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Friday, November 12, 2021

BRAIN Initiative

From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/BRAIN_Initiative

Understanding how the brain works is arguably one of the greatest scientific challenges of our time.

–Alivisatos et al.

The White House BRAIN Initiative (Brain Research through Advancing Innovative Neurotechnologies), is a collaborative, public-private research initiative announced by the Obama administration on April 2, 2013, with the goal of supporting the development and application of innovative technologies that can create a dynamic understanding of brain function.

This activity is a Grand Challenge focused on revolutionizing our understanding of the human brain, and was developed by the White House Office of Science and Technology Policy (OSTP) as part of a broader White House Neuroscience Initiative. Inspired by the Human Genome Project, BRAIN aims to help researchers uncover the mysteries of brain disorders, such as Alzheimer's and Parkinson's diseases, depression, and traumatic brain injury (TBI).

Participants in BRAIN and affiliates of the project include DARPA and IARPA as well as numerous private companies, universities, and other organizations in the United States, Australia, Canada, and Denmark.

Background

The BRAIN Initiative reflects a number of influences, stemming back over a decade. Some of these include: planning meetings at the National Institutes of Health that led to the NIH's Blueprint for Neuroscience Research; workshops at the National Science Foundation (NSF) on cognition, neuroscience, and convergent science, including a 2006 report on "Grand Challenges of Mind and Brain"; reports from the National Research Council and the Institute of Medicine's Forum on Neuroscience and Nervous System Disorders, including "From Molecules to Mind: Challenges for the 21st Century," a report of a June 25, 2008 Workshop on Grand Challenges in Neuroscience.; years of research and reports from scientists and professional societies; and congressional interest.

One important activity was the Brain Activity Map Project. In September 2011, molecular biologist Miyoung Chun of The Kavli Foundation organized a conference in London, at which scientists first put forth the idea of such a project. At subsequent meetings, scientists from US government laboratories, including members of the Office of Science and Technology Policy, and from the Howard Hughes Medical Institute and the Allen Institute for Brain Science, along with representatives from Google, Microsoft, and Qualcomm, discussed possibilities for a future government-led project.

Other influences included the interdisciplinary "Decade of the Mind" project led by James L. Olds, who is currently the Assistant Director for Biological Sciences at NSF, and the "Revolutionizing Prosthetics" project at DARPA, led by Dr. Geoffrey Ling and shown on 60 Minutes in April 2009.

Development of the plan for the BRAIN Initiative within the Executive Office of the President (EOP) was led by OSTP and included the following EOP staff: Philip Rubin, then Principal Assistant Director for Science and leader of the White House Neuroscience Initiative; Thomas Kalil, Deputy Director for Technology and Innovation; Cristin Dorgelo, then Assistant Director for Grand Challenges, and later Chief of Staff at OSTP; and Carlos Peña, Assistant Director for Emerging Technologies and currently the Division Director for the Division of Neurological and Physical Medicine Devices, in the Office of Device Evaluation, Center for Devices and Radiological Health (CDRH), at the U.S. Food and Drug Administration (FDA).

Announcement

NIH Director Dr. Francis Collins and President Barack Obama announcing the BRAIN Initiative

On April 2, 2013, at a White House event, President Barack Obama announced The BRAIN Initiative, with proposed initial expenditures for fiscal year 2014 of approximately $110 million from the Defense Advanced Research Projects Agency (DARPA), the National Institutes of Health (NIH), and the National Science Foundation (NSF). The President also directed the Presidential Commission for the Study of Bioethical Issues to explore the ethical, legal, and societal implications raised by the initiative and by neuroscience in general. Additional commitments were also made by the Allen Institute for Brain Science, the Howard Hughes Medical Institute, and The Kavli Foundation. The NIH also announced the creation of a working group of the Advisory Committee to the Director, led by neuroscientists Cornelia Bargmann and William Newsome and with ex officio participation from DARPA and NSF, to help shape NIH's role in the BRAIN Initiative. NSF planned to receive advice from its directorate advisory committees, from the National Science Board, and from a series of meetings bringing together scientists in neuroscience and related areas.

Experimental approaches

News reports said the research would map the dynamics of neuron activity in mice and other animals and eventually the tens of billions of neurons in the human brain.

In a 2012 scientific commentary outlining experimental plans for a more limited project, Alivisatos et al. outlined a variety of specific experimental techniques that might be used to achieve what they termed a "functional connectome", as well as new technologies that will have to be developed in the course of the project. They indicated that initial studies might be done in Caenorhabditis elegans, followed by Drosophila, because of their comparatively simple neural circuits. Mid-term studies could be done in zebrafish, mice, and the Etruscan shrew, with studies ultimately to be done in primates and humans. They proposed the development of nanoparticles that could be used as voltage sensors that would detect individual action potentials, as well as nanoprobes that could serve as electrophysiological multielectrode arrays. In particular, they called for the use of wireless, noninvasive methods of neuronal activity detection, either utilizing microelectronic very-large-scale integration, or based on synthetic biology rather than microelectronics. In one such proposed method, enzymatically produced DNA would serve as a "ticker tape record" of neuronal activity, based on calcium ion-induced errors in coding by DNA polymerase. Data would be analyzed and modeled by large scale computation. A related technique proposed the use of high-throughput DNA sequencing for rapidly mapping neural connectivity.

