance of acquired characteristics, Lysenkoism – first theories of evolution. Not supported by experiment, and rendered obsolete by Darwinian evolution and Mendelian genetics, combined in the modern synthesis which finds that genes in the form of DNA are the primary way parental characteristics are passed to descendants. Discoveries in epigenetics have shown that in some very limited ways, the life experiences of organisms can affect the development of their children.
• Vitalism – the theory that living things are alive because of some "vital force" independent of matter, as opposed to because of some appropriate assembly of matter. It was gradually discredited by the rise of organic chemistry, biochemistry, and molecular biology, fields that failed to discover any "vital force". Friedrich Wöhler's synthesis of urea from ammonium cyanate was only one step in a long road, not a great refutation.
• Maternal impression – the theory that the mother's thoughts created birth defects. No experimental support (a notion rather than a theory), and rendered obsolete by genetic theory (see also fetal origins of adult disease, genomic imprinting)
• Preformationism – the theory that all organisms have existed since the beginning of life, and that gametes contain a miniature but complete preformed individual, and in the case of humans, a homunculus. No support when microscopy became available. Rendered obsolete by cytology, discovery of DNA, and atomic theory.
• Recapitulation theory – the theory that "ontogeny recapitulates phylogeny". See Baer's laws of embryology.
• Telegony – the theory that an offspring can inherit characteristics from a previous mate of its mother's as well as its actual parents, often associated with racism.
• Out of Asia theory of human origin – The majority view is of a recent African origin of modern humans, although a multiregional origin of modern humans hypothesis has much support (which incorporates past evidence of Asian origins)
• Scientific racism – the theory that humanity consists of physically discrete superior or inferior races. Rendered obsolete by Human evolutionary genetics and modern anthropology.
• Mendelian genetics, classical genetics, Boveri–Sutton chromosome theory – first genetic theories. Not invalidated as such, but subsumed into molecular genetics.
• Germ line theory, explained immunoglobulin diversity by proposing that each antibody was encoded in a separate germline gene.

Chemistry

• Caloric theory – the theory that a self-repelling fluid called "caloric" was the substance of heat. Rendered obsolete by the mechanical theory of heat.
• Classical elements – All matter was once thought composed of various combinations of classical elements (most famously air, earth, fire, and water). Antoine Lavoisier finally refuted this in his 1789 publication, Elements of Chemistry, which contained the first modern list of chemical elements.
• Electrochemical dualism – the theory that all molecules are salts composed of basic and acidic oxides
• Phlogiston theory – The theory that combustible goods contain a substance called "phlogiston" that entered air during combustion. Replaced by Lavoisier's work on oxidation
• Point 2 of Dalton's Atomic Theory was rendered obsolete by discovery of isotopes, and point 3 by discovery of subatomic particles and nuclear reactions.
• Radical theory – the theory that organic compounds exist as combinations of radicals that can be exchanged in chemical reactions just as chemical elements can be interchanged in inorganic compounds
• Vitalism – See section on biology.
• Nascent state refers to the form of a chemical element (or sometimes compound) in the instance of their liberation or formation. Often encountered are atomic oxygen (O_nasc) and nascent hydrogen (H_nasc), and chlorine (Cl_nasc) or bromine (Br_nasc).
• Polywater, a hypothesized polymer form of water, the properties of which actually arose from contaminants such as sweat

Physics

• Emission theory of vision – the belief that vision is caused by rays emanating from the eyes was superseded by the intro-mission approach and more complex theories of vision
• Aristotelian physics – superseded by Newtonian physics
• Ptolemy's law of refraction, replaced by Snell's law
• Luminiferous aether – failed to be detected by the sufficiently sensitive Michelson–Morley experiment, made obsolete by Einstein's work.
• Caloric theory – Lavoisier's successor to phlogiston, discredited by Rumford's and Joule's work
• Contact tension – a theory on the source of electricity
• Vis viva – Gottfried Leibniz's elementary and limited early formulation of the principle of conservation of energy
• "Purely electrostatic" theories of the generation of voltage differences.
• Emitter theory – another now-obsolete theory of light propagation
• Electromotive force § History – the original theory by Alessandro Volta misunderstood the active agent of a voltaic cell to be a new type of force acting on the charges generated merely from contact of the electrodes. Michael Faraday later correctly explained the active agent was chemical reactions.
• Balance of nature – superseded by catastrophe theory and chaos theory
• Progression of atomic theory
  • Democritus, the originator of atomic theory, held that everything is composed of atoms that are indestructible. His claim that atoms are indestructible is not the reason it is superseded—as it was later scientists who identified the concept of atoms with particles, which later science showed are destructible. Democritus' theory is superseded because of his position that several kinds of atoms explain pure materials like water or iron, and characteristics that science now identifies with molecules rather than with indestructible primary particles. Democritus also held that between atoms, an empty space of a different nature than atoms allowed atoms to move. This view on space and matter persisted until Einstein described spacetime as being relative and connected to matter.
  • John Dalton's model of the atom, which held that atoms are indivisible and indestructible (superseded by nuclear physics) and that all atoms of a given element are identical in mass (superseded by discovery of atomic isotopes).
  • Plum pudding model of the atom—assuming the protons and electrons were mixed together in a single mass
  • Rutherford model of the atom with an impenetrable nucleus orbited by electrons
  • Bohr model with quantized orbits
  • Electron cloud model following the development of quantum mechanics in 1925 and the eventual atomic orbital models derived from the quantum mechanical solution to the hydrogen atom

