Family resemblance is also shaped by environmental factors,  temperature ,  light ,  nutrition , exposure to  drugs , the time that different family members spend in shared and non-shared environments, are examples of factors found to influence phenotype. [ 9 ] [ 10 ] [ 11 ]   Phenotypes found to be largely environmentally determined in humans include  personality ,  height , and  weight . [ 12 ] [ 10 ] [ 13 ] [ 14 ]  Twin studies have shown that more than half of the variation in a few major aspects of personality are environmentally determined, and that environmental factors even affect traits like  immune response  and how children handle  stress . [ 10 ] [ 15 ] [ 16 ]  Additionally, anomalous findings, such as  second-degree relatives  of  alcoholics , showing surprising similarities to them have led some researchers’ attempts in generating better models that account for the environmental impacts on influences like cultural inheritance,  family structure  and  head of household , which have been shown to influence family resemblance. [ 17 ]


A  gamete  ( / ˈ ɡ æ m iː t / ; from  Ancient Greek     γαμετή  ( gametḗ )  'wife', ultimately from  Ancient Greek     γάμος  ( gámos )  'marriage') is a  haploid cell  that fuses with another haploid cell during  fertilization  in  organisms  that  reproduce sexually . [ 1 ]  Gametes are an organism's  reproductive cells , also referred to as  sex cells . [ 2 ]  The name gamete was introduced by the German cytologist  Eduard Strasburger  in 1878. [ 3 ]


Gametes of both mating individuals can be the same size and shape, a condition known as  isogamy .  By contrast, in the majority of species, the gametes are of different sizes, a condition known as  anisogamy  or  heterogamy  that applies to humans and other mammals. The human ovum has approximately 100,000 times the volume of a single human sperm cell. The type of gamete an organism produces determines its  sex [ 4 ]  and sets the basis for the sexual roles and  sexual selection . [ 5 ]  In humans and other species that produce two  morphologically  distinct types of gametes, and in which  each individual produces only one type , a  female  is any individual that produces the larger type of gamete called an  ovum , and a  male  produces the smaller type, called a  sperm  cell or spermatozoon. Sperm cells are small and motile due to the presence of a tail-shaped structure, the  flagellum , that provides propulsion. In contrast, each egg cell or ovum is relatively large and non-motile. [ 2 ]


Oogenesis , the process of female gamete formation in animals, involves  meiosis  (including  meiotic recombination ) of a diploid primary  oocyte  to produce a haploid  ovum .  Spermatogenesis , the process of male gamete formation in animals, involves meiosis in a diploid primary  spermatocyte  to produce haploid  spermatozoa . In animals, ova are produced in the ovaries of females and sperm develop in the testes of males. During fertilization, a spermatozoon and an ovum, each carrying half of the  genetic information  of an individual, unite to form a  zygote  that develops into a new  diploid  organism. [ 2 ]


It is generally accepted that  isogamy  is the ancestral state from which  anisogamy  and  oogamy  evolved, although its evolution has left no fossil records. [ 6 ] [ 7 ] [ 8 ]  There are almost invariably only two gamete types, all analyses showing that intermediate gamete sizes are eliminated due to selection. [ 9 ] [ 10 ]  Since intermediate sized gametes do not have the same advantages as small or large ones, [ 11 ]  they do worse than small ones in mobility and numbers, and worse than large ones in supply. [ 12 ]


In contrast to a gamete, which has only one set of chromosomes, a diploid  somatic cell  has two sets of  homologous chromosomes , one of which is a copy of the  chromosome  set from the sperm and one a copy of the chromosome set from the egg cell.  Recombination of the genes  during meiosis ensures that the chromosomes of gametes are not exact duplicates of either of the sets of chromosomes carried in the parental diploid chromosomes but a mixture of the two. [ 13 ]


Artificial gametes, also known as in vitro derived gametes (IVD), stem cell-derived gametes (SCDGs), and in vitro generated gametes (IVG), are gametes derived from  stem cells . The use of such artificial gametes would "necessarily require  IVF  techniques". [ 14 ]  Research shows that artificial gametes may be a reproductive technique for same-sex male couples, although a  surrogate mother  would still be required for the gestation period. [ 14 ]   Women who have passed  menopause  may be able to produce eggs and bear genetically related children with artificial gametes. [ 14 ]  Robert Sparrow wrote, in the  Journal of Medical Ethics , that embryos derived from artificial gametes could be used to derive new gametes and this process could be repeated to create multiple human generations in the laboratory. [ 15 ]  This technique could be used to create  cell lines  for medical applications and for studying the heredity of  genetic disorders . [ 15 ]   Additionally, this technique could be used for  human enhancement  by  selectively breeding  for a desired genome or by using  recombinant DNA  technology to create enhancements that have not arisen in nature. [ 15 ]


Plants  that reproduce sexually also produce gametes. However, since plants have a life cycle involving  alternation of diploid and haploid generations  some differences from animal life cycles exist.  Plants use  meiosis  to produce spores that develop into  multicellular  haploid  gametophytes  which produce gametes by mitosis. In animals there is no corresponding multicellular haploid phase. The sperm of plants that reproduce using spores are formed by mitosis in an organ of the gametophyte known as the  antheridium  and the egg cells by mitosis in a flask-shaped organ called the  archegonium . [ 16 ]  Plant sperm cells are their only motile cells, often described as flagellate, but more correctly as ciliate. [ 17 ]  Bryophytes have 2 flagella, horsetails have up to 200 and the mature spermatozoa of the  cycad   Zamia pumila  has up to 50,000 flagella. [ 18 ]  Cycads and  Ginkgo biloba  are the only gymnosperms with motile sperm. [ 17 ]  In the  flowering plants , the female gametophyte is produced inside the  ovule  within the  ovary  of the flower.  When mature, the haploid gametophyte produces female gametes which are ready for fertilization. The male gametophyte is produced inside a  pollen  grain within the  anther  and is non-motile, but can be distributed by wind, water or animal vectors. When a pollen grain lands on a mature  stigma  of a flower it germinates to form a  pollen tube  that grows down the style into the ovary of the flower and then into the ovule. The pollen then produces non-motile sperm nuclei by mitosis that are transported down the pollen tube to the ovule where they are released for fertilization of the egg cell.


The  gene pool  is the set of all  genes , or  genetic information , in any  population , usually of a particular  species . [ 1 ]


A large gene pool indicates extensive  genetic diversity , which is associated with robust populations that can survive bouts of intense  selection . Meanwhile, low  genetic diversity  (see  inbreeding  and  population bottlenecks ) can cause reduced  biological fitness  and an increased chance of  extinction , although as explained by  genetic drift  new genetic variants, that may cause an increase in the  fitness  of organisms, are more likely to fix in the population if it is rather small.


When all individuals in a population are identical with regard to a particular  phenotypic  trait, the population is said to be 'monomorphic'. When the individuals show several variants of a particular trait they are said to be  polymorphic .


