Differences in gene expression are especially clear within  multicellular organisms , where cells all contain the same genome but have very different structures and behaviors due to the expression of different sets of genes. All the cells in a multicellular organism derive from a single cell, differentiating into variant cell types in response to external and  intercellular signals  and gradually establishing different patterns of gene expression to create different behaviors. As no single gene is responsible for the  development  of structures within multicellular organisms, these patterns arise from the complex interactions between many cells. [ citation needed ]


Within  eukaryotes , there exist structural features of  chromatin  that influence the transcription of genes, often in the form of modifications to DNA and chromatin that are stably inherited by daughter cells. [ 85 ]  These features are called " epigenetic " because they exist "on top" of the DNA sequence and retain inheritance from one cell generation to the next. Because of epigenetic features, different cell types  grown  within the same medium can retain very different properties. Although epigenetic features are generally dynamic over the course of development, some, like the phenomenon of  paramutation , have multigenerational inheritance and exist as rare exceptions to the general rule of DNA as the basis for inheritance. [ 86 ]


During the process of DNA replication, errors occasionally occur in the polymerization of the second strand. These errors, called mutations, can affect the phenotype of an organism, especially if they occur within the protein coding sequence of a gene. Error rates are usually very low—1 error in every 10–100 million bases—due to the "proofreading" ability of  DNA polymerases . [ 87 ] [ 88 ]  Processes that increase the rate of changes in DNA are called  mutagenic : mutagenic chemicals promote errors in DNA replication, often by interfering with the structure of base-pairing, while  UV radiation  induces mutations by causing damage to the DNA structure. [ 89 ]  Chemical damage to DNA occurs naturally as well and cells use  DNA repair  mechanisms to repair mismatches and breaks. The repair does not, however, always restore the original sequence. A particularly important source of DNA damages appears to be  reactive oxygen species [ 90 ]  produced by  cellular aerobic respiration , and these can lead to mutations. [ 91 ]


In organisms that use  chromosomal crossover  to exchange DNA and recombine genes, errors in alignment during meiosis can also cause mutations. Errors in crossover are especially likely when similar sequences cause partner chromosomes to adopt a mistaken alignment; this makes some regions in genomes more prone to mutating in this way. These errors create large structural changes in DNA sequence— duplications ,  inversions ,  deletions  of entire regions—or the accidental exchange of whole parts of sequences between different chromosomes,  chromosomal translocation . [ 92 ]


Mutations alter an organism's genotype and occasionally this causes different phenotypes to appear. Most mutations have little effect on an organism's phenotype, health, or reproductive  fitness . [ 93 ]  Mutations that do have an effect are usually detrimental, but occasionally some can be beneficial. [ 94 ]  Studies in the fly  Drosophila melanogaster  suggest that if a mutation changes a protein produced by a gene, about 70 percent of these mutations are harmful with the remainder being either neutral or weakly beneficial. [ 95 ]


Population genetics  studies the distribution of genetic differences within populations and how these distributions change over time. [ 96 ]  Changes in the  frequency of an allele  in a population are mainly influenced by  natural selection , where a given allele provides a selective or reproductive advantage to the organism, [ 97 ]  as well as other factors such as  mutation ,  genetic drift ,  genetic hitchhiking , [ 98 ]   artificial selection  and  migration . [ 99 ]


Over many generations, the genomes of organisms can change significantly, resulting in evolution. In the process called  adaptation , selection for beneficial mutations can cause a species to evolve into forms better able to survive in their environment. [ 100 ]  New species are formed through the process of  speciation , often caused by geographical separations that prevent populations from exchanging genes with each other. [ 101 ]


By comparing the  homology  between different species' genomes, it is possible to calculate the evolutionary distance between them and  when they may have diverged . Genetic comparisons are generally considered a more accurate method of characterizing the relatedness between species than the comparison of phenotypic characteristics. The evolutionary distances between species can be used to form  evolutionary trees ; these trees represent the  common descent  and divergence of species over time, although they do not show the transfer of genetic material between unrelated species (known as  horizontal gene transfer  and most common in bacteria). [ 102 ]


Although geneticists originally studied inheritance in a wide variety of organisms, the range of species studied has narrowed. One reason is that when significant research already exists for a given organism, new researchers are more likely to choose it for further study, and so eventually a few  model organisms  became the basis for most genetics research. Common research topics in model organism genetics include the study of  gene regulation  and the involvement of genes in  development  and  cancer . Organisms were chosen, in part, for convenience—short generation times and easy  genetic manipulation  made some organisms popular genetics research tools. Widely used model organisms include the gut bacterium  Escherichia coli , the plant  Arabidopsis thaliana , baker's yeast ( Saccharomyces cerevisiae ), the nematode  Caenorhabditis elegans , the common fruit fly ( Drosophila melanogaster ), the zebrafish ( Danio rerio ), and the common house mouse ( Mus musculus ). [ 103 ]


Medical genetics  seeks to understand how genetic variation relates to human health and disease. [ 104 ]  When searching for an unknown gene that may be involved in a disease, researchers commonly use genetic linkage and genetic  pedigree charts  to find the location on the genome associated with the disease. At the population level, researchers take advantage of  Mendelian randomization  to look for locations in the genome that are associated with diseases, a method especially useful for  multigenic traits  not clearly defined by a single gene. [ 105 ]  Once a candidate gene is found, further research is often done on the corresponding (or  homologous ) genes of model organisms. In addition to studying genetic diseases, the increased availability of genotyping methods has led to the field of  pharmacogenetics : the study of how genotype can affect drug responses. [ 106 ]


Individuals differ in their inherited tendency to develop  cancer , and cancer is a genetic disease. The process of cancer development in the body is a combination of events. Mutations occasionally occur within cells in the body as they divide. Although these mutations will not be inherited by any offspring, they can affect the behavior of cells, sometimes causing them to grow and divide more frequently. There are biological mechanisms that attempt to stop this process; signals are given to inappropriately dividing cells that should trigger  cell death , but sometimes additional mutations occur that cause cells to ignore these messages. An internal process of  natural selection  occurs within the body and eventually mutations accumulate within cells to promote their own growth, creating a cancerous  tumor  that grows and invades various tissues of the body. Normally, a cell divides only in response to signals called  growth factors  and  stops growing once in contact with surrounding cells  and in response to growth-inhibitory signals. It usually then divides a limited number of times and dies, staying within the  epithelium  where it is unable to migrate to other organs. To become a cancer cell, a cell has to accumulate mutations in a number of genes (three to seven). A cancer cell can divide without growth factor and ignores inhibitory signals. Also, it is immortal and can grow indefinitely, even after it makes contact with neighboring cells. It may escape from the epithelium and ultimately from the  primary tumor . Then, the escaped cell can cross the endothelium of a blood vessel and get transported by the bloodstream to colonize a new organ, forming deadly  metastasis . Although there are some genetic predispositions in a small fraction of cancers, the major fraction is due to a set of new genetic mutations that originally appear and accumulate in one or a small number of cells that will divide to form the tumor and are not transmitted to the progeny ( somatic mutations ). The most frequent mutations are a loss of function of  p53 protein , a  tumor suppressor , or in the p53 pathway, and gain of function mutations in the  Ras proteins , or in other  oncogenes . [ 107 ] [ 108 ]


DNA can be manipulated in the laboratory.  Restriction enzymes  are commonly used enzymes that cut DNA at specific sequences, producing predictable fragments of DNA. [ 109 ]  DNA fragments can be visualized through use of  gel electrophoresis , which separates fragments according to their length. [ 110 ]


The use of  ligation enzymes  allows DNA fragments to be connected. By binding ("ligating") fragments of DNA together from different sources, researchers can create  recombinant DNA , the DNA often associated with  genetically modified organisms . Recombinant DNA is commonly used in the context of  plasmids : short circular DNA molecules with a few genes on them. In the process known as  molecular cloning , researchers can amplify the DNA fragments by inserting plasmids into bacteria and then culturing them on plates of agar (to isolate  clones of bacteria cells ). "Cloning" can also refer to the various means of creating cloned ("clonal") organisms. [ 111 ]


DNA can also be amplified using a procedure called the  polymerase chain reaction  (PCR). [ 112 ]  By using specific short sequences of DNA, PCR can isolate and exponentially amplify a targeted region of DNA. Because it can amplify from extremely small amounts of DNA, PCR is also often used to detect the presence of specific DNA sequences. [ 113 ] [ 114 ]


DNA sequencing, one of the most fundamental technologies developed to study genetics, allows researchers to determine the sequence of nucleotides in DNA fragments. The technique of  chain-termination sequencing , developed in 1977 by a team led by  Frederick Sanger , is still routinely used to sequence DNA fragments. Using this technology, researchers have been able to study the molecular sequences associated with many human diseases. [ 115 ]


As sequencing has become less expensive, researchers have  sequenced the genomes  of many organisms using a process called  genome assembly , which uses computational tools to stitch together sequences from many different fragments. [ 116 ]  These technologies were used to sequence the human genome in the Human Genome Project completed in 2003. [ 41 ]  New  high-throughput sequencing  technologies are dramatically lowering the cost of DNA sequencing, with many researchers hoping to bring the cost of resequencing a human genome down to a thousand dollars. [ 117 ]


Next-generation sequencing  (or high-throughput sequencing) came about due to the ever-increasing demand for low-cost sequencing. These sequencing technologies allow the production of potentially millions of sequences concurrently. [ 118 ] [ 119 ]  The large amount of sequence data available has created the subfield of  genomics , research that uses computational tools to search for and analyze patterns in the full genomes of organisms. Genomics can also be considered a subfield of  bioinformatics , which uses computational approaches to analyze large sets of  biological data . A common problem to these fields of research is how to manage and share data that deals with human subject and  personally identifiable information . [ citation needed ]


On 19 March 2015, a group of leading biologists urged a worldwide ban on clinical use of methods, particularly the use of  CRISPR  and  zinc finger , to edit the human genome in a way that can be inherited. [ 120 ] [ 121 ] [ 122 ] [ 123 ]  In April 2015, Chinese researchers  reported  results of  basic research  to edit the DNA of non-viable  human embryos  using CRISPR. [ 124 ] [ 125 ]


Aspects of  genetics  including  mutation ,  hybridisation ,  cloning ,  genetic engineering , and  eugenics  have appeared in fiction since the 19th century.


Genetics is a young science, having started in 1900 with the rediscovery of  Gregor Mendel 's study on the inheritance of  traits  in pea plants. During the 20th century it developed to create new sciences and technologies including  molecular biology ,  DNA sequencing , cloning, and genetic engineering. The  ethical implications  were brought into focus with the eugenics movement.