Timeline

The timeline proposed by the Working Group in 2014 is:

  • 2016–2020: technology development and validation
  • 2020–2025: application of those technologies in an integrated fashion to make fundamental new discoveries about the brain

Working group

The advisory committee is:

Participants

As of December 2018, the BRAIN Initiative website lists the following participants and affiliates:

  • National Institutes of Health (Alliance Member)
  • National Science Foundation (Alliance Member)
  • U.S. Food and Drug Administration (Alliance Member)
  • Intelligence Advanced Research Projects Activity (IARPA) (Alliance Member)
  • White House BRAIN Initiative (Alliance Affiliate)
  • Defense Advanced Research Projects Agency (B.I. Participant)
  • Simons Foundation (Alliance Member)
  • National Photonics Initiative (B.I. Participant)
  • Allen Institute for Brain Science (Alliance Member)
  • Janelia/Howard Hughes Medical Institute (Alliance Affiliate)
  • Neurotechnology Architecting Network (B.I. Participant)
  • Pacific Northwest Neuroscience Neighborhood (B.I. Participant)
  • University of California System Cal-BRAIN (B.I. Participant)
  • University of Pittsburgh Brain Institute (B.I. Participant)
  • Blackrock Microsystems (B.I. Participant)
  • GlaxoSmithKline (B.I. Participant)
  • Brain & Behavior Research Foundation (B.I. Participant)
  • Boston University Center for Systems Neuroscience (B.I. Participant)
  • General Electric (B.I. Participant)
  • Boston Scientific (B.I. Participant)
  • Carnegie Mellon University BrainHub (B.I. Participant)
  • NeuroNexus (B.I. Participant)
  • Medtronic (B.I. Participant)
  • Pediatric Brain Foundation (B.I. Participant)
  • University of Texas System UT Neuroscience (B.I. Participant)
  • University of Arizona Center for Innovation in Brain Science (B.I. Participant)
  • Salk Institute for Biological Studies (B.I. Participant)
  • Second Sight (B.I. Participant)
  • Kavli Foundation (Alliance Member)
  • University of Utah Neurosciences Gateway (B.I. Participant)
  • Blackrock Microsystems (B.I. Participant)
  • Ripple (B.I. Participant)
  • Lawrence Livermore National Laboratory (B.I. Participant)
  • NeuroPace (B.I. Participant)
  • Google (B.I. Participant)
  • Inscopix (B.I. Participant)
  • Australian National Health and Medical Research Council (B.I. Participant)
  • Brain Canada Foundation (B.I. Participant)
  • Denmark's Lundbeck Foundation (B.I. Participant).

Reactions

Scientists offered differing views of the plan. Neuroscientist John Donoghue said that the project would fill a gap in neuroscience research between, on the one hand, activity measurements at the level of brain regions using methods such as fMRI, and, on the other hand, measurements at the level of single cells. Psychologist Ed Vul expressed concern, however, that the initiative would divert funding from individual investigator studies. Neuroscientist Donald Stein expressed concern that it would be a mistake to begin by spending money on technological methods, before knowing exactly what would be measured. Physicist Michael Roukes argued instead that methods in nanotechnology are becoming sufficiently mature to make the time right for a brain activity map. Neuroscientist Rodolfo Llinás declared at the first Rockefeller meeting "What has happened here is magnificent, never before in neuroscience have I seen so much unity in such a glorious purpose."

The projects face great logistical challenges. Neuroscientists estimated that the project would generate 300 exabytes of data every year, presenting a significant technical barrier. Most of the available high-resolution brain activity monitors are of limited use, as they must be invasively implanted surgically by opening the skull. Parallels have been drawn to past large-scale government-led research efforts including the map of the human genome, the voyage to the moon, and the development of the atomic bomb.

Human Brain Project

From Wikipedia, the free encyclopedia
 
Human Brain Project
Type of projectScientific research
LocationEurope
OwnerEuropean Union
Key peoplePaweł Świeboda, Director General
Katrin Amunts, Scientific Research Director
Established2013; 8 years ago
Websitewww.humanbrainproject.eu

The Human Brain Project (HBP) is a large ten-year scientific research project, based on exascale supercomputers, that aims to build a collaborative ICT-based scientific research infrastructure to allow researchers across Europe to advance knowledge in the fields of neuroscience, computing, and brain-related medicine.

The Project, which started on 1 October 2013, is a European Commission Future and Emerging Technologies Flagship. The HBP is coordinated by the École Polytechnique Fédérale de Lausanne and is largely funded by the European Union. The project coordination office is in Geneva, Switzerland.

Strategic goals and organisation

The 2013 HBP Summit–the inauguration of the Project–took place in the EPFL Learning Centre in October 2013. It brought together scientists from over 100 Partner Institutions.

Fundamental to the HBP approach is to investigate the brain on different spatial and temporal scales (i.e. from the molecular to the large networks underlying higher cognitive processes, and from milliseconds to years). To achieve this goal, the HBP relies on the collaboration of scientists from diverse disciplines, including neuroscience, philosophy and computer science, to take advantage of the loop of experimental data, modelling theories and simulations. The idea is that empirical results are used to develop theories, which then foster modelling and simulations which result in predictions that are in turn verified by empirical results.

The primary objective of the HBP is to create an ICT-based research infrastructure for brain research, cognitive neuroscience and brain-inspired computing, which can be used by researchers world-wide.

The Project is divided into 12 Subprojects. Six of these develop ICT-based platforms (Subprojects 5-10), which consist of prototype hardware, software, databases, and programming interfaces. These tools are available to researchers worldwide via the HBP Collaboratory. Three Subprojects gather data on empirical neuroscience and establish theoretical foundations (Subprojects 1–4) and one is responsible for ethics and society (Subproject 12). Subproject 11 coordinates the project.

  • SP1 Mouse Brain Organisation: Understanding the structure of the mouse brain, and its electrical and chemical functions
  • SP2 Human Brain Organisation: Understanding the structure of the human brain, and its electrical and chemical functions
  • SP3 Systems and Cognitive Neuroscience: Understanding how the brain performs its systems-level and cognitive functional activities
  • SP4 Theoretical Neuroscience: Deriving high-level mathematical models to synthesize conclusions from research data
  • SP5 Neuroinformatics Platform: Gathering, organising and making available brain data
  • SP6 Brain Simulation Platform: Developing data-driven reconstructions of brain tissue and simulation capabilities to explore these reconstructions
  • SP7 High-performance Analytics and Computing Platform: Providing the ICT capability to map the brain in unprecedented detail, construct complex models, run large simulations, and analyse large volumes of data
  • SP8 Medical Informatics Platform: Developing the infrastructure to share hospital and medical research data for the purpose of understanding disease clusters and their respective disease signatures
  • SP9 Neuromorphic Computing Platform: Developing and applying brain-inspired computing technology
  • SP10 Neurorobotics Platform: Developing virtual and real robots and environments for testing brain simulations
  • SP11 Management and Coordination: General coordination of the project
  • SP12 Ethics and Society: Exploring the ethical and societal impact of HBP's work

The HBP is coordinated by the École Polytechnique Fédérale de Lausanne and involves researchers from over 117 partner institutions in 19 countries across Europe. Notable Partner Institutions include the University of Heidelberg, Forschungszentrum Jülich, and the University Hospital of Lausanne.

