The  BET  (Bromodomains and Extra Terminal) family of proteins contain conserved motifs known as bromodomains (BDs) responsible for recognizing  acetylated  lysine on nucleosomal  histones. [ 14 ]  Recently, four members of the BET family, BRD2, 3, 4, and BRDT, each containing two bromodomains, were identified as important regulators of transcription. [ 15 ]  In order to probe bromodomain-specific functions of members of the BET family, small-molecule inhibitors JQ1 and I-BET were developed, but they lacked inter- and intra-BET (between BDs on the same protein) selectivity. [ 16 ]  The lab of  Alessio Ciulli  produced bump-and-hole pairs consisting of ET, a derivative of I-BET with an ethyl bump, and different members of the BET family with an L94A mutation in their BD1. [ 13 ]  ET was found to have a 160-fold greater specificity for hole-modified BD1 of BET mutants compared to compared to the BDs of wild type BET proteins, giving BD-specific inhibition. The BD-ET bump-and-hole pairs were used to show that selective inhibition of BD1 in a BET protein disrupts chromatin engagement. Recently, the Ciulli group developed a new bump-and-hole pair consisting of BET mutants with a Leu to Val mutation in a BD and the bumped small-molecule inhibitor 9-ME-1. This bumped inhibitor was found to have an IC50 of 200nM and over 100-fold specificity for the L/V BET mutant BD over wild type BDs. This bump-and-hole pair allowed selective inhibition of specific BDs in specific BET proteins, elucidating their role in human cells. It was found that while BD1 is important for chromatin localization of BET proteins, BD2 regulates gene expression by binding and recruiting non-histone acetylated proteins, such as  transcription factors. [ 17 ]


Glycosidases  are a family of enzymes that catalyzes the hydrolysis of  glycosidic bonds . These enzymes can cleave glycans from  glycosylated  proteins, one of the most common forms of  post-translational modification . In a recent therapeutic application of the bump-and-hole method, a hole-modified  galactosidase  was paired with a bumped galactosyl-pro-drug. Jingli Hou and colleagues sought to deliver  nitric oxide , an important messenger for promoting tissue growth processes like  angiogenesis  and  vasculogenesis , in a spatiotemporally controlled manner. They opted for a  pro-drug  system, wherein the NO-releasing drug,  NONOate , is initially glycosylated. Once the glycosylated NONOate enters cells and is exposed to glycosidases, NO is released. However, non-tissue-specific systemic release of NO, which can reduce therapeutic efficiency and cause harmful side effects, from these pro-drugs was evident due to widespread distribution of endogenous glycosidases. To get around this, Hou et al. developed a bumped pro-drug via  methylation  of the O6 of the galactose moiety of galactosyl-NONOate. They engineered a corresponding hole-modified β-galactosidase mutant, A4-β-GalH363A with specificity for the bumped galactosyl-NONOate. The bumped pro-drug evaded cleavage by wild type β-galactosidase due to the methylated O6 of the galactose moiety and strict  regioselectivity  of glycosidases. NO was released in tissues only in the presence of both the bumped galactosyl-NONOate and the hole-modified β-galactosidase mutant, giving spatiotemporal control of delivery. Hou et al. found markedly increased therapeutic efficiency of NO delivery via the bump-and-hole engineered system, compared to the unmodified pro-drug, in rat hindlimb  ischemia  and mouse  acute kidney injury  models. [ 18 ]


The  N- Acetylgalactosaminyl transferase (GalNac Ts) family transfers  N-Acetylgalactosamine  to the Ser/Thr side chains ( O-linked glycosylation ) of its substrates, using UDP-GalNac as a cofactor. Like kinases, substrate profiling for specific isoforms of GalNac Ts has been difficult to achieve. The absence of a glycosylation consensus sequence and the variability of glycan elaboration pose a challenge to studying O-GalNac  glycoproteins.  Further, GalNac transferase knockout strategies are ineffective because the activity of isoforms in the family is both redundant and competitive, such that compensation occurs upon KO. Recently, Schumann et al. applied the bump-and-hole strategy to engineer bumped alkyne-containing  UDP -GalNac analogs and double hole-modified I253A/L310A mutant GalNac Ts (BH GalNac Ts). The UDP-alkyne analogs were specific to complementary BH GalNac Ts, which were shown to maintain the biochemical competence of wild type GalNac Ts, with regards to structure, localization, and substrate specificity. This bump-and-hole pair attached a bio-orthogonal label, visualizable through  click chemistry , on the substrates of distinct GalNac T isoforms, deconvolving substrate profiles while displaying complexity of glycan elaboration in the secretory pathway. [ 19 ]


Function   Maize  gene for first step in biosynthesis of  benzoxazin , which aids in resistance to insect pests, pathogenic fungi and bacteria.


First report   Hamilton 1964, [ 1 ]  as a mutant sensitive to the herbicide  atrazine , and lacking benzoxazinoids (less than 1% of non-mutant plants).


Molecular characterization reveals that the BX1 protein is a  homologue  to the alpha-subunit of  tryptophan synthase . The reference mutant  allele  has a deletion of about 900 bp, located at the 5'-terminus and comprising sequence upstream of the transcription start site and the first  exon . Additional alleles are given by a  Mu   transposon  insertion in the fourth exon (Frey et al. 1997 [ 2 ]  ) and a  Ds  transposon  insertion in the maize inbred line W22 genetic background (Betsiashvili et al. 2014 [ 3 ] ).  Gene sequence  diversity analysis has been performed for 281 inbred lines of maize, and the results suggest that bx1 is responsible for much of the natural variation in DIMBOA (a benzoxazinoid compound) synthesis (Butron et al. 2010). [ 4 ]   Genetic variation in benzoxazinoid content influences maize resistance to several insect pests (Meihls et al. 2013; [ 5 ]  McMullen et al. 2009 [ 6 ] ).


AB  chromosome translocation  analyses place on short arm of  chromosome  4 (4S; Simcox and Weber 1985 [ 7 ]  ). There is close linkage to other genes in the  benzoxazinoid synthesis  pathway [ bx2, bx3, bx4, bx5  Frey et al. 1995, [ 8 ]  1997 [ 2 ]  ). Gene  bx1  is 2490  bp  from  bx2  (Frey et al. 1997 [ 2 ]  ); between  umc123  and  agrc94  on 4S (Melanson et al. 1997 [ 9 ]  ).  Mapping   probes :  SSR  p-umc1022 (Sharopova et al. 2002 [ 10 ]  ); Overgo (physical map probe) PCO06449 (Gardiner et al. 2004 [ 11 ]  ).


Mutants are viable, but may be distinguished from normal plants by FeCl 3  staining: plants able to synthesize benzoxinoids have pale blue color when crushed and treated with FeCl 3  solutions (Hamilton 1964, [ 1 ]  Simcox 1993 [ 12 ]  ).  Mutations  in the  bx1  gene reduce the resistance to first generation  European corn borer  ( Ostrinia nubilalis ) that is conferred by  benzoxazinoids  (Klun et al. 1970  [ 13 ] ).  Bx1  mutant maize deposited less callose in response to  chitosan  elicitation than isogenic wildtype plants (Ahmad et al. 2011  [ 14 ] ). Genetic mapping using  recombinant inbred lines  derived from maize inbred lines B73 and Mo17 showed that a 3.9 kb  cis-regulatory element  that is located approximately 140 kb upstream of  Bx1  causes higher 2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one ( DIMBOA ) accumulation in Mo17 than in B73 seedlings (Zheng et al. 2015  [ 15 ] ). This genetic variation is also associated with higher corn leaf aphid ( Rhopalosiphum maidis ) reproduction on B73 compared to Mo17 maize seedlings (Betsiashvili et al. 2014  [ 3 ] ). Relative to maize inbred line W22 , Bx1:: Ds  mutant maize plants are more sensitive to corn leaf aphids ( Rhopalosiphum maidis )  (Betsiashvili et al. 2014 [ 3 ] ) and beet armyworms ( Spodoptera exigua ) (Tzin et al. 2017  [ 16 ] ). Highly localized induction of benzoxazinoid accumulation in response to Egyptian cotton leafworm ( Spodoptera littoralis ) feeding is abolished in a maize  bx1  mutant (Maag et al. 2016  [ 17 ] ).


Catalyzes the first step in the  synthesis  of  DIMBOA , forming  indole  from indole-3-glycerol phosphate. The  enzyme  is called  indole-3-glycerol phosphate lyase ,  chloroplast , EC 4.1.2.8 and is located in the  chloroplast . The  X-ray structure  of BX1 protein has been resolved and compared with bacterial TSA ( tryptophan synthase  alpha subunit, Kulik et al. 2005). [ 18 ]  Three  homologs  of the BX1  protein  occur in maize. One is encoded by the gene  tsa1 ,  tryptophan synthase alpha1 (Frey et al. 1997, [ 2 ]  Melanson et al. 1997 [ 9 ]  ), on chromosome 7, another by  igl1 ,  indole-3-glycerol phosphate lyase1 (Frey et al. 1997, [ 2 ]  on chromosome 1, and another by  tsah1 , 'TSA like" and located near the  bx1   gene (Frey et al. 1997. [ 2 ]  ).