Since then, many  science fiction  novels and films have used aspects of genetics as plot devices, often taking one of two routes: a genetic accident with disastrous consequences; or, the feasibility and desirability of a planned genetic alteration. The treatment of science in these stories has been uneven and often unrealistic. The film  Gattaca  did attempt to portray science accurately but was criticised by scientists.


Modern genetics began with the work of the monk  Gregor Mendel  in the 19th century, on the inheritance of  traits  in pea plants. Mendel found that visible traits, such as whether peas were round or wrinkled, were  inherited discretely , rather than by  blending  the attributes of the two parents. [ 1 ]  In 1900,  Hugo de Vries  and other scientists rediscovered Mendel's research;  William Bateson  coined the term "genetics" for the new science, which soon investigated a wide range of phenomena including  mutation  (inherited changes caused by damage to the genetic material),  genetic linkage  (when some traits are to some extent inherited together), and  hybridisation  (crosses of different  species ). [ 2 ]


Eugenics , the production of better human beings by selective breeding, was named and advocated by  Charles Darwin 's cousin, the scientist  Francis Galton , in 1883. It had both a positive aspect, the breeding of more children with high intelligence and good health; and a negative aspect, aiming to suppress "race degeneration" by preventing supposedly "defective" families with attributes such as profligacy, laziness, immoral behaviour and a tendency to criminality from having children. [ 3 ] [ 4 ]


Molecular biology , the interactions and  regulation  of genetic materials, began with the identification in 1944 of  DNA  as the main genetic material; [ 5 ]  the  genetic code  and the  double helix  structure of DNA was determined by  James Watson  and  Francis Crick  in 1953. [ 6 ] [ 7 ]   DNA sequencing , the identification of an exact sequence of genetic information in an organism, was developed in 1977 by  Frederick Sanger . [ 8 ]


Genetic engineering , the modification of the genetic material of a live organism, became possible in 1972 when  Paul Berg  created the first  recombinant DNA  molecules (artificially assembled genetic material) using  viruses . [ 9 ]


Cloning , the production of genetically identical organisms from some chosen starting point, was shown to be practicable in a mammal with the creation of  Dolly the sheep  from an  ordinary body cell  in 1996 at the  Roslin Institute . [ 10 ]


Mutation  and  hybridisation  are widely used in fiction, starting in the 19th century with  science fiction  works such as Mary Shelley's 1818 novel  Frankenstein  and  H. G. Wells 's  1896  The Island of Dr. Moreau . [ 11 ]


In her 1977  Biological Themes in Modern Science Fiction , Helen Parker identified two major types of story: "genetic accident", the uncontrolled, unexpected and disastrous alteration of a species; [ 12 ] [ 13 ]  and "planned genetic alteration", whether controlled by humans or  aliens , and the question of whether that would be either feasible or desirable. [ 12 ] [ 13 ]  In science fiction up to the 1970s, the genetic changes were brought about by  radiation , breeding programmes, or manipulation with chemicals or  surgery  (and thus, notes Lars Schmeink, not necessarily by strictly genetic means). [ 13 ]  Examples include  The Island of Dr. Moreau  with its horrible manipulations;  Aldous Huxley 's 1932  Brave New World  with a breeding programme; and  John Taine 's 1951  Seeds of Life , using radiation to create supermen. [ 13 ]  After the discovery of the double helix and then recombinant DNA, genetic engineering became the focus for genetics in fiction, as in books like  Brian Stableford 's tale of a genetically modified society in his 1998  Inherit the Earth , or  Michael Marshall Smith 's story of  Organ farming  in his 1997  Spares . [ 13 ]


Comic books  have imagined mutated  superhumans  with extraordinary powers. The  DC Universe  (from 1939) imagines " metahumans "; the  Marvel Universe  (from 1961) calls them " mutants ", while the  Wildstorm  (from 1992) and  Ultimate Marvel  (2000–2015) Universes name them " posthumans ". [ 14 ]
Stan Lee introduced the concept of mutants in the Marvel X-Men books in 1963; the villain Magneto declares his plan to "make  Homo sapiens  bow to  Homo superior !", implying that mutants will be an evolutionary step up from current humanity. Later, the books speak of an X-gene that confers powers from  puberty  onwards. X-men powers include  telepathy ,  telekinesis , healing, strength, flight,  time travel , and the ability to emit blasts of energy. Marvel's god-like Celestials are later (1999) said to have visited Earth long ago and to have modified human DNA to enable mutant powers. [ 15 ]


James Blish 's 1952 novel  Titan's Daughter  (in  Kendell Foster Crossen 's  Future Tense  collection) featured stimulated  polyploidy  (giving organisms multiple sets of genetic material, something that can create new  species  in a single step), based on spontaneous polyploidy in  flowering plants , to create humans with more than normal height, strength, and lifespans. [ 16 ]


Cloning , too, is a familiar plot device.   Aldous Huxley 's 1931 dystopian novel  Brave New World  imagines the  in vitro  cloning of fertilised human  eggs . [ 17 ] [ 18 ]  Huxley was influenced by  J. B. S. Haldane 's 1924 non-fiction book  Daedalus; or, Science and the Future , which used the Greek myth of  Daedalus  to symbolise the coming revolution in genetics; Haldane predicted that humans would  control their own evolution  through directed  mutation  and  in vitro fertilisation . [ 19 ]  Cloning was explored further in stories such as  Poul Anderson 's 1953  UN-Man . [ 20 ]  In his 1976 novel,  The Boys from Brazil ,  Ira Levin  describes the creation of 96 clones of  Adolf Hitler , replicating for all of them the rearing of Hitler (including the death of his father at age 13), with the goal of resurrecting Nazism. In his 1990 novel  Jurassic Park ,  Michael Crichton  imagined the recovery of the complete  genome  of a  dinosaur  from  fossil  remains, followed by its use to recreate living animals of an  extinct  species. [ 11 ]


Cloning is a recurring theme in science fiction films like  Jurassic Park  (1993),  Alien Resurrection  (1997),  The 6th Day  (2000),  Resident Evil  (2002),  Star Wars: Episode II  (2002) and  The Island  (2005). The process of cloning is represented variously in fiction. Many works depict the artificial creation of humans by a method of growing cells from a tissue or DNA sample; the replication may be instantaneous, or take place through slow growth of human embryos in  artificial wombs . In the long-running British television series  Doctor Who , the  Fourth Doctor  and his companion  Leela  were cloned in a matter of seconds from DNA samples (" The Invisible Enemy ", 1977) and then—in an apparent  homage  to the 1966 film  Fantastic Voyage —shrunk to microscopic size in order to enter the Doctor's body to combat an alien virus. The clones in this story are short-lived, and can only survive a matter of minutes before they expire. [ 21 ]  Films such as  The Matrix  and  Star Wars: Episode II – Attack of the Clones  have featured human  foetuses  being cultured on an industrial scale in enormous tanks. [ 22 ]


Cloning humans from body parts is a common science fiction trope, one of several genetics themes parodied in  Woody Allen 's 1973 comedy  Sleeper , where an attempt is made to clone an assassinated dictator from his disembodied nose. [ 23 ]


Genetic engineering  features in many science fiction stories. [ 16 ]  Films such as  The Island   (2005) and  Blade Runner  (1982) bring the engineered creature to confront the person who created it or the being it was cloned from, a theme seen in some film versions of  Frankenstein . Few films have informed audiences about genetic engineering as such, with the exception of the 1978  The Boys from Brazil  and the 1993  Jurassic Park , both of which made use of a lesson, a demonstration, and a clip of scientific film. [ 11 ] [ 24 ]  In 1982,  Frank Herbert 's novel  The White Plague  described the deliberate use of genetic engineering to create a  pathogen  which specifically killed women. [ 16 ]  Another of Herbert's creations, the  Dune  series of novels, starting with  Dune  in 1965, emphasises genetics. It combines  selective breeding  by a powerful sisterhood, the  Bene Gesserit , to produce a supernormal male being, the Kwisatz Haderach, with the genetic engineering of the powerful but despised  Tleilaxu . [ 25 ]


Eugenics  plays a central role in films such as  Andrew Niccol 's 1997  Gattaca , the title alluding to the letters G, A, T, C for  guanine ,  adenine ,  thymine , and  cytosine , the four  nucleobases  of  DNA . Genetic engineering of humans is unrestricted, resulting in  genetic discrimination , loss of diversity, and adverse effects on society. The film explores the  ethical implications ; the production company, Sony Pictures, consulted with a gene therapy researcher,  French Anderson , to ensure that the portrayal of science was realistic, and test-screened the film with the Society of Mammalian Cell Biologists and the American  National Human Genome Research Institute  before its release. This care did not prevent researchers from attacking the film after its release. Philim Yam of  Scientific American  called it "science bashing"; in  Nature  Kevin Davies called it a ""surprisingly pedestrian affair"; and the  molecular biologist   Lee Silver  described the film's extreme  genetic determinism  as "a  straw man ". [ 26 ] [ 27 ]


The  geneticist  Dan Koboldt observes that while science and technology play major roles in fiction, from  fantasy  and science fiction to  thrillers , the representation of science in both literature and film is often unrealistic. [ 28 ]  In Koboldt's view, genetics in fiction is frequently oversimplified, and some myths are common and need to be debunked. For example, the  Human Genome Project  has not (he states) immediately led to a  Gattaca  world, as the relationship between  genotype  and  phenotype  is not straightforward. People do differ genetically, but only very rarely because they are missing a  gene  that other people have: people have different  alleles  of the same genes. Eye and hair colour are controlled not by one gene each, but by multiple genes. Mutations do occur, but they are rare: people are 99.99% identical genetically, the 3 million differences between any two people being dwarfed by the hundreds of millions of DNA bases which are identical; nearly all DNA variants are inherited, not acquired afresh by mutation. And, Koboldt writes, believable scientists in fiction should know their knowledge is limited. [ 29 ]


Genetics nursing  is a  nursing  specialty that focuses on providing  genetic  healthcare to patients.


The integration of genetics into nursing began in the 1980s and has been a slow but important process in improving the quality of healthcare for patients receiving  genetic  and  genomic  based care from nurses. Modeling the United Kingdom, the United States critically established a set of essential competencies as a set of guidelines for  registered nurses . Through the process of consensus the essential competencies were created by the steering committee, and provided the minimalist competency and scope of practice for  registered nurses  delivering  genetic  healthcare to patients.