The scientific direction is provided by representatives from each of the HBP's Subprojects, which form the Science and Infrastructure Board (SIB). Katrin Amunts from Forschungszentrum Jülich is the Chair of the SIB. Alois Knoll from TU Munich is Vice Chair of the SIB for software. The Directorate steers the daily work of the HBP – it is led by Andreas Mortensen from EPFL.

Funding

The HBP is funded by the European Commission Directorate General for Communications Networks, Content and Technology (DG CONNECT) under the FP7 framework, an EU Research and Innovation funding programme. It was one of the two initial Future Emerging Technologies (FET) Flagship projects.

The project is split into five phases, each supplied with separate funding. The call for funding for the Project's initial two-and-a-half-year 'Ramp-Up Phase' of EUR 54 million closed in November 2013 and the results were announced in March 2014. Twenty-two projects from thirty-two organisations were selected for the initial funding of EUR 8.3 million. The Ramp-Up Phase ended on 31 March 2016. Funding is reassessed every two years using Specific Grant Agreements (SGA); the first of which began in April 2016 (ending in April 2018), and the second with a total EU funding of 88 Million Euro starting in April 2018 (ending in March 2020). The HBP's total costs are estimated at EUR 1.019 billion, of which EUR 500 million will be provided by the European Commission, EUR 500 million by national, public and private organisations, and EUR 19 million by the Core Project Ramp-Up Phase Partners.

Obstacles

One of the Project's primary hurdles is the unsystematic nature of the information collected from previous brain research. Neurological research data varies by biological organisation schemes, species studied, and by developmental stages, making it difficult to collectively use the data to replicate the brain in a model that acts as a single system.

Other obstacles include engineering problems involving power consumption, memory, and storage. For example, detailed neuron representations are very computationally expensive, and whole brain simulation is at the leading edge of our computational capability.

Implications

The Human Brain Project moved to Campus Biotech in 2014.

Technologies generated by the HBP and other similar projects offer several possibilities to other fields of research. For instance, a brain model can be used to investigate signatures of disease in the brain and the impact of certain drugs, enabling the development of better diagnosis and treatment methods. Ultimately, these technologies will likely lead to more advanced medical options available to patients at a lower cost.

In addition, detailed brain simulation requires significant computing power, leading to developments in supercomputing and energy-efficient, brain-inspired computing techniques. Computational developments can be extended into areas such as data mining, telecommunications, appliances, and other industrial uses.

The long-term ethical consequences of the Project are also considered. The Project follows a policy of Responsible Research and Innovation, and its Ethics Advisory Board is responsible for monitoring the use of human volunteers, animal subjects, and the data collected. Implications on European society, industry, and economy are investigated by the HBP Ethics and Society Programme's Foresight Lab.

Criticism

An open letter was sent on 7 July 2014 to the European Commission by 154 European researchers (750 signatures as of 3 September 2014) complaining of the HBP's overly narrow approach, and threatening to boycott the project. Central to this controversy was an internal dispute about funding for cognitive scientists who study high level brain functions, such as thought and behaviour. However, the HBP stated that there is “no question that cognition and behaviour are vital to the HBP”, explaining that cognitive neuroscience research was repositioned in the project to allow the core project to focus on building the platforms. In addition, The open letter called on the EC to “reallocate the funding currently allocated to the HBP core and partnering projects to broad neuroscience-directed funding to meet the original goals of the HBP—understanding brain function and its effect on society”. In its response, the HBP said that “while neuroscience research generates a vast amount of valuable data, there is currently no technology for sharing, organising, analysing or integrating this information, beyond papers and even databases. The HBP will provide the critical missing layer to move towards a multi-level reconstruction and simulation of the brain”. It added that “cognitive and behavioural neuroscience will become the most significant component of neuroscience in HBP over the course of the project. However, for this to happen the platforms have to be in place first”.

Peter Dayan, director of computational neuroscience at University College London, argued that the goal of a large-scale simulation of the brain is radically premature, and Geoffrey Hinton said that "the real problem with that project is they have no clue how to get a large system like that to learn". Similar concerns as to the project's methodology were raised by Robert Epstein.

The HBP has said that its members share the uncertainty surrounding large-scale simulation, but that “reconstructing and simulating the human brain is a vision, a target; the benefits will come from the technology needed to get there. That technology, developed by the HBP, will benefit all of neuroscience as well as related fields”.

In 2015 the project underwent a review process and the three-member executive committee, led by Henry Markram, was dissolved and replaced by a 22-member governing board.

According to a 2019 article, "In 2013, the European Commission awarded his initiative—the Human Brain Project (HBP)—a staggering 1 billion euro grant (worth about $1.42 billion at the time)...the people I contacted struggled to name a major contribution that the HBP has made in the past decade."

Pleiotropy

From Wikipedia, the free encyclopedia

Simple genotype–phenotype map that only shows additive pleiotropy effects. G1, G2, and G3 are different genes that contribute to phenotypic traits P1, P2, and P3.

Pleiotropy (from Greek πλείων pleion, "more", and τρόπος tropos, "way") occurs when one gene influences two or more seemingly unrelated phenotypic traits. Such a gene that exhibits multiple phenotypic expression is called a pleiotropic gene. Mutation in a pleiotropic gene may have an effect on several traits simultaneously, due to the gene coding for a product used by a myriad of cells or different targets that have the same signaling function.

Pleiotropy can arise from several distinct but potentially overlapping mechanisms, such as gene pleiotropy, developmental pleiotropy, and selectional pleiotropy. Gene pleiotropy occurs when a gene product interacts with multiple other proteins or catalyzes multiple reactions. Developmental pleiotropy occurs when mutations have multiple effects on the resulting phenotype. Selectional pleiotropy occurs when the resulting phenotype has many effects on fitness (depending on factors such as age and gender).