The Russian geneticist  Alexander Sergeevich Serebrovsky  first formulated the concept in the 1920s as  genofond  (gene fund), a word that was imported to the United States from the Soviet Union by  Theodosius Dobzhansky , who translated it into English as "gene pool." [ 2 ]


Harlan and de Wet (1971) proposed classifying each crop and its related species by gene pools rather than by formal taxonomy. [ 3 ]


Gene pool centres refers to areas on the earth where important crop plants and domestic animals originated. They have an extraordinary range of the wild counterparts of cultivated plant species and useful tropical plants.
Gene pool centres also contain different sub tropical and temperate region species.


Genetic association  is when one or more  genotypes  within a population co-occur with a  phenotypic  trait  more often than would be expected by chance occurrence .


Studies of genetic association aim to test whether single-locus  alleles  or genotype frequencies or more generally, multilocus  haplotype  frequencies differ between two groups of individuals (usually  diseased subjects and healthy controls ). Genetic association studies are based on the principle that genotypes can be compared "directly", i.e. with the sequences of the actual  genomes  or  exomes  via  whole genome sequencing  or  whole exome sequencing . Before 2010, DNA sequencing methods were used.


Genetic association can be between phenotypes, such as visible characteristics such as flower color or height, between a phenotype and a genetic polymorphism, such as a   single nucleotide polymorphism  (SNP), or between two genetic polymorphisms. Association between genetic polymorphisms occurs when there is non-random association of their alleles as a result of their proximity on the same chromosome; this is known as  genetic linkage . [ citation needed ]


Linkage disequilibrium  (LD) is a term used in the study of population genetics for the non-random association of alleles at two or more loci, not necessarily on the same chromosome. It is not the same as linkage, which is the phenomenon whereby two or more loci on a chromosome have reduced recombination between them because of their physical proximity to each other. LD describes a situation in which some combinations of alleles or  genetic markers  occur more or less frequently in a population than would be expected from a random formation of haplotypes from alleles based on their frequencies. [ citation needed ]


Genetic association studies are performed to determine whether a genetic variant is associated with a disease or trait: if association is present, a particular allele, genotype or haplotype of a polymorphism or polymorphisms will be seen more often than expected by chance in an individual carrying the trait. Thus, a person carrying one or two copies of a high-risk variant is at increased risk of developing the associated disease or having the associated trait. [ citation needed ]


Case control  studies are a classical epidemiological tool. Case-control studies use subjects who already have a disease, trait or other condition and determine if there are characteristics of these patients that differ from those who do not have the disease or trait. In genetic case-control studies, the frequency of alleles or genotypes is compared between the cases and controls. The cases will have been diagnosed with the disease under study, or have the trait under test; the controls, who are either known to be unaffected, or who have been randomly selected from the population. A difference in the frequency of an allele or genotype of the polymorphism under test between the two groups indicates that the genetic marker may increase risk of the disease or likelihood of the trait, or be in linkage disequilibrium with a polymorphism which does. Haplotypes can also show association with a disease or trait.  One of the earliest successes in this field was finding a single base mutation in the non-coding region of the APOC3 gene (apolipoprotein C3 gene) that associated with  higher risks of hypertriglyceridemia and atherosclerosis [ 1 ]  using a case-control design.


One problem with the case-control design is that genotype and haplotype frequencies vary between ethnic or geographic populations. If the case and control populations are not well matched for ethnicity or geographic origin then false positive association can occur because of the confounding effects of  population stratification .


Family based association designs aim to avoid the potential confounding effects of population stratification by using the parents or unaffected siblings as controls for the case (the affected offspring/sibling). Two similar tests are most commonly used, the  transmission disequilibrium test  (TDT) and  haploid-relative-risk  (HRR). Both measure association of genetic markers in nuclear families by transmission from parent to offspring. If an allele increases the risk of having a disease then that allele is expected to be transmitted from parent to offspring more often in populations with the disease.


A quantitative trait (see  quantitative trait locus ) is a measurable trait that shows continuous variation, such as height or weight. Quantitative traits often have a 'normal' distribution in the population. In addition to the case control design, quantitative trait association can also be performed using an unrelated population sample or family trios in which the quantitative trait is measured in the offspring.


Evidence of the association is based on MNAs that are usually based on studies that include large sample sizes like genome-wide association studies. With only little empirical data associating study results and study design, bias in genetic association studies are not well understood. [ 2 ]


Based on traits either continuous or binary, heritability (going from 0 to 1 with 0 meaning non-hertiable) outcomes are usually reported respectively by the proportion of phenotypic variation that can be attributed to genetic variation or the proportion of variance attributed to genetic variation. [ 3 ]


Genetic equilibrium  is the condition of an  allele  or  genotype  in a gene pool (such as a population) where the frequency does not change from generation to generation. [ 1 ]   Genetic equilibrium describes a theoretical state that is the basis for determining whether and in what ways populations may deviate from it.  Hardy–Weinberg equilibrium  is one theoretical framework for studying genetic equilibrium. It is commonly studied using models that take as their assumptions those of Hardy-Weinberg, meaning:


It can describe other types of equilibrium as well, especially in modeling contexts. In particular, many models use a variation of the Hardy–Weinberg principle as their basis. Instead of all of the Hardy–Weinberg characters being present, these instead assume a balance between the diversifying effects of  genetic drift  and the homogenizing effects of migration between populations. [ 2 ]   A population not at equilibrium suggests that one of the assumptions of the model in question has been violated.


The Hardy–Weinberg principle provides the mathematical framework for genetic equilibrium. Genetic equilibrium itself, whether Hardy-Weinberg or otherwise, provides the groundwork for a number of applications, in including population genetics, conservation and evolutionary biology. With the rapid increase in whole genome sequences available as well as the proliferation of anonymous markers, models have been used to extend the initial theory to all manner of biological contexts. [ 3 ]   Using data from genetic markers such as  ISSRs  and  RAPDs  as well as the predictive potential of statistics, studies have developed models to infer what processes drove the lack of equilibrium. This includes local  adaptation , range contraction and expansion and lack of gene flow due to geographic or behavioral barriers, although equilibrium modeling has been applied to a wide range of topics and questions.


Equilibrium modeling have led to developments in the field. Because allelic dominance can disrupt predictions of equilibrium, [ 4 ]  some models have moved away from using genetic equilibrium as an assumption. Instead of the traditional F-statistics, they make use of Bayesian estimates. [ 5 ]    Holsinger et al. developed an analog to FST, called theta. [ 6 ]   Studies have found Bayesian estimates to be better predictors of the patterns observed. [ 7 ]   However, genetic equilibrium-based modeling remains a tool in population and conservation genetics-it can provide invaluable information about previous historical processes. [ 4 ]


Genetic equilibrium has been studied in a number of taxa. Some marine species in particular have been used as study systems. The life history of marine organisms like sea urchins appear to fulfill the requirements of genetic equilibrium modeling better than terrestrial species. [ 8 ]    They exist in large, panmictic populations that don’t appear to be strongly affected by geographic barriers. In spite of this, some studies have found considerable differentiation across the range of a species. Instead, when looking for genetic equilibrium, studies found large, widespread species complexes. [ 9 ]   This indicates that genetic equilibrium may be rare or difficult to identify in the wild, due to considerable local demographic changes on shorter time scales. [ 10 ]


In fact, although a large population size is a required condition for genetic equilibrium according to Hardy–Weinberg, some have argued that a large population size can actually slow the approach to genetic equilibrium. [ 11 ]    This can have implications for conservation, where genetic equilibrium can be used as a marker of a healthy and sustainable population.