The Nursing Code of Ethics and other ethical foundations were established for field of genetics nursing to provide regulations when ethical issues develop. [ 1 ]


Adopted from the early Christians in 30 AD, the term  nurse  was created from the Latin origin nutrire, which means to nurture or nourish. Establishing  nursing  as one of the oldest forms of healthcare and continues to be a growing field of medicine. [ 2 ]   Genetics , which is the study of inherited traits and their variation is a much more recent field of medicine. The experiments and theories of Gregor Mendel in the mid-19th century helped to introduce the field of  genetics  into medicine.  Genomics  is a subset of  genetics  that compares and analyzes  genomes  and how the genes interact with one another. Both  genetics  and  genomics  help to reveal how closely related we are to each other and to other species. [ 3 ]  This scientific study is ongoing and strives to interpret health, illness, disease risk, and treatment response. The progress in  genetics  and  genomics  is applicable to the entire spectrum of health care and all health professionals and as such to the entire  nursing  profession. [ 4 ]   Genetics  and  genomics  are important to healthcare because it provides information in the diagnosis, treatment, and prevention of diseases and illnesses. Even though  genetics  has been a growing field of medicine since the mid-19th century, the process of integrating  genomics  into the nursing curriculum, National Council Licensure Examinations, continuing education, and certification was not highlighted until the 1980s. [ 5 ]   Genetics  and  genomics  are fundamental to the  nursing  practice because the basis of  genetics  can recognize individuals at risk for certain illnesses and diseases, identify the risks of certain disease or illnesses when conceiving children, facilitate drug dosage or selection for certain illnesses or specific patients, and  genetics  promotes benefits in treatment of particular ailments. [ 6 ]


However, it took twenty more years until the Health Recourses and Services Administration (HRSA) stressed the significance of incorporating  genetics  into  nursing  education. [ 5 ]  After HRSA's proposal, there was minor advancement and the development that was established contained a lot of inconsistency. The progress of integration continued to be slow and limited. By fall of 2005, only 30% of academic nursing programs contained a curriculum thread in  genetics  and  genomics . [ 5 ]  One of the leading factors in the limited progress of  genetics  integration is the relevance to all nursing practice is not fully appreciated by many, and  genetics  is also seen by many nurses to be a  subspecialty . Also state boards of  nursing  do not require competency in  genomics  and  genetics  as part of  licensure  and  genetics  and  genomics  are not considered in the evaluations of accrediting bodies. The extremely large size and variation of the nursing workforce provides an extra challenge in the many existing barriers needed to be overcome for  genetics  to be implemented. [ 4 ]  Some of the first successful training of genetic practices in the nursing workforce can be seen in the  United Kingdom . The main aspect of the  U.K. ’s strategy was simplicity. They achieved this by constructing seven essential competencies that were applied to the entire nursing profession. In 2003, the U.K. National Health Service created the NHS National Genetics Education and Development Centre. The main functions of these programs were to enhance  genetics  education and to dispense materials and resources for educators of all  genetic  professions. The  United States  mirrored the efforts and ideas established in the  U.K.  and adopted similar methods and competencies. The  U.S.  National Human Genome Research Institute and the National Cancer Institute of the National Institutes of Health united to initiate strategies, training programs, committees, and define the competencies. [ 5 ]


The  genetic  and  genomic  competencies are important to the practice of all  nurses  regardless of academic preparation, practice setting, role, or specialty. [ 6 ]  The competencies are significant because they establish a foundation and set of guidelines for the nursing workforce on administering the minimal amount of  genetic  and  genomic  based healthcare. Since the competencies would only reflect the minimalist amount of  genetic  and  genomic  based healthcare, they were specifically drawn up to focus on the scope of practice for  registered nurses . This was done because a  registered nurse  is a general level of practice for nursing and requires that one has graduated from a college or university nursing program and has passed the  NCLEX . The  NCLEX  is a national licensing exam that signifies minimal competency in practicing nursing if passed. [ 5 ] [ 6 ] [ 7 ]


To begin the development of the competencies, the initial strategy of the  U.S.  National Human Genome Research Institute and the National Cancer Institute of the National Institutes of Health established the steering committee. It was composed of nurse leaders from a variety of professional nursing agencies, academic settings, and organizations. Two of the major nursing leaders, Jean Jenkins, RN, PhD, FAAN and Kathleen Calzone, RN, MSN, APNG, FAAN were chosen as the Co-Chairs of the committee. The committee's fundamental function was to generate a mechanism for establishing competencies by recognizing, examining, and comparing existing published competencies. [ 5 ] [ 6 ]  The published competencies that were being examined targeted all health care professionals, specifically those practicing  genetics , nurses with bachelor's degrees, and  advanced practice nurses . After the published competencies were reviewed carefully, the developing of the essential competencies was produced in four phases called the process of consensus.


During phase I of the process of consensus, a subset of the committee was created to synthesize competencies from the documents under review that would apply to all registered nurses; then the steering committee reviewed, modified, and approved the recommended competencies. [ 5 ]  In 2005, nurse representatives of the National Coalition for Health Professional Education in Genetics also reviewed the proposed competencies and made modifications. Throughout phase II, the American Nursing Association published the competencies during a meeting in 2006 and requested judgment, thoughts, and comments from the public, specifically targeting the insight from the nursing community. [ 5 ] [ 6 ]  The 10 comments that were received were recorded and evaluated and the majority of them showed support. Phase III consisted of establishing consensus on the final draft of the essential competencies by the steering committee and the consensus panel, which is also made up of a variety of nursing leaders in different organizations and settings. [ 5 ]  The steering committee also constructed strategies for integrating  genetic  and  genomic  information into education and practice such as the  NCLEX  exam, accreditation programs, certification processes, and nursing curriculum. In March 2006, phase IV occurred and consisted of endorsing the final document by the Nursing Organizations Alliance member organizations. [ 6 ]


The essential competencies consists of two domains: professional responsibilities and professional practice. Under the professional responsibilities domain, all professional activities by  registered nurses  are required to fall within the confines of the  Nursing: Scope and Standards of Practice  produced by the American Nurses Association. [ 6 ]


Also, competent nursing practice now requires the incorporation of  genetic  and  genomic  knowledge and skills in order to:


The competencies for the  registered nurse , under the professional practice domain, includes:  nursing assessment , which is the application and integration of  genetic  and  genomic  knowledge, identification, referral activities, and provision of education, care, and support. [ 5 ]


Nursing Assessment for the  registered nurse  includes:


Identification for the  registered nurse  includes:


Referral Activities for the  registered nurse  includes:


Provision of support, care, and education for the  registered nurse  includes:


Ethics  pertain to the ‘’rightness’’ and ‘’wrongness’’ of human actions, motives, and conduct. Complicated ethical issues in areas such as justice, privacy, and autonomy, tend to follow both the field of  genetics  and the field of  nursing . Ethical problems and dilemmas arise daily in healthcare settings for both the patient and health care provider. For example, all patients and individuals have the right to receive equal health care regardless of gender, religious beliefs, status, or race.  A Code of Ethics for Nursing was created by the American Nurses Association, which provides rules, regulations, and guidelines to follow when making a decision that is ethical based. These regulations were mainly established to help provide equal healthcare, protect the rights, safety, and privacy of the patient, and to hold  nurses  accountable for their actions and choices.  Genetics  can create ethical issues in nursing for a variety of different situations. Many scenarios, questions, and debates have been encountered such as what individuals can receive  genetic  testing or information? Who owns or controls the information received from the genetic test and how can the owner use that information? However, the code of  ethics  does not address  genetics  or  genomics  specifically, so ethical foundations were also established to help guide  genetics  into health care. The foundations provide a set of guidelines to understand and manage an ethical issue if one should arise, and to assist in the translation of  genetics  into the healthcare environment. [ 8 ] [ 9 ]


About 10–15% of human couples are  infertile , unable to conceive. In approximately in half of these cases, the underlying cause is related to the male. The underlying causative factors in the  male infertility  can be attributed to environmental toxins, systemic disorders such as,  hypothalamic–pituitary disease ,  testicular cancers  and  germ-cell   aplasia . Genetic factors including  aneuploidies  and single-gene mutations are also contributed to the male infertility. Patients with nonobstructive  azoospermia  or  oligozoospermia  show  microdeletions  in the long arm of the  Y chromosome  and/or chromosomal abnormalities, each with the respective frequency of 9.7% and 13%. A large percentage of human male infertility is estimated to be caused by mutations in genes involved in primary or secondary  spermatogenesis  and sperm quality and function.  Single-gene defects  are the focus of most research carried out in this field. [ 1 ] [ 2 ]


NR5A1  mutations are associated with male infertility, suggesting the possibility that these mutations cause the infertility. However, it is possible that these mutations individually have no major effect and only contribute to the male infertility by collaboration with other contributors such as environmental factors and other genomics variants. [ 3 ]  Vice versa, existence of the other alleles could reduce the phenotypic effects of impaired NR5A1 proteins and attenuate the expression of abnormal phenotypes and manifest male infertility solely.


Nuclear receptor subfamily 5 group A member 1 (NR5A1), also known as  SF1  or  Ad4BP  ( MIM  184757), is located on the long arm of  chromosome 9  (9q33.3). The NR5A1 is an orphan nuclear receptor that was first identified following the search for a common regulator of the cytochrome P450 steroid hydroxylase enzyme family. This receptor is a pivotal transcriptional regulator of an array of genes involved in reproduction, steroidogenesis and male sexual differentiation and also plays a crucial role in adrenal gland formation in both sexes. NR5A1 regulates the  Müllerian inhibitory substance  by binding to a conserved upstream regulatory element and directly participates in the process of mammalian sex determination through Müllerian duct regression. Targeted disruption of NR5A1 (Ftzf1) in mice results in gonadal and adrenal agenesis, persistence of Müllerian structures and abnormalities of the  hypothalamus  and pituitary gonadotropes.  Heterozygous  animals demonstrate a milder phenotype including an impaired adrenal stress response and reduced testicular size. In humans, NR5A1 mutations were first described in patients with 46, XY  karyotype  and  disorders of sex development  (DSD), Müllerian structures and primary  adrenal failure  (MIM 612965). After that, heterozygous NR5A1 mutations were described in seven patients showing 46, XY karyotype and ambiguous genitalia,  gonadal dysgenesis , but no adrenal insufficiency. Since then, studies have confirmed that mutations in NR5A1 in patients with 46, XY karyotype cause severe underandrogenisation, but no adrenal insufficiency, establishing dynamic and dosage-dependent actions for NR5A1. Subsequent studies revealed that NR5A1 heterozygous mutations cause primary ovarian insufficiency (MIM 612964). [ 4 ] [ 5 ] [ 6 ] [ 7 ]