An example of pleiotropy is phenylketonuria, an inherited disorder that affects the level of phenylalanine, an amino acid that can be obtained from food, in the human body. Phenylketonuria causes this amino acid to increase in amount in the body, which can be very dangerous. The disease is caused by a defect in a single gene on chromosome 12 that codes for enzyme phenylalanine hydroxylase, that affects multiple systems, such as the nervous and integumentary system. Pleiotropy not only affects humans, but also animals, such as chickens and laboratory house mice, where the mice have the "mini-muscle" allele.

Pleiotropic gene action can limit the rate of multivariate evolution when natural selection, sexual selection or artificial selection on one trait favors one allele, while selection on other traits favors a different allele. Some gene evolution is harmful to an organism. Genetic correlations and responses to selection most often exemplify pleiotropy.

History

Pleiotropic traits had been previously recognized in the scientific community but had not been experimented on until Gregor Mendel's 1866 pea plant experiment. Mendel recognized that certain pea plant traits (seed coat color, flower color, and axial spots) seemed to be inherited together; however, their correlation to a single gene has never been proven. The term "pleiotropie" was first coined by Ludwig Plate in his Festschrift, which was published in 1910. He originally defined pleiotropy as occurring when "several characteristics are dependent upon ... [inheritance]; these characteristics will then always appear together and may thus appear correlated". This definition is still used today.

After Plate's definition, Hans Gruneberg was the first to study the mechanisms of pleiotropy. In 1938 Gruneberg published an article dividing pleiotropy into two distinct types: "genuine" and "spurious" pleiotropy. "Genuine" pleiotropy is when two distinct primary products arise from one locus. "Spurious" pleiotropy, on the other hand, is either when one primary product is utilized in different ways or when one primary product initiates a cascade of events with different phenotypic consequences. Gruneberg came to these distinctions after experimenting on rats with skeletal mutations. He recognized that "spurious" pleiotropy was present in the mutation, while "genuine" pleiotropy was not, thus partially invalidating his own original theory. Through subsequent research, it has been established that Gruneberg's definition of "spurious" pleiotropy is what we now identify simply as "pleiotropy".

In 1941 American geneticists George Beadle and Edward Tatum further invalidated Gruneberg's definition of "genuine" pleiotropy, advocating instead for the "one gene-one enzyme" hypothesis that was originally introduced by French biologist Lucien Cuénot in 1903. This hypothesis shifted future research regarding pleiotropy towards how a single gene can produce various phenotypes.

In the mid-1950s Richard Goldschmidt and Ernst Hadorn, through separate individual research, reinforced the faultiness of "genuine" pleiotropy. A few years later, Hadorn partitioned pleiotropy into a "mosaic" model (which states that one locus directly affects two phenotypic traits) and a "relational" model (which is analogous to "spurious" pleiotropy). These terms are no longer in use but have contributed to the current understanding of pleiotropy.

By accepting the one gene-one enzyme hypothesis, scientists instead focused on how uncoupled phenotypic traits can be affected by genetic recombination and mutations, applying it to populations and evolution. This view of pleiotropy, "universal pleiotropy", defined as locus mutations being capable of affecting essentially all traits, was first implied by Ronald Fisher's Geometric Model in 1930. This mathematical model illustrates how evolutionary fitness depends on the independence of phenotypic variation from random changes (that is, mutations). It theorizes that an increasing phenotypic independence corresponds to a decrease in the likelihood that a given mutation will result in an increase in fitness. Expanding on Fisher's work, Sewall Wright provided more evidence in his 1968 book Evolution and the Genetics of Populations: Genetic and Biometric Foundations by using molecular genetics to support the idea of "universal pleiotropy". The concepts of these various studies on evolution have seeded numerous other research projects relating to individual fitness.

In 1957 evolutionary biologist George C. Williams theorized that antagonistic effects will be exhibited during an organism's life cycle if it is closely linked and pleiotropic. Natural selection favors genes that are more beneficial prior to reproduction than after (leading to an increase in reproductive success). Knowing this, Williams argued that if only close linkage was present, then beneficial traits will occur both before and after reproduction due to natural selection. This, however, is not observed in nature, and thus antagonistic pleiotropy contributes to the slow deterioration with age (senescence).

Mechanism

Pleiotropy describes the genetic effect of a single gene on multiple phenotypic traits. The underlying mechanism is genes that code for a product that is either used by various cells or has a cascade-like signaling function that affects various targets.

Polygenic Traits

Most genetic traits are polygenic in nature: controlled by many genetic variants, each of small effect. These genetic variants can reside in protein coding or non-coding regions of the genome. In this context pleiotropy refers to the influence that a specific genetic variant, e.g., a Single Nucleotide Polymorphism or SNP, has on two or more distinct traits.

Genome-wide association studies (GWAS) and machine learning analysis of large genomic datasets have led to the construction of SNP based polygenic predictors for human traits such as height, bone density, and many disease risks. Similar predictors exist for plant and animal species and are used in agricultural breeding.

One measure of pleiotropy is the fraction of genetic variance that is common between two distinct complex human traits: e.g., height vs bone density, breast cancer vs heart attack risk, or diabetes vs hypothyroidism risk. This has been calculated for hundreds of pairs of traits, with results shown in the Table. In most cases examined the genomic regions controlling each trait are largely disjoint, with only modest overlap.

Pleiotropy seems limited for many traits in humans since the SNP overlap, as measured by variance accounted for, between many polygenic predictors is small.

Thus, at least for complex human traits so far examined, pleiotropy is limited in extent.

Models for the origin

One basic model of pleiotropy's origin describes a single gene locus to the expression of a certain trait. The locus affects the expressed trait only through changing the expression of other loci. Over time, that locus would affect two traits by interacting with a second locus. Directional selection for both traits during the same time period would increase the positive correlation between the traits, while selection on only one trait would decrease the positive correlation between the two traits. Eventually, traits that underwent directional selection simultaneously were linked by a single gene, resulting in pleiotropy.

Other more complex models compensate for some of the basic model's oversights, such as multiple traits or assumptions about how the loci affect the traits. They also propose the idea that pleiotropy increases the phenotypic variation of both traits since a single mutation on a gene would have twice the effect.