Cell–cell fusogens  are  glycoproteins  that facilitate the  fusion of cell to cell membranes . Cell–cell fusion is critical for the merging of  gamete   genomes  and the development of organs in multicellular organisms. Cell-cell fusion occurs when both actin cytoskeleton and fusogenic proteins properly rearrange across the cell membrane. This process is led by actin-propelled membrane protrusions. [ 1 ]


EFF-AFF  are the identifiers for type 1  glycoproteins  that makeup cell–cell fusogens. They were first identified when EFF-1  mutants  were found to "block  cell fusion  in all  epidermal  and  vulval  epithelia" in the  roundworm ,  Caenorhabditis elegans . [ 2 ]  EFF-AFF is a family of type I  membrane glycoproteins  that act as cell–cell fusogens, named from ''Anchor cell fusion failure''. Because it was known that EFF-1 mutants successfully fused the anchor cell and (uterine seam) utse syncytium to produce a continuous uterine-vulval tube, where these connections failed, AFF-1 mutants were discovered. AFF-1 was deemed necessary for this process in addition to the fusion of  heterologous  cells in  C. elegans . [ 3 ]  The  transmembrane  forms of these  proteins , like most  viral  fusogens, possess an  N-terminal signal sequence  followed by a long  extracellular  portion, a predicted transmembrane domain, and a short  intracellular  tail. " A striking  conservation  in the position and number of all 16  cysteines  in the extracellular portion"  of EFF-AFF proteins from different nematode species suggests that these proteins are folded in a similar  3D structure  that is
essential for their fusogenic activity. [ 4 ]  C. elegans AFF-1 and EFF-1 proteins are essential for  developmental  cell-to-cell fusion and can merge insect cells. "Thus FFs comprise an ancient
family of cellular fusogens that can promote fusion when expressed on a viral particle." [ 5 ]


Cell–cell fusogens are proteins that promote plasma membrane fusion among different cells. To be considered a fusogen, it must be required for fusion, fuse unfamiliar membranes, and be present on the fusing membrane when need be. These cells include but are not limited too: gametes, trophoblasts, epithelial, and other developmental cells. These fusogens mediate cell-cell fusion and can perform neuron repairs, auto-fusion, and sealing of the phagosomes. Although these proteins promote similar functions among cells, they have individual mechanisms. These are called unilateral (one fusing membrane needed to be present) and bilateral (same or different fusogens present at both membranes) mechanisms. Most fusogen mechanisms begin with hemifusion, but the mechanism for cell-cell fusogens consists of four separate steps. [ 6 ]


Cell–cell fusogens have several different applications. These chemical agents can play a significant part in sexual and asexual reproduction by promoting the fusion of the membrane bilayers. [ 6 ]  With sexual reproduction, evidence found to prove that in mice, some mandatory sperm-egg fusogens are responsible for fusion; two particular proteins were IZUMO1 and CD9. After comparing the data of experiments done with plants, fungi, and invertebrates, it was seen that several crucial genes could have been responsible for fertilization. However, like yeasts, there were no genes found to be adequate for the fertilization process. [ 7 ]  As of late, another protein has been classified as a gamete fusogen (HAP2 or GCS1). Like the previous example, this protein is present in plants, protists, and invertebrates. This fusogen resembles the eukaryotic somatic fusogen mentioned earlier, EFF-1. The presence of HAP2 induces hemifusion and the mixing of cell content. [ 6 ]  Yet when considering asexual reproduction, somatic cells can also undergo cell-cell fusion or self-fusion. Two particular fusogens observed were SO and MAK-2. Evidence supports that these proteins control and regulate efficient protein concentration and localization. [ 7 ]


In the medical field, experiments are done to test for the uses of cell-cell fusogens in axonal nerve repairs and to determine their usefulness with other nerve cells. The current method for nerve repair is suturing the cut ends of nerves. This has a long recovery process, with a low functionality rate for the repaired nerves. When considering cell-cell fusogens as a potential answer, researchers divided these fusogens into two groups based on fusion mechanisms: cell aggregation and membrane modification. One fusogen PEG was found to fit in both groups. It was this fusogen that made restoring nerve cells in humans possible. Once operations were within a certain time frame (12 hours for human nerve repair and 24 hours for sciatic rat treatments), patient recovery was almost successful. With this research, there is potential for repairing human nerve grafts. Some potential uses of cell-cell fusogens studied are cancer vaccines and the regeneration of damaged cells. Additionally, any peripheral nerve in the body could be repaired, and transferred tissues could work as soon as the senses return. Finally, any surgery done on nerves could be repaired as well, thus resulting in a quicker recovery. [ 8 ]


In  genetics , a  centimorgan  (abbreviated  cM ) or  map unit  ( m.u. ) is a unit for measuring  genetic linkage .  It is defined as the distance between  chromosome  positions (also termed  loci  or  markers ) for which the expected average number of intervening  chromosomal crossovers  in a single generation is 0.01.  It is often used to infer distance along a chromosome. However, it is not a true physical distance.


The number of  base pairs  to which it corresponds varies widely across the  genome  (different regions of a chromosome have different propensities towards  crossover ) and it also depends on whether the  meiosis  in which the crossing-over takes place is a part of  oogenesis  (formation of female gametes) or  spermatogenesis  (formation of male gametes).


In humans one centimorgan corresponds to about 1  Mb  (1,000,000  base pairs  or  nucleotides ) on average. [ 1 ] [ 2 ]  The relationship is only rough, as the physical chromosomal distance corresponding to one centimorgan varies from place to place in the genome, and also varies between males and females since recombination during gamete formation in females is significantly more frequent than in males. Kong et al. calculated that the female genome is 4460 cM long, while the male genome is only 2590 cM long. [ 3 ]


In contrast,  in  Plasmodium falciparum  one centimorgan corresponds to about 15  kb ; markers separated by 15,000 nucleotides have an expected rate of chromosomal crossovers of 0.01 per generation.


Note that non- syntenic  genes (genes residing on different chromosomes) are inherently unlinked, and cM distances are not applicable to them.


Because  genetic recombination  between two markers is detected only if there are an odd number of chromosomal crossovers between the two markers, the distance in centimorgans does not correspond exactly to the probability of genetic recombination. Assuming the  Haldane Mapping Function , eponymously devised by  J. B. S. Haldane , the number of chromosomal crossovers is distributed according to a  Poisson distribution , [ 4 ]  a genetic distance of  d  centimorgans will lead to an odd number of chromosomal crossovers, and hence a detectable genetic recombination, with probability


where sinh is the  hyperbolic sine  function.  The probability of recombination is approximately  d /100 for small values of  d  and approaches 50% as  d  goes to infinity.


The formula can be inverted, giving the distance in centimorgans as a function of the recombination probability:


Genealogists often use "shared centimorgans" as a proxy for reciprocal of distance in a family tree, halving with each generational step. So if two individuals differ on average by:


etc. The margin of error increases with each step, so that beyond about 4 steps the ranges overlap to such an extent as to make it difficult to establish how many steps are involved, and beyond about 7 steps any relationship at all is tenuous.


The self/twin figure of 7050 cM corresponds to the sum of the cM lengths of human DNA for males and females.


When multiple genetic lines are inherited, they combine as root-sum-of-squares, so that full siblings share around 2493 cM or √2 times as much as half siblings.


Because some recombinations result in unviable gametes, or offspring that cannot themselves reproduce, the observed genetic distances in families tend to be lower (shared cM higher) than predicted by models based purely on physical recombination rates.  [ citation needed ]


The centimorgan was named in honor of geneticist  Thomas Hunt Morgan  by  J. B. S. Haldane . [ 5 ]  Its parent unit, the morgan, is rarely used today.


The  chaperone code  refers to  post-translational modifications  of molecular  chaperones  that control protein folding. Whilst the  genetic code  specifies how  DNA  makes proteins, and the  histone code  regulates histone-DNA interactions, the chaperone code controls how proteins are folded to produce a functional  proteome . [ 1 ] [ 2 ]


The chaperone code refers to the combinatorial array of  post-translational modifications  (enzymes add chemical modifications to amino acids that change their properties)  —i.e.  phosphorylation ,  acetylation ,  ubiquitination ,  methylation , etc.—that are added to molecular chaperones to modulate their activity. Molecular chaperones are proteins specialized in folding and unfolding of the other cellular proteins, and the assembly and dismantling of protein complexes. This is critical in the regulation of protein-protein interactions and many cellular functions. Because post-translational modifications are marks that can be added and removed rapidly, they provide an efficient mechanism to explain the plasticity observed in proteome organization during cell growth and development.


The chaperone code concept posits that combinations of post-translational modifications at the surface of chaperones, including phosphorylation, acetylation, [ 1 ]  methylation, [ 3 ]  ubiquitination, [ 4 ]  control protein folding/unfolding and protein complex assembly/disassembly by modulating:


1)  chaperone-substrate  affinity and specificity


2) chaperone ATPase and therefore its refolding activity


3) chaperone localization


4) chaperone-co-chaperone interaction. [ 5 ] [ 6 ]


The Chaperone code is incredibly complex with multiple layers of potential regulation. Studies of the chaperone code may include:


Level 1: Understanding the role and regulation of single PTMs on a single chaperone


Level 2: Cross-talk of different PTMs on a single amino acid or between PTMs on different amino acids (on a single chaperone)


Level 3: Understanding of why chaperone paralogs have different PTMs


Level 4: Cross-talk of PTMs between different chaperones i.e. between Hsp90 and Hsp70


Level 5: Understanding the role and regulation of single PTMs on a single co-chaperone molecule


Level 6: Understanding the entire chaperone code-all the PTMs on all major chaperones, co-chaperones that control all aspects of life.


Site-specific  phosphorylation  of chaperone proteins can affect their activity. In some cases phosphorylation may disrupt the interaction with a co-chaperone protein thus negatively affecting its activity. In other instances it may promote the activation of particular chaperone targets (referred to as clients). [ 7 ]  Enzymes such as  protein kinase A , casein kinase 1 and 2 ( CK1  and  CK2 ), and  glycogen synthase kinase B  serve as kinases for chaperone proteins. [ 2 ]   HSP70 , a major chaperone protein, was identified in 2012 as a hotspot of phospho-regulation. [ 8 ]  Subsequently, phosphorylation of chaperone protein HSP70 by a cyclin dependent kinase was shown to delay  cell cycle  progression in yeast and mammals by altering  cyclin D1  stability (a key regulator of the cell cycle). [ 9 ]  Phosphorylation of HSP90 (another major chaperone) at threonine 22, was shown to disrupt its interaction with co-chaperone proteins Aha1 and CD37 (interacting proteins required for function) and decrease its activity. [ 2 ] [ 10 ]  Certain pathogenic bacteria may manipulate host chaperone phosphorylation through bacterial effectors to promote their survival. HoPBF1, a family of bacterial effector protein kinases, phosphorylates HSP90 at Serine 99 to dampen immunity. [ 11 ]


Chaperone proteins are also regulated by methylation. This can occur through a conformational change (or a change in the structure of the protein), such that the interactions and activity of the protein are changed.  [ 2 ] [ 12 ]  For instance, the monomethylation of HSP90 lysine 616 by  Smyd2 , and its reversal by  LSD1 , regulate enzymatic activity of HSP90. [ 13 ] [ 14 ]


Chemical genetics  is the investigation of the function of  proteins  and  signal transduction  pathways in cells by the  screening  of  chemical libraries  of  small molecules . [ 1 ]  Chemical genetics is analogous to classical  genetic screen  where random mutations are introduced in organisms, the  phenotype  of these mutants is observed, and finally the specific gene mutation ( genotype ) that produced that phenotype is identified. In chemical genetics, the phenotype is disturbed not by introduction of mutations, but by exposure to small molecule tool compounds.  Phenotypic screening  of chemical libraries is used to identify drug targets ( forward genetics  or  chemoproteomics ) or to validate those targets in experimental models of disease ( reverse genetics ). [ 2 ]  Recent applications of this topic have been implicated in signal transduction, which may play a role in discovering new cancer treatments. [ 3 ]  Chemical genetics can serve as a unifying study between chemistry and biology. [ 4 ] [ 5 ]  The approach was first proposed by  Tim Mitchison  in 1994 in an opinion piece in the journal  Chemistry & Biology  entitled "Towards a pharmacological genetics". [ 6 ]