Recently, NR5A1 mutations have been related to human male infertility (MIM 613957). These findings substantially increase the number of NR5A1 mutations reported in humans and show that mutations in NR5A1 can be found in patients with a wide range of phenotypic features, ranging from 46,XY sex reversal with primary adrenal failure to male infertility. For the first time, Bashamboo et al. (2010) conducted a study on the nonobstructive infertile men (a non-Caucasian mixed ancestry n = 315), which resulted in the report of all missense mutations in the NR5A1 gene with 4% frequency. Functional studies of the missense mutations revealed impaired transcriptional activation of NR5A1-responsive target genes. Subsequently, three missense mutations were identified as associated with and most likely the cause of the male infertility, according to computational analyses. [ 8 ]  The study indicated that the mutation frequency is below 1% ( Caucasian   German  origin, n = 488). [ 8 ]  In another study the coding sequence of NR5A1 has been analysed in a cohort of 90 well-characterised idiopathic Iranian azoospermic infertile men versus 112 fertile men. [ 9 ]  Heterozygous NR5A1 mutations were found in 2 of 90 (2.2%) of cases. [ 9 ]  These two patients harboured missense mutations within the hinge region (p.P97T) and ligand-binding domain (p.E237K) of the NR5A1 protein. [ 9 ]


Small supernumerary marker chromosome  (sSMCs) are extra  chromosomes  consisting of parts of virtually any other chromosome(s). By definition, they are smaller than one of the smaller chromosomes, chromosome 20. sSMCs typically develop in individuals as a result of abnormal chromosomal events occurring in one of their parent's eggs, sperms, or  zygotes  but in less common cases are directly inherited from a parent carrier of the sSMC. [ 10 ]  sSMCs occur in 0.125% of all infertility cases, [ 11 ]  are 7.5-fold more common in men, [ 11 ]  and in women are often associated with  ovarian failure . [ 12 ]  The sSMCs associated with infertility can consist of parts of virtually any other chromosome. While only a small percentage of these sSMCs have had their genetic material defined, those that have include sSMCs containing:  a)   band  11.1 from the short arm of chromosome 15 (notated as (15)q11.1)(this sSMC is associated with premature ovarian failure);  b)  band ll.2 from the short arm of chromosome 13 (notated as (13)q11.2)(this sSMC is associated with oligoasthenoteratozoospermia, i.e.  oligozoospermia  [low sperm count],  teratozoospermia  [presence of sperm with abnormal shapes], and asthenozoospermia [sperm with reduced motility]); [ 12 ]   c)  band 11 from the short arm of chromosome 14 (notated as (14)q11.1)(this sCMC is associated with otherwise uncharacterized infertility; and  d)  band 11 on the short arm of chromosome 22 notated as (22)q11)(this sSMC is associated with repeated abortions). [ 13 ]


The  genetic influences of  post-traumatic stress disorder  ( PTSD ) are not understood well due to the limitations of any genetic study of mental illness; in that, it cannot be  ethically  induced in selected groups. Because of this, all studies must use naturally occurring groups with genetic similarities and differences, thus the amount of data is limited. Still, genetics play some role in the development of PTSD.


Approximately 30% of the variance in PTSD is caused by genetics alone. [ 1 ]  For  twins  exposed to  combat  in the  Vietnam War , a monozygotic (identical) twin with PTSD was associated with an increased risk of the co-twin having PTSD, as compared to dizygotic (non-identical) twins; [ 2 ]  additionally, assaultive trauma (compared to non-assaultive trauma) was more likely to exacerbate these effects. [ 3 ]


There is also evidence that those with a genetically smaller  hippocampus  are more likely to develop PTSD following a traumatic event. [ citation needed ]


Research has also found that PTSD shares many genetic influences common to other psychiatric disorders.  Panic  and  generalized anxiety disorders  and PTSD share 60% of the same genetic variance. Alcohol, nicotine, and  drug dependence  share greater than 40% genetic similarities. [ 1 ]  Additional disorders—such as  depression ,  schizophrenia , and  bipolar disorder —share the same fundamental genetic phenotypes as PTSD.


An individual's potential for onset of many psychological disorders is heavily affected by genetic  phenotypes , yet this is not the only contributing factor. Environment plays an important role as well, especially for trauma-based disorders such as PTSD, considering that certain life experiences can trigger the activation of an underlying genetic phenotype which might have been previously dormant. [ 4 ]  This can be further understood by examining the  diathesis-stress model  for the onset of psychological disorders, which explains that certain individuals, due to their genetic phenotypes, are more susceptible to psychological disorders when encountering the same stressful life situations or stimuli as other individuals without these same underlying genetic phenotypes. [ 5 ]


Gamma-aminobutyric acid  (GABA) is the major inhibitory  neurotransmitter  in the brain. A 2009 study [ 6 ]  reported a significant interaction between three  single nucleotide polymorphisms  (SNP) in the GABA alpha-2 receptor gene and the severity of childhood trauma in predicting PTSD in adults. [ 1 ]  Another study [ 7 ]  found an association between a specific SNP of the  RGS2  gene [ note 1 ]  and PTSD symptoms in adults who experienced high environmental stress (hurricane exposure) and low social support. [ 1 ]


Studies in 2008 found that several SNPs in the  FKBP5  (FK506 binding protein 5) gene interact with childhood trauma to predict severity of adult PTSD. [ 8 ] [ 9 ]  These findings suggest that individuals with these SNPs who are abused as children are more susceptible to PTSD as adults. This is particularly important given that  FKBP5  SNPs have previously been associated with  peritraumatic  dissociation in medically injured children (that is,  dissociation  at the time of the childhood trauma), [ 10 ] [ 11 ]  which has itself been shown to be predictive of PTSD. [ 12 ] [ 13 ]  Furthermore, FKBP5 may be less  expressed  in those with current PTSD. [ 14 ]


In 2011, another study found that a single SNP in a putative  estrogen response element  on the  ADCYAP1R1  gene [ note 2 ]  predicts PTSD diagnosis and symptoms in females. [ 15 ]  Incidentally, this SNP is also associated with fear discrimination. The study suggests that perturbations in the  PACAP /PAC1 pathway are involved in abnormal stress responses underlying PTSD.


PTSD is a  psychiatric disorder  that requires an environmental event that individuals may variously respond to. Because of this,  gene-environment  studies tend to be the most indicative of their effect on the probability of PTSD than studies of the main effect of the gene. Studies have demonstrated the interaction between the  FKBP5  gene and childhood environment to predict the severity of PTSD.  Polymorphisms  in  FKBP5  have been associated with peritraumatic dissociation in mentally ill children. [ 1 ]


A 2008 study of highly traumatized, inner city African Americans demonstrated that four polymorphisms of the  FKBP5  gene interacted with severity of childhood abuse to predict severity of adult PTSD symptoms. This finding was partially replicated in a 2010 study, which reported that within the African American population, the TT genotype of the  FKBP5  gene is associated with the highest risk of PTSD among those having experienced childhood adversity, while those with this genotype that experienced no childhood adversity had the lowest risk of PTSD. [ 1 ]  In addition,  alcohol dependence  interacts with the  FKBP5  polymorphisms and childhood adversity to increase the risk of PTSD in these populations.


A 2005 study found that FKPB5 mRNA was differentially expressed in emergency room trauma patients who were later diagnosed with PTSD. However, a 2009 study found FKPB5 mRNA expression was reduced in  9/11  survivors diagnosed with PTSD. [ 1 ]


Catechol-O-methyl transferase  (COMT) is an  enzyme  that catalyzes the extraneuronal breakdown of  catecholamines . The gene that codes for COMT has a functional polymorphism in which a  valine  has been replaced with a  methionine  at codon 158. This polymorphism has lower enzyme activity and has been tied to a slower breakdown of the catecholamines. A study of  Rwandan genocide  survivors indicated that carriers of the Val allele demonstrated the expected response relationship between the higher number of lifetime traumatic events and a lifetime diagnosis of PTSD. However, those with homozygotes for the Met/Met genotype demonstrated a high risk of lifetime PTSD independent of the number of traumatic experiences. Those with Met/Met genotype also demonstrated a reduced extinction of conditioned fear responses which may account for the high risk for PTSD experienced by this genotype. [ 1 ]


Many genes impact the limbic-frontal neurocircuitry as a result of its complexity. The main effect of the D2A1 allele of the  dopamine receptor D2  ( DRD2 )  gene has a strong association with the diagnosis of PTSD. The D2A1 allele has also shown a significant association to PTSD in those having engaged in harmful drinking. In addition, a polymorphism in the  dopamine transporter   SLC6A3  gene has a significant association with chronic PTSD. A polymorphism of the  serotonin receptor  2A gene has been associated with PTSD in Korean women. The short allele of the promoter region of the  serotonin transporter  (5-HTTLPR) has been shown to be less efficient than the long allele and is associated with the  amygdala  response for the extinction of fear conditioning. However, the short allele is associated with a decreased risk of PTSD in a low-risk environment, but a high risk of PTSD in a high-risk environment. The s/s genotype demonstrated a high risk for the development of PTSD even in response to a small number of traumatic events, but those with the l allele demonstrate increased rates of PTSD with increasing traumatic experiences. [ 1 ]


A  genome-wide association study  (GWAS) offers an opportunity to identify novel risk variants for PTSD that will in turn inform our understanding of the  etiology  of the disorder. Early results indicate the feasibility and potential power of GWAS to identify  biomarkers  for anxiety-related behaviors that suggest a future of PTSD. These studies will lead to the discovery of novel loci for the susceptibility and symptomatology of anxiety disorders including PTSD. [ dubious  –  discuss ] [ 1 ]


Epigenetic  modification is an environmentally induced change in DNA that alters a gene's function rather than its structure. Its biological mechanism typically involves the  methylation  of  cytosine  within a gene, which leads to decreased  transcription  and thus reduced expression of the gene. Epigenetic modification can offer insight into the importance of developmental timing of stressor exposure in producing the phenotypic changes associated with PTSD. [ 1 ]


Neuroendocrine  alterations seen in animal models parallel those of PTSD in humans, where low basal  cortisol  and enhanced suppression of cortisol in response to synthetic  glucocorticoid  becomes  hereditary . Lower levels of glucocorticoid receptor (GR) mRNA have been demonstrated in the  hippocampus  of suicide victims with histories of childhood abuse. Although it has not been possible to monitor the state of methylation over time, the interpretation is that early developmental methylation changes are long-lasting and enduring. It is hypothesized that epigenetic-mediated changes in the  HPA axis  could be associated with an increased vulnerability to PTSD following traumatic events. These findings support the mechanism in which early life trauma strongly validates as a risk factor for PTSD development in adulthood by recalibrating the set point and stress-responsivity of the HPA axis. [ 1 ]