Evolution

Pleiotropy can have an effect on the evolutionary rate of genes and allele frequencies. Traditionally, models of pleiotropy have predicted that evolutionary rate of genes is related negatively with pleiotropy – as the number of traits of an organism increases, the evolutionary rates of genes in the organism's population decrease. However, this relationship has not been clearly found in empirical studies.

In mating, for many animals the signals and receptors of sexual communication may have evolved simultaneously as the expression of a single gene, instead of the result of selection on two independent genes, one that affects the signaling trait and one that affects the receptor trait. In such a case, pleiotropy would facilitate mating and survival. However, pleiotropy can act negatively as well. A study on seed beetles found that intralocus sexual conflict arises when selection for certain alleles of a gene that are beneficial for one sex causes expression of potentially harmful traits by the same gene in the other sex, especially if the gene is located on an autosomal chromosome.

Pleiotropic genes act as an arbitrating force in speciation. William R. Rice and Ellen E. Hostert (1993) conclude that the observed prezygotic isolation in their studies is a product of pleiotropy's balancing role in indirect selection. By imitating the traits of all-infertile hybridized species, they noticed that the fertilization of eggs was prevented in all eight of their separate studies, a likely effect of pleiotropic genes on speciation. Likewise, pleiotropic gene's stabilizing selection allows for the allele frequency to be altered.

Studies on fungal evolutionary genomics have shown pleiotropic traits that simultaneously affect adaptation and reproductive isolation, converting adaptations directly to speciation. A particularly telling case of this effect is host specificity in pathogenic ascomycetes and specifically, in venturia, the fungus responsible for apple scab. These parasitic fungi each adapts to a host, and are only able to mate within a shared host after obtaining resources. Since a single toxin gene or virulence allele can grant the ability to colonize the host, adaptation and reproductive isolation are instantly facilitated, and in turn, pleiotropically causes adaptive speciation. The studies on fungal evolutionary genomics will further elucidate the earliest stages of divergence as a result of gene flow, and provide insight into pleiotropically induced adaptive divergence in other eukaryotes.

Antagonistic pleiotropy

Sometimes, a pleiotropic gene may be both harmful and beneficial to an organism, which is referred to as antagonistic pleiotropy. This may occur when the trait is beneficial for the organism's early life, but not its late life. Such "trade-offs" are possible since natural selection affects traits expressed earlier in life, when most organisms are most fertile, more than traits expressed later in life.

This idea is central to the antagonistic pleiotropy hypothesis, which was first developed by G. C. Williams in 1957. Williams suggested that some genes responsible for increased fitness in the younger, fertile organism contribute to decreased fitness later in life, which may give an evolutionary explanation for senescence. An example is the p53 gene, which suppresses cancer but also suppresses stem cells, which replenish worn-out tissue.

Unfortunately, the process of antagonistic pleiotropy may result in an altered evolutionary path with delayed adaptation, in addition to effectively cutting the overall benefit of any alleles by roughly half. However, antagonistic pleiotropy also lends greater evolutionary "staying power" to genes controlling beneficial traits, since an organism with a mutation to those genes would have a decreased chance of successfully reproducing, as multiple traits would be affected, potentially for the worse.

Sickle cell anemia is a classic example of the mixed benefit given by the staying power of pleiotropic genes, as the mutation to Hb-S provides the fitness benefit of malaria resistance to heterozygotes, while homozygotes have significantly lowered life expectancy. Since both of these states are linked to the same mutated gene, large populations today are susceptible to sickle cell despite it being a fitness-impairing genetic disorder.

Examples

Peacock with albinism

Albinism

Albinism is the mutation of the TYR gene, also termed tyrosinase. This mutation causes the most common form of albinism. The mutation alters the production of melanin, thereby affecting melanin-related and other dependent traits throughout the organism. Melanin is a substance made by the body that is used to absorb light and provides coloration to the skin. Indications of albinism are the absence of color in an organism's eyes, hair, and skin, due to the lack of melanin. Some forms of albinism are also known to have symptoms that manifest themselves through rapid-eye movement, light sensitivity, and strabismus.

Autism and schizophrenia

Pleiotropy in genes has been linked between certain psychiatric disorders as well. Deletion in the 22q11.2 region of chromosome 22 has been associated with schizophrenia and autism. Schizophrenia and autism are linked to the same gene deletion but manifest very differently from each other. The resulting phenotype depends on the stage of life at which the individual develops the disorder. Childhood manifestation of the gene deletion is typically associated with autism, while adolescent and later expression of the gene deletion often manifests in schizophrenia or other psychotic disorders. Though the disorders are linked by genetics, there is no increased risk found for adult schizophrenia in patients who experienced autism in childhood.

A 2013 study also genetically linked five psychiatric disorders, including schizophrenia and autism. The link was a single nucleotide polymorphism of two genes involved in calcium channel signaling with neurons. One of these genes, CACNA1C, has been found to influence cognition. It has been associated with autism, as well as linked in studies to schizophrenia and bipolar disorder. These particular studies show clustering of these diseases within patients themselves or families. The estimated heritability of schizophrenia is 70% to 90%, therefore the pleiotropy of genes is crucial since it causes an increased risk for certain psychotic disorders and can aid psychiatric diagnosis.

Phenylketonuria (PKU)

The blood of a two-week-old infant is collected for a PKU screening.

