Aquatic plants, especially the  Monocotyledons , include a large number of polyploids. [ 85 ]


The induction of polyploidy is a common technique to overcome the sterility of a hybrid species during plant breeding. For example,  triticale  is the hybrid of  wheat  ( Triticum turgidum ) and  rye  ( Secale cereale ). It combines sought-after characteristics of the parents, but the initial hybrids are sterile. After polyploidization, the hybrid becomes fertile and can thus be further propagated to become triticale.


In some situations, polyploid crops are preferred because they are sterile. For example, many seedless fruit varieties are seedless as a result of polyploidy. Such crops are propagated using asexual techniques, such as  grafting .


Polyploidy in crop plants is most commonly induced by treating seeds with the chemical  colchicine .


Some crops are found in a variety of ploidies:  tulips  and  lilies  are commonly found as both diploid and triploid;  daylilies  ( Hemerocallis  cultivars) are available as either diploid or tetraploid; apples and  kinnow mandarins  can be diploid, triploid, or tetraploid.


Besides plants and animals, the evolutionary history of various  fungal species  is dotted by past and recent whole-genome duplication events (see Albertin and Marullo 2012 [ 89 ]  for review). Several examples of polyploids are known:


In addition, polyploidy is frequently associated with  hybridization  and reticulate evolution that appear to be highly prevalent in several fungal taxa. Indeed,  homoploid speciation  (hybrid speciation without a change in  chromosome  number) has been evidenced for some fungal species (such as the  basidiomycota   Microbotryum violaceum [ 97 ] ).


As for plants and animals, fungal hybrids and polyploids display structural and functional modifications compared to their progenitors and diploid counterparts. In particular, the structural and functional outcomes of polyploid  Saccharomyces  genomes strikingly reflect the evolutionary fate of plant polyploid ones. Large chromosomal rearrangements [ 98 ]  leading to  chimeric  chromosomes [ 99 ]  have been described, as well as more punctual genetic modifications such as gene loss. [ 100 ]  The homoealleles of the allotetraploid yeast  S. pastorianus  show unequal contribution to the  transcriptome . [ 101 ]   Phenotypic  diversification is also observed following polyploidization and/or hybridization in fungi, [ 102 ]  producing the fuel for  natural selection  and subsequent  adaptation  and speciation.


Other eukaryotic  taxa  have experienced one or more polyploidization events during their evolutionary history (see Albertin and Marullo, 2012 [ 89 ]  for review). The  oomycetes , which are non-true fungi members, contain several examples of paleopolyploid and polyploid species, such as within the genus  Phytophthora . [ 103 ]  Some species of brown  algae  ( Fucales , Laminariales [ 104 ]  and  diatoms [ 105 ] ) contain apparent polyploid genomes. In the  Alveolata  group, the remarkable species  Paramecium  tetraurelia  underwent three successive rounds of whole-genome duplication [ 106 ]  and established itself as a major model for paleopolyploid studies.


Each  Deinococcus radiodurans   bacterium  contains 4-8 copies of its  chromosome . [ 107 ]  Exposure of  D. radiodurans  to  X-ray  irradiation or  desiccation  can shatter its  genomes  into hundred of short random fragments. Nevertheless,  D. radiodurans  is highly resistant to such exposures. The mechanism by which the genome is accurately restored involves RecA-mediated  homologous recombination  and a process referred to as extended  synthesis-dependent strand annealing (SDSA) . [ 108 ]


Azotobacter vinelandii  can contain up to 80 chromosome copies per cell. [ 109 ]  However this is only observed in fast growing cultures, whereas cultures grown in synthetic minimal media are not polyploid. [ 110 ]


The  archaeon   Halobacterium salinarium  is polyploid [ 111 ]  and, like  Deinococcus radiodurans , is highly resistant to X-ray irradiation and desiccation, conditions that induce  DNA  double-strand breaks. [ 112 ]  Although chromosomes are shattered into many fragments, complete chromosomes can be regenerated by making use of overlapping fragments. The mechanism employs single-stranded  DNA binding protein  and is likely  homologous recombinational  repair. [ 113 ]


PTC tasting  is a classic  genetic marker  in  human population genetics  investigations.


In 1931 Arthur Fox, a chemist at DuPont, in Wilmington, Delaware, synthesized phenylthiocarbamide (PTC). Some researchers reported a bitter taste when entering his laboratory, while others, including Fox himself, experienced no such sensation. [ 1 ]  Further study of this phenomenon by L.H. Snyder in 1931 led to the conclusion that the inability to taste PTC is a recessive trait. [ 2 ]
In 1932, Albert Blakeslee conducted a large-scale study involving the inheritance of PTC tasting within families that concluded that PTC tasting sensitivity is very likely a complex Mendelian trait whose variance is overwhelmingly dependent on a single gene locus; however, it is likely that a few other genes have a smaller effect as well. [ 3 ]


In 1939 Fisher et al. found that the genetic frequency of PTC tasting was the same in chimps and humans. This similarity suggests that whatever gene controls for PTC tasting must have some sort of a selective advantage in order to have either evolved and been maintained for millions of years since before humans and chimps diverged into separate species, or to have evolved in two separate events after species divergence. [ 4 ]  Since finding out that PTC tasting had an apparent naturally selective advantage, scientists began to hypothesize that this advantage was that the ability to taste natural chemicals similar to PTC helped human ancestors stay away from some toxic plants. Substances that resemble PTC today are in some vegetables from the cabbage family ( Brassicaceae ), such as broccoli and Brussels sprouts. [ 5 ] [ circular reference ]


In 1950, William Boyd found evidence that the same gene that controls for PTC tasting also controls for the "tasting" of a different compound that acts as an antithyroid drug similar to that found in cabbage plants. [ 6 ]  Despite all of this compelling evidence for PTC "tasters" to have a selective advantage over "non-tasters," there was no explanation for the consistent proportions of "non-taster" in human and chimp populations until scientists discovered that subjects with a "PTC non-taster" phenotype were able to taste a different bitter compound that "PTC tasters" could not. This compound was juice from an  antidesma  plant and notably, this study found a perfectly inverse relationship between PTC and antidesma tasting. [ 7 ]  These results were replicated in 2005 by another team of researchers who found the same inverse relationship between PTC and antidesma tasting [ 8 ]  However, in 2018, Davide Risso and colleagues expanded upon this relationship when they discovered a notable difference from previous studies. What they found was that there appeared to be a small population of people who could taste both "PTC" and antidesma as bitter. [ 9 ]  This finding could suggest a possible advantage for heterozygotes given their ability to taste both bitter compounds.


In 1999, Mark Hoon and a team of researchers discovered a gene family that codes for taste receptors, specifically for the "bitter" flavor which they called the TAS2R gene family. The locus of the gene (or genes) that control for PTC tasting is hypothesized to be a part of this TAS2R gene family. In 2003,  Dennis Drayna  and his colleagues at the  National Institutes of Health  (NIH), [ 10 ]  as well as a team of researchers led by Un-kyung Kim, [ 11 ]  discovered that a variation at the  TAS2R38  gene locus is responsible for an overwhelming majority of the variance in PTC tasting sensitivity (50-80%).


It has been suggested that taste and smell receptors are controlled by  TAS2R38 , with a small intron gene of about 1000 nucleotides. It is a member of the family of G protein-coupled or 7 trans membrane cross  receptors . The binding of a ligand to the extracellular region of the receptor sets an action potential that sends an impulse to the sensory cortex of the brain, where it is interpreted as a bitter taste.


This allows an experimental test for  SNP  at position 145 that has the highest correlation to the sample 3 polymorphisms. The test isolates DNA from cheek cells by a simple salt mouthwash and amplification of a region of the gene  TAS2R38 . The amplified fragment (amplicon) is incubated with the restriction enzyme  HaeIII , comprising the SNP in their recognition sequence GGCC. HaeIII cuts the taster allele (having the sequence GGCC); this generates a length  polymorphism , and the 2 alleles can be easily separated in an agarose gel.


Virtually all non-tasters (dd) cannot taste PTC, while homozygous tasters ( TT ) occasionally report an inability or weak ability to taste the chemical. The heterozygous  genotype  ( Tt ) has the "leakiest"  phenotype  as reduced or absent tasting ability is relatively common. This is formally called a  heterozygous effect .


In 1949, Harris and Kalmus developed a method for differentiation of bimodal threshold stimuli for tasting  PTC . They proposed a series of 13 solutions of these substances with serial water by halves from the initial concentration of 0.13%, so that the solution in the final test contained only a few molecules of this substance. Pure water was used as the fourteenth test liquid to provide a control. Differentiation between the two  phenotypes  of "tasters" and "non-tasters" occurred with the fifth solution. Then assuming that the conditional  dimorphism  controlled by two  allele  of the corresponding  gene  locus, the allele which controls the absence of sensitivity to taste PTC is  recessive   homozygote . [ 12 ] [ 13 ]


Although the view of the genetics of individual sensitivity to taste PTC changed, practically all the current data on the PTC taste (in)ability established certain of these substances originate from research by Harris and Kalmus, and such investigations are still taken. This is probably because it is not suggested a better method for mass  population genetics  projects.


In  genetics , a  reciprocal cross  is a breeding experiment designed to test the role of parental sex on a given inheritance pattern. [ 1 ]   All parent organisms must be  true breeding  to properly carry out such an experiment.  In one cross, a male expressing the trait of interest will be crossed with a female not expressing the trait.  In the other, a female expressing the trait of interest will be crossed with a male not expressing the trait. It is the cross that could be made either way or independent of the sex of the parents.
For example, suppose a biologist wished to identify whether a hypothetical allele Z, a variant of some gene A, is on the male or female sex chromosome. They might first cross a Z-trait female with an A-trait male and observe the offspring. Next, they would cross an A-trait female with a Z-trait male and observe the offspring. Via principles of dominant and recessive alleles, they could then (perhaps after cross-breeding the offspring as well) make an inference as to which sex chromosome contains the gene Z, if either in fact did.


Given that the trait of interest is either  autosomal  or  sex-linked  and follows by either  complete dominance  or  incomplete dominance , a reciprocal cross following two generations will determine the mode of inheritance of the trait.


Sex linkage  was first reported by Doncaster and Raynor in 1906 [ 2 ]  who studied the inheritance of a colour mutation in a moth,  Abraxas grossulariata .  Thomas Hunt Morgan  later showed that a new white-eye mutation in  Drosophila melanogaster  was also sex-linked.  He found that a white-eyed male crossed with a red-eyed female produced only red-eyed offspring.  However, when they crossed a red-eyed male with a white-eyed female, the male offspring had white eyes while the female offspring had red eyes.  The reason was that the white eye allele is sex-linked (more specifically, on the X chromosome) and recessive.