Epigenetic mechanisms may also be relevant to the intrauterine environment. Pregnant mothers who developed PTSD from the 9/11 attacks produced infants with lower salivary cortisol levels, but only if the traumatic exposure occurred during the third trimester of gestation. These changes occur via transmission of hormonal responses to the fetus, leading to a reprogramming of the glucocorticoid responsivity in the offspring. [ 1 ]  Separate studies have reported an increased risk for PTSD and low cortisol levels in the offspring of female  Holocaust  survivors with PTSD. [ 1 ]


Evolutionary psychology  interprets fear responses as  adaptations  that may have been useful in the ancestral environment to avoid or cope with various threats. In general,  mammals  display several defensive behaviors roughly dependent on how close the threat is: avoidance, vigilant immobility, withdrawal, aggressive defense, appeasement, and finally complete frozen immobility (the last possibly to confuse a predator's attack reflex or to simulate a dead and contaminated body). PTSD may correspond to and be caused by overactivation of such fear circuits. Thus, PTSD avoidance behaviors may correspond to mammal avoidance of and withdrawal from threats. Heightened memory of past threats may increase avoidance of similar situations in the future as well as be a prerequisite for analyzing the past threat and develop better defensive behaviors if the threat should recur. PTSD  hyperarousal  may correspond to vigilant immobility and aggressive defense.  Complex post-traumatic stress disorder  (and phenomena such as the  Stockholm syndrome ) may in part correspond to the appeasement stage and possibly the frozen immobility stage. [ 16 ] [ 17 ]


There may be evolutionary explanations for differences in resilience to traumatic events. For instance, PTSD is five to ten times less common following traumatic fires than physical abuse or combat. This may be explained by events such as forest fires long being part of the evolutionary history of mammals. [ 18 ]  In contrast, PTSD is much more common following modern warfare, perhaps because prolonged modern combat is an evolutionarily new development and very unlike the quick inter-group raids that are argued to have characterized the  Paleolithic . [ 19 ] [ 20 ]


The  genetic mechanism of  synesthesia  has long been debated, with researchers previously claiming it was a single  X-linked trait  due to seemingly higher prevalence in women and no evidence of male-male transmission  [ 1 ]  This is where the only synesthetic parent is male and the male child has synesthesia, [ 2 ] [ 3 ]  meaning that the trait cannot be solely linked to the  X chromosome .


The  Mendelian  nature of the trait was further disproven when case studies showed that the  Phenotype  of synesthesia could be differentially expressed in monozygotic (genotypically identical) twins  [ 4 ]  While both twins had the same genome with the potential for phenotypic expression of synesthesia, only one had documented synesthesia. Therefore, the condition is now thought to be  oligogenic , with  Locus heterogeneity  and multiple forms of inheritance, and expression, [ 5 ]  implying that synesthesia is determined by more than one gene, more than one location in those genes, and a complex mode of inheritance. Several full genome  linkage scans  have shown particular areas of the genome whose inheritance seem to correlate with the inheritance of synesthesia.


Using the  LOD score  which describes the likelihood that two genes are near each other on a chromosome, and thus will be inherited together, areas of  strong or suggestive linkage  with inheritance of synesthesia were found. [ 6 ]  The area with the highest LOD score in the genome of an individual with auditory-visual synesthesia has been shown to be linked with autism as well, [ 7 ]  another disorder with sensory and perceptual abnormalities. Other regions of linkage include genes that are related to the development of the cerebral cortex (TBR1), dyslexia, and apoptosis (EFHC1), [ 8 ]  the last of which could be potentially related to the retention of the neonatal synesthetic pathways in the universal synesthesia/pruning hypothesis. This hypothesis posits that every person is born a synesthete and the ‘extra’ connections are pruned during normal neurodevelopment in non-synesthetes, and not pruned in synesthetes. [ 9 ]


More potential support for that hypothesis comes from another region identified with strong linkage, which contains a gene (DPYSL3) which is involved in  axonal  growth,  neuroplasticity , and neuronal  differentiation . [ 10 ]  Additionally, this gene is not expressed in the adult brain but is highly expressed in the late-fetal and early post-natal brain and spinal cord, providing more support for a universal “neonatal synesthesia” that is pruned away through natural development. [ 11 ]


Another genome scan  [ 12 ]  revealed a different area of linkage for an individual with colored sequence synesthesia: one which associates days of the week with colors. In that individual, the linked region contained genes that produces proteins important for intercellular communication (GABARAPL2), genes that are involved in brain development (NDRG4), genes linked to neuron  myelination  (PLLP), genes that produce enzymes involved in  neuronal pruning  (KATNB1), genes that produce  Apoptosis  inhibitors expressed in fetal brains (CIAPIN1), and genes that produce proteins that have differential expression in individuals with schizophrenia (GNAO1).


Due to the prevalence of synesthesia among the first-degree relatives of synesthetes, [ 13 ]  there is evidence that synesthesia might have a genetic basis, however the monozygotic twins case studies indicate there is an  epigenetic  component. Synesthesia might also be an  oligogenic  condition, with  Locus heterogeneity , multiple forms of inheritance (including Mendelian in some cases), and continuous variation in gene expression.


Genevestigator  is an application consisting of a gene expression database and tools to analyse the data. It exists in two versions, biomedical and plant, depending on the species of the underlying  microarray  and  RNAseq  as well as  single-cell RNA-sequencing  data. It was started in January 2004 by scientists from  ETH Zurich  and is currently developed and commercialized by Nebion AG.


Researchers and scientists from academia and industry use it to identify, characterize and validate novel drug targets and biomarkers, identify appropriate research models and in general to understand how gene expression changes with different treatments.


The Genevestigator database comprises transciptomic data from numerous public repositories including  GEO , Array Express and renowned cancer research projects as  TCGA . Depending on the license agreement, it may also contain data from private gene expression studies. All data are manually curated, quality-controlled and enriched for sample and experiment descriptions derived from corresponding scientific publications.


The number of species from where the samples are derived is constantly increasing. Currently, the biomedical version contains data from  human ,  mouse , and  rat  used in biomedical research. Gene expression studies are from various research areas including oncology, immunology, neurology, dermatology and cardiovascular diseases. Samples comprise tissue biopsies and cell lines.


The plant version (no longer available) contained both, widely used model species such as  arabidopsis  and  medicago  as well as major crop species such as  maize ,  rice ,  wheat  and  soybean . After the acquisition of Nebion AG by Immunai Inc. in July 2021, plant data began to be phased out as the biotech company prioritized their focus on biopharma data. As of 2023, the plant data is being maintained on a separate server for remaining users with a license to the plant version of Genevestigator.


More than 60,000 scientists from academia and industry use Genevestigator for their work in  molecular biology ,  toxicogenomics ,  biomarker  discovery and target validation. The original scientific publication has been cited over 3,500 times.


The analysis tools are divided into three major sets:


Genome-wide CRISPR-Cas9 knockout screens  aim to elucidate the relationship between genotype and phenotype by ablating gene expression on a genome-wide scale and studying the resulting phenotypic alterations. The approach utilises the  CRISPR-Cas9  gene editing system, coupled with libraries of  single guide RNAs (sgRNAs) , which are designed to target every gene in the genome. Over recent years, the genome-wide CRISPR screen has emerged as a powerful tool for performing large-scale loss-of-function screens, with low noise, high knockout efficiency and minimal off-target effects.


Early studies in  Caenorhabditis elegans [ 1 ]  and  Drosophila melanogaster [ 2 ] [ 3 ]  saw large-scale, systematic  loss of function  (LOF) screens performed through  saturation mutagenesis , demonstrating the potential of this approach to characterise genetic pathways and identify genes with unique and essential functions. The saturation mutagenesis technique was later applied in other organisms, for example zebrafish [ 4 ] [ 5 ]  and mice. [ 6 ] [ 7 ]


Targeted approaches for gene knockdown emerged in the 1980s with techniques such as  homologous recombination , [ 8 ] [ 9 ]   trans-cleaving ribozymes , [ 10 ] [ 11 ]  and  antisense technologies . [ 12 ] [ 13 ]


By the year 2000,  RNA interference  (RNAi) technology had emerged as a fast, simple, and inexpensive technique for targeted  gene knockdown , and was routinely being used to study  in vivo  gene function in  C. elegans . [ 14 ] [ 15 ] [ 16 ] [ 17 ]  Indeed, in the span of only a few years following its discovery by Fire  et al . (1998), [ 18 ]  almost all of the ~19,000 genes in  C. elegans  had been analysed using  RNAi-based knockdown . [ 19 ]


The production of RNAi libraries facilitated the application of this technology on a genome-wide scale, and RNAi-based methods became the predominant approach for genome-wide knockdown screens. [ citation needed ]


Nevertheless, RNAi-based approaches to genome-wide knockdown screens have their limitations. For one, the high off-target effects cause issues with false-positive observations. [ 20 ] [ 21 ]  Additionally, because RNAi reduces gene expression at the post-transcriptional level by targeting RNA, RNAi-based screens only result in partial and short-term suppression of genes. Whilst partial knockdown may be desirable in certain situations, a technology with improved targeting efficiency and fewer off-target effects was needed. [ citation needed ]


Since initial identification as a prokaryotic adaptive immune system, [ 22 ]  the bacterial type II  clustered regularly interspaced short palindrome repeats (CRISPR) / Cas9  system has become a simple and efficient tool for generating targeted LOF mutations. [ 23 ]  It has been successfully applied to edit human genomes, and has started to displace RNAi as the dominant tool in mammalian studies. [ 24 ]  In the context of genome-wide knockout screens, recent studies have demonstrated that CRISPR/Cas9 screens are able to achieve highly efficient and complete protein depletion, and overcome the off-target issues seen with RNAi screens. [ 25 ] [ 26 ]  In summary, the recent emergence of CRISPR-Cas9 has dramatically increased our ability to perform large-scale LOF screens. The versatility and programmability of Cas9, coupled with the low noise, high knockout efficiency and minimal off-target effects, have made CRISPR the platform of choice for many researchers engaging in gene targeting and editing. [ 24 ] [ 27 ]