Astronomy and cosmology

• Ptolemaic system – superseded by Nicolaus Copernicus' heliocentric model.
• Geocentric universe – superseded by Copernicus
• Copernican system - superseded by Tychonic system
• Heliocentric universe – made obsolete by discovery of the structure of the Milky Way and the redshift of most galaxies. Heliocentrism only applies to the selected Solar System, and only approximately, since the Sun's center is not at the Solar System's center of mass.
• Aristotelian Dynamics of the celestial spheres superseded by the Elliptic orbit and Kepler's laws of planetary motion
• Tychonic system – superseded by Newton's laws of motion
• Luminiferous aether theory
• Steady state theory, a model developed by Hermann Bondi, Thomas Gold, and Fred Hoyle whereby the expanding universe was in a steady state, and had no beginning. It was a competitor of the Big Bang model until evidence supporting the Big Bang and falsifying the steady state was found.

Geography and climate

• Buenaventura River
• Flat Earth theory, generally known to be false among educated people in various ancient and medieval societies
• Terra Australis, which technically is Antarctica, but the original idea was based on an unproven belief that land in the Northern hemisphere must have a Southern counterpart for balance.
• Hollow Earth theory
• The Open Polar Sea, an ice-free sea once supposed to surround the North Pole
• Rain follows the plow – the theory that human settlement increases rainfall in arid regions (only true to the extent that crop fields evapotranspirate more than barren wilderness)
• Island of California – the theory that California was not part of mainland North America but rather a large island
• Inland sea of Australia
• Pre-modern Environmental determinism (as explanations for moral behavior, as opposed to modern theories such as factor endowments, state formation, and theories of the social effects of global warming)

• Climatic determinism
• Topographic determinism
• Moral geography
• Cultural acclimatization

• Global cooling
• Drainage divides as always being made up by hills and mountains.

Geology

• Abiogenic petroleum origin – While some of the petroleum is almost certainly abiogenic, the vast majority has origins as living organisms
• Catastrophism was largely replaced by uniformitarianism and neocatastrophism
• Cryptoexplosion craters, now discarded in favour of impact craters and ordinary volcanism.
• Flood geology replaced by modern geology and stratigraphy
• Neptunism replaced by plutonism and volcanism
• Granitization, a discredited alternative to a magmatic origin of granites
• Monoglaciation, the idea that the Earth had a single ice age, replaced by polyglaciation, the idea that the Earth has gone through several periods of widespread ice cover.
• Oscillation theory of land-level rise and subsidence during deglaciation
• The following were superseded by plate tectonics:
  • Elevation crater theory
  • Expanding Earth theory (superseded by subduction)
  • Contracting Earth
  • Geosyncline theory
  • Haarman's Oscillation theory
  • Various lost landmasses including Lemuria

Psychology

• Pure behaviorist explanations for language acquisition in infancy, falsified by the study of cognitive adaptations for language.
• Psychomotor patterning, a pseudoscientific approach to the treatment of intellectual disabilities, brain injury, learning disabilities, and other cognitive diseases.

Medicine

• Theory of the four bodily humours (see also Four temperaments)
  • Heroic medicine – a therapeutic method derived from the belief in bodily humour imbalances as the cause of ailments.
• Miasma theory of disease – the theory that diseases are caused by "bad air". No experimental support, and rendered obsolete by the germ theory of disease.
• Phrenology – a theory of highly localised brain function popular in 19th century medicine.
• Homeopathy – a theory according to which a disease can be cured by infinitesimal doses of the substance that caused it
• Eclectic medicine – Transformed into alternative medicine, and is no longer considered a scientific theory
• Physiognomy, related to phrenology, held that inner character was strongly correlated with physical appearance
• Tooth worm, an erroneous theory of the cause of dental caries, periodontitis, and toothaches

Obsolete branches of enquiry

• Alchemy, which led to the development of chemistry
• Astrology, which led to the development of astronomy
• Phrenology, a pseudoscience
• Numerology, a pseudoscience

Theories now considered incomplete

These theories that are no longer considered the most complete representation of reality but remain useful in particular domains or under certain conditions. For some theories, a more complete model is known, but for practical use, the coarser approximation provides good results with much less calculation.

• Newtonian mechanics was extended by the theory of relativity and by quantum mechanics. Relativistic corrections to Newtonian mechanics are immeasurably small at velocities not approaching the speed of light, and quantum corrections are usually negligible at atomic or larger scales; Newtonian mechanics is totally satisfactory in engineering and physics under most circumstances. The anomalous perihelion precession of Mercury was the first observational evidence that relativity was a more accurate model than Newtonian gravity.
• Classical electrodynamics is a very close approximation to quantum electrodynamics except at very small scales and low field strengths.
• Bohr model of the atom was extended by the quantum mechanical model of the atom.
• The formula known as Newton's sine-square law of air resistance for the force of a fluid on a body, though not actually formulated by Newton but by others using a method of calculation used by Newton, has been found incorrect and not useful except for high-speed hypersonic flow.
• The once-popular cycle of erosion is now considered one of many possibilities for landscape evolution.
• The theory of continental drift was incorporated into and improved upon by plate tectonics.