The analysis can be more easily shown with  Punnett squares :


Red eye Female


White eye Male


Red eye Male


As shown in Table 1, the male offspring are white-eyed and the female offspring are red-eyed.  The female offspring are carrying the mutant white-eye allele X(mut), but do not express it phenotypically because it is recessive.  Although the males carry only one mutant allele like the females, the X-chromosome takes precedence over the Y and the recessive phenotype is shown.


As shown in Table 2, all offspring are Red-eyed.  The males are free of the mutation.  The females however, are  carriers . [ 3 ]


Genetic diversity  is often a major consideration in e g forest crops.


Consider the gene pool of a  seed orchard  crop or other source of seeds with parents. The gene pool is large as there are many seeds in a seed crop, so there is no  genetic drift . The probability that the first gene originates from genotype i in the seed orchard is p i , and the probability that the second originates from genotype j is p j . The probability that these two genes originate from the orchard genotypes i and j are identical by descent (IBD) is θ ij . This is the  Malecot's method of coancestry [ 1 ]   (or "coefficient of kinship"; "coefficient of relationship" is a similar measure which can be computed) between genotype i and j.  The probability that any pair of genes is IBD, Θ, can be found by adding over all possible pairs of genes from N parents. The formula for the group coancestry (from which gene diversity can be obtained) of seed orchard crops is: [ 2 ]


Θ=

 ∑

 i
 =
 1

 N

 ∑

 j
 =
 1

 N

 {\displaystyle \sum _{i=1}^{N}\sum _{j=1}^{N}}

   p i p j θ ij .


The group coancestry of a seed orchard crop can be divided in two terms, one for self-coancestry and one for cross-coancestry:


Θ=

 ∑

 i
 =
 1

 N

 {\displaystyle \sum _{i=1}^{N}}

   p i 2 (1+F i )/2 +

 ∑

 i
 =
 1

 N

 {\displaystyle \sum _{i=1}^{N}}

 ∑

 j
 =
 1

 N

 {\displaystyle \sum _{j=1}^{N}}

   p i p j θ ij , the last summation excluding j=i.


Let’s consider a simple case. If the seed orchard genotypes are unrelated the second term is zero, if there is no inbreeding, the first term becomes simple. For no relatedness and no inbreeding, status number (N S , effective number of parents) becomes:


N S  = 1/

 ∑

 i
 =
 1

 N

 {\displaystyle \sum _{i=1}^{N}}

   p i 2


Similar but less developed expressions has been used many times before, it has similarities to the concept of effective population size as defined by A. Robertson in 1961. [ 3 ]


Mendelian  traits behave according to the model of monogenic or simple  gene  inheritance in which one gene corresponds to one trait.  Discrete  traits (as opposed to continuously varying traits such as height) with simple Mendelian inheritance patterns are relatively rare in nature, and many of the clearest examples in humans cause  disorders . Discrete traits found in humans are common examples for teaching genetics.


According to the model of  Mendelian inheritance ,  alleles  may be  dominant  or recessive, one allele is inherited from each parent, and only those who inherit a recessive allele from each parent exhibit the recessive  phenotype . Offspring with either one or two copies of the dominant allele will display the dominant phenotype.


Very few phenotypes are purely Mendelian traits. Common violations of the Mendelian model include  incomplete dominance ,  codominance ,  genetic linkage ,  environmental effects , and quantitative contributions from a number of genes (see:  gene interactions ,  polygenic inheritance ,  oligogenic inheritance ). [ 1 ] [ 2 ]


OMIM  (Online Mendelian Inheritance in Man) [ 3 ]  is a comprehensive database of human genotype–phenotype links. Many visible human traits that exhibit high heritability were included in the older McKusick's  Mendelian Inheritance in Man . Before the discovery of  genotyping , they were used as  genetic markers  in medicolegal practice, including in cases of disputed  paternity .


In  genetics , the term  synteny  refers to two related concepts:


The Encyclopædia Britannica gives the following description of synteny, using the modern definition: [ 2 ]


Genomic sequencing and mapping have enabled comparison of the general structures of genomes of many different species. The general finding is that organisms of relatively recent divergence show similar blocks of genes in the same relative positions in the genome. This situation is called synteny, translated roughly as possessing common chromosome sequences. For example, many of the genes of humans are syntenic with those of other mammals—not only apes but also cows, mice, and so on. Study of synteny can show how the genome is cut and pasted in the course of evolution.


Synteny  is a  neologism  meaning "on the same ribbon";  Greek :  σύν ,  syn  "along with" +  ταινία ,  tainiā  "band". This can be interpreted classically as "on the same chromosome", or in the modern sense of having the same order of genes on two (homologous) strings of DNA (or chromosomes).


The classical concept is related to  genetic linkage : Linkage between two loci is established by the observation of lower-than-expected  recombination  frequencies between them. In contrast, any loci on the same chromosome are by definition syntenic, even if their recombination frequency cannot be distinguished from unlinked loci by practical experiments. Thus, in theory, all linked loci are syntenic, but not all syntenic loci are necessarily linked. Similarly, in  genomics , the genetic loci on a chromosome are syntenic regardless of whether this relationship can be established by experimental methods such as  DNA sequencing /assembly,  genome walking , physical localization or  hap-mapping .


Students of (classical) genetics employ the term synteny to describe the situation in which two genetic loci have been assigned to the same chromosome but still may be separated by a large enough distance in map units that genetic linkage has not been demonstrated.


Shared synteny (also known as conserved synteny) describes preserved co-localization of genes on chromosomes of different species. During  evolution , rearrangements to the genome such as  chromosome translocations  may separate two loci, resulting in the loss of synteny between them. Conversely, translocations can also join two previously separate pieces of chromosomes together, resulting in a gain of synteny between loci. Stronger-than-expected shared synteny can reflect selection for functional relationships between syntenic genes, such as combinations of alleles that are advantageous when inherited together, or shared regulatory mechanisms. [ 3 ]


In light of the more recent shift in the meaning of  synteny , this conservation of gene content and linkage without preservation of order has also been termed  mesosynteny . [ 4 ]


The term is currently (since ~2000) more commonly used to describe preservation of the precise order of genes on a chromosome passed down from a common ancestor, [ 5 ] [ 6 ] [ 7 ] [ 8 ]  despite more "old school" geneticists rejecting what they perceive as a misappopriation of the term, [ 9 ]  preferring  collinearity  instead. [ 10 ]


The analysis of synteny in the gene order sense has several applications in genomics. Shared synteny is one of the most reliable criteria for establishing the  orthology  of genomic regions in different species. Additionally, exceptional conservation of synteny can reflect important functional relationships between genes. For example, the order of genes in the " Hox cluster ", which are key determinants of the  animal   body plan  and which interact with each other in critical ways, is essentially preserved throughout the animal kingdom. [ 11 ]


Synteny is widely used in studying complex genomes, as  comparative genomics  allows the presence and possibly function of genes in a simpler, model organism to infer those in a more complex one. For example, wheat has a very large, complex genome which is difficult to study. In 1994 research from the  John Innes Centre  in England and the National Institute of Agrobiological Research in Japan demonstrated that the much smaller rice genome had a similar structure and gene order to that of wheat. [ 12 ]  Further study found that many cereals are syntenic  [ 13 ]  and thus plants such as  rice  or the grass  Brachypodium  could be used as a model to find genes or genetic markers of interest which could be used in wheat breeding and research. In this context, synteny was also essential in identifying a highly important region in wheat, the Ph1 locus involved in genome stability and fertility, which was located using information from syntenic regions in rice and Brachypodium. [ 14 ]


Synteny is also widely used in microbial genomics. In  Hyphomicrobiales  and  Enterobacteriales , syntenic genes encode a large number of essential cell functions and represent a high level of functional relationships. [ 15 ]


Patterns of shared synteny or synteny breaks can also be used as  characters  to infer the  phylogenetic  relationships among several species, and even to infer the genome organization of extinct ancestral species. A qualitative distinction is sometimes drawn between  macrosynteny , preservation of synteny in large portions of a chromosome, and  microsynteny , preservation of synteny for only a few genes at a time.


Shared synteny between different species can be inferred from their genomic sequences. This is typically done using a version of the MCScan algorithm, which finds syntenic blocks between species by comparing their homologous genes and looking for common patterns of collinearity on a chromosomal or  contig  scale. Homologies are usually determined on the basis of high bit score  BLAST  hits that occur between multiple genomes. From here,  dynamic programming  is used to select the best scoring path of shared homologous genes between species, taking into account potential gene loss and gain which may have occurred in the species' evolutionary histories. [ 16 ]


Under the  law of dominance  in  genetics , an individual expressing a  dominant   phenotype  could contain either two copies of the dominant  allele  ( homozygous  dominant) or one copy of each dominant and  recessive  allele ( heterozygous  dominant). [ 1 ]  By performing a test cross, one can determine whether the individual is heterozygous or homozygous dominant. [ 1 ]


In a test cross, the individual in question is bred with another individual that is homozygous for the recessive trait and the  offspring  of the test cross are examined. [ 2 ]  Since the homozygous recessive individual can only pass on recessive alleles, the allele the individual in question passes on determines the phenotype of the offspring. [ 3 ]  Thus, this test yields 2 possible situations:


The first uses of test crosses were in  Gregor Mendel ’s  experiments in plant hybridization . While studying the inheritance of dominant and recessive traits in pea plants, he explains that the “signification” (now termed  zygosity ) of an individual for a dominant trait is determined by the expression patterns of the following generation. [ 4 ]


Rediscovery of Mendel’s work in the early 1900s led to an explosion of experiments employing the principles of test crosses. From 1908-1911,  Thomas Hunt Morgan  conducted test crosses while determining the inheritance pattern of a white eye-colour mutation in  Drosophila . [ 5 ]  These test cross experiments became hallmarks in the discovery of  sex-linked traits .


A test cross involves crossing an individual organism with a dominant genotype or phenotype with another organism exhibiting a recessive genotype or phenotype. To better grasp the concept of test crossing, let's explore various types of crosses involving one or more genes of interest.


Monohybrid crossing is a fertilization process which entails two purebred parents that consist of a difference in only one characteristic, where the resulting offspring become monohybrids. It is utilized to test only one type of gene or phenotype. [ 6 ]


Monohybrid, also called “single gene test cross”, is used to observe how homozygous offspring express heterozygous genotypes inherited from their parents.


The implantation of monohybrid crossing includes signifying the alleles by using characters – recessive allele often is indicated with a lower-case letter, and the dominant allele is indicated with an upper-case letter. The phenotype and the genotype of both parents being crossed are noted, including the genotype of the gametes from the parental generation. The predictions of the combinations of the gametes will be constructed on a  Punnett square . [ citation needed ]


In conducting a monohybrid cross, Mendel initiated the experiment with a pair of pea plants exhibiting contrasting traits, one being tall and the other dwarf. Through cross-pollination, the resulting offspring plants manifested the tall trait. These first-generation hybrids were termed  F1 , with their offspring referred to as Filial or F1 progeny.