The  clustered regularly interspaced short palindrome repeats (CRISPR) / Cas9  system is a gene-editing technology that can introduce  double-strand breaks (DSBs)  at a target genomic locus. By using a  single guide RNA (sgRNA) , the  endonuclease  Cas9 can be delivered to a specific DNA sequence where it cleaves the nucleotide chain. [ 28 ]  The specificity of the sgRNA is determined by a 20-nt sequence, homologous to the genomic locus of interest, and the binding to Cas9 is mediated by a constant scaffold region of the sgRNA. The desired target site must be immediately followed (5’ to 3’) by a conserved 3 nucleotide  protospacer adjacent motif  (PAM). [ 29 ] [ 30 ]  In order to repair the DSBs, the cell may use the highly error prone  non-homologous end joining , or  homologous recombination . By designing suitable sgRNAs, planned insertions or deletions can be introduced into the genome. In the context of genome-wide LOF screens, the aim is to cause gene disruption and knockout. [ citation needed ]


To perform CRISPR knockouts on a genome-wide scale, collections of sgRNAs known as sgRNA libraries, or CRISPR knockout libraries, must be generated. The first step in creating a sgRNA library is to identify genomic regions of interest based on known sgRNA targeting rules. [ 31 ]  For example, sgRNAs are most efficient when targeting the coding regions of genes and not the 5’ and 3’  UTRs . Conserved exons present as attractive targets, and position relative to the transcription start site should be considered. [ 31 ]  Secondly, all the possible PAM sites are identified and selected for. [ 31 ]  On- and off-target activity should be analysed, as should GC content, and homopolymer stretches should be avoided. [ 31 ]  The most commonly used Cas9 endonuclease, derived from  Streptococcus pyogenes , recognises a PAM sequence of NGG. [ 32 ]


Furthermore, specific nucleotides appear to be favoured at specific locations. Guanine is strongly favoured over cytosine on position 20 right next to the PAM motif, and on position 16 cytosine is preferred over guanine. [ 33 ]  For the variable nucleotide in the NGG PAM motif, it has been shown that cytosine is preferred and thymine disfavoured. [ 33 ]  With such criteria taken into account, the sgRNA library is computationally designed around the selected PAM sites. [ 31 ] [ 33 ] [ 34 ]


Multiple sgRNAs (at least 4–6) should be created against every single gene to limit false-positive detection, and negative control sgRNAs with no known targets should be included. [ 31 ] [ 33 ]  The sgRNAs are then created by  in situ  synthesis, amplified by PCR, and cloned into a vector delivery system.


Developing a new sgRNA library is a laborious and time-consuming process. In practice, researchers may select an existing library depending on their experimental purpose and cell lines of interest.
As of February 2020, the most widely used resources for genome-wide CRISPR knockout screens have been the two  Genome-Scale CRISPR Knock-Out (GeCKO)  libraries created by the Zhang lab. [ 35 ]  Available through Addgene, these lentiviral libraries respectively target human and mouse exons, and both are available as a one-vector system (where the sgRNAs and Cas9 are present on the same plasmid) or as a two-vector system (where the sgRNAs and Cas9 are present on separate plasmids). Each library is delivered as two half-libraries, allowing researchers to screen with 3 or 6 sgRNAs/gene. [ 36 ]


Aside from GeCKO, a number of other CRISPR libraries have been generated and made available through Addgene. The Sabatini & Lander labs currently have 7 separate human and mouse libraries, including targeted sublibraries for distinct subpools such as kinases and ribosomal genes (Addgene #51043–51048). Further, improvements to the specificity of sgRNAs have resulted in ‘second generation’ libraries, such as the Brie (Addgene #73632) and Brunello (Addgene #73178) libraries generated by the Doench and Root labs, and the Toronto knockout (TKO) library (Addgene #1000000069) generated by the Moffat lab. [ 36 ]


Targeted gene knockout using CRISPR/Cas9 requires the use of a delivery system to introduce the sgRNA and Cas9 into the cell. Although a number of different delivery systems are potentially available for CRISPR, [ 37 ] [ 38 ]  genome-wide loss-of-function screens are predominantly carried out using third generation lentiviral vectors. [ 35 ] [ 39 ] [ 40 ]  These  lentiviral vectors  are able to efficiently transduce a broad range of cell types and stably integrate into the genome of dividing and non-dividing cells. [ 41 ] [ 42 ]
Third generation lentiviral particles are produced by co-transfecting 293T human embryonic kidney (HEK) cells with:


The lentiviral particle-containing supernatant is harvested, concentrated and subsequently used to infect the target cells. [ 45 ]  The exact protocol for lentiviral production will vary depending on the research aim and applied library. [ 35 ] [ 43 ] [ 44 ]  If a two vector-system is used, for example, cells are sequentially transduced with Cas9 and sgRNA in a two-step procedure. [ 35 ] [ 44 ]  Although more complex, this has the advantage of a higher titre for the sgRNA library virus. [ 35 ]


In general, there are two different formats of genome-wide CRISPR knockout screens: arrayed and pooled. In an arrayed screen, each well contains a specific and known sgRNA targeting a specific gene. [ 46 ]  Since the sgRNA responsible for each phenotype is known based on well location, phenotypes can be identified and analysed without requiring genetic sequencing. This format allows for the measurement of more specific cellular phenotypes, perhaps by fluorescence or luminescence, and allows researchers to use more library types and delivery methods. [ 46 ]  For large-scale LOF screens, however, arrayed formats are considered low-efficiency, and expensive in terms of financial and material resources because cell populations have to be isolated and cultured individually. [ 46 ]


In a pooled screen, cells grown in a single vessel are transduced in bulk with viral vectors collectively containing the entire sgRNA library. To ensure that the amount of cells infected by more than one sgRNA-containing particle is limited, a low multiplicity of infection (MOI) (typically 0.3-0.6) is used. [ 46 ] [ 47 ]  Evidence so far has suggested that each sgRNA should be represented in a minimum of 200 cells. [ 48 ] [ 23 ]  Transduced cells will be selected for, followed by positive or negative selection for the phenotype of interest, and genetic sequencing will be necessary to identify the integrated sgRNAs. [ 46 ]


Following phenotypic selection, genomic DNA is extracted from the selected clones, alongside a control cell population. [ 23 ] [ 46 ] [ 49 ]  In the most common protocols for genome-wide knockouts, a 'Next-generation sequencing (NGS) library' is created by a two step polymerase chain reaction (PCR). [ 23 ] [ 46 ]  The first step amplifies the sgRNA region, using primers specific to the lentiviral integration sequence, and the second step adds Illumina i5 and i7 sequences. [ 23 ]  NGS of the PCR products allows the recovered sgRNAs to be identified, and a quantification step can be used to determine the relative abundance of each sgRNA. [ 23 ]


The final step in the screen is to computationally evaluate the significantly enriched or depleted sgRNAs, trace them back to their corresponding genes, and in turn determine which genes and pathways could be responsible for the observed phenotype. Several algorithms are currently available for this purpose, with the most popular being the Model-based Analysis of Genome-wide CRISPR/Cas9 Knockout (MAGeCK) method. [ 50 ]  Developed specifically for CRISPR/Cas9 knockout screens in 2014, MAGeCK demonstrated better performance compared with alternative algorithms at the time, [ 50 ]  and has since demonstrated robust results and high sensitivity across different experimental conditions. [ 51 ]  As of 2015, the MAGeCK algorithm has been extended to introduce quality control measurements, and account for the previously overlooked sgRNA knockout efficiency. [ 51 ]  A web-based visualisation tool (VISPR) was also integrated, allowing users to interactively explore the results, analysis, and quality controls. [ 51 ]


Over recent years, the genome-wide CRISPR screen has emerged as a powerful tool for studying the intricate networks of cellular signaling. [ 52 ]  Cellular signaling is essential for a number of fundamental biological processes, including cell growth, proliferation, differentiation, and  apoptosis .


One practical example is the identification of genes required for proliferative signaling in cancer cells. Cells are transduced with a CRISPR sgRNA library, and studied for growth over time. By comparing sgRNA abundance in selected cells to a control, one can identify which sgRNAs become depleted and in turn which genes may be responsible for the proliferation defect. Such screens have been used to identify cancer-essential genes in  acute myeloid leukemia [ 53 ]  and  neuroblastoma , [ 54 ]  and to describe tumor-specific differences between cancer cell lines. [ 55 ]


Targeted cancer therapies  are designed to target the specific genes, proteins, or environments contributing to tumor cell growth or survival. After a period of prolonged treatment with these therapies, however, tumor cells may develop resistance. Although the mechanisms behind cancer drug resistance are poorly understood, potential causes include: target alteration, drug degradation, apoptosis escape, and epigenetic alterations. [ 56 ]  Resistance is well-recognised and poses a serious problem in cancer management. [ citation needed ]


To overcome this problem, a  synthetic lethal  partner can be identified. Genome-wide LOF screens using CRISPR-Cas9 can be used to screen for synthetic lethal partners. [ 57 ]  For this, a wild-type cell line and a tumor cell line containing the resistance-causing mutation are transduced with a CRISPR sgRNA library. The two cell lines are cultivated, and any under-represented or dead cells are analyzed to identify potential synthetic lethal partner genes. A recent study by Hinze  et al.  (2019) [ 58 ]  used this method to identify a synthetic lethal interaction between the chemotherapy drug  asparaginase  and two genes in the  Wnt signalling pathway  NKD2 and LGR6.


Due to their small genomes and limited number of encoded proteins, viruses exploit host proteins for entry, replication, and transmission. Identification of such host proteins, also termed host dependency factors (HDFs), is particularly important for identifying therapeutic targets. Over recent years, many groups have successfully used genome-wide CRISPR/Cas9 as a screening strategy for HDFs in viral infections. [ 59 ]


One example is provided by Marceau  et al.  (2017), [ 60 ]  who aimed to dissect the host factors associated with  dengue  and  hepatitis C  (HCV) infection (two viruses in family  Flaviviridae ).  ELAVL1 , an RNA-binding protein encoded by the ELAVL1 gene, was found to be a critical receptor for HCV entry, and a remarkable divergence in host dependency factors was demonstrated between the two flaviviridae. [ 60 ]


Additional reported applications of genome-wide CRISPR screens include the study of: mitochondrial metabolism, [ 61 ]  bacterial toxin resistance, [ 62 ]  genetic drivers of metastasis, [ 63 ]  cancer drug resistance, [ 64 ]  West Nile virus-induced cell death, [ 65 ]  and immune cell gene networks. [ 66 ] [ 67 ]


This section will specifically address genome-wide CRISPR screens. For a review of CRISPR limitations see Lino et al. (2018) [ 38 ]


Genome-wide CRISPR screens will ultimately be limited by the properties of the chosen sgRNA library. Each library will contain a different set of sgRNAs, and average coverage per gene may vary. Currently available libraries tend to be biased towards sgRNAs targeting early (5’) protein-coding exons, rather than those targeting the more functional protein domains. [ 58 ]  This problem was highlighted by Hinze  et al.  (2019), [ 58 ]  who noted that genes associated with  asparaginase  sensitivity failed to score in their genome-wide screen of asparaginase-resistant leukemia cells.