A common example of pleiotropy is the human disease phenylketonuria (PKU). This disease causes mental retardation and reduced hair and skin pigmentation, and can be caused by any of a large number of mutations in the single gene on chromosome 12 that codes for the enzyme phenylalanine hydroxylase, which converts the amino acid phenylalanine to tyrosine. Depending on the mutation involved, this conversion is reduced or ceases entirely. Unconverted phenylalanine builds up in the bloodstream and can lead to levels that are toxic to the developing nervous system of newborn and infant children. The most dangerous form of this is called classic PKU, which is common in infants. The baby seems normal at first but actually incurs permanent intellectual disability. This can cause symptoms such as mental retardation, abnormal gait and posture, and delayed growth. Because tyrosine is used by the body to make melanin (a component of the pigment found in the hair and skin), failure to convert normal levels of phenylalanine to tyrosine can lead to fair hair and skin. The frequency of this disease varies greatly. Specifically, in the United States, PKU is found at a rate of nearly 1 in 10,000 births. Due to newborn screening, doctors are able to detect PKU in a baby sooner. This allows them to start treatment early, preventing the baby from suffering from the severe effects of PKU. PKU is caused by a mutation in the PAH gene, whose role is to instruct the body on how to make phenylalanine hydroxylase. Phenylalanine hydroxylase is what converts the phenylalanine, taken in through diet, into other things that the body can use. The mutation often decreases the effectiveness or rate at which the hydroxylase breaks down the phenylalanine. This is what causes the phenylalanine to build up in the body. The way to treat PKU is to manage one's diet. Phenylalanine is ingested through food, so a diet should decrease types of foods that have high amounts of phenylalanine. Foods with high levels of protein must be avoided. These include breast milk, eggs, chicken, beef, pork, fish, nuts, and other foods. A special PKU formula can be obtained in order for the body to have protein.

Sickle cell anemia

Photomicrograph of normal-shaped and sickle-shape red blood cells from a patient with sickle cell disease

Sickle cell anemia is a genetic disease that causes deformed red blood cells with a rigid, crescent shape instead of the normal flexible, round shape. It is caused by a change in one nucleotide, a point mutation in the HBB gene. The HBB gene encodes information to make the beta-globin subunit of hemoglobin, which is the protein red blood cells use to carry oxygen throughout the body. Sickle cell anemia occurs when the HBB gene mutation causes both beta-globin subunits of hemoglobin to change into hemoglobin S (HbS).

Sickle cell anemia is a pleiotropic disease because the expression of a single mutated HBB gene produces numerous consequences throughout the body. The mutated hemoglobin forms polymers and clumps together causing the deoxygenated sickle red blood cells to assume the disfigured sickle shape. As a result, the cells are inflexible and cannot easily flow through blood vessels, increasing the risk of blood clots and possibly depriving vital organs of oxygen. Some complications associated with sickle cell anemia include pain, damaged organs, strokes, high blood pressure, and loss of vision. Sickle red blood cells also have a shortened lifespan and die prematurely.

Marfan syndrome

Patient with Marfan Syndrome

Marfan syndrome (MFS) is an autosomal dominant disorder which affects 1 in 5–10,000 people. MFS arises from a mutation in the FBN1 gene, which encodes for the glycoprotein fibrillin-1, a major constituent of extracellular microfibrils which form connective tissues. Over 1,000 different mutations in FBN1 have been found to result in abnormal function of fibrillin, which consequently relates to connective tissues elongating progressively and weakening. Because these fibers are found in tissues throughout the body, mutations in this gene can have a widespread effect on certain systems, including the skeletal, cardiovascular, and nervous system, as well as the eyes and lungs.

Without medical intervention, prognosis of Marfan syndrome can range from moderate to life-threatening, with 90% of known causes of death in diagnosed patients relating to cardiovascular complications and congestive cardiac failure. Other characteristics of MFS include an increased arm span and decreased upper to lower body ratio.

"Mini-muscle" allele

A gene recently discovered in laboratory house mice, termed "mini-muscle", causes, when mutated, a 50% reduction in hindlimb muscle mass as its primary effect (the phenotypic effect by which it was originally identified). In addition to smaller hindlimb muscle mass, the mutant mice exhibit lower heart rates during physical activity, and a higher endurance. Mini Muscle Mice also exhibit larger kidneys and livers. All of these morphological deviations influence the behavior and metabolism of the mouse. For example, mice with the Mini Muscle mutation were observed to have a higher per-gram aerobic capacity. The mini-muscle allele shows a mendelian recessive behavior. The mutation is a single nucleotide polymorphism (SNP) in an intron of the myosin heavy polypeptide 4 gene.

DNA repair proteins

DNA repair pathways that repair damage to cellular DNA use many different proteins. These proteins often have other functions in addition to DNA repair. In humans, defects in some of these multifunctional proteins can cause widely differing clinical phenotypes. As an example, mutations in the XPB gene that encodes the largest subunit of the basal Transcription factor II H have several pleiotropic effects. XPB mutations are known to be deficient in nucleotide excision repair of DNA and in the quite separate process of gene transcription. In humans, XPB mutations can give rise to the cancer-prone disorder xeroderma pigmentosum or the noncancer-prone multisystem disorder trichothiodystrophy. Another example in humans is the ERCC6 gene, which encodes a protein that mediates DNA repair, transcription, and other cellular processes throughout the body. Mutations in ERCC6 are associated with disorders of the eye (retinal dystrophy), heart (cardiac arrhythmias), and immune system (lymphocyte immunodeficiency).

Chickens

Chicken exhibiting the frizzle feather trait

Chickens exhibit various traits affected by pleiotropic genes. Some chickens exhibit frizzle feather trait, where their feathers all curl outward and upward rather than lying flat against the body. Frizzle feather was found to stem from a deletion in the genomic region coding for α-Keratin. This gene seems to pleiotropically lead to other abnormalities like increased metabolism, higher food consumption, accelerated heart rate, and delayed sexual maturity.

Domesticated chickens underwent a rapid selection process that led to unrelated phenotypes having high correlations, suggesting pleiotropic, or at least close linkage, effects between comb mass and physiological structures related to reproductive abilities. Both males and females with larger combs have higher bone density and strength, which allows females to deposit more calcium into eggshells. This linkage is further evidenced by the fact that two of the genes, HAO1 and BMP2, affecting medullary bone (the part of the bone that transfers calcium into developing eggshells) are located at the same locus as the gene affecting comb mass. HAO1 and BMP2 also display pleiotropic effects with commonly desired domestic chicken behavior; those chickens who express higher levels of these two genes in bone tissue produce more eggs and display less egg incubation behavior.

Atavism

From Wikipedia, the free encyclopedia
Early embryos of various species display some ancestral features, like the tail on this human embryo. These features normally disappear in later development, but it may not happen if the animal has an atavism.