Mendel observed that characteristics that were absent in F1 generation had reappeared in the F2 generation. He referred the suppressed characteristic as recessive and the expressed characteristics as dominant characteristic. [ citation needed ]


Mendel furthermore determined to explore the outcome of crossing two plants that were hybrids for a single trait. This investigation aimed to determinate the inheritance patterns of two characteristics simultaneously and to verify the hypothesis that the inheritance of one trait would remain independent of the other. Termed a dihybrid cross or “two-gene test cross”, this experiment was grounded in the principle of  segregation . When conducting a dihybrid test cross, two dominant phenotypic characteristics are selected and crossed with parents displaying double recessive traits. The phenotypic characteristics of the F1 generation are then analyzed. In such a test cross, if the individual being tested is heterozygous, a phenotypic ratio of 1:1:1:1 is typically observed. [ 7 ]


To test Mendel’s idea, he performed complex crosses with plants that were purebred for two characteristics: seed color (yellow and green), seed shape (round and wrinkled). He crossed plants with wrinkled and yellow seeds and plants with round and green seeds. Due to earlier cross testing with monohybrids, Mendel anticipated that the round and yellow seeds were dominant with the purebred crossing, and that is what he observed. [ 8 ]


Test crosses have a variety of applications.  Model organisms , such as  Caenorhabditis elegans  and  Drosophila melanogaster , are commonly used for test crosses. Basic procedures for performing test crosses in these organisms are provided below:


To perform a test cross with  C. elegans , place worms with a known recessive genotype with worms of an unknown genotype on an agar plate. Allow the male and hermaphrodite worms time to mate and produce offspring. Using a microscope, the ratio of recessive versus dominant phenotype will elucidate the genotype of the dominant parent. [ 9 ]


To perform a test cross with  D. melanogaster , select a trait with a known dominant and recessive phenotype. Red eye colour is dominant and white is recessive. Obtain virgin females with white eyes, young males with red eyes, and put them into a single tube. Once offspring begin to appear as larvae, remove parental lines and observe the phenotype of adult offsprings. [ 10 ]


There are many limitations to test crosses. It can be a time-consuming process as some organisms require a long growing time in each generation to show the necessary phenotype. [ 11 ]  A large number of offspring are also required to have reliable data due to statistics. [ 12 ]  Test crosses are only useful if dominance is complete. Incomplete dominance is when the dominant allele and recessive allele come together to form a blend of the two phenotypes in the offspring. Test crosses are also not applicable with  codominant  genes, where both phenotypes of a heterozygote trait will be expressed. Another limitation is for  epistatic mutations  where the expression of a gene will be overpowered by the expression of another gene. [ 13 ]  A trait can also be determined by multiple genes, known as  polygenic inheritance . Genes also have different levels of  penetrance , which determines how much they will be expressed. In addition, the environment affects the expression of numerous genes, therefore making the test cross inapplicable in many cases.


As more advanced techniques to determine genotype emerge, the test cross is becoming less prevalent in genetics.  Genetic testing  and  genome mapping  are modern advances which allow for more efficient and detailed information about one’s genotype to be determined. [ 14 ]  Test crosses, however, are still used to this day and have created an excellent foundation for the development of more sophisticated techniques.


The term  transheterozygote  is used in modern genetics periodicals in two different ways. In the first, the transheterozygote has one mutant (-) and one wildtype  allele  (+) at each of two different  genes  (A-/A+ and B-/B+ where A and B are different genes). In the second, the transheterozygote carries two different mutated alleles of the same gene (A*/A', see example below). This second definition also applies to the term "heteroallelic combination".


Organisms with one mutant and one wildtype allele at one locus are called simply  heterozygous , not  trans heterozygous.


Transheterozygotes are useful in the study of  genetic interactions  and  complementation  testing.


A  transheterozygote  is a  diploid  organism that is heterozygous at two different  loci  (genes). Each of the two loci has one natural (or  wild type ) allele and one  allele  that differs from the natural allele because of a  mutation . Such an organism can be created by crossing together two organisms that carry one mutation each, in two different genes, and selecting for the presence of both mutations simultaneously in an individual offspring. The offspring will have one mutant allele and one wildtype allele at each of the two genes being studied.


Transheterozygotes are useful in the study of  genetic interactions . An example from  Drosophila  research: the wing vein phenotype of a recessive mutation in the Epidermal growth factor receptor (Egfr), a gene required for communication between cells, can be dominantly enhanced by a recessive mutation in Notch, another cell-signalling gene. [ 1 ]  A transheterozygote between Egfr and Notch has the genotype  Notch/+ ; Egfr/+  (where  Notch  and  Egfr  represent mutant alleles, and + represents wildtype alleles). The dominant interaction between Egfr and Notch suggested that the Egfr and Notch signalling pathways act together within the cell to affect the pattern of veins in the fly's wings.


Transheterozygote  refers to a  diploid  organism for which both  alleles  are different  mutated  versions of the normal (or  wild type ) allele. The presence of two different mutant alleles at the same locus are often referred to as a  heteroallelic combination .


A transheterozygous (heteroallelic) organism can be created by first crossing together two mutants, each with a different mutation affecting the same locus, and screening for the presence of both alleles simultaneously in an individual offspring. A recent research paper using this definition [ 2 ]  reported cases of  transvection  between different alleles of Hsp90.


This second definition is also sometimes applied to the situation where two different chromosomal deletions exist in trans (on the different homologous chromosomes) and fail to complement because they disrupt one or more common genes. (For example, Df(E1)/Df(GN50) in Stowers, et al. 2000 [ 3 ] ).


By way of example, transheterozygote (heteroallelic combination) can result from a cross between two organisms with  genotypes  AA* and AA', where A is the wild type allele of a given gene, and A* and A' are two different mutant alleles of that gene. As can be seen in the following  Punnett square , approximately one fourth of the offspring of this cross will inherit both the A* and A' mutant alleles, resulting in a transheterozygote genotype of A*A'.


Transheterozygotes are useful in  complementation  testing, as pioneered by  geneticist   Edward B. Lewis . If a transheterozygote inheriting two unknown  recessive  mutations continues to show the mutant  phenotype , it can be concluded that both mutations must be in the same  gene , because inheritance of just one recessive mutation in each of two different genes would result in an organism displaying the  dominant  wild type phenotype.


In  genetics ,  underdominance , also known as  homozygote advantage ,  heterozygote disadvantage , or  negative overdominance, " [ 1 ]  is the opposite of  overdominance . It is the  selection  against the  heterozygote , causing  disruptive selection [ 2 ]  and divergent  genotypes . Underdominance exists in situations where the heterozygotic  genotype  is inferior in  fitness  to either the dominant or recessive homozygotic genotype. Compared to examples of overdominance in actual populations, underdominance is considered more unstable [ 3 ] [ 4 ]  and may lead to the  fixation  of either allele. [ 1 ] [ 5 ] [ 6 ]


An example of stable underdominance may occur in individuals who are heterozygotic for polymorphisms that would make them better suited for one of two  niches . [ 7 ]  Consider a situation in which a population is completely homozygotic for an "A"  allele , allowing exploitation of a particular resource. Eventually, a polymorphic "a" allele may be introduced into the population, resulting in an individual who is capable of exploiting a different resource. This would result in an "aa" homozygotic invasion of the population due to nonexistent competition of the unexploited resource. The frequency of "aa" individuals would increase until the abundance of the "a" resource begins to decline. Eventually, the "AA" and "aa" genotypes would reach equilibrium with each other, with "Aa" heterozygotic individuals potentially experiencing a reduced fitness compared to those individuals who are homozygotic for utilization of either resource. This example of underdominance is stable because any shift in equilibrium would result in selection for the rare allele due to increased resource abundance. This compensatory selection would ultimately return the dimorphic system to underdominant  equilibrium . [ 7 ]


An example of stable underdominance can be found in the African butterfly species  Pseudacraea eurytus , which utilizes  Batesian mimicry  to escape  predation . This species possesses two alleles which each confer an appearance similar to that of another local butterfly species that is toxic to its predator. Individuals who are heterozygous for this trait appear to be intermediate in appearance and thus experience increased predation and lowered overall fitness. [ 8 ]


Models of stable underdominance have shown potential in driving the introduction of refractory genes into pest populations that are responsible for the spread of infective diseases such as  malaria  and  dengue fever . [ 9 ]  A refractory gene alone would not have higher fitness than the native genes, but engineered underdominance may prove effective as a mechanism to spread such a gene. In this model, two genetics constructs are introduced into two non- homologous chromosomes . Each construct is lethal when expressed individually but can be suppressed by the other construct. In this way, individuals with only one of the two constructed genes (heterozygotes) are selected against, but homozygotes with both or neither construct are genetically healthy. Analysis of this model using simple population genetics shows that successful spread of refractory genes using this engineered underdominance is possible with relatively small release of the constructed genotype into the population. [ 9 ]


A similar system of manipulation of pest populations was achieved in a population of  Drosophila melanogaster  by using a  knock-down /rescue system. [ 10 ]  The genetic construct in this system employs a dsRNAi knockdown of a  C-reactive protein , RpL14, as well as a rescue element (a complete copy of the  wild type  RpL14 gene). Individuals that are heterozygous for this construct experience lowered fitness due to limited restoration of the RpL14 gene, which results in reduced female fertility and delayed development, along with various other mutations that ultimately lower fitness by 70-80%. [ 10 ]  This system of underdominance allowed manipulation of the population and ultimate fixation of the constructed genotype and has potential applications in a number of settings, including agriculture and the reduction of various pest-carried diseases.


white , abbreviated  w , was the first  sex-linked   mutation  discovered, found in the  fruit fly  Drosophila melanogaster . In 1910  Thomas Hunt Morgan  and  Lilian Vaughan Morgan  collected a single male white-eyed  mutant  from a  population  of  Drosophila melanogaster  fruit flies, which usually have dark brick red  compound eyes . Upon crossing this male with  wild-type  female flies, they found that the offspring did not conform to the expectations of  Mendelian inheritance . [ 1 ]  The first generation (the F1) produced 1,237 red-eyed offspring and three white-eyed male flies. The second generation (the F2) produced 2,459 red-eyed females, 1,011 red-eyed males, and 782 white-eyed males. Further experimental crosses led them to the conclusion that this mutation was somehow physically connected to the "factor" that determined sex in  Drosophila . This led to the discovery of  sex linkage , in which the gene for a trait is found on a  sex chromosome . Morgan named this trait  white , now abbreviated  w . [ 2 ]  Flies possessing the  white   allele  are frequently used to introduce high school and college students to genetics.