Chemical genetic screens are performed using libraries of  small molecules  that have known activities or simply diverse chemical structures. These screens can be done in a  high-throughput  mode, using 96 well-plates, where each well contains cells treated with a unique compound.  In addition to cells,  Xenopus  or  zebrafish  embryos can also be screened in 96 well format where compounds are dissolved in the media in which embryos grow. Embryos are developed until the stage of interest and then the phenotype can be analyzed. Several concentrations can be tested in order to determine the toxic and the optimal concentrations. [ 7 ] [ 8 ]


Adding compounds to developing embryos allow comprehension of mechanism of action of drugs, their toxicity and developmental processes involving their targets. Chemical screens have been mostly performed on either wild type or transgenic  Xenopus  and  zebrafish  organisms as they produce a large amount of synchronized, fast-to-develop and transparent eggs easy to visually score. [ 9 ] [ 10 ]  The use of chemicals in developmental biology offers two main advantages. Firstly, it is easy to perform high-throughput screen using wide spectrum or specific target compounds and reveal important genes or pathways involved in developmental processes. Secondly, it allows narrowing the time of action of a particular gene. [ 11 ]  It can also be used as a tool in drug development to test toxicity in whole organism. Procedures such as FETAX  (Frog Embryo Teratogenesis Assay – Xenopus) are being developed to implement chemical screenings to test toxicity. [ 12 ]  Zebrafish and  Xenopus  embryos have also been used to identify new drugs targeting a particular gene of interest. [ 13 ]


Chemogenetics  is the process by which  macromolecules  can be engineered to interact with previously unrecognized small molecules. Chemogenetics as a term was originally coined to describe the observed effects of mutations on  chalcone isomerase  activity on substrate specificities in the flowers of  Dianthus caryophyllus . [ 1 ]  This method is very similar to  optogenetics ; however, it uses chemically engineered molecules and ligands instead of light and light-sensitive channels known as  opsins .


In recent research projects, chemogenetics has been widely used to understand the relationship between brain activity and behavior. Prior to chemogenetics, researchers used methods such as  transcranial magnetic stimulation  and  deep brain stimulation  to study the relationship between neuronal activity and behavior. [ 2 ]


Optogenetics  and chemogenetics are the more recent and popular methods used to study this relationship. Both of these methods target specific  brain circuits  and cell population to influence cell activity. However, they use different procedures to accomplish this task. Optogenetics uses light-sensitive channels and pumps that are virally introduced into neurons. Cells' activity, having these channels, can then be manipulated by light. Chemogenetics, on the other hand, uses chemically engineered receptors and exogenous molecules specific for those receptors, to affect the activity of those cells. The engineered macromolecules used to design these receptors include  nucleic acid hybrids , [ 3 ]   kinases , [ 4 ]  variety of  metabolic enzymes , [ 5 ] [ 6 ]  and  G-protein coupled receptors  such as  DREADDs . [ 7 ] [ 8 ] [ 9 ] [ 10 ]


DREADDs are the most common G protein–coupled receptors used in chemogenetics. [ 11 ]  These receptors solely get activated by the drug of interest (inert molecule) and influence physiological and neural processes that take place within and outside of the central nervous system. [ citation needed ]


Chemogenetics has recently been favored over optogenetics, and it avoids some of the challenges of optogenetics. Chemogenetics does not require the expensive light equipment, and therefore, is more accessible. The resolution in optogenetics declines due to light scattering and illuminance declined levels as the distance between the subject and the light source increases. These factors, therefore, don’t allow for all cells to be affected by light and lead to a lower spatial resolution. Chemogenetics, however, does not require light usage and therefore can achieve a higher spatial resolution. [ 12 ]


G-protein coupled receptors' usage and chemogenetics are nowadays the targets for many of the pharmaceutical companies to cure and alleviate symptoms of diseases that involve all tissues of the body. [ 13 ]  More specifically, DREADDs have been used to explore treatment options for various neurodegenerative and psychological conditions such as Parkinson’s disease, depression, anxiety, and addiction. These aforementioned conditions involve processes that occur within and outside of the nervous system involving neurotransmitters such as  gamma-aminobutyric acid  and  glutamate . [ 14 ]  Chemogenetics has therefore been used in pharmacology to adjust the levels of such neurotransmitters in specific neuron while minimizing the side effects of treatment. To treat and relieve the symptoms of any disease using the DREADDs, these receptors are delivered to the area of interest via viral transduction. [ citation needed ]


Recently some studies have considered using a new method called retro DREADDs. This method allows specific neuronal pathways to be studied under cellular resolution. Unlike classic DREADDs, this method is usually used in wild type animals, and these receptors are given to the targeted cells via injection of two viral vectors. [ 2 ]


DREADDS have been used in many animal models (e.g., mice and other non-primate animals) to target and influence the activity of various cells. Chemogenetics used in animals assists with demonstrating human disease models such as  Parkinson's disease . Having this information allows scientists understand whether viral expression of DREADD proteins, both in-vivo enhancers and inhibitors of neuronal function can be used to bidirectionally affect the behaviors and the activity of the involved neurons. Recent studies have shown that DREADDs were successfully used to treat the motor deficits of rats modeling Parkinson's disease. [ 15 ]  Other studies have had successes linking the usage of DREADDs and influencing drug seeking and drug sensitization behavior. [ 14 ]


The progression of chemogenetics from rodents to non-human primates has been slow due to increased demand in time and expense surrounding these projects. However, some recent studies in 2016 have been able to demonstrate successes showing that silencing the activity of neurons in the  orbitofrontal cortex  along with the removal of  rhinal cortex , restricted the reward task performance in macaques. [ 16 ]


Chemogenetics and usage of DREADDs have allowed researchers to advance in biomedical research areas including many  neurodegenerative  and psychiatric conditions. Chemogenetics have been used in these fields to induce specific and reversible brain lesions and therefore, study specific activities of neuron population. Although chemogenetics offers specificity and high spatial resolution, it still faces some challenges when used in investigating  neuropsychiatric  disorders. Neuropsychiatric disorders usually have a complex nature where lesions in the brain have not been identified as the main cause. Chemogenetics has been used to reverse some of the deficits revolving such conditions; however, it has not been able to identify the main cause of neuropsychiatric diseases and cure these conditions completely due to complex nature of these conditions. Nevertheless, chemogenetics has been used successfully in a preclinical model of drug-resistant  epilepsy , where seizures arise from a discrete part of the brain. [ 17 ]


A  Chi site  or  Chi sequence  is a short stretch of  DNA  in the  genome  of a  bacterium  near which  homologous recombination  is more likely to occur than on average across the genome. Chi sites serve as stimulators of DNA  double-strand break repair  in bacteria, which can arise from  radiation  or chemical treatments, or result from  replication fork  breakage during  DNA replication . The  sequence  of the Chi site is unique to each group of closely related organisms; in  E. coli  and other enteric bacteria, such as Salmonella, the core sequence is  5' -GCTGGTGG- 3'  plus important nucleotides about 4 to 7 nucleotides to the 3' side of the core sequence. The existence of Chi sites was originally discovered in the genome of  bacteriophage lambda , a  virus  that infects  E. coli , but is now known to occur about 1000 times in the  E. coli  genome.


The Chi sequence serves as a signal to the  RecBCD  helicase- nuclease  that triggers a major change in the activities of this enzyme. Upon encountering the Chi sequence as it unwinds DNA, RecBCD cuts the DNA a few nucleotides to the 3’ side of Chi, within the important sequences noted above; depending on the reaction conditions, this cut is either a simple nick on the 3'-ended strand or the change of nuclease activity from cutting the 3’-ended strand to cutting the 5’-ended strand. In either case the resulting 3’ single-stranded DNA (ssDNA) is bound by multiple molecules of  RecA  protein that facilitate "strand invasion," in which one strand of a homologous double-stranded DNA is displaced by the RecA-associated ssDNA. Strand invasion forms a joint DNA molecule called a  D-loop .  Resolution of the D-loop is thought to occur by replication primed by the 3’ end generated at Chi (in the D-loop). Alternatively, the D-loop may be converted into a  Holliday junction  by cutting of the D-loop and a second exchange of DNA strands; the Holliday junction can be converted into linear duplex DNA by cutting of the Holliday junction and ligation of the resultant nicks.  Either type of resolution can generate recombinant DNA molecules if the two interacting DNAs are genetically different, as well as repair the initially broken DNA.


Chi sites are sometimes referred to as "recombination hot spots". The name "Chi" is an abbreviation of  c rossover  h otspot  i nstigator. In reference to  E. coli  phage lambda, the term is sometimes written as "χ site", using the Greek letter  chi ; for  E. coli  and other bacteria the term "Chi" is proper.


In  genetics , a  chiasma  ( pl. :  chiasmata ) is the point of contact, the physical link, between two (non-sister)  chromatids  belonging to  homologous chromosomes . At a given chiasma, an exchange of genetic material can occur between both chromatids, what is called a  chromosomal crossover , but this is much more frequent during  meiosis  than  mitosis . [ 1 ]  In  meiosis , absence of a chiasma generally results in improper chromosomal segregation and  aneuploidy . [ 2 ]


Points of crossing over become visible as chiasma after the synaptonemal complex dissembles and the homologous  chromosomes  slightly apart from each other.


The phenomenon of genetic chiasmata ( chiasmatypie ) was discovered and described in 1909 by  Frans Alfons Janssens , a Professor at the  University of Leuven  in  Belgium . [ 3 ] [ 4 ]


When each  tetrad , which is composed of two pairs of sister  chromatids , begins to split, the only points of contact are at the chiasmata. The chiasmata become visible during the diplotene stage of prophase I of  meiosis , but the actual "crossing-overs" of genetic material are thought to occur during the previous  pachytene  stage. Sister chromatids also form chiasmata between each other (also known as a chi structure), but because their genetic material is identical, it does not cause any noticeable change in the resulting daughter cells.