Genetic heterogeneity  occurs through the production of single or similar phenotypes through different genetic mechanisms. There are two types of genetic heterogeneity:  allelic heterogeneity , which occurs when a similar phenotype is produced by different alleles within the same gene; and  locus  heterogeneity , which occurs when a similar phenotype is produced by mutations at different  loci . [ 1 ]


Marked genetic heterogeneity is correlated to multiple levels of causation in many common human diseases including  cystic fibrosis ,  Alzheimer's disease ,  autism spectrum disorders , inherited predisposition to  breast cancer , and non-syndromic hearing loss. These levels of causation are complex and occur through: (1) rare, individual mutations that when combined contribute to the development of common diseases; (2) the accumulation of many different rare, individual mutations within the same gene that contribute to the development of the same common disease within different individuals; (3) the accumulation of many different rare, individual mutations within the same gene that contribute to the development of  different phenotypic variations  of the same common disease within different individuals; and (4) the development of the same common disease in different individuals through different mutations. [ 2 ]  Increased understanding of the role of genetic heterogeneity and the mechanisms through which it produces common disease phenotypes will facilitate the development of effective prevention and treatment methods for these diseases. [ 3 ]


Cystic fibrosis  is an inherited autosomal recessive genetic disorder that occurs through a mutation in a single gene that codes for the  cystic fibrosis transmembrane conductance regulator . Research has identified over 2,000 cystic fibrosis associated mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator at varying degrees of frequency within the disease carrying population. [ 4 ]   These mutations also produce varying degrees of disease phenotypes, and may also work in combinations to produce additive phenotypic effects. [ 5 ]


Alzheimer's disease  is a complicated neurodegenerative disorder with multiple phenotypic subtypes, including clinical and preclinical, that result from different genetic origins. [ 6 ]  Current research on the amyloid cascade hypothesis has identified rare mutations in three genes that encode the amyloid precursor protein ( APP ), presenilin 1 ( PS-1 ), and presenilin 2 ( PS-2 ) that cause the autosomal dominant, early-onset form of familial Alzheimer's disease. [ 7 ]  Research has also discovered the association of a fourth allele, apolipoprotein E4 ( ApoE4 ), in the development of late-onset and sporadic forms of the disease, although the pathology of its role is still largely unknown. [ 8 ]


Autism spectrum disorders  are among the most highly heritable psychiatric disorders and display high levels of phenotypic variability. [ 9 ]  Disorders on the Autism spectrum have high levels of genetic heterogeneity and result from multiple genetic pathways including single gene mutation disorders (such as  Fragile X Syndrome ), regional and submicroscopic variations in the number of gene copies (either heritable or de novo), rare and common genetic variants, and chromosomal aberrations. [ 10 ]


Mutations in ten different genes have been found to contribute to a heritable increased risk of breast cancer and other cancer syndromes. These genes, when functional, contribute to a pathway that serves to preserve genomic integrity. [ 11 ]  Mutations in  BRCA1  and  BRCA2  result in a high risk of both breast and ovarian cancers. [ 12 ]   Mutations in  p53  and  PTEN  increase risks of breast cancer associated with rare cancer syndromes. Mutations in  CHECK2 ,  ATM ,  NBS1 ,  RAD50 ,  BRIP1 , and  PALB2  can double the risk of breast cancer development. [ 13 ]  Biallelic mutations, in which both copies of a particular gene are mutated, in BRCA2, BRIP1, and PALB2 also cause  Fanconi anemia , a recessive syndrome that leads to progressive bone marrow failure. [ 14 ]


Non-syndromic hearing loss can occur through multiple pathways including  autosomal dominant ,  autosomal recessive ,  X-linked , and  Y-linked  inheritance patterns. [ 15 ]  69 genes and 145 loci have been discovered to be involved in the genetic heterogeneity of non-syndromic hearing loss, and the phenotype of the disorder is largely associated with its pattern of inheritance. [ 16 ]


Initial research on genetic heterogeneity was conducted using genetic linkage analyses, which map genetic loci of related individuals to identify genomic differences. [ 17 ]  Current research now relies largely on  genome-wide association studies  which examine the association of  single-nucleotide polymorphisms  (SNPs) to a particular disease in a population. [ 18 ]


Genetic linkage  is the tendency of  DNA sequences  that are close together on a  chromosome  to be inherited together during the  meiosis  phase of  sexual reproduction . Two  genetic markers  that are physically near to each other are unlikely to be separated onto different  chromatids  during  chromosomal crossover , and are therefore said to be more  linked  than markers that are far apart. In other words, the nearer two  genes  are on a chromosome, the lower the chance of  recombination  between them, and the more likely they are to be inherited together. Markers on different chromosomes are perfectly  unlinked , although the  penetrance  of potentially deleterious alleles may be influenced by the presence of other alleles, and these other alleles may be located on other chromosomes than that on which a particular potentially deleterious allele is located. [ 1 ]


Genetic linkage is the most prominent exception to  Gregor Mendel 's  Law of Independent Assortment . The first experiment to demonstrate linkage was carried out in 1905. At the time, the reason why certain traits tend to be inherited together was unknown. Later work revealed that genes are physical structures related by physical distance.


The typical unit of genetic linkage is the  centimorgan  (cM). A distance of 1 cM between two markers means that the markers are separated to different chromosomes on average once per 100 meiotic product, thus once per 50 meioses.


Gregor Mendel 's  Law of Independent Assortment  states that every trait is inherited independently of every other trait. But shortly after  Mendel's work was rediscovered , exceptions to this rule were found. In 1905, the  British  geneticists  William Bateson ,  Edith Rebecca Saunders  and  Reginald Punnett  cross-bred pea plants in experiments similar to Mendel's. [ 2 ] [ 3 ]  They were interested in trait inheritance in the sweet pea and were studying two genes—the gene for flower colour ( P , purple, and  p , red) and the gene affecting the shape of pollen grains ( L , long, and  l , round). They crossed the pure lines  PPLL  and  ppll  and then self-crossed the resulting  PpLl  lines. [ citation needed ]


According to  Mendelian genetics , the expected  phenotypes  would occur in a 9:3:3:1 ratio of PL:Pl:pL:pl.  To their surprise, they observed an increased frequency of PL and pl and a decreased frequency of Pl and pL: [ citation needed ]


Their experiment revealed linkage between the  P  and  L  alleles and the  p  and  l  alleles. The frequency of  P  occurring together with  L  and  p  occurring together with  l  is greater than that of the recombinant  Pl  and  pL . The  recombination  frequency is more difficult to compute in an F2 cross than a backcross, [ 4 ]  but the lack of fit between observed and expected numbers of progeny in the above table indicate it is less than 50%. This indicated that two factors interacted in some way to create this difference by masking the appearance of the other two phenotypes. This led to the conclusion that some traits are related to each other because of their near proximity to each other on a chromosome. [ citation needed ]