The protein coded by the  white  gene functions as an  ATP-binding cassette (ABC) transporter . It carries the precursors of the red and brown eye color pigments,  guanine  and  tryptophan , into the developing eyes during pupation. [ 4 ]  White-eyed flies are not blind; instead they are easily temporarily blinded by bright light at certain frequencies because they lack the protection provided by the red and brown pigments. [ 5 ]  The human version of  white  is  ABCG1 , and is involved in transporting lipids and  cholesterol  into cells.


Drosophila melanogaster  with the white eye mutation typically have shorter life spans than wildtype  Drosophila . They also experience many neurological deficiencies in addition to eye defects. Some of the deficiencies that they experience includes difficulty in mobility, and a low stress tolerance.  Drosophila melanogaster  with the white eye mutation often experience an increased sensitivity to light and a decrease in visual acuity. They have significantly less in the number of synaptic vesicles of photoreceptors.


White eye mutants of  Drosophila melanogaster  experience a lower rate of reproduction than their wildtype counterparts because they experience a reduced rate of sexual arousal during daylight. [ 6 ]  Ectopic expression of  white+  induces male-male courtship in  Drosophila . [ 7 ]   White+  controls the copulation success in  Drosophila melanogaster . [ 8 ]


The  wild type  ( WT ) is the  phenotype  of the typical form of a  species  as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard [ 1 ]  "normal"  allele  at a locus, in contrast to that produced by a non-standard, " mutant " allele.  "Mutant" alleles can vary to a great extent, and even become the wild type if a genetic shift occurs within the population.  Continued advancements in genetic mapping technologies have created a better understanding of how mutations occur and interact with other genes to alter phenotype. [ 2 ]  It is now appreciated that most or all gene loci exist in a variety of allelic forms, which vary in  frequency  throughout the geographic range of a species, and that a uniform wild type does not exist. In general, however, the most prevalent allele – i.e., the one with the highest gene frequency – is the one deemed wild type. [ 3 ]


The concept of wild type is useful in some experimental organisms such as fruit flies  Drosophila melanogaster , in which the standard phenotypes for features such as eye color or wing shape are known to be altered by particular  mutations  that produce distinctive phenotypes, such as "white eyes" or "vestigial wings".  Wild-type alleles are indicated with a "+" superscript, for example  w +  and  vg +  for red eyes and full-size wings, respectively.  Manipulation of the genes behind these traits led to the current understanding of how organisms form and how traits mutate within a population.  Research involving the manipulation of wild-type alleles has application in many fields, including fighting disease and commercial food production.


The genetic sequence for wild-type versus "mutant" phenotypes and how these genes interact in expression is the subject of much research.  Better understanding of these processes is hoped to bring about methods for preventing and curing diseases that are currently incurable such as infection with the herpes virus. [ 4 ]  One example of such promising research in these fields was the study done examining the link between wild-type mutations and certain types of lung cancer. [ 5 ]   Research is also being done dealing with the manipulation of certain wild-type traits in viruses to develop new vaccines. [ 6 ]  This research may lead to new ways to combat deadly viruses such as the  Ebola virus [ 7 ]  and  HIV . [ 8 ]  Research using wild-type mutations is also being done to establish how viruses transition between species to identify harmful viruses with the potential to infect humans. [ 9 ]


Selective breeding  to enhance the most beneficial traits is the structure upon which agriculture is built, this expedited the evolution process to make crop plants and animals larger and more disease resistant. Genetic manipulation went further. [ 10 ] [ 11 ]  Genetic alteration of plants leads to not only larger crop production, but also more nutritious products, allowing isolated populations to receive vital vitamins and minerals that would otherwise be unavailable to them.  Utilization of these wild-type mutations has also led to plants capable of growing in extremely arid environments, making more of the planet habitable than ever before. [ 12 ]   As more is understood about these genes, agriculture will continue to become a more efficient process, which will be relied upon to sustain a continually growing population. Amplification of advantageous genes allows the best traits in a population to be present at much higher percentages than normal, although this practice has been the subject of some  ethical debate .  These changes have also been the reason behind certain plants and animals being almost unrecognizable when compared to their ancestral lines. [ citation needed ]


Y linkage , also known as  holandric inheritance  (from  Ancient Greek  ὅλος  hólos , "whole" + ἀνδρός  andrós , "male"), [ 1 ]  describes traits that are produced by genes located on the  Y chromosome . It is a form of  sex linkage .


Y linkage can be difficult to detect. This is partly because the Y chromosome is small and contains fewer genes than the  autosomal chromosomes  or the  X chromosome . It is estimated to contain about 200 genes. Earlier, the human Y chromosome was thought to have little importance;. [ 2 ]  Although the Y-chromosome is sex-determining in humans and some other species, not all genes that play a role in sex determination are Y-linked. The Y-chromosome, generally does not undergo  genetic recombination  and only small regions called  pseudoautosomal regions  exhibit recombination. The majority of the Y-chromosome genes that do not recombine are located in the "non-recombining region". [ 3 ]


For a trait to be considered Y linkage, it must exhibit these characteristics:


These requirements were established by the pioneer of Y linkage, Curt Stern. Stern detailed in his paper genes he suspected to be Y-linked. [ 4 ]  His requirements at first made Y linkage hard to prove. In the 1950s using human pedigrees, many genes were incorrectly determined to be Y-linked. [ 5 ]  Later research adopted more advanced techniques and more sophisticated statistical analysis. [ 6 ]  Hairy ears are an example of a gene once thought to be Y-linked in humans; however, that hypothesis was discredited. [ 5 ]  Due to advancements in  DNA sequencing , Y linkage is getting easier to determine and prove. The Y-chromosome has been entirely mapped, [ 7 ]  revealing many Y-linked traits. [ 8 ]


Y linkage is similar to, but different from X linkage; although, both are forms of  sex linkage . X linkage can be genetically linked and sex-linked, while Y linkage can only be genetically linked. This is because males' cells have only one copy of the Y-chromosome. X-chromosomes have two copies, one from each parent permitting recombination. The  X chromosome  contains more genes and is substantially larger.


Some ostensibly Y-linked traits have not been confirmed. One example is hearing impairment. Hearing impairment was tracked in one specific family and through seven generations all males were affected by this trait. However, this trait occurs rarely and has not been entirely resolved. [ 9 ]


Y-chromosome  deletions  are a frequent genetic cause of  male infertility .


In guppies, Y-linked genes help determine sex selection. This is done indirectly by traits that allow the guppy to appear more attractive to a prospective mate. These traits were shown to be on the Y-chromosome and thus Y-linked. [ 10 ]  Also in guppies, it appears that the four measures of sexual activity is Y-linked. [ 11 ]


Hypertension , or high blood pressure, appears to be Y-linked in the hypertensive rat. One loci was autosomal. However, the second component appeared to be Y-linked. This held through the third generation of rats. Male offspring with a hypertensive father had significantly higher blood pressure than male offspring with a hypertensive mother indicating that a component of the trait was Y-linked. The results were not the same in females as in males, further hinting at a Y-component. [ 12 ]


Hairy ears were thought to be a Y-linked trait, [ 13 ]  but this was disproven. [ 5 ]


In general, traits that exist on the Y chromosome are Y-linked because they only occur on that chromosome and do not change in recombination.


As of 2000, a number of genes were known to be Y-linked, including: [ 14 ]


Zygosity  (the noun,  zygote , is from the Greek  zygotos  "yoked," from  zygon  "yoke")  ( / z aɪ ˈ ɡ ɒ s ɪ t i / ) is the degree to which both copies of a  chromosome  or  gene  have the same genetic sequence. In other words, it is the degree of similarity of the  alleles  in an organism.


Most  eukaryotes  have two matching sets of  chromosomes ; that is, they are  diploid . Diploid organisms have the same  loci  on each of their two sets of  homologous chromosomes  except that the sequences at these loci may differ between the two chromosomes in a matching pair and that a few chromosomes may be mismatched as part of a chromosomal  sex-determination system . If both alleles of a diploid organism are the same, the organism is  homozygous  at that locus. If they are different, the organism is  heterozygous  at that locus. If one allele is missing, it is  hemizygous , and, if both alleles are missing, it is  nullizygous .


The DNA sequence of a gene often varies from one individual to another. These gene variants are called  alleles . While some genes have only one allele because there is low variation, others have only one allele because deviation from that allele can be harmful or fatal. But most genes have two or more alleles. The frequency of different alleles varies throughout the population. Some genes may have alleles with equal distributions. Often, the different variations in the genes do not affect the normal functioning of the organism at all. For some genes, one allele may be common, and another allele may be rare. Sometimes, one allele is a  disease -causing variation while another allele is healthy. [ citation needed ]


In diploid organisms, one allele is inherited from the male parent and one from the female parent. Zygosity is a description of whether those two alleles have identical or different DNA sequences. In some cases the term "zygosity" is used in the context of a single chromosome. [ 1 ]


The words  homozygous ,  heterozygous , and  hemizygous  are used to describe the  genotype  of a diploid organism at a single  locus  on the DNA.  Homozygous  describes a genotype consisting of two identical alleles at a given locus,  heterozygous  describes a genotype consisting of two different alleles at a locus,  hemizygous  describes a genotype consisting of only a single copy of a particular gene in an otherwise diploid organism, and  nullizygous  refers to an otherwise-diploid organism in which both copies of the gene are missing. [ citation needed ]


A cell is said to be homozygous for a particular gene when identical alleles of the gene are present on both  homologous chromosomes . [ 2 ]


An individual that is  homozygous-dominant  for a particular trait carries two copies of the allele that codes for the  dominant trait . This allele, often called the "dominant allele", is normally represented by the uppercase form of the letter used for the corresponding recessive trait (such as "P" for the dominant allele producing purple flowers in pea plants). When an organism is homozygous-dominant for a particular trait, its genotype is represented by a doubling of the symbol for that trait, such as "PP". [ citation needed ]


An individual that is  homozygous-recessive  for a particular trait carries two copies of the allele that codes for the  recessive trait . This allele, often called the "recessive allele", is usually represented by the lowercase form of the letter used for the corresponding dominant trait (such as, with reference to the example above, "p" for the recessive allele producing white flowers in pea plants). The genotype of an organism that is homozygous-recessive for a particular trait is represented by a doubling of the appropriate letter, such as "pp". [ citation needed ]


A  diploid  organism is heterozygous at a gene locus when its cells contain two different  alleles  (one wild-type allele and one mutant allele) of a gene. [ 3 ]  The cell or organism is called a  heterozygote   specifically  for the allele in question, and therefore, heterozygosity refers to a specific genotype. Heterozygous genotypes are represented by an uppercase letter (representing the dominant/wild-type allele) and a lowercase letter (representing the recessive/mutant allele), as in "Rr" or "Ss". Alternatively, a heterozygote for gene "R" is assumed to be "Rr". The uppercase letter is usually written first. [ citation needed ]