In biology, an atavism is a modification of a biological structure whereby an ancestral genetic trait reappears after having been lost through evolutionary change in previous generations. Atavisms can occur in several ways; one of which is when genes for previously existing phenotypic features are preserved in DNA, and these become expressed through a mutation that either knocks out the dominant genes for the new traits or makes the old traits dominate the new one. A number of traits can vary as a result of shortening of the fetal development of a trait (neoteny) or by prolongation of the same. In such a case, a shift in the time a trait is allowed to develop before it is fixed can bring forth an ancestral phenotype. Atavisms are often seen as evidence of evolution.

In social sciences, atavism is the tendency of reversion. For example, people in the modern era reverting to the ways of thinking and acting of a former time.

The word atavism is derived from the Latin atavus—a great-great-great-grandfather or, more generally, an ancestor.

Biology

Evolutionarily traits that have disappeared phenotypically do not necessarily disappear from an organism's DNA. The gene sequence often remains, but is inactive. Such an unused gene may remain in the genome for many generations. As long as the gene remains intact, a fault in the genetic control suppressing the gene can lead to it being expressed again. Sometimes, the expression of dormant genes can be induced by artificial stimulation.

Atavisms have been observed in humans, such as with infants born with vestigial tails (called a "coccygeal process", "coccygeal projection", or "caudal appendage"). Atavism can also be seen in humans who possess large teeth, like those of other primates. In addition, a case of "snake heart", the presence of "coronary circulation and myocardial architecture [that closely] resemble those of the reptilian heart", has also been reported in medical literature. Atavism has also recently been induced in avian dinosaur (bird) fetuses to express dormant ancestral non-avian dinosaur (non-bird) features, including teeth.

Other examples of observed atavisms include:

Culture

Atavism is a term in Joseph Schumpeter's explanation of World War I in twentieth-century liberal Europe. He defends the liberal international relations theory that an international society built on commerce will avoid war because of war's destructiveness and comparative cost. His reason for World War I is termed "atavism", in which he asserts that senescent governments in Europe (those of the German Empire, Russian Empire, Ottoman Empire, and Austro-Hungarian Empire) pulled the liberal Europe into war, and that the liberal regimes of the other continental powers did not cause it. He used this idea to say that liberalism and commerce would continue to have a soothing effect in international relations, and that war would not arise between nations which are connected by commercial ties. This latter idea is very similar to the later Golden Arches theory.

University of London professor Guy Standing has identified three distinct sub-groups of the precariat, one of which he refers to as "atavists", who long for what they see as a lost past.

Social Darwinism

During the interval between the acceptance of evolution in the mid-1800s and the rise of the modern understanding of genetics in the early 1900s, atavism was used to account for the reappearance in an individual of a trait after several generations of absence—often called a "throw-back". The idea that atavisms could be made to accumulate by selective breeding, or breeding back, led to breeds such as the Heck cattle. This had been bred from ancient landraces with selected primitive traits, in an attempt of "reviving" the aurochs, an extinct species of wild cattle. The same notions of atavisms were used by social Darwinists, who claimed that inferior races displayed atavistic traits, and represented more primitive traits than other races.[citation needed] Both atavism's and Ernst Haeckel's recapitulation theory are related to evolutionary progress, as development towards a greater complexity and a superior ability.

In addition, the concept of atavism as part of an individualistic explanation of the causes of criminal deviance was popularised by the Italian criminologist Cesare Lombroso in the 1870s. He attempted to identify physical characteristics common to criminals and labeled those he found as atavistic, 'throw-back' traits that determined 'primitive' criminal behavior. His statistical evidence and the closely related idea of eugenics have long since been abandoned by the scientific community, but the concept that physical traits may affect the likelihood of criminal or unethical behavior in a person still has some scientific support.

 

Exaptation

From Wikipedia, the free encyclopedia

Exaptation and the related term co-option describe a shift in the function of a trait during evolution. For example, a trait can evolve because it served one particular function, but subsequently it may come to serve another. Exaptations are common in both anatomy and behaviour.

Bird feathers are a classic example. Initially they may have evolved for temperature regulation, but later were adapted for flight. When feathers were first used to aid in flight, that was an exaptive use. They have since then been shaped by natural selection to improve flight, so in their current state they are best regarded as adaptations for flight. So it is with many structures that initially took on a function as exaptations, once molded for that new function they become adapted for that function

Interest in exaptation relates to both the process and products of evolution: the process that creates complex traits and the products (functions, anatomical structures, biochemicals, etc.) that may be imperfectly developed. The term "exaptation" was proposed by Stephen Jay Gould and Elisabeth Vrba, as a replacement for 'pre-adaptation', which they considered to be a teleologically loaded term.

History and definitions

Charles Darwin

The idea that the function of a trait might shift during its evolutionary history originated with Charles Darwin (Darwin 1859). For many years the phenomenon was labeled "preadaptation", but since this term suggests teleology in biology, appearing to conflict with natural selection, it has been replaced by the term exaptation.

The idea had been explored by several scholars when in 1982 Stephen Jay Gould and Elisabeth Vrba introduced the term "exaptation". However, this definition had two categories with different implications for the role of adaptation.

(1) A character, previously shaped by natural selection for a particular function (an adaptation), is coopted for a new use—cooptation. (2) A character whose origin cannot be ascribed to the direct action of natural selection (a nonaptation), is coopted for a current use—cooptation. (Gould and Vrba 1982, Table 1)

The definitions are silent as to whether exaptations had been shaped by natural selection after cooption, although Gould and Vrba cite examples (e.g., feathers) of traits shaped after cooption. Note that the selection pressure upon a trait is likely to change if it is (especially, primarily or solely) used for a new purpose, potentially initiating a different evolutionary trajectory.

To avoid these ambiguities, Buss et al. (1998) suggested the term "co-opted adaptation", which is limited to traits that evolved after cooption. However, the commonly used terms of "exaptation" and "cooption" are ambiguous in this regard.

Preadaptation

In some circumstances, the "pre-" in preadaptation can be interpreted as applying, for non-teleological reasons, prior to the adaptation itself, creating a meaning for the term that is distinct from exaptation. For example, future environments (say, hotter or drier ones), may resemble those already encountered by a population at one of its current spatial or temporal margins. This is not actual foresight, but rather the luck of having adapted to a climate which later becomes more prominent. Cryptic genetic variation may have the most strongly deleterious mutations purged from it, leaving an increased chance of useful adaptations, but this represents selection acting on current genomes with consequences for the future, rather than foresight.

