Understanding how the brain works is arguably one of the greatest scientific challenges of our time.
–Alivisatos et al.
The White HouseBRAIN 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.
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.
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).
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 voltagesensors that would detect individual action potentials, as well as nanoprobes that could serve as electrophysiologicalmultielectrode arrays. In particular, they called for the use of wireless, noninvasive methods of neuronal activity detection, either utilizing microelectronicvery-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
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.
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 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 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."
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 fungalevolutionary 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.
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.
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.
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.
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 enzymephenylalanine hydroxylase, which converts the amino acidphenylalanine 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.
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 hemoglobinS (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 (MFS) is an autosomaldominant 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 polypeptide4 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, XPBmutations 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.
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 Latinatavus—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.
Atavism is a term in Joseph Schumpeter's explanation of World War I in twentieth-century liberalEurope. 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 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 basalfish, 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.
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