If the trait in question is determined by simple (complete) dominance, a heterozygote will express only the trait coded by the dominant allele, and the trait coded by the recessive allele will not be present. In  more complex dominance schemes  the results of heterozygosity can be more complex. [ citation needed ]


A heterozygous genotype can have a higher relative fitness than either the homozygous-dominant or homozygous-recessive genotype – this is called a  heterozygote advantage . [ citation needed ]


A chromosome  in a diploid organism is hemizygous when only one copy is present. [ 2 ]  The cell or organism is called a  hemizygote . Hemizygosity is also observed when one copy of a gene is deleted, or, in the  heterogametic sex , when a gene is located on a sex chromosome. Hemizygosity is not the same as  haploinsufficiency , which describes a mechanism for producing a phenotype. For organisms in which the male is heterogametic, such as humans, almost all X-linked genes are hemizygous in males with normal chromosomes, because they have only one  X chromosome  and few of the same genes are on the  Y chromosome . Transgenic mice generated through exogenous DNA  microinjection  of an embryo's  pronucleus  are also considered to be hemizygous, because the introduced allele is expected to be incorporated into only one copy of any locus. A transgenic individual can later be bred to homozygosity and maintained as an inbred line to reduce the need to confirm the genotype of each individual. [ citation needed ]


In cultured mammalian cells, such as the  Chinese hamster ovary cell  line, a number of genetic loci are present in a functional hemizygous state, due to mutations or deletions in the other alleles. [ 4 ]


A nullizygous organism carries two mutant alleles for the same gene. The mutant alleles are both complete  loss-of-function  or 'null' alleles, so homozygous null and nullizygous are synonymous. [ 2 ]  The mutant cell or organism is called a  nullizygote . [ citation needed ]


Zygosity may also refer to the origin(s) of the alleles in a genotype. When the two alleles at a locus originate from a common ancestor by way of nonrandom mating ( inbreeding ), the genotype is said to be  autozygous . This is also known as being "identical by descent", or IBD. When the two alleles come from different sources (at least to the extent that the descent can be traced), the genotype is called  allozygous . This is known as being "identical by state", or IBS. [ clarification needed ]


Because the alleles of autozygous genotypes come from the same source, they are always homozygous, but allozygous genotypes may be homozygous too. Heterozygous genotypes are often, but not necessarily, allozygous because different alleles may have arisen by mutation some time after a common origin. Hemizygous and nullizygous genotypes do not contain enough alleles to allow for comparison of sources, so this classification is irrelevant for them. [ citation needed ]


As discussed above, "zygosity" can be used in the context of a specific genetic locus (example [ 5 ] ). The word  zygosity  may also be used to describe the genetic similarity or dissimilarity of twins. [ 6 ]  Identical twins are  monozygotic , meaning that they develop from one zygote that splits and forms two embryos. Fraternal twins are  dizygotic  because they develop from two separate  oocytes  (egg cells) that are fertilized by two separate  sperm .  Sesquizygotic  twins are halfway between monozygotic and dizygotic and are believed to arise after two sperm fertilize a single oocyte which subsequently splits into two  morula . [ 7 ]


Zygosity is an important factor in human medicine. If one copy of an essential gene is mutated, the (heterozygous) carrier is usually healthy. However, more than 1,000 human genes appear to require both copies, that is, a single copy is insufficient for health. This is called  haploinsufficiency . [ 8 ]  For instance, a single copy of the  Kmt5b  gene leads to haploinsufficiency and results in a  skeletal muscle  developmental deficit. [ 9 ]


In  population genetics , the concept of heterozygosity is commonly extended to refer to the population as a whole, i.e., the fraction of individuals in a population that are heterozygous for a particular locus. It can also refer to the fraction of loci within an individual that are heterozygous. [ citation needed ]


In an  admixed population , whose members derive ancestry from two or more separate sources, its heterozygosity is proven to be at least as great as the least heterozygous source population and potentially more than the heterozygosity of all the source populations. It reflects the contributions of its multiple ancestral groups. Admixed populations show high levels of  genetic variation  due to the fusion of source populations with different genetic variants. [ 11 ]


Typically, the observed (

 H

 o

 {\displaystyle H_{o}}

 ) and expected (

 H

 e

 {\displaystyle H_{e}}

 ) heterozygosities are compared, defined as follows for diploid individuals in a population: [ citation needed ]


where

 n

 {\displaystyle n}

  is the number of individuals in the population, and

 a

 i
 1

 ,

 a

 i
 2

 {\displaystyle a_{i1},a_{i2}}

  are the alleles of individual

 i

 {\displaystyle i}

  at the target locus.


where

 m

 {\displaystyle m}

  is the number of alleles at the target locus, and

 f

 i

 {\displaystyle f_{i}}

  is the  allele frequency  of the

 i

 t
 h

 {\displaystyle i^{th}}

  allele at the target locus.


Allele frequency , or  gene frequency , is the relative frequency of an  allele  (variant of a  gene ) at a particular  locus  in a  population , expressed as a fraction or percentage. [ 1 ]  Specifically, it is the fraction of all chromosomes in the population that carry that allele over the total population or sample size.  Microevolution  is the change in allele frequencies that occurs over time within a population.


Given the following:


then the allele frequency is the fraction of all the occurrences  i  of that allele and the total number of chromosome copies across the population,  i /( nN ).


The allele frequency is distinct from the  genotype frequency , although they are related, and allele frequencies can be calculated from genotype frequencies. [ 1 ]


In  population genetics , allele frequencies are used to describe the amount of variation at a particular locus or across multiple loci. When considering the ensemble of allele frequencies for many distinct loci, their distribution is called the  allele frequency spectrum .


The actual frequency calculations depend on the  ploidy  of the species for autosomal genes.


The frequency ( p ) of an allele  A  is the fraction of the number of copies ( i ) of the  A  allele and the population or sample size ( N ), so


If

 f
 (

 A
 A

 )

 {\displaystyle f(\mathbf {AA} )}

 ,

 f
 (

 A
 B

 )

 {\displaystyle f(\mathbf {AB} )}

 , and

 f
 (

 B
 B

 )

 {\displaystyle f(\mathbf {BB} )}

  are the frequencies of the three genotypes at a locus with two alleles, then the frequency  p  of the  A -allele and the frequency  q  of the  B -allele in the population are obtained by counting alleles. [ 2 ]


Because  p  and  q  are the frequencies of the only two alleles present at that locus, they must sum to 1. To check this:


If there are more than two different allelic forms, the frequency for each allele is simply the frequency of its homozygote plus half the sum of the frequencies for all the heterozygotes in which it appears.


(For 3 alleles see  Allele § Genotype frequencies )


Allele frequency can always be calculated from  genotype frequency , whereas the reverse requires that the  Hardy–Weinberg conditions  of random mating apply.


Consider a locus that carries two alleles,  A  and  B . In a diploid population there are three possible genotypes, two  homozygous  genotypes ( AA  and  BB ), and one  heterozygous  genotype ( AB ). If we sample 10 individuals from the population, and we observe the genotype frequencies


then there are

 6
 ×
 2
 +
 3
 =
 15

 {\displaystyle 6\times 2+3=15}

  observed copies of the  A  allele and

 1
 ×
 2
 +
 3
 =
 5

 {\displaystyle 1\times 2+3=5}

  of the  B  allele, out of 20 total chromosome copies. The frequency  p  of the  A  allele is  p  = 15/20 = 0.75, and the frequency  q  of the  B  allele is  q  = 5/20 = 0.25.


Population genetics describes the genetic composition of a population, including allele frequencies, and how allele frequencies are expected to change over time. The  Hardy–Weinberg law  describes the expected equilibrium  genotype frequencies  in a diploid population after random mating. Random mating alone does not change allele frequencies, and the Hardy–Weinberg equilibrium assumes an infinite population size and a selectively neutral locus. [ 1 ]


In natural populations  natural selection  ( adaptation  mechanism),  gene flow , and  mutation  combine to change allele frequencies across generations.  Genetic drift  causes changes in allele frequency from random sampling due to offspring number variance in a finite population size, with small populations experiencing larger per generation fluctuations in frequency than large populations. There is also a theory that second adaptation mechanism exists –  niche construction [ 3 ]  According to  extended evolutionary synthesis  adaptation occur due to natural selection, environmental induction, non-genetic inheritance, learning and cultural transmission. [ 4 ]  An allele at a particular locus may also confer some fitness effect for an individual carrying that allele, on which natural selection acts. Beneficial alleles tend to increase in frequency, while deleterious alleles tend to decrease in frequency. Even when an allele is selectively neutral, selection acting on nearby genes may also change its allele frequency through  hitchhiking  or  background selection .


While heterozygosity at a given locus decreases over time as alleles become fixed or lost in the population, variation is maintained in the population through new mutations and gene flow due to migration between populations. For details, see  population genetics .


Cheung, KH; Osier MV; Kidd JR; Pakstis AJ; Miller PL; Kidd KK (2000).  "ALFRED: an allele frequency database for diverse populations and DNA polymorphisms" .  Nucleic Acids Research .  28  (1):  361– 3.  doi : 10.1093/nar/28.1.361 .  PMC   102486 .  PMID   10592274 .


Middleton, D; Menchaca L; Rood H; Komerofsky R (2002).  "New allele frequency database: www.allelefrequencies.net" .  Tissue Antigens .  61  (5):  403– 7.  doi : 10.1034/j.1399-0039.2003.00062.x .  PMID   12753660 .


A  chromosomal abnormality ,  chromosomal anomaly ,  chromosomal aberration ,  chromosomal mutation , or  chromosomal disorder  is a missing, extra, or irregular portion of  chromosomal  DNA. [ 1 ] [ 2 ]  These can occur in the form of numerical abnormalities, where there is an atypical number of chromosomes, or as structural abnormalities, where one or more individual chromosomes are altered.  Chromosome mutation  was formerly used in a strict sense to mean a change in a chromosomal segment, involving more than one  gene . [ 3 ]  Chromosome anomalies usually occur when there is an error in  cell division  following  meiosis  or  mitosis . Chromosome abnormalities may be detected or confirmed by comparing an individual's  karyotype , or full set of chromosomes, to a typical karyotype for the  species  via  genetic testing .


Sometimes chromosomal abnormalities arise in the early stages of an  embryo ,  sperm , or  infant . [ 4 ]  They can be caused by various environmental factors. The implications of chromosomal abnormalities depend on the specific problem, they may have quite different ramifications. Some examples are  Down syndrome  and  Turner syndrome .