The understanding of linkage was expanded by the work of  Thomas Hunt Morgan . Morgan's observation that the amount of  crossing over  between linked genes differs led to the idea that crossover frequency might indicate the distance separating genes on the  chromosome . The  centimorgan , which expresses the frequency of crossing over, is named in his honour. [ citation needed ]


A  linkage map  (also known as a  genetic map ) is a table for a species or experimental population that shows the position of its known  genes  or  genetic markers  relative to each other in terms of recombination frequency, rather than a specific physical distance along each chromosome. Linkage maps were first developed by  Alfred Sturtevant , a student of  Thomas Hunt Morgan . [ citation needed ]


A linkage map is a map based on the frequencies of  recombination  between markers during  crossover  of  homologous chromosomes . The greater the frequency of recombination (segregation) between two genetic markers, the further apart they are assumed to be. Conversely, the lower the frequency of recombination between the markers, the smaller the physical distance between them. Historically, the markers originally used were detectable  phenotypes  (enzyme production, eye colour) derived from  coding DNA  sequences; eventually, confirmed or assumed  noncoding DNA  sequences such as  microsatellites  or those generating restriction fragment length polymorphisms ( RFLPs ) have been used. [ citation needed ]


Linkage maps help researchers to locate other markers, such as other genes by testing for genetic linkage of the already known markers.  In the early stages of developing a linkage map, the data are used to assemble  linkage groups , a set of genes which are known to be linked. As knowledge advances, more markers can be added to a group, until the group covers an entire chromosome. [ 6 ]  For well-studied organisms the linkage groups correspond one-to-one with the chromosomes. [ citation needed ]


A linkage map is  not  a physical map (such as a  radiation reduced hybrid  map) or  gene map . [ citation needed ]


Linkage analysis is a genetic method that searches for chromosomal segments that  cosegregate  with the ailment phenotype through families. [ 7 ]  It can be used to map genes for both binary and quantitative traits. [ 7 ]  Linkage analysis may be either parametric (if we know the relationship between phenotypic and genetic similarity) or non-parametric. Parametric linkage analysis is the traditional approach, whereby the probability that a gene important for a disease is linked to a genetic marker is studied through the LOD score, which assesses the probability that a given pedigree, where the disease and the marker are cosegregating, is due to the existence of linkage (with a given linkage value) or to chance. Non-parametric linkage analysis, in turn, studies the probability of an allele being  identical by descent  with itself. [ citation needed ]


The  LOD score  (logarithm (base 10) of odds), developed by  Newton Morton , [ 8 ]  is a statistical test often used for linkage analysis in human, animal, and plant populations. The LOD score compares the likelihood of obtaining the test data if the two loci are indeed linked, to the likelihood of observing the same data purely by chance. Positive LOD scores favour the presence of linkage, whereas negative LOD scores indicate that linkage is less likely. Computerised LOD score analysis is a simple way to analyse complex family pedigrees in order to determine the linkage between  Mendelian  traits (or between a trait and a marker, or two markers). [ citation needed ]


The method is described in greater detail by Strachan and Read. [1]  Briefly, it works as follows: [ citation needed ]


The LOD score is calculated as follows:


NR denotes the number of non-recombinant offspring, and R denotes the number of recombinant offspring. The reason 0.5 is used in the denominator is that any alleles that are completely unlinked (e.g. alleles on separate chromosomes) have a 50% chance of recombination, due to independent assortment.  θ  is the recombinant fraction, i.e. the fraction of births in which recombination has happened between the studied genetic marker and the putative gene associated with the disease. Thus, it is equal to  R  / ( NR  +  R ) . [ citation needed ]


By convention, a LOD score greater than 3.0 is considered evidence for linkage, as it indicates 1000 to 1 odds that the linkage being observed did not occur by chance. On the other hand, a LOD score less than −2.0 is considered evidence to exclude linkage. Although it is very unlikely that a LOD score of 3 would be obtained from a single pedigree, the mathematical properties of the test allow data from a number of pedigrees to be combined by summing their LOD scores. A LOD score of 3 translates to a  p -value  of approximately 0.05, [ 9 ]  and no  multiple testing correction  (e.g.  Bonferroni correction ) is required. [ 10 ]


Linkage analysis has a number of methodological and theoretical limitations that can significantly increase the  type-1 error  rate and reduce the power to map human quantitative trait loci (QTL). [ 11 ]  While linkage analysis was successfully used to identify genetic variants that contribute to rare disorders such as  Huntington disease , it did not perform that well when applied to more common disorders such as  heart disease  or different forms of  cancer . [ 12 ]  An explanation for this is that the genetic mechanisms affecting common disorders are different from those causing some rare disorders. [ 13 ]


Recombination frequency is a measure of genetic linkage and is used in the creation of a genetic linkage map. Recombination frequency ( θ ) is the frequency with which a single  chromosomal crossover  will take place between two  genes  during  meiosis . A  centimorgan  (cM) is a unit that describes a recombination frequency of 1%. In this way we can measure the genetic distance between two loci, based upon their recombination frequency. This is a good estimate of the real distance. Double crossovers would turn into no recombination. In this case we cannot tell if crossovers took place. If the loci we're analysing are very close (less than 7 cM) a double crossover is very unlikely. When distances become higher, the likelihood of a double crossover increases. As the likelihood of a double crossover increases one could systematically underestimate the genetic distance between two loci, unless one used an appropriate mathematical model. [ citation needed ]


Double linkage is more of a historical concern for plants. In animals, double crossover happens rarely. In humans, for example, one chromosome has two crossovers on average during meiosis. Furthermore, modern geneticists have enough genes that only nearby genes need to be linkage-analyzed, unlike the early days when only a few genes were known. [ 14 ]


During meiosis, chromosomes assort randomly into  gametes , such that the segregation of  alleles  of one gene is independent of alleles of another gene.  This is stated in  Mendel's Second Law  and is known as  the law of independent assortment . The law of independent assortment always holds true for genes that are located on different chromosomes, but for genes that are on the same chromosome, it does not always hold true. [ citation needed ]


As an example of independent assortment, consider the crossing of the pure-bred  homozygote  parental strain with  genotype   AABB  with a different pure-bred strain with genotype  aabb .  A and a and B and b represent the alleles of genes A and B.  Crossing these homozygous parental strains will result in F1 generation offspring that are double  heterozygotes  with genotype AaBb.  The F1 offspring AaBb produces gametes that are  AB ,  Ab ,  aB , and  ab  with equal frequencies (25%) because the alleles of gene A assort independently of the alleles for gene B during meiosis.  Note that 2 of the 4 gametes (50%)— Ab  and  aB —were not present in the parental generation.  These gametes represent  recombinant gametes .  Recombinant gametes are those gametes that differ from both of the  haploid  gametes that made up the original  diploid  cell.  In this example, the recombination frequency is 50% since 2 of the 4 gametes were recombinant gametes. [ citation needed ]


The recombination frequency will be 50% when two genes are located on different  chromosomes  or when they are widely separated on the same chromosome. This is a consequence of independent assortment. [ citation needed ]


When two genes are close together on the same chromosome, they do not assort independently and are said to be linked. Whereas genes located on different chromosomes assort independently and have a recombination frequency of 50%, linked genes have a recombination frequency that is less than 50%. [ citation needed ]


As an example of linkage, consider the classic experiment by  William Bateson  and  Reginald Punnett . [ 15 ]   They were interested in trait inheritance in the sweet pea and were studying two genes—the gene for flower colour ( P , purple, and  p , red) and the gene affecting the shape of pollen grains ( L , long, and  l , round).  They crossed the pure lines  PPLL  and  ppll  and then self-crossed the resulting  PpLl  lines.  According to  Mendelian genetics , the expected  phenotypes  would occur in a 9:3:3:1 ratio of PL:Pl:pL:pl.  To their surprise, they observed an increased frequency of PL and pl and a decreased frequency of Pl and pL (see table below).