In humans, there seems to be one chiasma per chromosome arm, [ 5 ]  and in mammals, the number of chromosome arms is a good predictor of the number of crossovers. [ 6 ]  Yet, in humans and possibly other species, evidence shows that the number of crossovers is regulated at the level of an entire chromosome and not an arm. [ 2 ]


The grasshopper  Melanoplus femurrubrum  was exposed to an acute dose of X-rays during each individual stage of meiosis, and chiasma frequency was measured. [ 7 ]   Irradiation during the leptotene-zygotene stages of meiosis, that is, prior to the pachytene period in which crossover recombination occurs, was found to increase subsequent chiasma frequency.  Similarly, in the grasshopper  Chorthippus brunneus , exposure to X-irradiation during the zygotene-early pachytene stages caused a significant increase in mean cell chiasma frequency. [ 8 ]   Chiasma frequency was scored at the later diplotene-diakinesis stages of meiosis.  These results suggest that X-rays induce  DNA  damages, likely including double-strand breaks, and these damages are repaired by a  crossover  pathway leading to chiasma formation.


In genetics, the  coefficient of coincidence (c.o.c.)  is a measure of  interference  in the formation of  chromosomal crossovers  during  meiosis . It is generally the case that, if there is a crossover at one spot on a chromosome, this decreases the likelihood of a crossover in a nearby spot. [ 1 ]  This is called interference.


The coefficient of coincidence is typically calculated from recombination rates between three genes. If there are three genes in the order A B C, then we can determine how closely  linked  they are by frequency of recombination. Knowing the recombination rate between A and B and the recombination rate between B and C, we would naively expect the double recombination rate to be the  product  of these two rates.


The coefficient of coincidence is calculated by dividing the  actual  frequency of double recombinants by this expected frequency: [ 1 ]


Interference is then defined as follows: [ 1 ]


This figure tells us how strongly a crossover in one of the DNA regions (AB or BC) interferes with the formation of a crossover in the other region.


Drosophila  females of  genotype   a + a b + b c + c  were crossed with males of genotype  aa bb cc . This led to 1000 progeny of the following  phenotypes :


From these numbers it is clear that the b + /b  locus  lies between the a + /a locus and the c + /c locus.


There are 23 + 152 + 148 + 27 = 350 progeny showing recombination between genes A and B. And there are 81 + 23 + 27 + 89 = 220 progeny showing recombination between genes B and C. Thus the expected rate of double recombination is (350 / 1000) * (220 / 1000) = 0.077, or 77 per 1000.


However, there are actually only 23 + 27 = 50 double recombinants. The coefficient of coincidence is therefore 50 / 77 = 0.65.


Interference is 1 − 0.65 = 0.35.


When three genetic markers, a, b and c, are all nearby (e.g. within the same  gene ) the coefficient of coincidence (calculated as in the above example) is generally found to be significantly greater than 1.  This implies that any individual  recombination  event tends to be more closely associated with another nearby recombination event than would be expected by chance.  This type of association is known as “negative interference”.  When the coefficient of coincidence is substantially greater than 1, it is known as “high negative interference".  High negative interference has been reported in  bacteriophage T4  (e.g.  [ 2 ] [ 3 ]  ) and in human immunodeficiency virus ( HIV ) infections. [ 4 ] [ 5 ]


During the latter half of the 20th century, the fields of  genetics  and  molecular biology  matured greatly, significantly increasing understanding of  biological   heredity . [ 1 ] [ 2 ] [ 3 ] [ 4 ]  As with other complex and evolving  fields of knowledge , the  public awareness  of these advances has primarily been through the  mass media , and a number of  common misunderstandings of genetics  have arisen.


It is a popular misconception that all patterns of an animal's behaviour, and more generally its  phenotype , are rigidly determined by its genes. Although many examples of animals exist that display certain well-defined behaviour that is genetically programmed, [ 5 ]  these examples cannot be extrapolated to all animal behaviour. There is good evidence that some basic aspects of human behaviour, such as  circadian rhythms [ 6 ]  are genetically based, but it is clear that many other aspects are not.


In the first place, much phenotypic variability does not stem from genes themselves. For example:


In the early years of genetics it was suggested that there might be "a gene for" a wide range of particular characteristics. This was partly because the examples studied from  Mendel  onwards inevitably focused on genes whose effects could be readily identified; partly that it was easier to teach science that way; and partly because the mathematics of evolutionary dynamics is simpler if there is a simple mapping between genes and phenotypic characteristics. [ 8 ]


These have led to the general perception that there is "a gene for" arbitrary traits, [ 9 ]
leading to controversy in particular cases such as the purported " gay gene ". [ 10 ]  However, in light of the known complexities of gene expression networks (and phenomena such as  epigenetics ), it is clear that instances where a single gene "codes for" a single, discernible phenotypic effect are rare, and that media presentations of "a gene for  X " grossly oversimplify the vast majority of situations.


It is widely believed that genes provide a "blueprint" for the body in much the same way that  architectural  or  mechanical engineering  blueprints describe buildings or machines. [ 11 ]  At a superficial level, genes and conventional blueprints share the common property of being low  dimensional  (genes are organised as a one-dimensional string of  nucleotides ; [ 12 ]  blueprints are typically two-dimensional drawings on paper) but containing information about fully three-dimensional structures. However, this view ignores the fundamental differences between genes and blueprints in the nature of the mapping from low order information to the high order object.


In the case of biological systems, a long and complicated chain of interactions separates genetic information from  macroscopic  structures and functions. The following simplified diagram of causality illustrates this:


Even at the small scale, the relationship between genes and proteins (once thought of as " one gene, one polypeptide ") [ 13 ]  is more complicated, because of  alternative splicing .


Also, the causal chains from genes to functionality are not separate or isolated but are entangled together, most obviously in  metabolic pathways  (such as the  Calvin  and  citric acid cycles ) which link a succession of  enzymes  (and, thus, gene products) to form a coherent  biochemical  system. Furthermore, information flow in the chain is not exclusively one-way. While the  central dogma of molecular biology  describes how information cannot be passed back to inheritable genetic information, the other causal arrows in this chain can be  bidirectional , with complex feedbacks ultimately regulating  gene expression .


Instead of being a simple, linear mapping, this complex relationship between genotype and phenotype is not straightforward to  decode . Rather than describing genetic information as a blueprint, some have suggested that a more appropriate  analogy  is that of a  recipe  for  cooking , [ 12 ]  where a collection of  ingredients  is combined via a set of instructions to form an  emergent structure , such as a cake, that is not described explicitly in the recipe itself. [ 14 ]


It is popularly supposed that a gene is "a linear sequence of nucleotides along a segment of DNA that provides the coded instructions for synthesis of RNA" [ 15 ]  and even some current medical dictionaries define a gene as "a hereditary unit that occupies a specific location on a chromosome, determines a particular characteristic in an organism by directing the formation of a specific protein, and is capable of replicating itself at each cell division." [ 16 ]


In fact, as the diagram illustrates schematically, genes are much more complicated and elusive concepts. A reasonable modern definition of a gene is "a locatable region of genomic sequence, corresponding to a unit of inheritance, which is associated with regulatory regions, transcribed regions and/or other functional sequence regions." [ 17 ]


This kind of misperception is perpetuated when mainstream media report that an organism's genome has been "deciphered" when they mean that it has simply been  sequenced . [ 18 ]


Genetic ancestry tests  advertised by companies such as  23andMe  and  AncestryDNA  do not actually reveal a person's geographical ancestral origins or determine their race and ethnicity. [ 19 ] [ 20 ] [ 21 ]  They estimate the  genetic ancestry  and population group of a certain person. [ 22 ]  They compare a person's DNA markers to that of modern populations collected in a company's database. A person's DNA markers being matched to a particular location does not necessarily indicate that their ancestors are from that location, due to the fact human populations have migrated all throughout history, and the geopolitical borders of modern nations are not the same as they were in the past. [ 23 ]  There are no genes that are unique to specific ethnic groups, as ethnic groups are created by human society rather than genetics. The actual genetic variation that exists among humans does not correlate with socially defined ethnic and racial categories, [ 24 ]  yet there are patterns of genetic variation in some population groups that are more common than others. [ 25 ]  Genetic ancestry is distinct from genealogical ancestry; as an individual's genealogical ancestors become more distant, they will become less genetically related to those ancestors, and a greater number of other individuals across the world will share those same ancestors. [ 26 ] [ 27 ]  These tests can be used for specific connections and cases like detecting a close relative. [ 28 ]  Underrepresented populations may not receive as accurate results if the company has less data on their group, [ 29 ]  although as the technology improves with tools like mid-pass whole genome sequencing this will likely change and improve. [ 30 ]


In  medical genetics ,  compound heterozygosity  is the condition of having two or more heterogeneous  recessive   alleles  at a particular locus that can cause  genetic disease  in a  heterozygous  state; that is, an organism is a compound heterozygote when it has two recessive alleles for the same gene, but with those two alleles being different from each other (for example, both alleles might be mutated but at different locations). Compound heterozygosity reflects the diversity of the mutation base for many  autosomal recessive  genetic disorders; mutations in most disease-causing genes have arisen many times. This means that many cases of disease arise in individuals who have two unrelated alleles, who technically are  heterozygotes , but both the alleles are defective. [ citation needed ]


These disorders are often best known in some classic form, such as the homozygous recessive case of a particular  mutation  that is widespread in some population. In its compound heterozygous forms, the disease may have lower  penetrance , because the mutations involved are often less deleterious in combination than for a  homozygous  individual with the classic symptoms of the disease. As a result, compound heterozygotes often become ill later in life, with less severe symptoms. Although compound heterozygosity as a cause of genetic disease had been suspected much earlier, widespread confirmation of the phenomenon was not feasible until the 1980s, when  polymerase chain reaction  techniques for amplification of DNA made it cost-effective to sequence genes and identify polymorphic alleles. [ citation needed ]


Compound heterozygosity is one of the causes of variation in genetic disease. The diagnosis and nomenclature for such disorders sometimes reflects history, because most diseases were first observed and classified based on  biochemistry  and  pathophysiology  before genetic diagnosis was available. Some genetic disorders are really a family of related disorders that occur in the same  metabolic pathway , or in related pathways. Naming conventions for the disease became established before precise molecular diagnosis was possible. [ citation needed ]


For example,  hemochromatosis  is the name given to several different heritable diseases with the same outcome, excess absorption of iron. These variants all reflect a failure in a metabolic pathway associated with  iron   metabolism , however mutations that cause hemochromatosis can occur at different gene loci. Mutations have occurred at each locus many times, and a few such mutations have become widespread in some population. The fact that multiple loci are involved is the primary cause for the variant forms of hemochromatosis and its outcome. This variation is caused not by compound heterozygosity, but rather by the fact that several different enzyme defects can cause the disease. Clinically, most cases of hemochromatosis are found in homozygotes for the most common mutation in the  HFE gene . [ 1 ]  But at each gene locus associated with the disease, there is the possibility of compound heterozygosity, often caused by inheritance of two unrelated alleles, of which one is a common or classic mutation, while the other is a rare or even novel one. [ 2 ]