Function may not always come before form: developed structures could change or alter the primary functions they were intended for due to some structural or historical cause.

Examples

Bird feathers of various colors

Exaptations include the co-option of feathers, which initially evolved for heat regulation, for display, and later for use in bird flight. Another example is the lungs of many basal fish, which evolved into the lungs of terrestrial vertebrates but also underwent exaptation to become the gas bladder, a buoyancy control organ, in derived fish. A third is the repurposing of two of the three bones in the reptilian jaw to become the malleus and incus of the mammalian ear, leaving the mammalian jaw with just one hinge.

A behavioural example pertains to subdominant wolves licking the mouths of lead wolves as a sign of submissiveness. (Similarly, dogs, which are wolves who through a long process were domesticated, lick the faces of their human owners.) This trait can be explained as an exaptation of wolf pups licking the faces of adults to encourage them to regurgitate food.

Arthropods provide the earliest identifiable fossils of land animals, from about 419 million years ago in the Late Silurian, and terrestrial tracks from about 450 million years ago appear to have been made by arthropods. Arthropods were well pre-adapted to colonize land, because their existing jointed exoskeletons provided support against gravity and mechanical components that could interact to provide levers, columns and other means of locomotion that did not depend on submergence in water.

Metabolism can be considered an important part of exaptation. As one of the oldest biological systems and being central to life on the Earth, studies have shown that metabolism may be able to use exaptation in order to be fit, given some new set of conditions or environment. Studies have shown that up to 44 carbon sources are viable for metabolism to successfully take place and that any one adaptation in these specific metabolic systems is due to multiple exaptations. Taking this perspective, exaptations are important in the origination of adaptations in general. A recent example comes from Richard Lenski's E. coli long-term evolution experiment, in which aerobic growth on citrate arose in one of twelve populations after 31,000 generations of evolution. Genomic analysis by Blount and colleagues showed that this novel trait was due to a gene duplication that caused a citrate transporter that is normally expressed only under anoxic conditions to be expressed under oxic conditions, thus exapting it for aerobic use. Metabolic systems have the potential to innovate without adaptive origins.

Gould and Brosius took the concept of exaptation to the genetic level. It is possible to look at a retroposon, originally thought to be simply junk DNA, and deduce that it may have gotten a new function to be termed as an exaptation. Given an emergency situation in the past, a species may have used junk DNA for a useful purpose in order to evolve and be able to survive. This may have occurred with mammalian ancestors when confronted with a large mass extinction about 250 million years ago and substantial increase in the level of oxygen in Earth's atmosphere. More than 100 loci have been found to be conserved only among mammalian genomes and are thought to have essential roles in the generation of features such as the placenta, diaphragm, mammary glands, neocortex, and auditory ossicles. It is believed that as a result of exaptation, or making previously "useless" DNA into DNA that could be used in order to increase survival chance, mammals were able to generate new brain structures as well as behavior to better survive the mass extinction and adapt to new environments. Similarly, viruses and their components have been repeatedly exapted for host functions. The functions of exapted viruses typically involve either defense from other viruses or cellular competitors or transfer of nucleic acids between cells, or storage functions. Koonin and Krupovic suggested that virus exaptation can reach different depths, from recruitment of a fully functional virus to exploitation of defective, partially degraded viruses, to utilization of individual virus proteins.

Adaptation and exaptation cycle

It was speculated by Gould and Vrba in one of the first papers written about exaptation, that when an exaptation arises, it may not be perfectly suited for its new role and may therefore develop new adaptations to promote its use in a better manner. In other words, the beginning of developing a particular trait starts out with a primary adaptation toward a fit or specific role, followed by a primary exaptation (a new role is derived using the existing feature but may not be perfect for it), which in turn leads to the development of a secondary adaptation (the feature is improved by natural selection for better performance), promoting further development of an exaptation, and so forth.

Once again, feathers are an important example, in that they may have first been adapted for thermoregulation and with time became useful for catching insects, and therefore served as a new feature for another benefit. For instance, large contour feathers with specific arrangements arose as an adaptation for catching insects more successfully, which eventually led to flight, since the larger feathers served better for that purpose.

Implications

Evolution of complex traits

One of the challenges to Darwin's theory of evolution was explaining how complex structures could evolve gradually, given that their incipient forms may have been inadequate to serve any function. As George Jackson Mivart (a critic of Darwin) pointed out, 5 percent of a bird wing would not be functional. The incipient form of complex traits would not have survived long enough to evolve to a useful form.

As Darwin elaborated in the last edition of The Origin of Species, many complex traits evolved from earlier traits that had served different functions. By trapping air, primitive wings would have enabled birds to efficiently regulate their temperature, in part, by lifting up their feathers when too warm. Individual animals with more of this functionality would more successfully survive and reproduce, resulting in the proliferation and intensification of the trait.

Eventually, feathers became sufficiently large to enable some individuals to glide. These individuals would in turn more successfully survive and reproduce, resulting in the spread of this trait because it served a second and still more beneficial function: that of locomotion. Hence, the evolution of bird wings can be explained by a shifting in function from the regulation of temperature to flight.

Jury-rigged design

Darwin explained how the traits of living organisms are well-designed for their environment, but he also recognized that many traits are imperfectly designed. They appear to have been made from available material, that is, jury-rigged. Understanding exaptations may suggest hypotheses regarding subtleties in the adaptation. For instance, that feathers evolved initially for thermal regulation may help to explain some of their features unrelated to flight (Buss et al., 1998). However, this is readily explained by the fact that they serve a dual purpose.

Some of the chemical pathways for physical pain and pain from social exclusion overlap. The physical pain system may have been co-opted to motivate social animals to respond to threats to their inclusion in the group.

Evolution of technology

Exaptation has received increasing attention in innovation and management studies inspired by evolutionary dynamics, where it has been proposed as a mechanism that drives the serendipitous expansion of technologies and products in new domains.

Degenerative disc disease

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