If an appropriate library is not available, creating and amplifying a new sgRNA library is a lengthy process which may take many months. Potential challenges include: (i) effective sgRNA design; (ii) ensuring comprehensive sgRNA coverage throughout the genome; (iii) lentiviral vector backbone design; (iv) producing sufficient amounts of high-quality lentivirus; (v) overcoming low transformation efficiency; (vi) proper scaling of the bacterial culture. [ 68 ]


One of the largest hurdles for genome-wide CRISPR screening is ensuring adequate coverage of the sgRNA library across the cell population. [ 23 ]  Evidence so far has suggested that each sgRNA should be represented and maintained in a minimum of 200-300 cells. [ 23 ] [ 48 ]


Considering that the standard protocol uses a multiplicity of infection of ~0.3, and a transduction efficiency of 30-40% [ 44 ] [ 23 ]  the number of cells required to produce and maintain suitable coverage becomes very large. By way of example, the most popular human sgRNA library is the  GeCKO v2 library  created by the Zhang lab; [ 30 ]  it contains 123,411 sgRNAs. Studies using this library commonly transduce more than 1x10 8  cells  [ 58 ] [ 59 ] [ 69 ]


As CRISPR continues to exhibit low noise and minimal off-target effects, an alternative strategy is to reduce the number of sgRNAs per gene for a primary screen. Less stringent cut-offs are used for hit selection, and additional sgRNAs are later used in a more specific secondary screen. This approach is demonstrated by Doench  et al . (2016), [ 33 ]  who found that >92% of genes recovered using the standard protocol were also recovered using fewer sgRNAs per gene. They suggest that this strategy could be useful in studies where scale-up is prohibitively costly. [ citation needed ]


Lentiviral vectors have certain general limitations. For one, it is impossible to control where the viral genome integrates into the host genome, and this may affect important functions of the cell. Vannucci  et al. [ 70 ]  provide an excellent review of viral vectors along with their general advantages and disadvantages. In the specific context of genome-wide CRISPR screens, producing and transducing the lentiviral particles is relatively laborious and time-consuming, taking about two weeks in total. [ 44 ]  Additionally, because the DNA integrates into the host genome, lentiviral delivery leads to long-term expression of Cas9, potentially leading to off-target effects. [ citation needed ]


In an arrayed screen, each well contains a specific and known sgRNA targeting a specific gene. Arrayed screens therefore allow for detailed profiling of a single cell, but are limited by high costs and the labour required to isolate and culture the high number of individual cell populations. [ 46 ]  Conventional pooled CRISPR screens are relatively simple and cost effective to perform, but are limited to the study of the entire cell population. This means that rare phenotypes may be more difficult to identify, and only crude phenotypes can be selected for e.g. cell survival, proliferation, or reporter gene expression. [ citation needed ]


The choice of  culture medium  might affect the physiological relevance of findings from cell culture experiments due to the differences in the nutrient composition and concentrations. [ 71 ]  A systematic bias in generated datasets was recently shown for  CRISPR  and  RNAi   gene silencing  screens (especially for metabolic genes), [ 72 ]  and for metabolic profiling of cancer  cell lines . [ 71 ]  For example, a stronger dependence on  ASNS  (asparagine synthetase) was found in cell lines cultured in  DMEM , which lacks asparagine, compared to cell lines cultured in  RPMI  or F12 (containing asparagine). [ 72 ]  Avoiding such bias might be achieved by using a uniform media for all screened cell lines, and ideally, using a  growth medium  that better represents the physiological levels of nutrients. Recently, such media types, as Plasmax [ 73 ]  and Human Plasma Like Medium (HPLM), [ 74 ]  were developed.


Emerging technologies are aiming to combine pooled CRISPR screens with the detailed resolution of massively parallel  single-cell RNA-sequencing (RNA-seq) . Studies utilising “CRISP-seq”, [ 75 ]  “CROP-seq”, [ 76 ]  and “PERTURB-seq” [ 77 ]  have demonstrated rich genomic readouts, accurately identifying gene expression signatures for individual gene knockouts in a complex pool of cells. These methods have the added benefit of producing transcriptional profiles of the sgRNA-induced cells. [ 78 ]


Genomic convergence  is a multifactor approach used in genetic  research  that combines different kinds of genetic  data  analysis to identify and prioritize susceptibility  genes  for a complex  disease .


In January 2003, Michael Hauser along with fellow researchers at the Duke Center for Human Genetics (CHG) coined the term “genomic convergence” to describe their endeavor to identify genes affecting the expression of  Parkinson disease (PD) . Their work successfully combined serial analysis of gene expression (SAGE) with genetic linkage analysis. The authors explain, “While both linkage and expression analyses are powerful on their own, the number of possible genes they present as candidates for  PD  or any complex disorder remains extremely large”. [ 1 ]  The convergence of the two methods allowed researchers to decrease the number of possible PD genes to consider for further study.


Their success prompted further use of the genomic convergence method at the CHG, and in July 2003 Yi-Ju Li,  et al.  published a paper revealing that glutathione S-transferase omega-1 (GSTO1) modifies the  age-at-onset (AAO)  of  Alzheimer disease (AD)  and PD. [ 2 ]


In May 2004, Dr.  Margaret Pericak-Vance , currently the director of the John P. Hussman Institute for Human Genomics at the University of Miami Miller School of Medicine and then the director of the CHG, articulated the value of the genomic convergence method at a New York Academy of Sciences (NYAS) keynote address entitled "Novel Methods in Genetic Exploration of Neurodegenerative Disease." She stated, "No single method is going to get us where we need to be with these  complex traits . It is going to take a combination of methods to dissect the underlying  etiology  of these disorders". [ 3 ]


Genomic convergence has a countless number of creative applications that combine the strengths of different analyses and studies. Maher Noureddine et al., note in their 2005 paper, “One of the growing problems in the study of complex diseases is how to prioritize research and make sense of the immense amount of  data  now readily available at the click of a computer mouse...The best approach may be to take advantage of the strengths of both…SAGE …and  microarrays ”. [ 4 ]


The results of combining methods of analysis have continued to be promising. Sofia Oliveira et al. (2005) combined gene expression, linkage data, and “iterative association mapping” to identify several genes associated with  PD   AAO . [ 5 ]


Future studies will continue to apply genomic convergence to elucidate the etiology of complex diseases. Dr. Jeff Vance, Director of the Morris K. Udall PD Research Center of Excellence, notes, “Genomic convergence is really no different from mathematical convergence – the more angles from which you can come at a problem, the better chance you have of solving it”. [ 6 ]


Genopolitics  is the study of the genetic basis of political behavior and attitudes. It combines  behavior genetics ,  psychology , and  political science  and it is closely related to the emerging fields of  neuropolitics  (the study of the neural basis of political attitudes and behavior) and political physiology (the study of biophysical correlates of political attitudes and behavior).


In 2008,  The Chronicle of Higher Education  reported on the increase in academicians' recognition of and engagement in genopolitics as a discrete field of study, [ 1 ]  and  New York Times Magazine  included genopolitics in its "Eighth Annual Year in Ideas" for the same year, noting that the term was originally coined by  James Fowler . [ 2 ]  Critics of genopolitics have argued that it is "a fundamentally misguided undertaking", and that it is inconsistent with evidence in the fields of  genetics ,  neuroscience , and  evolutionary biology . [ 3 ]


Psychologists and behavior geneticists began using twin studies in the 1980s to study variation in social attitudes, and these studies suggested that both genes and environment played a role. In particular,  Nick Martin  and his colleagues published an influential  twin study  of social attitudes in  Proceedings of the National Academy of Sciences  in 1986. [ 4 ]


However, this early work did not specifically analyze whether or not political orientations were heritable, and political scientists remained mostly unaware of the heritability of social attitudes until 2005.  In that year, the  American Political Science Review  published a reanalysis of political questions on Martin's social attitude survey of twins in that the suggested liberal and conservative ideology is heritable. [ 5 ]  The article sparked considerable debate between critics, the authors and their defenders. [ 6 ] [ 7 ] [ 8 ] [ 9 ] [ 10 ] [ 11 ]


A more recent analysis of multiple twin studies finds that political views are approximately 40 percent heritable.  [ 12 ]


Initial twin studies suggested that predispositions toward espousal of certain political ideas are heritable, but they said little about political behavior (patterns of voting and/or activism) or predispositions toward it. A 2008 article published in the  American Political Science Review  matched publicly available voter registration records to a  twin registry  in Los Angeles, analyzed self-reported  voter turnout  in the  National Longitudinal Study of Adolescent Health  (Add Health), and studied other forms of  political participation . In all three cases, both genes and environment contributed significantly to variation in political behavior. [ 13 ]


However, other studies showed that the decision to affiliate with any political party and the strength of this attachment are significantly influenced by genes. [ 14 ] [ 15 ]


Scholars therefore recently turned their attention to specific genes that might be associated with political behaviors and attitudes. In the first-ever research to link specific genes to political phenotypes, a direct association was established between voter turnout and monoamine oxidase A (MAO-A) and a gene–environment interaction between turnout and the serotonin transporter (5HTT) gene among those who frequently participated in religious activities. [ 16 ]  In other research scholars have also found an association between voter turnout and a dopamine receptor (DRD2) gene that is mediated by a significant association between that gene and the tendency to affiliate with a political party. [ 17 ] [ clarification needed ]  More recent studies show an interaction between friendships and the dopamine receptor (DRD4) gene that is associated with political ideology. [ 18 ]  Although this work is preliminary and needs replication, it suggests that neurotransmitter function has an important effect on political behavior.


The candidate genes approach to genopolitics received substantial criticism in a 2012 article, published in the  American Political Science Review , which argued that many of the candidate genes identified in the above research are associated with innumerable traits and behaviors. The degree to which these genes are associated with so many outcomes thus undermines the apparent important of evidence linking a gene to any particular outcome. [ 19 ]


Employing a more general approach, researchers used genome-wide  linkage  analysis to identify chromosomal regions associated with political attitudes assessed using scores on a liberalism-conservativism scale. [ 20 ]  Their analysis identified several significant linkage peaks and the associated chromosomal regions implicate a possible role for NMDA and glutamate related receptors in forming political attitudes. However, this role is speculative as linkage analysis cannot identify the effect of individual genes.