Their experiment revealed  linkage  between the  P  and  L  alleles and the  p  and  l  alleles.  The frequency of  P  occurring together with  L  and with  p  occurring together with  l  is greater than that of the recombinant  Pl  and  pL .  The recombination frequency is more difficult to compute in an F2 cross than a backcross, [ 4 ]  but the lack of fit between observed and expected numbers of progeny in the above table indicate it is less than 50%. [ citation needed ]


The progeny in this case received two dominant alleles linked on one chromosome (referred to as  coupling  or  cis arrangement ). However, after crossover, some progeny could have received one parental chromosome with a dominant allele for one trait (e.g. Purple) linked to a recessive allele for a second trait (e.g. round) with the opposite being true for the other parental chromosome (e.g. red and Long). This is referred to as  repulsion  or a  trans arrangement . The  phenotype  here would still be purple and long but a test cross of this individual with the recessive parent would produce progeny with much greater proportion of the two crossover phenotypes. While such a problem may not seem likely from this example, unfavourable repulsion linkages do appear when breeding for disease resistance in some crops. [ citation needed ]


The two possible arrangements, cis and trans, of alleles in a double heterozygote are referred to as  gametic phases , and  phasing  is the process of determining which of the two is present in a given individual. [ citation needed ]


When two genes are located on the same chromosome, the chance of a  crossover  producing recombination between the genes is related to the distance between the two genes.  Thus, the use of recombination frequencies has been used to develop  linkage maps  or  genetic maps . [ citation needed ]


However, it is important to note that recombination frequency tends to underestimate the distance between two linked genes. This is because as the two genes are located farther apart, the chance of double or even number of crossovers between them also increases. Double or even number of crossovers between the two genes results in them being cosegregated to the same gamete, yielding a parental progeny instead of the expected recombinant progeny. As mentioned above, the  Kosambi and Haldane transformations  attempt to correct for multiple crossovers. [ 16 ]


In the early 1950s the prevailing view was that the genes in a  chromosome  are discrete entities, indivisible by  genetic recombination  and arranged like beads on a string.  During 1955 to 1959, Benzer performed  genetic recombination  experiments using  rII  mutants of  bacteriophage T4 .  He found that, on the basis of recombination tests, the sites of  mutation  could be mapped in a linear order. [ 17 ] [ 18 ]  This result provided evidence for the key idea that the gene has a linear structure equivalent to a length of  DNA  with many sites that can independently mutate. [ citation needed ]


Edgar et al. [ 19 ]  performed mapping experiments with r mutants of bacteriophage T4 showing that recombination frequencies between rII mutants are not strictly additive. The recombination frequency from a cross of two rII mutants (a x d) is usually less than the sum of recombination frequencies for adjacent internal sub-intervals (a x b) + (b x c) + (c x d). Although not strictly additive, a systematic relationship was observed [ 20 ]  that likely reflects the underlying molecular mechanism of  genetic recombination .


While recombination of chromosomes is an essential process during meiosis, there is a large range of frequency of cross overs across organisms and within species. Sexually dimorphic rates of recombination are termed heterochiasmy, and are observed more often than a common rate between male and females. In mammals, females often have a higher rate of recombination compared to males. It is theorised that there are unique selections acting or meiotic drivers which influence the difference in rates. The difference in rates may also reflect the vastly different environments and conditions of meiosis in oogenesis and spermatogenesis. [ 21 ]


Mutations  in  genes  that encode proteins involved in the processing of DNA often affect  recombination  frequency.  In  bacteriophage T4 , mutations that reduce expression of the replicative  DNA polymerase  [gene product 43 (gp43)] increase recombination (decrease linkage) several fold. [ 22 ] [ 23 ]   The increase in recombination may be due to  replication  errors by the defective DNA polymerase that are themselves recombination events such as template switches, i.e. copy choice recombination events. [ 24 ]  Recombination is also increased by mutations that reduce the expression of  DNA ligase  (gp30) [ 25 ] [ 23 ]  and dCMP hydroxymethylase (gp42), [ 22 ] [ 23 ]  two enzymes employed in  DNA synthesis .


Recombination is reduced (linkage increased) by mutations in genes that encode proteins with  nuclease  functions (gp46 and gp47) [ 25 ] [ 23 ]  and a  DNA-binding protein  (gp32) [ 23 ]   Mutation in the bacteriophage uvsX gene also substantially reduces recombination. [ 26 ]   The uvsX gene is analogous to the well studied  recA  gene of  Escherichia coli  that plays a central role in recombination. [ 27 ]


With very large pedigrees or with very dense genetic marker data, such as from whole-genome sequencing, it is possible to precisely locate recombinations. With this type of genetic analysis, a meiosis indicator is assigned to each position of the genome for each  meiosis  in a pedigree. The indicator indicates which copy of the parental chromosome contributes to the transmitted gamete at that position. For example, if the allele from the 'first' copy of the parental chromosome is transmitted, a '0' might be assigned to that meiosis. If the allele from the 'second' copy of the parental chromosome is transmitted, a '1' would be assigned to that meiosis. The two alleles in the parent came, one each, from two grandparents. These indicators are then used to determine identical-by-descent (IBD) states or inheritance states, which are in turn used to identify genes responsible for diseases. [ citation needed ]


A  genetic screen  or  mutagenesis screen   is an experimental technique used to identify and select individuals who possess a  phenotype  of interest in a mutagenized population. [ 1 ]   Hence a genetic screen is a type of  phenotypic screen . Genetic screens can provide important information on  gene  function as well as the molecular events that underlie a biological process or pathway.  While  genome projects  have identified an extensive inventory of genes in many different organisms, genetic screens can provide valuable insight as to how those genes function. [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ]


Forward genetics  (or a forward genetic screen) starts with a phenotype and then attempts to identify the causative mutation and thus gene(s) responsible for the phenotype. For instance, the famous screen by  Christiane Nüsslein-Volhard  and  Eric Wieschaus  mutagenized fruit flies and then set out to find the genes causing the observed mutant phenotypes. [ 7 ]


Successful forward genetic screens often require a defined genetic background and a simple experimental procedure. That is, when multiple individuals are mutagenized they should be genetically identical so that their wild-type phenotype is identical too and mutant phenotypes are easier to identify.  A simple screening method allows for a larger number of individuals to be screened, thereby increasing the probability of generating and identifying mutants of interest. [ 3 ]