An abnormal number of chromosomes is known as  aneuploidy , and occurs when an individual is either missing a chromosome from a pair (resulting in  monosomy ) or has more than two chromosomes of a pair ( trisomy ,  tetrasomy , etc.). [ 5 ] [ 6 ]  Aneuploidy can be full, involving a whole chromosome missing or added, or partial, where only part of a chromosome is missing or added. [ 5 ]  Aneuploidy can occur with  sex chromosomes  or  autosomes . [ citation needed ]


Rather than having monosomy, or only one copy, the majority of aneuploid people have trisomy, or three copies of one chromosome. [ citation needed ]  An example of trisomy in humans is  Down syndrome , which is a developmental disorder caused by an extra copy of chromosome 21; the disorder is therefore also called trisomy 21. [ 7 ]


An example of monosomy in humans is  Turner syndrome , where the individual is born with only one sex chromosome, an X. [ 8 ]


Exposure of males to certain lifestyle, environmental and/or occupational hazards may increase the risk of  aneuploid  spermatozoa. [ 9 ]  In particular, risk of aneuploidy is increased by  tobacco smoking , [ 10 ] [ 11 ]  and occupational exposure to  benzene , [ 12 ]   insecticides , [ 13 ] [ 14 ]  and  perfluorinated compounds . [ 15 ]  Increased aneuploidy is often associated with increased DNA damage in spermatozoa.


When the chromosome's structure is altered, this can take several forms: [ 16 ]


Chromosome instability syndromes  are a group of disorders characterized by chromosomal instability and breakage. They often lead to an increased tendency to develop certain types of malignancies.


Most chromosome abnormalities occur as an accident in the egg cell or sperm, and therefore the anomaly is present in every cell of the body. Some anomalies, however, can happen after conception, resulting in  Mosaicism  (where some cells have the anomaly and some do not). Chromosome anomalies can be inherited from a parent or be " de novo ".  This is why chromosome studies are often performed on parents when a child is found to have an anomaly.  If the parents do not possess the abnormality it was not initially  inherited ; however, it may be transmitted to subsequent generations. [ citation needed ]


Most cancers, if not all, could cause chromosome abnormalities, [ 17 ]  with either the formation of hybrid genes and fusion proteins, deregulation  of genes and overexpression of proteins, or loss of tumor suppressor genes (see the "Mitelman Database"  [ 18 ]  and the  Atlas of Genetics and Cytogenetics in Oncology and Haematology , [ 19 ] ). Furthermore, certain consistent chromosomal abnormalities can turn normal cells into a leukemic cell such as the translocation of a gene, resulting in its inappropriate expression. [ 20 ]


During the  mitotic  and  meiotic  cell divisions of mammalian  gametogenesis ,  DNA repair  is effective at removing  DNA damages . [ 21 ]   However, in  spermatogenesis  the ability to repair DNA damages decreases substantially in the latter part of the process as haploid  spermatids  undergo major nuclear  chromatin  remodeling into highly compacted  sperm  nuclei.  As reviewed by Marchetti et al., [ 22 ]  the last few weeks of sperm development before  fertilization  are highly susceptible to the accumulation of sperm DNA damage.  Such sperm DNA damage can be transmitted unrepaired into the egg where it is subject to removal by the maternal repair machinery.  However, errors in maternal DNA repair of sperm DNA damage can result in  zygotes  with chromosomal structural aberrations. [ citation needed ]


Melphalan  is a bifunctional  alkylating agent  frequently used in  chemotherapy .  Meiotic inter-strand DNA damages caused by melphalan can escape paternal repair and cause chromosomal aberrations in the zygote by maternal misrepair. [ 22 ]   Thus both pre- and post-fertilization DNA repair appear to be important in avoiding chromosome abnormalities and assuring the  genome  integrity of the  conceptus . [ citation needed ]


Depending on the information one wants to obtain, different techniques and samples are needed. [ citation needed ]


The  International System for Human Cytogenomic Nomenclature  (ISCN) is an international standard for  human chromosome   nomenclature , which includes band names, symbols and abbreviated terms used in the description of human chromosome and chromosome abnormalities. Abbreviations include a minus sign (-) for chromosome deletions, and  del  for deletions of parts of a chromosome. [ 24 ]


Fitness  (often denoted

 w

 {\displaystyle w}

  or  ω  in  population genetics  models) is a  quantitative  representation of individual  reproductive success . It is also equal to the  average contribution  to the  gene pool  of the next generation, made by the same individuals of the specified genotype or phenotype. Fitness can be defined either with respect to a  genotype  or to a  phenotype  in a given environment or time. The fitness of a genotype is manifested through its phenotype, which is also affected by the developmental environment. The fitness of a given phenotype can also be different in different selective environments.


With  asexual reproduction , it is sufficient to assign fitnesses to genotypes. With  sexual reproduction , recombination scrambles  alleles  into different genotypes every generation; in this case, fitness values can be assigned to alleles by averaging over possible genetic backgrounds. Natural selection tends to make alleles with higher fitness more common over time, resulting in  Darwinian  evolution.


The term "Darwinian fitness" can be used to make clear the distinction with  physical fitness . [ 1 ]  Fitness does not include a measure of survival or life-span;  Herbert Spencer 's  well-known phrase " survival of the fittest " should be interpreted as: "Survival of the form (phenotypic or genotypic) that will leave the most copies of itself in successive generations."


Inclusive fitness  differs from individual fitness by including the ability of an allele in one individual to promote the survival and/or reproduction of other individuals that share that allele, in preference to individuals with a different allele. To avoid double counting, inclusive fitness excludes the contribution of other individuals to the survival and reproduction of the focal individual. One mechanism of inclusive fitness is  kin selection .


Fitness is often defined as a  propensity  or probability, rather than the actual number of offspring. For example, according to  Maynard Smith , "Fitness is a property, not of an individual, but of a class of individuals—for example homozygous for allele A at a particular locus. Thus the phrase 'expected number of offspring' means the average number, not the number produced by some one individual. If the first human infant with a gene for levitation were struck by lightning in its pram, this would not prove the new genotype to have low fitness, but only that the particular child was unlucky." [ 2 ]


Alternatively, "the fitness of the individual—having an array x of  phenotypes —is the probability, s(x), that the individual will be included among the group selected as parents of the next generation." [ 3 ]


In order to avoid the complications of sex and recombination, the concept of fitness is presented below in the restricted setting of an asexual population without  genetic recombination . Thus, fitnesses can be assigned directly to genotypes. There are two commonly used operationalizations of fitness – absolute fitness and relative fitness.


The absolute fitness (

 W

 {\displaystyle W}

 ) of a genotype is defined as the proportional change in the abundance of that genotype over one generation attributable to selection. For example, if

 n
 (
 t
 )

 {\displaystyle n(t)}

  is the abundance of a genotype in generation

 t

 {\displaystyle t}

  in an infinitely large population (so that there is no  genetic drift ), and neglecting the change in genotype abundances due to  mutations , then [ 4 ]


An absolute fitness larger than 1 indicates growth in that genotype's abundance; an absolute fitness smaller than 1 indicates decline.


Whereas absolute fitness determines changes in genotype abundance, relative fitness (

 w

 {\displaystyle w}

 ) determines changes in genotype  frequency . If

 N
 (
 t
 )

 {\displaystyle N(t)}

  is the total population size in generation

 t

 {\displaystyle t}

 , and the relevant genotype's frequency is

 p
 (
 t
 )
 =
 n
 (
 t
 )

 /

 N
 (
 t
 )

 {\displaystyle p(t)=n(t)/N(t)}

 , then


where

 w
 ¯

 {\displaystyle {\overline {w}}}

  is the mean relative fitness in the population (again setting aside changes in frequency due to drift and mutation). Relative fitnesses only indicate the change in prevalence of different genotypes relative to each other, and so only their values relative to each other are important; relative fitnesses can be any nonnegative number, including 0. It is often convenient to choose one genotype as a reference and set its relative fitness to 1. Relative fitness is used in the standard  Wright–Fisher  and  Moran models  of population genetics.


Absolute fitnesses can be used to calculate relative fitness, since

 p
 (
 t
 +
 1
 )
 =
 n
 (
 t
 +
 1
 )

 /

 N
 (
 t
 +
 1
 )
 =
 (
 W

 /

 W
 ¯

 )
 p
 (
 t
 )

 {\displaystyle p(t+1)=n(t+1)/N(t+1)=(W/{\overline {W}})p(t)}

  (we have used the fact that

 N
 (
 t
 +
 1
 )
 =

 W
 ¯

 N
 (
 t
 )

 {\displaystyle N(t+1)={\overline {W}}N(t)}

 , where

 W
 ¯

 {\displaystyle {\overline {W}}}

  is the mean absolute fitness in the population). This implies that

 w

 /

 w
 ¯

 =
 W

 /

 W
 ¯

 {\displaystyle w/{\overline {w}}=W/{\overline {W}}}

 , or in other words, relative fitness is proportional to

 W

 /

 W
 ¯

 {\displaystyle W/{\overline {W}}}

 . It is not possible to calculate absolute fitnesses from relative fitnesses alone, since relative fitnesses contain no information about changes in overall population abundance

 N
 (
 t
 )

 {\displaystyle N(t)}

 .


Assigning relative fitness values to genotypes is mathematically appropriate when two conditions are met: first, the population is at demographic equilibrium, and second, individuals vary in their birth rate, contest ability, or death rate, but not a combination of these traits. [ 5 ]


The change in genotype frequencies due to selection follows immediately from the definition of relative fitness,


Thus, a genotype's frequency will decline or increase depending on whether its fitness is lower or greater than the mean fitness, respectively.


In the particular case that there are only two genotypes of interest (e.g. representing the invasion of a new mutant allele), the change in genotype frequencies is often written in a different form. Suppose that two genotypes

 A

 {\displaystyle A}

  and

 B

 {\displaystyle B}

  have fitnesses

 w

 A

 {\displaystyle w_{A}}

  and

 w

 B

 {\displaystyle w_{B}}

 , and frequencies

 p

 {\displaystyle p}

  and

 1
 −
 p

 {\displaystyle 1-p}

 , respectively. Then

 w
 ¯

 =

 w

 A

 p
 +

 w

 B

 (
 1
 −
 p
 )

 {\displaystyle {\overline {w}}=w_{A}p+w_{B}(1-p)}

 , and so


Thus, the change in genotype

 A

 {\displaystyle A}

 's frequency depends crucially on the difference between its fitness and the fitness of genotype

 B

 {\displaystyle B}

 . Supposing that

 A

 {\displaystyle A}

  is more fit than

 B

 {\displaystyle B}

 , and defining the  selection coefficient

 s

 {\displaystyle s}

  by

 w

 A

 =
 (
 1
 +
 s
 )

 w

 B

 {\displaystyle w_{A}=(1+s)w_{B}}

 , we obtain


where the last approximation holds for

 s
 ≪
 1

 {\displaystyle s\ll 1}

 . In other words, the fitter genotype's frequency grows approximately  logistically .