For some genetic diseases, environmental cofactors are an important determinant of variation and outcome. In the case of hemochromatosis,  penetrance  is incomplete, even for the classic HFE mutation, and is affected by gender, diet, and behaviors such as alcohol consumption. Compound heterozygotes are often observed only through subclinical symptoms such as excess iron. Disease is rarely observed in such compound heterozygotes unless other causal factors (such as  alcoholism ) are present. As a result, compound heterozygosity for hemochromatosis may be more common than diagnosis based on pathology would suggest. [ 3 ]


Some genetic diseases are named more precisely, and represent a  single point of failure  on a metabolic pathway. For example,  Tay–Sachs disease ,  GM2-gangliosidosis, AB variant , and  Sandhoff disease  might easily have been defined together as a single disease, because the three disorders are associated with failure of the same enzyme and have the same outcome. However, the three were discovered and named separately, and each represents a distinct molecular point of failure in a subunit that is required for activation of the enzyme. For all three disorders, compound heterozygosity is responsible for variant forms. For example, both TSD and Sandhoff disease have a more common infantile form and several late-onset variants. Post-infantile forms, which are rare, are generally caused by the inheritance of two unrelated alleles, of which one is usually a classic mutation, while the other is a rare or even novel one. [ citation needed ]


Copy number analysis  is the process of analyzing data produced by a test for DNA  copy number variation  in an organism's sample. One application of such analysis is the detection of chromosomal  copy number variation  that may cause or may increase risks of various critical disorders. [ 1 ] [ 2 ]  Copy number variation can be detected with various types of tests such as  fluorescent in situ hybridization ,  comparative genomic hybridization  and with high-resolution array-based tests based on  array comparative genomic hybridization  (or aCGH),  SNP array  technologies and high resolution microarrays that include copy number probes as well an SNPs. Array-based methods have been accepted as the most efficient in terms of their resolution and high-throughput nature and the highest coverage (choose an array with over 2 million probes) [ 3 ]  and they are also referred to as  virtual karyotype . Data analysis for an array-based DNA copy number test can be very challenging though due to very high volume of data that come out of an array platform.


BAC ( Bacterial Artificial Chromosome ) arrays were historically the first  microarray  platform to be used for DNA  copy number  analysis. This platform is used to identify gross deletions or amplifications in DNA. Such anomalies for example are common in cancer and can be used for diagnosis of many developmental disorders. Data produced by such platforms are usually low to medium resolution in terms of genome coverage. Usually, log-ratio measurements are produced by this technology to represent deviation of patient's copy number state from normal. Such measurements then are studied and those that significantly differ from zero value are announced to represent a part of a chromosome with an anomaly (an abnormal copy number state). Positive log-ratios indicate a region of DNA copy number gain and negative log-ratio values mark a region of DNA copy number loss. Even a single data point can be declared an indication of a copy number gain or a copy number loss in BAC arrays.


Cotransformation  is the simultaneous  transformation  of two or more  genes .


Only genes in the same  chromosomal  vicinity can be transformed; the closer together the genes lie, the more frequently they will be cotransformed. By contrast, genes sufficiently far apart that they cannot appear together on a fragment of foreign  DNA  will almost never be cotransformed, because transformation is so inefficient that recipient cells usually take up only a single DNA.


In one study of  natural transformation , investigators isolated  B. subtilis   bacteria  with two  mutations — trpC2  and  hisB2 —that made them Trp- , His- auxotrophs. These double auxotrophs served as the recipient in the study, wild-type cells (Trp+ , His+ ) were the donors. In this study, the numbers of Trp+ and His+  transformants were equal. Further tests showed that 40 of every 100 Trp+ transferred  colonies  were also His+. Similarly, tests of the His+ transformants showed that roughly 40% are also Trp+ . Thus, in 40% of the analyzed colonies, the  trpC+  and  hisB+  genes had been cotransformed.


Since during transformation, donor DNA replaces only a small percentage of the recipient's  chromosome , why are the two  B.subtilis  genes cotransformed with such high frequency? Because the  trpC  and  hisB  genes lie very close together on the chromosome and are thus genetically linked. Although the donor chromosome is fragmented into small pieces of about 20 kb during its extraction for the transformation process, the wild-type  trpC+  and  hisB+   alleles  are so close that they often appear in the same donor DNA  molecule .  Sequence analysis  shows that  trpC  and  hisB  genes are only about 7 kb apart.


Countergradient variation  is a type of  phenotypic plasticity  that occurs when the  phenotypic  variation determined by a biological population's  genetic  components opposes the phenotypic variation caused by an environmental gradient. [ 1 ] [ 2 ]  This can cause different populations of the same organism to display similar phenotypes regardless of their underlying genetics and differences in their environments. [ 1 ]


To illustrate a common example known as countergradient growth rate, consider two populations. The two populations live in different environments that affect growth differently due to many ecological factors, such as the temperature and available food. One population is genetically predisposed to have an increased growth rate but inhabits an environment that reduces growth rate, such as a cool environment, and thereby limits the opportunities to take full advantage of any genetic predisposition. The second population is genetically predisposed to have a decreased growth rate but inhabits an environment that supports an increased growth rate, such as a warm environment, and allows members of the population to grow faster despite their genetic disadvantage. Since the genetic influence directly counteracts the environmental influence in each population, both populations will have a similar intermediate growth rate. Countergradient variation can reduce apparent variability by creating similar phenotypes, but it is still possible for the two populations to show phenotypic diversity if either the genetic gradient or the environmental gradient has a stronger influence.


Many examples of countergradient variation have been discovered through the use of  transplant experiments . Countergradient variation of growth rate is one of the most common examples. Growth rate and body size have important ecological implications, such as how they impact an organism's survival, life history, and  fecundity . [ 3 ]  Countergradient variation has been described in many  ectothermic  animals, since ectotherms rely on environmental temperature to regulate their metabolic rates, and thus, their growth rates. Ectotherms grow at a slower rate as latitude increases due to this impact of temperature. However, under countergradient variation, when these same animals are placed in a common environment with their low-latitude relatives, they grow faster relative to the low-latitude population. These studies are useful in predicting how animals can adapt to and will survive in different environmental conditions.


Countergradient variation, originally termed "contra-gradient variation", was coined by  Richard Levins  in his 1968 book  Evolution in Changing Environments. [ 2 ]   Levins first used the term when describing patterns of body size across an altitudinal gradient in populations of  Drosophila , [ 4 ]  and since then many other instances of countergradient variation have been discovered. A study by Keith Berven and others was the first to find countergradient variation in a vertebrate. [ 5 ]  Specifically, they found that in comparing montane, high altitude, populations to lowland, low altitude populations of the green frog ( Lithobates clamitans , formerly  Rana clamitans ), rates of growth and development were higher in the montane populations. This is counter to what is expected since high altitude populations grow slower than low altitude ones in their respective environments. Similar to the results of this study, most of the known instances of countergradient variation are associated with a latitudinal or altitudinal gradient having an effect on growth rate (see Examples section).


The following are among the discovered cases of countergradient variation. The species name is followed by the trait affected and the environmental gradient studied.


Countergradient variation is the opposite of  cogradient variation , in which the environmental effect on the phenotype enhances the genetic effect on the phenotype. [ 2 ]  One common way to test for both of these patterns is with  transplant experiments . [ 1 ]  By bringing the two populations to the same environment, the environmental effect on phenotype is eliminated and only the genetic effect will cause variation. If cogradient variation is occurring, the same relationship will be seen in the common environment as the two natural environments. However, if countergradient variation is occurring the opposite relationship of what is seen in the natural environments will be seen in the common environment. [ 13 ]  For example, if Population 1 has higher growth than Population 2 in their respective natural environments, countergradient variation can be detected if, when brought to the same environment, Population 1 now has lower growth than Population 2. Many of the examples listed above were discovered through these types of experiments. However, the mechanisms of how these differential growth rates arise is not fully understood.


Take the example of  Sceloporus undulatus ,  the eastern fence lizard. These lizards demonstrate countergradient variation in growth rate across a latitudinal gradient. That is, in a common environment eggs from populations from the northern part of their range hatch out sooner than the eggs from populations at a more southern range. [ 8 ]  This is opposite the pattern seen in their native habitats. One explanation for this could be that the northern eggs are also naturally larger, so they have more yolk energy available. Originally this maternal investment in larger eggs was thought to support increased developmental rate. However when yolk is removed from the eggs so that the populations have equal energy sources, there is still a substantial difference in growth. [ 8 ]  Therefore, the mechanism behind this differential growth rate may lie in the efficiency of energy use. [ 14 ]


Populations that inhabit high latitudes experience shorter growing seasons than those that inhabit low latitudes due to the differences in seasonality. Because of this, it is thought that countergradient variation of growth is a means to compensate for the short amount of time juveniles have to prepare for winter. [ 13 ]  With a genetic disposition to grow faster, these individuals can reach a large enough body size to survive through the winter. Increased body size is also associated with higher reproductive output. [ 3 ]  Additionally, when countergradient variation acts on developmental rates, embryos that develop sooner or hatch out larger will have more time to grow or require less resources, respectively.


Since these inherently fast growth rates are not observed in all populations, it seems there are potential trade-offs that would prevent this from being beneficial in low latitude populations. One proposed detriment of enhanced embryonic growth is that animals use too much of their supplied nutrients or yolk during development. In some species of lizards the yolk remaining after hatching is absorbed into the body and used as energy for growth as a hatchling. [ 15 ]  The use of more yolk energy during development diminishes the reserves available for hatchling growth and can impact hatchling survival. [ 15 ] [ 16 ]  Another hypothesis is that animals that grow quickly do not expend as much energy on differentiation or cellular maintenance because they have shorter incubation times. [ 8 ]  This allows more energy to be used for growth, but less energy for differentiation. Increased growth has been shown to lead to higher occurrences of defects or complications that cause higher rates of mortality. Some examples include rapid growth leading to bone deformities in sandhill cranes [ 17 ]  and increased risk of cardiovascular problems in Atlantic salmon. [ 18 ]


Animals are able to employ different strategies for growth and development to counteract environmental challenges. However, the fact that all individuals do not grow faster and the presence of the mentioned potential fitness trade-offs show that there must be some limit to how much animals can use countergradient growth to compensate for environmental conditions that cause slow growth. Studies of countergradient variation are being explored as a useful way to predict the evolutionary constraints animals face in differing environmental conditions.