Since natural  allelic  mutations are rare prior to screening geneticists often mutagenize a population of individuals by exposing them to a known  mutagen , such as a chemical or radiation, thereby generating a much higher frequency of  chromosomal mutations . [ 1 ]   In some organisms  mutagens  are used to perform  saturation screens , that is, a screen used to uncover  all  genes involved in a particular phenotype.  Christiane Nüsslein-Volhard  and  Eric Wieschaus  were the first individuals to perform this type of screening procedure in animals. [ 8 ]


Reverse genetics  (or a reverse genetic screen), starts with a known gene and assays the effect of its disruption by analyzing the resultant phenotypes. For example, in a knock-out screen, one or more genes are completely deleted and the deletion mutants are tested for phenotypes. Such screens have been done for all genes in many bacteria and even complex organisms, such as  C. elegans . [ 1 ]  A reverse genetic screen typically begins with a gene sequence followed by targeted inactivation. [ 9 ]  Moreover, it induces mutations in model organisms to learn their role in disease. [ 10 ]  Reverse genetics is also used to provide extremely accurate statistics on mutations that occur in specific genes. From these screens you are able to determine how fortuitous the mutations are, and how often the mutations occur. [ 11 ]


Many screening variations have been devised to elucidate a gene that leads to a mutant phenotype of interest.


An  enhancer screen  begins with a mutant individual that has an affected process of interest with a known gene mutation.  The screen can then be used to identify additional genes or gene mutations that play a role in that biological or physiological process. A genetic enhancer screen identifies mutations that enhance a phenotype of interest in an already mutant individual.  The phenotype of the double mutant (individual with both the enhancer and original background mutation) is more prominent than either of the single mutant phenotypes.  The enhancement must surpass the expected phenotypes of the two mutations on their own, and therefore each mutation may be considered an enhancer of the other.  Isolating enhancer mutants can lead to the identification of interacting genes or genes which act redundantly with respect to one another. [ 12 ]


A  suppressor screen  is used to identify  suppressor mutations  that alleviate or revert the phenotype of the original mutation, in a process defined as  synthetic viability . [ 13 ]  Suppressor mutations can be described as second mutations at a site on the chromosome distinct from the mutation under study, which suppress the phenotype of the original mutation. [ 14 ]  If the mutation is in the same gene as the original mutation it is known as  intragenic suppression , whereas a mutation located in a different gene is known as  extragenic suppression or intergenic suppression . [ 1 ]  Suppressor mutations are extremely useful to define the functions of biochemical pathways within a cell and the relationships between different biochemical pathways.


A  temperature-sensitive screen  involves performing temperature shifts to enhance a mutant phenotype.  A population grown at low temperatures would have a normal phenotype; however, the mutation in the particular gene would make it unstable at a higher temperature.  A screen for temperature sensitivity in fruit flies, for example, might involve raising the  temperature  in the cage until some flies faint, then opening a portal to let the others escape. Individuals selected in a screen are liable to carry an unusual version of a  gene  involved in the phenotype of interest. An advantage of alleles found in this type of screen is that the mutant phenotype is  conditional  and can be activated by simply raising the temperature. A  null mutation  in such a gene may be lethal to the embryo and such mutants would be missed in a basic screen. A famous temperature-sensitive screen was carried out independently by  Lee Hartwell  and  Paul Nurse  to identify mutants defective in the cell cycle in  S. cerevisiae  and  S. pombe , respectively.


RNA interference (RNAi)  screen is essentially a forward genetics screen using a reverse genetics technique. Similar to classical genetic screens in the past, large-scale RNAi surveys success depends on a careful development of phenotypic assays and their interpretation. [ 9 ]  In  Drosophila , RNAi has been applied in cultured cells or in vivo to investigate gene functions and to effect the function of single genes on a genome-wide scale. RNAi is used to silence gene expression in Drosophila by injecting dsRNA into early embryos, and interfering with  Frizzled  and Frizzled2 genes creating defects in embryonic patterning that mimic loss of wingless function. [ 15 ]


CRISPR/Cas  is primarily used for reverse genetic screens. CRISPR has the ability to create libraries of thousands of precise genetic mutations and can identify new tumors as well as validate older tumors in cancer research.  Genome-scale CRISPR-Cas9 knockout (GeCKO)  library targeting 18,080 genes with 64,751 unique guide sequences identify genes essential for cell viability in cancer. Bacterial  CRISPR–Cas9  system for engineering both loss of function (LOF) and gain of function (GOF) mutations in untransformed human intestinal organoids in order to demonstrate a model of  Colorectal cancer (CRC) . It can also be used to study functional consequences of mutations in vivo by enabling direct genome editing in somatic cells. [ 10 ]


By the  classical genetics  approach, a researcher would then locate (map) the gene on its  chromosome  by  crossbreeding  with individuals that carry other unusual  traits  and collecting statistics on how frequently the two traits are inherited together. Classical geneticists would have used phenotypic traits to map the new mutant  alleles . With the advent of genomic sequences for model systems such as  Drosophila melanogaster ,   Arabidopsis thaliana  and  C. elegans  many  single nucleotide polymorphisms  (SNPs) have now been identified that can be used as traits for mapping. In fact, the  Heidelberg screen , allowing mass testing of mutants and developed in 1980 by  Nüsslein-Volhard  and  Wieschaus , cleared the way for future scientists in this field. [ 4 ]  SNPs are the preferred traits for mapping since they are very frequent, on the order of one difference per 1000 base pairs, between different varieties of organism. Mutagens such as random DNA insertions by  transformation  or active  transposons  can also be used to generate new mutants. These techniques have the advantage of tagging the new alleles with a known molecular  (DNA) marker  that can facilitate the rapid identification of the gene. [ 8 ]


Positional cloning is a method of gene identification in which a gene for a specific phenotype is identified only by its approximate chromosomal location (but not the function); this is known as the  candidate region .  Initially, the candidate region can be defined using techniques such as  linkage analysis , and positional cloning is then used to narrow the candidate region until the gene and its mutations are found.  Positional cloning typically involves the isolation of partially overlapping DNA segments from genomic libraries to progress along the chromosome toward a specific gene. During the course of positional cloning, one needs to determine whether the DNA segment currently under consideration is part of the gene.


Tests used for this purpose include cross-species hybridization, identification of unmethylated  CpG islands ,  exon trapping , direct  cDNA  selection, computer analysis of DNA sequence, mutation screening in affected individuals, and tests of gene expression. For genomes in which the regions of  genetic polymorphisms  are known, positional cloning involves identifying polymorphisms that flank the mutation. This process requires that DNA fragments from the closest known genetic marker are progressively cloned and sequenced, getting closer to the mutant allele with each new clone.  This process produces a  contig map  of the  locus  and is known as  chromosome walking .  With the completion of genome sequencing projects such as the  Human Genome Project , modern positional cloning can use ready-made contigs from the genome sequence databases directly.


For each new  DNA clone  a polymorphism is identified and tested in the mapping population for its  recombination  frequency compared to the mutant phenotype. When the DNA clone is at or close to the mutant allele, the recombination frequency should be close to zero.  If the chromosome walk proceeds through the mutant allele, the new polymorphisms will start to show increase in recombination frequency compared to the mutant phenotype.  Depending on the size of the mapping population, the mutant allele can be narrowed down to a small region (<30 Kb).  Sequence comparison between  wild type  and  mutant  DNA in that region is then required to locate the DNA  mutation  that causes the phenotypic difference.