Associations between genetic markers and political behavior are often assumed to predict a causal connection between the two. Scholars have little incentive to be skeptical of this presumed causal link. Yet it is possible that a confounding factor exists which makes the genetic relationship with politics purely correlative. For instance work on Irish parties, which shows some evidence of a genetic basis for the otherwise inexplicable distinction between the historically two main parties there, is also and more easily explained by socialization. [ 21 ]


Genotropism  is defined as the reciprocal attraction between carriers of the same or related latent recessive  genes . [ 1 ]  Developed by the Hungarian psychiatrist  Léopold Szondi  in the 1930s, the theory concludes that  instinct  is biological and  genetic  in origin. Szondi believed that these genes regulated the "possibilities of fate" and was the working principle of the familial  unconscious .


Genotropism consists of the theory that  genes  influence human  behavior . While identified as entities, genes exist in groups because  evolution  favors cooperation. Within each gene group, it is possible to detect specific needs that function as mechanisms of  screening  and  natural selection .


Szondi arrived a sort of genetic determinism, a philosophical theory of predestination. "The latent hereditary factors in human beings, the recessive genes, do not remain dormant or inactive within the human organism, but exert a very important and even decisive influence upon its behavior. This latent or recessive gene theory claims that these non-dominant hereditary factors determine the Object selection, voluntary and involuntary, of the individual. The drives resulting from these latent genes, therefore, direct the individual's selection of love objects, friendships, occupations, diseases, and forms of death. Hence, from the very beginning of the human's existence there is a hidden plan of life guided by 'Instinctual drives'." [ 2 ]


In Szondi's theory, each "need" (a link between genes and behavior) comprises a polarity of positive and negative tendencies. Needs also group together in polarities to form larger wholes called "instinctual drives." Together, behavior tendencies, needs, and drives combine to form patterned wholes.


Szondi created a drive theory that determines that every drive has at least four genes. "The four Szondian drives are (1) contact, (2) sexual, (3) paroxysmal, and (4) ego. They are implicated in their corresponding psychiatric disorders and equivalents: (1) manic-depression, (2) sexual abnormality, (3) epilepsy and hysteria, and (4) schizophrenia." [ 3 ]  By locating mental disorders in biological drives, one can illustrate that illness is a disharmony of basic needs.


Genotropism is the working principle of the familial unconscious, the quantitative sharing of genes across the generations of family. Offspring may inherit several genes from both parents, while others receive fewer genes and exhibit spectrum conditions. (For example, while one child is diagnosed with epilepsy, the other only shows various symptoms over a period of time).


Szondi observed that when families pass down genes for specific diseases, the same family transmits defenses against those disorders. Known to Szondi as  heterosis , it is currently known as "balancing selection."


Szondi concluded that genetic traits confer needs and tendencies that shape decision making. "Genetic tendencies can be decoded by constructing genealogies, indicating recurrent patterns of marriage, friendship, and vocational choices in relation to types of illness and modes of death.  Destiny  comprises all of the hereditary tendencies in the familial unconscious which are expressed primarily through marriage and vocational selections." [ 1 ]  Basically, the needs and tendencies in which humans exhibit will guide similar genes to one another.


While Szondi accepted the  Oedipus  complex, he found that it existed only under the following conditions: when the mother sees her father or brother represented in her son, or when the father sees his mother or sister in his daughter. Therefore, the son takes after the genes represented in his maternal grandfather or uncles, and the daughter after her paternal grandmother or aunt. [ 4 ]


Although it was mostly abandoned by psychologists in the years after Szondi's death, recent discoveries in  evolutionary psychology  might be bringing it back in a revised form, through the study of  homogamy  and  psychopathology .


The  genotype–phenotype distinction  is drawn in  genetics . The " genotype " is an organism's full  hereditary  information. The " phenotype " is an organism's actual observed properties, such as  morphology ,  development , or  behavior . This distinction is fundamental in the study of  inheritance  of  traits  and their  evolution .


The terms "genotype" and "phenotype" were created by  Wilhelm Johannsen  in 1911, [ 2 ]  although the meaning of the terms and the significance of the distinction have evolved since they were introduced. [ 3 ]


It is the organism's physical properties that directly determine its chances of survival and reproductive output, but the inheritance of physical properties is dependent on the inheritance of genes. Therefore, understanding the theory of evolution via  natural selection  requires understanding the genotype–phenotype distinction. The genes contribute to a trait, and the phenotype is the observable manifestation of the genes (and therefore the genotype that affects the trait). If a white mouse had recessive genes that caused the genes responsible for color to be inactive, its genotype would be responsible for its phenotype (the white color). [ citation needed ]


The  mapping  of a set of genotypes to a set of phenotypes is sometimes referred to as the  genotype–phenotype map . [ 4 ]


An organism's genotype is a major (the largest by far for  morphology ) influencing factor in the development of its phenotype, but it is not the only one. Even two organisms with identical genotypes may differ in their phenotypes, due to  phenotypic plasticity . To what extent a particular genotype influences a phenotype depends on the relative  dominance ,  penetrance , and  expresivity  of the alleles in question.


One experiences this in everyday life with  monozygous (i.e. identical) twins . Identical twins share the same genotype, since their genomes are identical; but they never have the same phenotype, although their phenotypes may be very similar. This is apparent in the fact that close relations can always tell them apart, even though others might not be able to see the subtle differences. Further, identical twins can be distinguished by their  fingerprints , which are never completely identical. [ citation needed ]


The concept of  phenotypic plasticity  defines the degree to which an organism's phenotype is determined by its genotype. A high level of plasticity means that  environmental factors  have a strong influence on the particular phenotype that develops. If there is little plasticity, the phenotype of an organism can be reliably predicted from knowledge of the genotype, regardless of  environmental  peculiarities during development. An example of high plasticity can be observed in  larval   newts 1 : when these larvae sense the presence of  predators  such as  dragonflies , they develop larger heads and tails relative to their body size and display darker  pigmentation . Larvae with these traits have a higher chance of  survival  when exposed to the predators, but grow more slowly than other phenotypes. [ citation needed ]


In contrast to phenotypic plasticity, the concept of  genetic canalization  addresses the extent to which an organism's phenotype allows conclusions about its genotype. A phenotype is said to be canalized if  mutations  (changes in the genome) do not noticeably affect the physical properties of the organism. This means that a canalized phenotype may form from a large variety of different genotypes, in which case it is not possible to exactly predict the genotype from knowledge of the phenotype (i.e. the genotype–phenotype map is not invertible). If canalization is not present, small changes in the genome have an immediate effect on the phenotype that develops.


According to  Lewontin , [ 5 ]  the theoretical task for population genetics is a process in two spaces: a "genotypic space" and a "phenotypic space". The challenge of a  complete  theory of population genetics is to provide a set of laws that predictably map a population of  genotypes  ( G 1 ) to a  phenotype  space ( P 1 ), where  selection  takes place, and another set of laws that map the resulting population ( P 2 ) back to genotype space ( G 2 ) where  Mendelian  genetics can predict the next generation of genotypes, thus completing the cycle. Even if non-Mendelian aspects of  molecular genetics  are ignored, this is a gargantuan task. Visualizing the transformation schematically:


(adapted from Lewontin 1974, p. 12).  T 1  represents the genetic and  epigenetic  laws, the aspects of functional biology, or  development , that transform a genotype into phenotype. This is the " genotype–phenotype map ".  T 2  is the transformation due to natural selection,  T 3  are epigenetic relations that predict genotypes based on the selected phenotypes and finally  T 4  the rules of Mendelian genetics.


In practice, there are two bodies of evolutionary theory that exist in parallel, traditional population genetics operating in the genotype space and the  biometric  theory used in  plant  and  animal breeding , operating in phenotype space. The missing part is the mapping between the genotype and phenotype space. This leads to a "sleight of hand" (as Lewontin terms it) whereby variables in the equations of one domain, are considered parameters or  constants , where, in a full-treatment, they would be transformed themselves by the evolutionary process and are  functions  of the state variables in the other domain. The "sleight of hand" is assuming that the mapping is known. Proceeding as if it is understood is enough to analyze many cases of interest. For example, if the phenotype is almost one-to-one with genotype ( sickle-cell disease ) or the time-scale is sufficiently short, the "constants" can be treated as such; however, there are also many situations where that assumption does not hold.


The  genotype–phenotype map  is a conceptual model in  genetic architecture . Coined in a 1991 paper by  Pere Alberch , [ 1 ]  it models the interdependency of  genotype  (an organism's full  hereditary  information) with  phenotype  (an organism's actual observed properties).


The map visualises a relationship between genotype & phenotype which, crucially: [ 2 ]


In the field of  genetic sequencing ,  genotyping by sequencing , also called  GBS , is a method to discover  single nucleotide polymorphisms  (SNP) in order to perform  genotyping  studies, such as genome-wide association studies ( GWAS ). [ 1 ]  GBS uses  restriction enzymes  to reduce genome complexity and genotype multiple DNA samples. [ 2 ]  After digestion,  PCR  is performed to increase fragments pool and then GBS libraries are sequenced using next generation sequencing technologies, usually resulting in about 100bp single-end reads. [ 3 ]  It is relatively inexpensive and has been used in  plant breeding . [ 2 ]  Although GBS presents an approach similar to  restriction-site-associated DNA sequencing  (RAD-seq) method, they differ in some substantial ways. [ 4 ] [ 5 ] [ 6 ]


GBS is a robust, simple, and affordable procedure for SNP discovery and mapping. Overall, this approach reduces genome complexity with restriction enzymes (REs) in high-diversity, large genomes species for efficient high-throughput, highly multiplexed sequencing. By using appropriate REs, repetitive regions of genomes can be avoided and lower copy regions can be targeted, which reduces alignments problems in genetically highly diverse species. The method was first described by Elshire et al. (2011). [ 1 ]  In summary, high  molecular weight  DNAs are extracted and digested using a specific RE previously defined by cutting frequently [ 7 ]  in the major repetitive fraction of the genome.  ApeKI  is the most used RE. Barcode adapters are then ligated to  sticky ends  and  PCR amplification  is performed.  Next-generation sequencing technology is performed resulting in about 100 bp single-end reads. Raw sequence data are filtered and aligned to a reference genome using usually  Burrows–Wheeler  alignment tool (BWA) or  Bowtie 2 . The next step is to identify SNPs from aligned tags and score all discovered SNPs for various coverage, depth and genotypic statistics. Once a large-scale, species-wide SNP production has been run, it is possible to quickly call known SNPs in newly sequenced samples. [ 8 ]