CRT  is the  gene cluster  responsible for the  biosynthesis  of  carotenoids . Those genes are found in eubacteria, [ 1 ]  in algae [ 2 ]  and are  cryptic  in  Streptomyces griseus . [ 3 ]


Carotenoid synthesis is probably present in the common ancestor of  Bacteria  and  Archaea ; the phytoene synthase gene  crtB  is universal among carotenoid synthesizers. Among eukaryotes, plants and algae inherited the cyanobacterial pathway via biosynthesis of their  plastids , while fungi retain a archaeal-like pathway. [ 4 ]  Among all these synthesizers, several possible selection and arrangements of biosynthetic genes exist, consisting of one gene cluster cluster, several clusters, or no clustering at all. [ 5 ] [ a ]


The  CRT  gene cluster consists of twenty-five genes such as  crtA, crtB, crtC, crtD, crtE, crtF, crtG, crtH, crtI, crtO, crtP, crtR, crtT, crtU, crtV, and crtY, crtZ . These genes play a role in varying stages of the  Astaxanthin  biosynthesis and  Carotenoid  biosynthesis (Table 1). [ 6 ]


crtE  encodes for an enzyme known as geranylgeranyl diphosphate synthase known to catalyze the condensation reaction of  isopentenyl pyrophosphate  (IPP) and  dimethylallyl pyrophosphate  (DMAPP) into  geranylgeranyl diphosphate  (GGDP). [ 7 ] [ 8 ]  Two GGDP molecules are subsequently converted into a single  phytoene  molecule by  phytoene synthase , an enzyme encoded by  crtB , known as  PSY  in Chlorophyta. [ 2 ] [ 7 ] [ 8 ]  The following desaturation of phytoene into ζ-carotene is catalyzed by the phytoene desaturase encoded by  crtI, crtP,  and/or  PDS. [ 2 ] [ 7 ] [ 8 ]  ζ -carotene can also be obtained through phytoene using the carotene 2,4-desaturase enzyme ( crtD ). [ 2 ] [ 9 ]  Depending on the species, varying carotenoids are accumulated following these steps. [ 1 ] [ 10 ]


Spirilloxanthin is obtained from lycopene following a hydration, desaturation, and methylation reaction. These reactions are catalyzed by carotene hydratase ( crtC ), carotene 3,4- desaturase ( crtD ), and carotene methyltransferase ( crtF ), respectively. [ 8 ] [ 1 ]


Lycopene is cyclized through two enzymes lycopene cyclase and β-C-4-oxygenase/β-carotene ketolase encoded on the  crtY  (in Chlorophyta) / crtL  (in cyanobacteria), and  crtW , respectively.  crtY  cyclizes lycopene into β-carotene, which is subsequently oxygenated by  crtW  to form canthaxanthin. [ 8 ]


Zeaxanthin and lutein are obtained through hydroxylation of α- and β-carotene. [ 1 ]  Hydroxylation of Zeaxanthin occurs by β-carotene hydroxylase an enzyme encoded on the  crtR  (in cyanobacteria) and  crtZ  gene (in Chlorophyta). [ 8 ]


Zeaxanthin can be further processed to obtain zeaxanthin-diglucoside by Zeaxanthin glucosyl transferase ( crtX ).


Echinenone  is obtained from β -carotene through the catalyzing enzyme β-C-4-oxygenase/β-carotene ketolase ( crtO ). [ 11 ]   CrtO , also known as  bkt2  in Chlorophyta, is also involved in the conversion of other carotenoids into Canthaxanthin, 3-Hydroxyechinenone, 3'-Hydroxyechinenone, Adonixanthin, and Astaxanthin. [ 11 ] [ 12 ] CrtZ , similarly to  crtO , is also capable of converting carotenoids into β-cryptoxanthin, Zeaxanthin, 3-Hydroxyechinenone, 3'-Hydroxyechinenone, Astaxanthin, Adonixanthin, and  Adonirubin. [ 11 ]


crtH  catalyzes the isomerization of cis-carotenes into trans-carotenes through carotenoid isomerase. [ 2 ]


crtG  encodes for carotenoid 2,2'- β-hydroxylase, this enzyme leads to the formation of 2-hydroxylated and 2,2′-dihydroxylated products in  E coli . [ 13 ]


Previous studies have indicated through phylogenetic analysis that evolutionary patterns of  crt  genes are characterized by  horizontal gene transfer  and  gene duplication  events. [ 14 ]


Horizontal gene transfer has been hypothesized to have occurred between  cyanobacteria  and  Chlorophyta , as similarities in these genes have been found across taxa. [ 14 ]  Note, however, that some cyanobacteria retained their nature. Horizontal gene transfer among species occurred with a high probability in genes involved in the initial steps of the carotenoid biosynthesis pathway such as  crtE, crtB, crtY, crtL, PSY , and  crtQ . These genes are often well conserved while others involved in the later stages of Carotenoid biosynthesis such as  crtW  and  crtO  are less conserved. [ 1 ]  The less conserved nature of these genes allowed for the expansion of the carotenoid biosynthesis pathway and its end products. Amino acid variations within  crt  genes have evolved due to purifying and adaptive selection. [ 2 ]


Gene duplications are suspected to have occurred due to the presence of multiple copies of ctr clusters or genes within a single species. [ 2 ]  An example of this can be seen in the  Bradyrhizobium  ORS278  strain, where initial  crt  genes can be found (excluding  crtC, crtD,  and  crtF  genes) as well as a second  crt  gene cluster. This second gene cluster has been shown to also be involved in carotenoid biosynthesis using its  crt   paralogs . [ 8 ] [ 15 ]


Cultural hitchhiking  is a hypothesized  gene-culture coevolutionary  process through which cultural selection,  sexual selection  based on cultural preference, limits the diversity at genetically neutral loci being transmitted in parallel to selective cultural traits. The process is thought to account for exceptionally low diversity in neutral loci such as  control regions  of the mitochondrial genome unaccounted for by any other selective forces. Simply put, selection for certain learned social and cultural behaviors can manifest in specific shaping of a population’s genetic makeup. While the notion that culture plays a significant role in shaping community genetics is widely accepted in the context of human populations it had not been considered or documented in non-human organisms until the late 1990s. The term was coined by the cetologist  Hal Whitehead  who studies the cultures and population genetics of matrilineal whale communities.


Cultural hitchhiking has been proposed as a cause for reduced  genetic diversity  at certain loci in prehistoric   Homo sapiens ,  dolphins ,  killer whales , and  sperm whales . [ 1 ]


Cultural hitchhiking is a significant hypothesis because it investigates the relationship between population  genetics  and  culture . By understanding how social behavior can shape the genetic makeup of communities scientists are better able to explain why certain communities have genetic traits distinct from the larger population.


The process was initially proposed by Whitehead in a 1998 paper as an explanation for the low genetic diversity in  matrilineal  whale species. In these communities, female individuals remain grouped together with their mothers and other female relatives. [ 2 ]  They appear to select mates from outside their immediate community based on culturally valued social traits and aptitude. Sequencing of the  mitochondrial genome  of individuals within these communities revealed them to have a significantly reduced diversity in certain control loci compared to comparable  panmictic  populations. Whitehead discovered that the relative frequency of  mitochondrial haplotypes  characteristic of groups exhibiting more highly adaptive socially learned traits would increase, while the frequency of these haplotypes in groups with less adaptive socially learned traits would decrease. This coincidental selective pressure is thought to have led to an overall reduction in haplotype diversity across the entire species population.


In 2014 a team of biologists from the  University of South Wales  attributed a remarkable geographic distribution of mitochondrial haplotypes among adjacent populations of  bottlenose dolphins  in a bay in Western Australia to cultural hitchhiking. [ 3 ] [ 4 ]  The researchers found Whitehead’s hypothesis that selection for learned social traits affected diversity in neutral gene loci fit well with their observations. It was discovered that dolphins with two of three mitochondrial haplotypes were found predominantly in water deeper than 10 m while those with the third haplotypes were found predominantly in depths less than 10 m. This geographic distinction between these populations is also associated with different learned behaviors. Some of the dolphins predominantly found in deeper waters exhibit foraging strategies that implement tools such as a sponge placed on their beak. This "sponging" behavior is found to be spread through vertical social transmission along a matrilineal pattern (i.e. the mothers teach the behavior to their offspring). All dolphins exhibiting one of the deepwater haplotypes belong to a single matriline. The researchers ultimately concluded that these fine-scale genetic structures, the distinct mitochondrial haplotypes, have probably arisen based on socially transmitted behaviors or in other words, through cultural hitchhiking. A study in the same area and species showed that  shelling  is also marginally learned from associates. [ 5 ]


Cultural hitchhiking has been proposed as an explanation for a widely inferred and abrupt  Y-chromosome population bottleneck  across several  Old World  (Africa, Europe, Asia) populations around 4000-6000 BC. This bottleneck is thought to suggest a significant decline in the effective male population during  Neolithic  times to an estimated 1/20th its original size. Though mitochondrial sequence records seem to indicate uninhibited population increase at this time meaning there was likely an extreme divergence in the size of male and female effective population sizes during the bottleneck period. A team of international genetics, archaeology, and anthropology researchers in a 2018 article hypothesized that the bottleneck was a consequence of intergroup competition between patrilineal kin groups, which caused cultural hitchhiking between Y-chromosomes and cultural groups and reduction in Y-chromosomal diversity. [ 6 ]  The authors Zeng et al. argue that competition between patrilineal kin communities produces two mechanisms with limiting effect on Y-chromosome diversity. One mechanism being these patrilineal groups by virtue of common descent produce elevated levels of Y-chromosome homogeneity and high inter-group diversity. The second mechanism is violent inter-group competition which disproportionately results in male group member casualties and therefore concentration of like y-chronotypes and in some cases extinction complete extinction of entire lineages.


The  Cytodeme  is the total assembly of organisms that use an identical suite of chromosomes to carry their genes. [ citation needed ]  The term was first printed in the 1950s in a book by Heslop-Harrison. [ 1 ]  Discussing the  Deme Terminology [ 2 ]  - he continued  "cytodeme, a population differing in some distinctive cytological feature from others."  In most cases the suite is composed of several pairs of  homologous chromosomes  with or without a pair of  sex chromosomes . Since the only acceptable proof of the identity ( homology ) of chromosomes lies in their ability to pair fully from end to end during  meiosis  it follows that:


As a general rule for most species all of its members are of the same cytodeme excepting only the infrequent  aneuploid  aberrants. However some species are known to include several chromosome races which must necessarily belong to different cytodemes. Although it is not intrinsic in the formal definition it is a matter of common observation that members of different cytodemes are essentially cross-incompatible and any hybrids that do arise are usually highly infertile.