Modern positional cloning can more directly extract information from genomic sequencing projects and existing data by analyzing the genes in the candidate region.  Potential disease genes from the candidate region can then be prioritized, potentially reducing the amount of work involved.  Genes with expression patterns consistent with the disease phenotype, showing a (putative) function related to the phenotype, or homologous to another gene linked to the phenotype are all priority candidates.  Generalization of positional cloning techniques in this manner is also known as positional gene discovery.


Positional cloning is an effective method to isolate disease genes in an unbiased manner and has been used to identify disease genes for  Duchenne muscular dystrophy ,  Huntington's disease , and  cystic fibrosis .  However, complications in the analysis arise if the disease exhibits locus heterogeneity.


Genocopy   is a trait that is a  phenotypic  copy of a  genetic  trait but is caused by a different  genotype . [ 1 ]  When a genetic  mutation  or  genotype  in one locus results in a  phenotype  similar to one that is known to be caused by another mutation or genotype in another locus, it is said to be a genocopy. [ 2 ]  However, genocopies may also be referred to as "genetic mimics", in which the same mutation or specific genotype can result in two unique phenotypes in two different patients. [ 3 ]  The term “Genocopy” was coined by Dr. H. Nachstheim in 1957, [ 4 ]  in which he discusses “false” phenocopies. In comparison to when a phenotype is the result of an environmental condition that had the same effect as a previously known genetic factor such as mutation. [ 5 ]  While offspring may inherit specific mutations or genotypes that result in genocopies, phenocopies are not heritable. [ 6 ]  Two types of elliptocytosis that are genocopies of each other, but are distinguished by the fact that one is linked to the Rh blood group locus and the other is not. [ 7 ]  The way to distinguish a recessive genocopy from a  phenotype  caused by a different  allele  would be by carrying out a  test cross , breeding the two together, if they  F1 hybrid  segregates 1:2:1 then we can determine that it was a genocopy. [ 8 ]


Since  Mitochondria  carry out such a variety of functions in different tissues, there are often hundreds of Mitochondrial diseases that might be harder to diagnose in early stages. Considering that there is a complex relationship between cells and genes to have metabolism at its optimum, identical  Mitochondrial DNA  mutations may not show up as identical diseases. Genocopies are often seen as diseases that might be caused by the same mutation but do not result in identical expression. [ 9 ]  Diseases associated with  mtDNA  are often as a result of mutations in  tRNA  that play a role in Mitochondrial protein synthesis. These mutations that change protein-encoding genes or both. How each category of cause of Mitochondrial disease produces genocopies is still unknown. [ 10 ]


The genocopy event between  TBX1  and 22q11.2 mutations is one that shows grave symptoms. The  22q11.2  mutation leads to   DiGeorge or velocardiofacial syndromes . Similarly, the mutations in the TBX1 genome exhibit the same symptoms. [ 11 ]  The TBX1 haploinsufficiency is responsible for many of the traits that are also seen in 22q11.2 mutations. It has 2 mutations that are similar to the two mutations of 22q11.2 -  deletion  and  duplication . [ 12 ]  The first mutation is L411P and is a  de novo mutation . [ 12 ]  This mutation affects a conserved amino acid within a putative  transactivation domain  and is likely to affect the protein's functionality. [ 12 ]  The second mutation is one that converts a  cytosine  to  thymine  in the 5’ UTR region of the TBX1 gene. This mutation increases TBX1 translational efficiency during key points in development, which is the functional equivalent to 22q11.2 duplication. [ 12 ]  This shows us that genocopy is not just a discrete genomic event but can also be seen in serious diseases.


Genomovar  is a term commonly used within the genera  Burkholderia  and  Agrobacterium  to denote strains which are  phylogenetically  differentiable, but are  phenotypically  indistinguishable. A genomovar cannot be identified by standard biochemical tests, but it is classified as a species when a biochemical test allows it to be identified. [ 1 ]


Hand clasping  or  hand folding  is the interlocking of the  fingers  of one  hand  with the fingers of another. It is commonly used to express authority above or respect for others. It is also common to clasp the hands during  prayer .


When clasping the hands, a person tends to interlace the fingers in one of two ways. People who hold the fingers of the right hand above the left fingers are classified as  phenotype   R  (right), while those who hold the fingers of the left hand above those of the right are phenotype  L  (left).


Although some people do not prefer one type of hand clasping, most do. Once adopted, hand clasping tends to be consistent throughout life. When an individual attempts to clasp the hands in the opposite configuration from the usual one, that person may feel a sense that something is out of the ordinary.


Lai and Walsh (1965) suspect that  genetic factors  are important in determining these characteristics. They looked at a sample of 18 families. [ 1 ]


Based on the comparison of a series of monozygotic and dizygotic  twins , Freire-Maia (1961) concluded that the preference in the type of hand clasping was affected by certain genetic factors, and (perhaps) to a significant extent. [ 2 ]


Falk and Ayala (1971) found a significant correlation between parent-offspring and for this feature suggested model polygenic inheritance. [ 3 ]


Martin (1975) presented the results of studies of  twins  and found that genetic factors are still determining the phenotypic expression of this trait. [ 4 ]


Reiss (1999) found that 55% of the  population  belongs to the phenotype  L , and 44% have a "right type" clasping; the remaining 1% did not care. [ 5 ] [ 6 ]


In support of the hypothesis about the significant influence of genetic factors on the  phenotypic expression  of the extreme  dimorphism  clearly demarcated by the data on a very wide range of variation in the frequency of phenotypes tested parts of the world's population. [ clarification needed ]


Hand wringing is a gesture characterized by repeatedly rubbing or twisting one's hands together, often as a sign of distress or  nervousness , while folding or clasping. Hand wringing has been studied in psychology to understand its underlying motivations and implications for mental well-being, of which include nonverbal communication and self-soothing behavior. It is often attributed to physical, cognitive, and mental conditions.


The act of hand wringing, along other motor actions, has been observed common in people with  Rett syndrome , a genetic brain disorder, for decades. [ 17 ] [ 18 ] [ 19 ]  In a study investigating stereotypical hand movements in individuals with the syndrome, hand wringing was identified as one of the most prevalent stereotypies, observed in approximately 60% of subjects. [ 20 ]  It found that hand wringing tended to be more prevalent in women aged 19 years or older. Additionally, associations were noted between specific mutations and hand-wringing behavior, with certain mutations being more commonly associated with this stereotypical movement. However, there were no clear relationships between hand-wringing and the severity of mutations.


Hand wringing is also common in people with  autism [ 21 ] [ 22 ]  and  obsessive-compulsive disorder . [ 23 ] [ 24 ]


Some studies suggest that when attempting to mitigate certain behaviors through interventions like response blocking, unintended consequences may arise. [ 25 ]  For instance, in the treatment of stereotypic behavior such as head and tooth tapping, blocking these behaviors may inadvertently lead to an increase in other stereotypic responses, such as hand wringing. This collateral effect, observed in individuals diagnosed with autism, indicates that the reduction in the targeted behavior may result in the emergence or exacerbation of alternative behaviors.