The  British   sociologist   Herbert Spencer  coined the phrase " survival of the fittest "  in his 1864 work  Principles of Biology  to characterise what  Charles Darwin  had called  natural selection . [ 6 ]


The British-Indian biologist  J.B.S. Haldane  was the first to quantify fitness, in terms of the  modern evolutionary synthesis  of Darwinism and  Mendelian genetics  starting with his 1924 paper  A Mathematical Theory of Natural and Artificial Selection . The next further advance was the introduction of the concept of  inclusive fitness  by the British biologist  W.D. Hamilton  in 1964 in his paper on  The Genetical Evolution of Social Behaviour .


Genetic load  measures the average fitness of a population of individuals, relative either to a theoretical genotype of optimal fitness, or relative to the most fit genotype actually present in the population. [ 7 ]  Consider n genotypes

 A

 1

 …

 A

 n

 {\displaystyle \mathbf {A} _{1}\dots \mathbf {A} _{n}}

 , which have the fitnesses

 w

 1

 …

 w

 n

 {\displaystyle w_{1}\dots w_{n}}

  and the  genotype frequencies

 p

 1

 …

 p

 n

 {\displaystyle p_{1}\dots p_{n}}

  respectively. Ignoring  frequency-dependent selection , then genetic load (

 L

 {\displaystyle L}

 ) may be calculated as:


Genetic load may increase when deleterious mutations, migration,  inbreeding , or  outcrossing  lower mean fitness. Genetic load may also increase when beneficial mutations increase the maximum fitness against which other mutations are compared; this is known as the  substitutional load or cost of selection .


2AS5 ,  2A07


O15409 Q75MZ5 Q0PRL4 Q8N6B6


NM_053242 NM_212435 NM_001286607


NP_683698 NP_001166237.1 NP_683697.2


NP_001273536 NP_444472 NP_997600


Forkhead box protein P2  ( FOXP2 ) is a  protein  that, in humans, is encoded by the  FOXP2   gene . FOXP2 is a member of the  forkhead box  family of  transcription factors , proteins that  regulate gene expression  by  binding to DNA . It is expressed in the brain, heart, lungs and digestive system. [ 5 ] [ 6 ]


FOXP2  is found in many  vertebrates , where it plays an important role in mimicry in birds (such as  birdsong ) and  echolocation  in bats.  FOXP2  is also required for the proper development of speech and language in humans. [ 7 ]  In humans, mutations in  FOXP2  cause the severe speech and language disorder  developmental verbal dyspraxia . [ 7 ] [ 8 ]  Studies of the gene in mice and songbirds indicate that it is necessary for vocal imitation and the related motor learning. [ 9 ] [ 10 ] [ 11 ]  Outside the brain,  FOXP2  has also been implicated in development of other tissues such as the lung and digestive system. [ 12 ]


Initially identified in 1998 as the genetic cause of a  speech disorder  in a British family designated the  KE family ,  FOXP2  was the first gene discovered to be associated with speech and language [ 13 ]  and was subsequently dubbed "the language gene". [ 14 ]  However, other genes are necessary for human language development, and a 2018 analysis confirmed that there was no evidence of recent positive  evolutionary selection  of  FOXP2  in humans. [ 15 ] [ 16 ]


As a  FOX protein , FOXP2 contains a forkhead-box domain. In addition, it contains a  polyglutamine tract , a  zinc finger  and a  leucine zipper . The protein attaches to the DNA of other proteins and controls their activity through the forkhead-box domain. Only a few targeted genes have been identified, however researchers believe that there could be up to hundreds of other genes targeted by the FOXP2 gene. The forkhead box P2 protein is active in the brain and other tissues before and after birth, and many studies show that it is paramount for the growth of nerve cells and transmission between them. The FOXP2 gene is also involved in synaptic plasticity, making it imperative for learning and memory. [ 17 ]


FOXP2  is required for proper brain and lung development.  Knockout mice  with only one functional copy of the  FOXP2  gene have significantly reduced vocalizations as pups. [ 18 ]  Knockout mice with no functional copies of  FOXP2  are runted, display abnormalities in brain regions such as the  Purkinje layer , and die an average of 21 days after birth from inadequate lung development. [ 12 ]


FOXP2  is expressed in many areas of the brain, [ 19 ]  including the  basal ganglia  and inferior  frontal cortex , where it is essential for brain maturation and speech and language development. [ 20 ]  In mice, the gene was found to be twice as highly expressed in male pups than female pups, which correlated with an almost double increase in the number of vocalisations the male pups made when separated from mothers. Conversely, in human children aged 4–5, the gene was found to be 30% more expressed in the  Broca's areas  of female children. The researchers suggested that the gene is more active in "the more communicative sex". [ 21 ] [ 22 ]


The expression of  FOXP2  is subject to  post-transcriptional regulation , particularly  microRNA  (miRNA), causing the repression of the FOXP2  3' untranslated region . [ 23 ]


Three amino acid substitutions distinguish the human  FOXP2  protein from that found in mice, while two amino acid substitutions distinguish the human  FOXP2  protein from that found in chimpanzees, [ 19 ]  but only one of these changes is unique to humans. [ 12 ]  Evidence from genetically manipulated mice [ 24 ]  and human neuronal cell models [ 25 ]  suggests that these changes affect the neural functions of  FOXP2 .


The FOXP2 gene has been implicated in several cognitive functions including; general brain development, language, and synaptic plasticity. The FOXP2 gene region acts as a transcription factor for the forkhead box P2 protein. Transcription factors affect other regions, and the forkhead box P2 protein has been suggested to also act as a transcription factor for hundreds of genes. This prolific involvement opens the possibility that the FOXP2 gene is much more extensive than originally thought. [ 17 ]  Other targets of transcription have been researched without correlation to FOXP2. Specifically, FOXP2 has been investigated in correlation with autism and dyslexia, however with no mutation was discovered as the cause. [ 26 ] [ 8 ]  One well identified target is language. [ 27 ]  Although some research disagrees with this correlation, [ 28 ]  the majority of research shows that a mutated FOXP2 causes the observed production deficiency. [ 17 ] [ 27 ] [ 29 ] [ 26 ] [ 30 ] [ 31 ]


There is some evidence that the linguistic impairments associated with a mutation of the  FOXP2  gene are not simply the result of a fundamental deficit in motor control. Brain imaging of affected individuals indicates functional abnormalities in language-related cortical and basal ganglia regions, demonstrating that the problems extend beyond the motor system. [ 32 ]


Mutations in FOXP2 are among several (26 genes plus 2 intergenic) loci which correlate to  ADHD  diagnosis in adults – clinical ADHD is an umbrella label for a heterogeneous group of genetic and neurological phenomena which may result from FOXP2 mutations or other causes. [ 33 ]


A 2020  genome-wide association study  (GWAS) implicates  single-nucleotide polymorphisms  (SNPs) of FOXP2 in susceptibility to  cannabis use disorder . [ 34 ]


It is theorized that the translocation of the 7q31.2 region of the FOXP2 gene causes a severe language impairment called  developmental verbal dyspraxia  (DVD) [ 27 ]  or childhood apraxia of speech (CAS) [ 35 ]  So far this type of mutation has only been discovered in three families across the world including the original KE family. [ 31 ]  A missense mutation causing an arginine-to-histidine substitution (R553H) in the DNA-binding domain is thought to be the abnormality in KE. [ 36 ]  This would cause a normally basic residue to be fairly acidic and highly reactive at the body's pH. A heterozygous nonsense mutation, R328X variant, produces a truncated protein involved in speech and language difficulties in one KE individual and two of their close family members. R553H and R328X mutations also affected nuclear localization, DNA-binding, and the transactivation (increased gene expression) properties of FOXP2. [ 8 ]


These individuals present with deletions, translocations, and missense mutations. When tasked with repetition and verb generation, these individuals with DVD/CAS had decreased activation in the putamen and Broca's area in fMRI studies. These areas are commonly known as areas of language function. [ 37 ]  This is one of the primary reasons that FOXP2 is known as a language gene. They have delayed onset of speech, difficulty with articulation including slurred speech, stuttering, and poor pronunciation, as well as dyspraxia. [ 31 ]  It is believed that a major part of this speech deficit comes from an inability to coordinate the movements necessary to produce normal speech including mouth and tongue shaping. [ 27 ]  Additionally, there are more general impairments with the processing of the grammatical and linguistic aspects of speech. [ 8 ]  These findings suggest that the effects of FOXP2 are not limited to motor control, as they include comprehension among other cognitive language functions. General mild motor and cognitive deficits are noted across the board. [ 29 ]  Clinically these patients can also have difficulty coughing, sneezing, or clearing their throats. [ 27 ]


While FOXP2 has been proposed to play a critical role in the development of speech and language, this view has been challenged by the fact that the gene is also expressed in other mammals as well as birds and fish that do not speak. [ 38 ]  It has also been proposed that the FOXP2 transcription-factor is not so much a hypothetical 'language gene' but rather part of a regulatory machinery related to externalization of speech. [ 39 ]


The  FOXP2  gene is highly conserved in  mammals . [ 19 ]  The human gene differs from that in  non-human primates  by the substitution of two amino acids, a  threonine  to  asparagine  substitution at position 303 (T303N) and an asparagine to  serine  substitution at position 325 (N325S). [ 36 ]  In mice it differs from that of humans by three substitutions, and in  zebra finch  by seven amino acids. [ 19 ] [ 40 ] [ 41 ]  One of the two amino acid differences between human and chimps also arose independently in carnivores and bats. [ 12 ] [ 42 ]  Similar  FOXP2  proteins can be found in  songbirds ,  fish , and  reptiles  such as  alligators . [ 43 ] [ 44 ]


DNA sampling from  Homo neanderthalensis  bones indicates that their  FOXP2  gene is a little different though largely similar to those of  Homo sapiens  (i.e. humans). [ 45 ] [ 46 ]  Previous genetic analysis had suggested that the  H. sapiens  FOXP2 gene became fixed in the population around 125,000 years ago. [ 47 ]  Some researchers consider the Neanderthal findings to indicate that the gene instead swept through the population over 260,000 years ago, before our most recent common ancestor with the Neanderthals. [ 47 ]  Other researchers offer alternative explanations for how the  H. sapiens  version would have appeared in Neanderthals living 43,000 years ago. [ 47 ]


According to a 2002 study, the  FOXP2  gene showed indications of recent  positive selection . [ 19 ] [ 48 ]  Some researchers have speculated that positive selection is crucial for the  evolution of language in humans . [ 19 ]  Others, however, were unable to find a clear association between species with learned vocalizations and similar mutations in  FOXP2 . [ 43 ] [ 44 ]  A 2018 analysis of a large sample of globally distributed genomes confirmed there was no evidence of positive selection, suggesting that the original signal of positive selection may be driven by sample composition. [ 15 ] [ 16 ]  Insertion of both human  mutations  into mice, whose version of  FOXP2  otherwise differs from the human and  chimpanzee  versions in only one additional base pair, causes changes in vocalizations as well as other behavioral changes, such as a reduction in exploratory tendencies, and a decrease in maze learning time. A reduction in dopamine levels and changes in the morphology of certain nerve cells are also observed. [ 24 ]