The current surge of interest in cytodemes stems from the realisation that membership of the cytodeme is not necessarily restricted to the members of one species: frequently two or more species are in fact of the same cytodeme. Although fully intercompatible and yielding fertile hybrids when they do cross these species never or rarely cross-breed in the natural environment because they are spatially isolated, geographically and/or ecologically. Typically the species involved are members of the same genus. There are now a substantial number of cases in which two or more species of the same cytodeme are clearly different and even in different genera. Thus all five  diploid  species recognised in the genus  Brassicella  and both species recognised in the genus  Hutera  (7spp. in total) are in the same cytodeme. [ 3 ]  Perhaps the most extreme case on record concerns the wild grass,  teosinte ,  Euchlaena mexicana  and the strikingly different Maize, or Indian Corn,  Zea mays , both 2n=20, fully interfertile and yielding fertile  hybrids . [ 4 ]  There is perhaps a remote possibility that two such very different species could have evolved independently from distinct sources and converged in their chromosomal ideotype until they became members of the same cytodeme (including the capacity to cross-breed). It is more likely, though, that the cytodeme arose first complete with its suite of chromosomes and breeding patterns all intact and then, remaining constant in its fundamentals, it diversified into species sometimes so different as to merit generic distinction. Thus, in what may be termed the  cytodeme adjunct  to Darwinian theory, evolution becomes a two-stage process - first, the establishment of distinct cytodemes reproductively isolated both from one another and from all previously existing cytodemes; second, diversification within cytodeme to yield taxonomically recognisable (but not reproductively isolated) species.


Whereas the second stage is  Natural Selection  as expounded by  Darwin , [ 5 ]  the first stage is not necessarily Darwinian [ citation needed ] . In the special case of  polyploidy  it is known that the first stage is not Darwinian. Doubling the chromosome number of the  sterile  hybrid between two diploid cytodemes yields an  allotetraploid  which is both fertile within its bounds and essentially incompatible with all previous life forms.


As yet no mechanism is known which could account for the origin of new diploid cytodemes - nor is there any proof that there are any diploid cytodemes of recent origin. Indeed, the evidence is that cytodemes are remarkably long lived. Presumably the  Platanus  cytodeme existed on  Pangaea  before that land fragmented. The present day forms of  Platanus  -  P. orientalis  in Europe and  P. occidentalis  in America - are fully intercompatible when brought together artificially in Botanic Gardens yielding fertile hybrids like the London plane, [ 6 ]  establishing not only that they are in the same cytodeme as one another but also that they are both in the same cytodeme as their common ancestor of approximately 200 million years ago.


Cytotaxonomy  is the classification of organisms using comparative studies of  chromosomes  during  meosis .


Cytotaxonomy is a branch of taxonomy that uses the characteristics of cellular structures to classify organisms. In cytotaxonomy, the chromosomal configuration of an organism is the most widely used parameter to infer the relationship between two organisms. The inference of species relationships is based on the assumption that closely related species share similar characteristics in their chromosomal setup (referred to as  karyotype ). [ 1 ] [ 2 ]  By analysing the similarities and differences in the chromosomes, karyotype evolution and species evolution can be reconstructed.


The number, structure, and behaviour of chromosomes is of great value in  taxonomy , with  chromosome number  being the most widely used and quoted character. Chromosome numbers are usually determined at the  metaphase  stage during  mitosis . Usually, the  diploid  chromosome number (2n) is referenced, unless dealing with a  polyploid  series in which case the base number or number of chromosomes in the genome of the original haploid is quoted. Another useful taxonomic character is the position of the  centromere .  Meiotic  behaviour may show the  heterozygosity  of inversions. This may be constant for a taxon, offering further taxonomic evidence.


Often, cytological evidence is accompanied and strengthened by other analyses, including  genomics  and DNA-based  phylogenies .


Cytology has contributed to tracking the evolutionary history of many organisms, especially primates and flowering plants. As example, karyotype comparisons have largely clarified the evolution of  Arabidopsis thaliana [ 3 ]  and of  saffron crocus , [ 4 ]  though there are many more studies that deserve highlighting.


De novo   domestication  is a process where new  species  are genetically altered to meet  human  needs, such as  agriculture  or  companionship . It is performed both by farmers and scientists, and can be done through traditional  selective breeding  or modern  biotechnological methods . Targets for  de novo  domestication are often species that have never been under cultivation, but may also include  wild relatives  of already domesticated species.


De novo  domestication refers to the process by which wild species are intentionally transformed into domesticated varieties. [ 1 ]  The majority of domesticated species has been under domestication for millenia, with the first  animal , the  dog , having been under domestication for between 40,000-30,000 years, and the first  plants  since the start of the  Neolithic Revolution , approximately 12,000 years ago. [ 2 ] [ 3 ]  This initial process of domestication is hypothesized to have been a passive process, resulting from the subconcious selection of individuals performing better in agricultural contexts. [ 4 ]  The scientific field of  de novo  domestication seeks to domesticate new species in an accelerated manner as opposed to over the course of thousands of years, as more domesticated species may provide an advantage to humanity, especially in agriculture. [ 1 ]  Newly domesticated crop species may allow for alternatives to  agricultural extensification  in regions where yields are plateauing, make agricultural systems more resilient to  climate change , and increase the sustainability of agriculture. [ 5 ] [ 6 ] [ 7 ]


It is important to note that  de novo  domestication does not only happen in a scientific context, but that the active domestication of new species is also performed by farmers, especially in the  Global South . The collection and subsequent agricultural integration of traditionally wild-gathered food plants still happens to this day, and also constitutes  de novo  domestication. [ 8 ]


The  terminology  in the scientific field of domestication is improperly standardized, with the same term meaning different things to different scientists. [ citation needed ]  This means that in some cases,  de novo  domestication is solely used for species that have no history of domestication, while in other cases, it can be used to describe further studies into  semi-domesticated crops , which already have gone through (early) stages of domestication. [ 9 ]


The study of  de novo  domestication is most prevalent in plants, due to the implications new  crops  may bring to agriculture. There are two potential applications to the study of  de novo  domestication in  plant sciences : the introduction of novel crops into agricultural systems and the redomestication of wild relatives of conventionally domesticated crops. [ 1 ]


The introduction of novel species into agricultural systems has the potential to radically alter their workings. One set of candidates for  de novo  domestication are  perennial grains , cereal crops that can be harvested for multiple seasons after planting, as opposed to the  annual grains  that dominate agriculture. [ 10 ]  The successful  de novo  domestication of a perennial grain would drastically reduce the need for yearly  plowing , seedling protection and energy spent on reaching maturity, thus decreasing environmental impact and labour use. [ 7 ]  The  de novo  domestication of  tropical   fruit trees  is suggested to be able to help address 14 out of 17 of the  Sustainable Development Goals  set by the  United Nations , either directly or indirectly. [ 11 ]


Another use for  de novo  domestication is the redomestication of wild relatives of domesticated crops. Through millennia under selection, most domesticated crops have undergone many  genetic bottlenecks , drastically reducing their  genetic diversity , and thus the ability to breed in new traits. [ 12 ]  Meanwhile, these bottlenecked crops have been spread over the entire world, and are often grown in areas with  climates  that differ significantly from their  genetic center of origin . [ 13 ]  Redomestication of crop wild relatives may offer a solution to long-term, repetitive plant breeding projects seeking to integrate wild relative  DNA  from the center of origin into established  hybrid   cultivars . [ 1 ] [ 14 ] [ 15 ]  This is especially relevant for crops that are reproductively incompatible with their wild relatives through processes such as  polyploidization , such as  hexaploid wheat , where integration of wild relative DNA through traditional breeding projects is difficult. [ 16 ]


The  de novo  domestication of animals has less scientific traction than that of plants, but one notable project is that undertaken by the  Russian   Institute of Cytology and Genetics  to domesticate the  fox . [ 17 ]  This project aimed to study the  theory of evolution  and  domestication syndrome  by attempting the domestication of foxes, but was not primarily aimed at providing a new domesticated animal. [ 17 ]   De novo  domestication of fish, either in the ornamental  aquarium trade  or for the purposes of  pisciculture  is also ongoing. [ 18 ] [ 19 ]


Fungiculture , the cultivation of fungi such as mushrooms, has historically been less important than  horticulture  or  animal husbandry  in providing food for humans. Mushrooms were often gathered from the wild, but the knowledge to do so has largely disappeared in the  Global North  due to lifestyle changes and  urbanization , prompting an increased need for mushroom cultivation. [ 20 ]  As a result, many fungi were  de novo  domesticated, such as  snow fungus  (1866),  oyster mushroom  (1917), and  milky white mushroom  (1974). [ 21 ]  A fungus that has been notoriously difficult to bring under cultivation is  white truffle , and projects to  de novo  domesticate it are running. [ 22 ]


In  biology , a  deme , in the strict sense, is a group of individuals that belong to the same  taxonomic group . [ 1 ]  However, when biologists, and especially ecologists, use the term ‘deme’ they usually refer to it as the definition of a gamodeme: [ 2 ]  a local group of individuals (from the same taxon) that interbreed with each other and share a  gene pool . [ 1 ]  The latter definition of a deme is only applicable to  sexual reproducing  species, while the former is more neutral and also takes  asexual reproducing  species into account, such as certain plant species. In the following sections the latter (and most frequently used) definition of a deme will be used.


In  evolutionary computation , a "deme" often refers to any isolated  subpopulation  subjected to  selection  as a unit rather than as individuals.


A  population  of a species usually has multiple demes. Environments between these demes can differ. Demes could, therefore, become  locally adapted  to their environment. A good example of this is the Adaptive Deme Formation (ADF) hypothesis in  insects . [ 3 ]  The ADF hypothesis states that herbivorous insects can become adapted to specific host plants in their local environment because local plants can have unique nutrient patches to which insects may become adapted. This hypothesis predicts that less mobile insect demes are more likely to become locally adapted than more dispersive insect. However, a  meta-analysis , based on 17 studies on this subject, showed that dispersive insect demes were as likely to become locally adapted as less mobile insects. [ 3 ]  Moreover, this study found a small indication that feeding  behaviour  might stimulate the local adaptation of demes. Endophagous insects were more likely to become locally adapted than exophagous insects. The explanation for this could be that endophagous insects come in more close and continuous contact to the plant's mechanical, chemical and phenological  defensive mechanisms . [ 3 ]


Speciation  could occur at the level of demes. When a deme gets geographically isolated from other demes of the same species,  gene-flow  between these demes will stop which could lead to speciation after a long time. This is called  allopatric speciation  and is generally a slow process. [ 4 ]


On the contrary,  sympatric speciation  can be more rapid when a species has multiple small demes. [ 5 ]  This rapid speciation is both observed in plants [ 6 ]  and vertebrates. [ 5 ]  Rapid speciation is explained by the  ecology  and  social structure  of demes. Species that behave more territorial, live in patchy environments and/or have a  polygynous  breeding system with only one reproductive male tend to have smaller deme sizes. Interbreeding between small demes is rare due to these factors. Furthermore,  alleles  fixate more rapidly in smaller demes. Small demes could, therefore, become genetically distinct from each other. [ 5 ]


Primates , for example, have the second highest speciation rate among mammals, with one speciation event per lineage every 3 million years. [ 5 ]  However, not all primate species have a high speciation rate; this is reflected in their deme size and social structure. Guenons ( Cercopithecus ), for example, live together in small polygynous troops and are a quite diverse  genus . On the other hand, baboons ( Papio ) have a much lower speciation rate. Baboons have larger deme sizes because they live in polygynous multi-male troops. These baboon demes are usually allopatric but gene-flow still exists between demes with  hybridization  being common. [ 5 ]


Various populations of  gorillas  can be understood by their geographical separation and have been assessed to determine distinct and disjointed gene pools. [ 7 ]  The  polar bear ,  Ursus maritimus , is understood to have 19 identifiable demes, even though their circumpolar distribution allows some interchange among the demes. [ 8 ]


Dermatoglyphics  (from  Ancient Greek   derma , "skin", and  glyph , "carving") is the scientific study of  fingerprints , lines, mounts and shapes of hands, as distinct from the superficially similar  pseudoscience  of  palmistry .


Dermatoglyphics also refers to the making of naturally occurring ridges on certain body parts, namely palms, fingers, soles, and toes. These are areas where hair usually does not grow, and these ridges allow for increased leverage when picking up objects or walking barefoot.


In a 2009 report, the scientific basis underlying dermatoglyphics was questioned by the  National Academy of Sciences , for the discipline's reliance on subjective comparisons instead of conclusions drawn from the  scientific method . [ 1 ]


1823 marks the beginning of the scientific study of  papillary ridges  of the hands and feet, with the work of  Jan Evangelista Purkyně . [ 2 ]


By 1858,  Sir William Herschel, 2nd Baronet , while in India, became the first European to realize the value of fingerprints for identification.


Sir  Francis Galton  conducted extensive research on the importance of skin-ridge patterns, demonstrating their permanence and advancing the science of fingerprint identification with his 1892 book  Fingerprints .


In 1893, Sir  Edward Henry  published the book  The classification and uses of fingerprints , which marked the beginning of the modern era of fingerprint identification and is the basis for other classification systems.


In 1929,  Harold Cummins  and Charles Midlo M.D., together with others, published the influential book  Fingerprints, Palms and Soles , a bible in the field of dermatoglyphics.


In 1945,  Lionel Penrose , inspired by the works of Cummins and Midlo, conducted his own dermatoglyphic investigations as a part of his research into  Down syndrome  and other congenital medical disorders.


In 1976, Schaumann and Alter published the book  Dermatoglyphics in Medical Disorders , which summarizes the findings of dermatoglyphic patterns under disease conditions.


In 1982, Seltzer, et al., conducted a study on patients with breast cancer, and concluded that the presence of six or more whorls on a woman's fingertips indicated her being at high risk for breast cancer.


Although the study of dermatoglyphics has some adjunctive value in the diagnosis of genetic syndromes (see examples below), there is insufficient evidence to indicate that there is any value in the examination of dermal ridge patterns for the diagnosis of disease or for identifying disease susceptibility.


Dermatoglyphics, when correlated with  genetic abnormalities , aids in the diagnosis of  congenital malformations  at birth or soon after.


The relationship between different dermatoglyphic traits and various medical diseases have been widely evaluated.


Developmental homeostasis  is a process in which animals develop more or less normally, despite defective  genes  and deficient environments. [ 1 ]  It is an organism's ability to overcome certain circumstances in order to develop normally. This can be a circumstance that interferes with either a physical or mental trait. Many species have a specific norm, where those who fit that norm prosper while those who don't, don't survive or find it difficult to thrive. It is important that the animal be able to interact with the other group members effectively. Animals must learn their species' norms while they're young to live a normal, successful life for that species.


Developmental homeostasis determines how a species adapts to live a normal life. Therefore, it has been the focus of many experiments. These experiments are geared and designed to test the threshold for certain species to overcome and prosper despite certain circumstances. [ 2 ] [ 3 ]


Due to the fact that survival of the species is based on the ability to interact with their own kind in a normal manner, these experiments—which usually interfere with that—walk a fine line for animal rights and what is acceptable. One experiment that researches mental development homeostasis used rhesus monkeys. These experiments showed how young monkeys need physical contact with other monkeys to learn the social behaviors and interact with each other effectively. One way physical developmental homeostasis was tested was in the facial symmetry experiment where people were asked to rate which of the faces they saw as better looking. This experiment resulted in the pictures with more symmetrical faces being called better looking. This is not just found in humans but other experiments such as the brush-legged wolf spider and the barn swallow birds. Favored traits give the bearer an advantage in attracting high quality mates.


In species that value developmental homeostasis, both physically and mentally, the ability of one to adapt to social norms seems to increase the likelihood of having a reproductive advantage at being able to attract mates and leave offspring. [ 1 ] [ 4 ]


Developmental homeostasis attributes to the way many animals develop. This contains the way they develop normally or abnormally despite faulty genes and an insufficient environment. This property of development reduces the variation around a mean value for a phenotype, and reflects the ability of developmental processes to suppress some outcomes in order to generate an adaptive phenotype more reliably. [ 5 ]


The effects of developmental homeostasis were demonstrated in an experiment conducted in 1966 by Margaret and Harry Harlow. They wanted to test what the consequences of infant  rhesus monkeys  would be from being separated from their mothers and having little interaction with other monkeys. First, they were separated from their mothers for six to twelve hours after birth and placed with a human made mechanical substitute in which they called the "surrogate mother." [ 6 ]  These surrogates were made either of a wire cylinder structure or a terry cloth structure and were placed with the babies in a cage. The terry cloth structure was also placed with a nursing bottle. The monkeys preferred and clung to the cloth surrogate mother. In a short period of time the monkeys took on side effects of weight loss and abnormal physical development. Once the monkeys reached an age where they could eat solid foods, they were separated from their cloth mothers for three days. When they were reunited with their mothers, they clung to them and did not wander off. Young rhesus monkeys in their natural habitat normally explore and venture off. Harlow concluded from this that the need for contact comfort was stronger than the need to explore. Being isolated from social interaction also caused negative outcomes later in their life. The surrogate-raised monkeys exhibited depression and aggressive behavior as they would clutch to themselves, rock constantly back and forth, and avoid interaction with others. Not only affecting their social behavior, it also impacted their sexual interacting. The monkeys underwent little if any sexual posturing or reproduction in their lifetime. [ 7 ] [ better source needed ]


To test how much social experience is necessary or needed in normal development, the Harlows performed another experiment where they isolated young rhesus monkeys by limiting the interaction time with other monkeys. They gave them fifteen minutes a day with three other monkeys to interact. In the beginning, the monkeys would attach to each other and begin to play. Normal behavior of these monkeys in their natural habitat is that after the age of one month, they play with other monkeys of their own species and by six months are constantly interacting in groups. Results showed that over time, the monkeys developed relatively normal behavior and that limiting their social interaction as babies did not affect them interacting sexually and socially. They also did not exhibit any abnormal aggression or depression when socializing with other monkeys. [ 1 ]


In 1960,  Harry Harlow  began studying partial and total isolation of infant monkeys by raising them in cages. Partial isolation involved raising monkeys in bare wire cages that allowed them to see, smell, and hear other monkeys, but did not give them the opportunity for physical contact. Total social isolation involved rearing monkeys in isolation chambers that took away any and all contact with other monkeys. The results showed that when the monkeys were placed in partial isolation they displayed various abnormal behaviors such as blank staring, circling in their cages numerous times, and self-mutilation. The cages were placed in several locations. A few of the monkeys remained being tested in solitary confinement for fifteen years. [ 8 ]


In the total isolation experiments the baby monkeys were left alone for three, six, twelve, or twenty-four months. The experiments resulted in the monkeys being severely psychologically disturbed and abnormally developed. When first removed from isolation, they usually went into emotional shock by clutching to themselves and rocking multiple times. One of six monkeys isolated for three months refused to eat after release and died five days later. The longer the time in isolation, the more detrimental it was for the monkeys to act socially when placed with other monkeys. Harlow pointed out that no monkey had actually died during isolation. Harlow tried to reintegrate the monkeys who had been isolated for six months by placing them with monkeys who had been reared normally. He stated that it produced “severe deficits in virtually every aspect of social behavior” and that it “achieved only limited recovery of simple social responses.”  [ 9 ]


Developmental homeostasis plays a role in the development of symmetrical and asymmetrical bodies. This effect in species shows that individuals in species who have symmetrical features are more likely to obtain a mate over one who has asymmetrical features.


The  symmetry  in the facial features of humans could be found as appealing to men and women. This could be due to the ability to find prospective mates in responding positively to either body or facial symmetry. This could be because attributes announce the individual's capacity to overcome challenges to normal development. [ 1 ]  The human preference for symmetry can be explained by humans looking at  mate choice , mainly because symmetry is a reliable indicator in the genetic quality mates look for. The cognitive mechanisms and adaptive significance of facial attractiveness have been an interest of psychologists. Men and women find traits such as averageness, symmetry, and masculinity (in males) or femininity (in females) in faces attractive. [ 10 ]  It is noted that humans find symmetrical faces more attractive than asymmetrical faces. Disruptions to development caused by mutations or by an inability to secure critical material resources early in life could generate asymmetries in appearance. If body asymmetry reflects sub-optimal development of the brain or other important organs, a preference for symmetrical traits could enable the selective individual to acquire a partner with "good genes" to transfer to their offspring. [ 1 ]  Disruptions to development could be caused by stress, illness, or genetic factors.