FOXP2 is known to regulate  CNTNAP2 ,  CTBP1 , [ 49 ]   SRPX2  and  SCN3A . [ 50 ] [ 20 ] [ 51 ]


FOXP2 downregulates  CNTNAP2 , a member of the  neurexin  family found in neurons.  CNTNAP2  is associated with common forms of language impairment. [ 52 ]


FOXP2 also downregulates   SRPX2 , the 'Sushi Repeat-containing Protein X-linked 2'. [ 53 ] [ 54 ]  It directly reduces its expression, by binding to its gene's  promoter . SRPX2 is involved in  glutamatergic   synapse formation  in the  cerebral cortex  and is more highly expressed in childhood. SRPX2 appears to specifically increase the number of glutamatergic synapses in the brain, while leaving inhibitory  GABAergic  synapses unchanged and not affecting  dendritic spine  length or shape. On the other hand, FOXP2's activity does reduce dendritic spine length and shape, in addition to number, indicating it has other regulatory roles in dendritic morphology. [ 53 ]


In chimpanzees, FOXP2 differs from the human version by two amino acids. [ 55 ]  A study in Germany sequenced FOXP2's complementary DNA in chimps and other species to compare it with human complementary DNA in order to find the specific changes in the sequence. [ 19 ]  FOXP2 was found to be functionally different in humans compared to chimps. Since FOXP2 was also found to have an effect on other genes, its effects on other genes is also being studied. [ 56 ]  Researchers deduced that there could also be further clinical applications in the direction of these studies in regards to illnesses that show effects on human language ability. [ 25 ]


In a mouse  FOXP2   gene knockouts , loss of both copies of the gene causes severe motor impairment related to cerebellar abnormalities and lack of  ultrasonic   vocalisations  normally elicited when pups are removed from their mothers. [ 18 ]  These vocalizations have important communicative roles in mother–offspring interactions. Loss of one copy was associated with impairment of ultrasonic vocalisations and a modest developmental delay. Male mice on encountering female mice produce complex ultrasonic vocalisations that have characteristics of song. [ 57 ]  Mice that have the R552H point mutation carried by the KE family show cerebellar reduction and abnormal  synaptic plasticity  in striatal and  cerebellar  circuits. [ 9 ]


Humanized FOXP2 mice display altered  cortico-basal ganglia  circuits. The human allele of the FOXP2 gene was transferred into the mouse embryos through  homologous recombination  to create humanized FOXP2 mice. The human variant of FOXP2 also had an effect on the exploratory behavior of the mice. In comparison to knockout mice with one non-functional copy of  FOXP2 , the humanized mouse model showed opposite effects when testing its effect on the levels of dopamine, plasticity of synapses, patterns of expression in the striatum and behavior that was exploratory in nature. [ 24 ]


When FOXP2 expression was altered in mice, it affected many different processes including the learning motor skills and the plasticity of synapses. Additionally, FOXP2 is found more in the  sixth layer  of the cortex than in the  fifth , and this is consistent with it having greater roles in sensory integration. FOXP2 was also found in the  medial geniculate nucleus  of the mouse brain, which is the processing area that auditory inputs must go through in the thalamus. It was found that its mutations play a role in delaying the development of language learning. It was also found to be highly expressed in the Purkinje cells and cerebellar nuclei of the cortico-cerebellar circuits. High FOXP2 expression has also been shown in the spiny neurons that express  type 1 dopamine receptors  in the striatum,  substantia nigra ,  subthalamic nucleus  and  ventral tegmental area . The negative effects of the mutations of FOXP2 in these brain regions on motor abilities were shown in mice through tasks in lab studies. When analyzing the brain circuitry in these cases, scientists found greater levels of dopamine and decreased lengths of dendrites, which caused defects in  long-term depression , which is implicated in motor function learning and maintenance. Through  EEG  studies, it was also found that these mice had increased levels of activity in their striatum, which contributed to these results. There is further evidence for mutations of targets of the FOXP2 gene shown to have roles in  schizophrenia ,  epilepsy ,  autism ,  bipolar disorder  and intellectual disabilities. [ 58 ]


FOXP2  has implications in the development of  bat   echolocation . [ 36 ] [ 42 ] [ 59 ]  Contrary to apes and mice,  FOXP2  is extremely diverse in  echolocating bats . [ 42 ]  Twenty-two sequences of non-bat  eutherian  mammals revealed a total number of 20 nonsynonymous mutations in contrast to half that number of bat sequences, which showed 44 nonsynonymous mutations. [ 42 ]  All  cetaceans  share three amino acid substitutions, but no differences were found between echolocating  toothed whales  and non-echolocating  baleen cetaceans . [ 42 ]  Within bats, however, amino acid variation correlated with different echolocating types. [ 42 ]


In  songbirds ,  FOXP2  most likely regulates genes involved in  neuroplasticity . [ 10 ] [ 60 ]   Gene knockdown  of  FOXP2  in area X of the  basal ganglia  in songbirds results in incomplete and inaccurate song imitation. [ 10 ]  Overexpression of  FOXP2  was accomplished through injection of  adeno-associated virus  serotype 1 (AAV1) into area X of the brain. This overexpression produced similar effects to that of knockdown; juvenile zebra finch birds were unable to accurately imitate their tutors. [ 61 ]  Similarly, in adult canaries, higher  FOXP2  levels also correlate with song changes. [ 41 ]


Levels of  FOXP2  in adult zebra finches are significantly higher when males direct their song to females than when they sing song in other contexts. [ 60 ]  "Directed" singing refers to when a male is singing to a female usually for a courtship display. "Undirected" singing occurs when for example, a male sings when other males are present or is alone. [ 62 ]  Studies have found that FoxP2 levels vary depending on the social context. When the birds were singing undirected song, there was a decrease of FoxP2 expression in Area X. This downregulation was not observed and FoxP2 levels remained stable in birds singing directed song. [ 60 ]


Differences between song-learning and non-song-learning birds have been shown to be caused by differences in  FOXP2   gene expression , rather than differences in the amino acid sequence of the  FOXP2  protein.


In  zebrafish , FOXP2 is expressed in the ventral and  dorsal thalamus ,  telencephalon ,  diencephalon  where it likely plays a role in nervous system development. The zebrafish FOXP2 gene has an 85% similarity to the human FOX2P ortholog. [ 63 ]


FOXP2  and its gene were discovered as a result of investigations on an English family known as the  KE family , half of whom (15 individuals across three generations) had a speech and language disorder called  developmental verbal dyspraxia . Their case was studied at the  Institute of Child Health of University College London . [ 64 ]  In 1990,  Myrna Gopnik , Professor of Linguistics at  McGill University , reported that the disorder-affected KE family had severe speech impediment with incomprehensible talk, largely characterized by grammatical deficits. [ 65 ]  She hypothesized that the basis was not of learning or cognitive disability, but due to genetic factors affecting mainly grammatical ability. [ 66 ]  (Her hypothesis led to a popularised existence of "grammar gene" and a controversial notion of grammar-specific disorder. [ 67 ] [ 68 ] ) In 1995, the  University of Oxford  and the Institute of Child Health researchers found that the disorder was purely genetic. [ 69 ]  Remarkably, the inheritance of the disorder from one generation to the next was consistent with  autosomal dominant  inheritance, i.e., mutation of only a single gene on an  autosome  (non- sex chromosome ) acting in a dominant fashion. This is one of the few known examples of  Mendelian  (monogenic) inheritance for a disorder affecting speech and language skills, which typically have a complex basis involving multiple genetic risk factors. [ 70 ]


In 1998, Oxford University geneticists  Simon Fisher ,  Anthony Monaco , Cecilia S. L. Lai, Jane A. Hurst, and  Faraneh Vargha-Khadem  identified an autosomal dominant monogenic inheritance that is localized on a small region of  chromosome 7  from DNA samples taken from the affected and unaffected members. [ 5 ]  The chromosomal region (locus) contained 70 genes. [ 71 ]  The locus was given the official name "SPCH1" (for speech-and-language-disorder-1) by the Human Genome Nomenclature committee. Mapping and sequencing of the chromosomal region was performed with the aid of  bacterial artificial chromosome  clones. [ 6 ]  Around this time, the researchers identified an individual who was unrelated to the KE family but had a similar type of speech and language disorder. In this case, the child, known as CS, carried a chromosomal rearrangement (a  translocation ) in which part of chromosome 7 had become exchanged with part of chromosome 5. The site of breakage of chromosome 7 was located within the SPCH1 region. [ 6 ]


In 2001, the team identified in CS that the mutation is in the middle of a protein-coding gene. [ 7 ]  Using a combination of  bioinformatics  and  RNA  analyses, they discovered that the gene codes for a novel protein belonging to the  forkhead-box  (FOX) group of  transcription factors . As such, it was assigned with the official name of FOXP2. When the researchers sequenced the  FOXP2  gene in the KE family, they found a  heterozygous   point mutation  shared by all the affected individuals, but not in unaffected members of the family and other people. [ 7 ]  This mutation is due to an amino-acid substitution that inhibits the DNA-binding domain of the  FOXP2  protein. [ 72 ]  Further screening of the gene identified multiple additional cases of  FOXP2  disruption, including different point mutations [ 8 ]  and chromosomal rearrangements, [ 73 ]  providing evidence that damage to one copy of this gene is sufficient to derail speech and language development.


Genetic distance  is a measure of the  genetic  divergence between  species  or between  populations  within a species, whether the distance measures time from  common ancestor  or degree of differentiation. [ 2 ]  Populations with many similar  alleles  have small genetic distances. This indicates that they are closely related and have a recent common ancestor.


Genetic distance is useful for reconstructing the history of populations, such as the multiple human expansions  out of Africa . [ 3 ]  It is also used for understanding the origin of  biodiversity . For example, the genetic distances between different breeds of domesticated animals are often investigated in order to determine which breeds should be protected to maintain genetic diversity. [ 4 ]


Life on earth began from very simple  unicellular  organisms evolving into most complex  multicellular  organisms through the course of over three billion years. [ 5 ]  Creating a comprehensive  tree of life  that represents all the organisms that have ever lived on earth is important for understanding the evolution of life in the face of all challenges faced by living organisms to deal with similar challenges in future. Evolutionary biologists have attempted to create evolutionary or  phylogenetic  trees encompassing as many organisms as possible based on the available resources.  Fossil   dating  and  molecular clock  are the two means of generating evolutionary history of living organisms. Fossil record is random, incomplete and does not provide a continuous chain of events like a movie with missing frames cannot tell the whole plot of the movie. [ 5 ]