Hand clasping holds significance in several religious and spiritual practices around the world, often symbolizing different aspects of faith. While not explicitly addressed in religious texts or practices, individuals may engage in the behavior during moments of spiritual reflection such as prayer or meditation.


In Christianity, hand clasping can be seen during prayer or as a gesture of fellowship and unity among believers. It often symbolizes solidarity in faith and mutual support within the community. In some Christian ceremonies, such as weddings or baptisms, hand clasping may signify the joining of two individuals or families in a sacred bond.


Buddhism employs hand gestures, or  mudras , as part of spiritual practice. Some of which include clasped hands, such as  ushas mudra , symbolizing reverence, gratitude, and mindfulness. Hand clasping may also be used in meditation as a means of focusing on one's intention and connecting with inner peace.


In  Mandaeism , the  Mandaic  term  kushta  (which also means 'truth') refers to a sacred handclasp that is used during Mandaean rituals such as the  masbuta ,  masiqta , and priestly initiation ceremonies. [ 26 ] [ 27 ]


A  haplotype  is a group of  alleles  in an organism that are inherited together from a single parent, [ 1 ] [ 2 ]  and a  haplogroup  ( haploid  from the  Greek :  ἁπλοῦς ,  haploûs , "onefold, simple" and English:  group ) is a group of similar haplotypes that share a common ancestor with a  single-nucleotide polymorphism   mutation . [ 3 ]  More specifically, a haplotype is a combination of  alleles  at different chromosomal regions that are closely linked and tend to be inherited together. As a haplogroup consists of similar haplotypes, it is usually possible to predict a haplogroup from haplotypes. Haplogroups pertain to a single  line of descent . As such, membership of a haplogroup, by any individual, relies on a relatively small proportion of the genetic material possessed by that individual.


Each haplogroup originates from, and remains part of, a preceding single haplogroup (or  paragroup ). As such, any related group of haplogroups may be precisely modelled as a  nested hierarchy , in which each  set  (haplogroup) is also a  subset  of a single broader set (as opposed, that is, to biparental models, such as human family trees).  Haplogroups can be further divided into subclades.


Haplogroups are normally identified by an initial letter of the alphabet, and refinements consist of additional number and letter combinations, such as (for example)  A → A1 → A1a . The alphabetical nomenclature was published in 2002 by the  Y Chromosome Consortium . [ 4 ]


In  human genetics , the haplogroups most commonly studied are  Y-chromosome (Y-DNA) haplogroups  and  mitochondrial DNA (mtDNA) haplogroups , each of which can be used to define  genetic populations . Y-DNA is passed solely along the  patrilineal  line, from father to son, while mtDNA is passed down the  matrilineal  line, from mother to offspring of both sexes. Neither  recombines , and thus Y-DNA and mtDNA change only by chance mutation at each generation with no intermixture between parents' genetic material.


Mitochondria  are small  organelles  that lie in the  cytoplasm  of  eukaryotic cells , such as those of humans. Their primary function is to provide energy to the cell. Mitochondria are thought to be reduced descendants of  symbiotic   bacteria  that were once free living. One indication that mitochondria were once free living is that each contains a circular  DNA , called  mitochondrial DNA  (mtDNA), whose structure is more similar to bacteria than eukaryotic organisms (see  endosymbiotic theory ). The overwhelming majority of a human's DNA is contained in the  chromosomes  in the  nucleus  of the cell, but mtDNA is an exception.
An individual inherits their cytoplasm and the organelles contained by that cytoplasm exclusively from the maternal ovum (egg cell);  sperm  only pass on the chromosomal DNA, all paternal mitochondria are digested in the  oocyte . When a  mutation  arises in a mtDNA molecule, the mutation is therefore passed down in a direct female line of descent. Mutations are changes in the nitrogen bases of the  DNA sequence . Single changes from the original sequence are called  single nucleotide polymorphisms  (SNPs). [ dubious  –  discuss ]


Human  Y chromosomes  are male-specific  sex chromosomes ; nearly all humans that possess a Y chromosome will be  morphologically  male. Although Y chromosomes are situated in the cell nucleus and paired with  X chromosomes , they only  recombine  with the X chromosome at the  ends of the Y chromosome ; the remaining 95% of the Y chromosome does not recombine. Therefore, the Y chromosome and any mutations that arise in it are passed down in a direct male line of descent.


Other chromosomes,  autosomes  and  X chromosomes  (when another X chromosome is available to pair with it),  share their genetic material  during  meiosis , the process of  cell division  which produces  gametes . Effectively this means that the genetic material from these chromosomes gets mixed up in every generation, and so any new mutations are passed down randomly from parents to offspring.


The special feature that both Y chromosomes and mtDNA display is that mutations can accrue along a certain segment of both molecules and these mutations remain fixed in place on the DNA. Furthermore, the historical sequence of these mutations can also be inferred. For example, if a set of ten Y chromosomes (derived from ten different individuals) contains a mutation, A, but only five of these chromosomes contain a second mutation, B, then it is overwhelmingly likely that mutation B occurred after mutation A.


Furthermore, all ten individuals who carry the chromosome with mutation A are the direct male line descendants of the same man who was the first person to carry this mutation. The first man to carry mutation B was also a direct male line descendant of this man, but is also the direct male line ancestor of all men carrying mutation B. Series of mutations such as this form molecular lineages. Furthermore, each mutation defines a set of specific Y chromosomes called a haplogroup.


All humans carrying mutation A form a single haplogroup, and all humans carrying mutation B are part of this haplogroup, but mutation B also defines a more recent haplogroup (which is a subgroup or  subclade ) of its own to which humans carrying only mutation A do not belong. Both mtDNA and Y chromosomes are grouped into lineages and haplogroups; these are often presented as tree-like diagrams.


Human  Y chromosome  DNA (Y-DNA) haplogroups are named from A to T, and are further subdivided using numbers and lower case letters. Y chromosome haplogroup designations are established by the Y Chromosome Consortium. [ 5 ]


Y-chromosomal Adam  is the name given by researchers to the male who is the  most recent common patrilineal (male-lineage) ancestor  of all living humans.


Major Y-chromosome haplogroups, and their geographical regions of occurrence (prior to
the recent European colonization), include:


(mutation M168 occurred ~50,000 bp)


(mutation M89 occurred ~45,000 bp)


(mutation M9 occurred ~40,000  bp )


Human  mtDNA  haplogroups are lettered:
 A ,
 B ,
 C ,
 CZ ,
 D ,
 E ,
 F ,
 G ,
 H ,
 HV ,
 I ,
 J ,
 pre- JT ,
 JT ,
 K ,
 L0 ,
 L1 ,
 L2 ,
 L3 ,
 L4 ,
 L5 ,
 L6 ,
 M ,
 N ,
 O ,
 P ,
 Q ,
 R ,
 R0 ,
 S ,
 T ,
 U ,
 V ,
 W ,
 X ,
 Y , and
 Z . The most up-to-date version of the mtDNA tree is maintained by Mannis van Oven on the PhyloTree website. [ 9 ]


Mitochondrial Eve  is the name given by researchers to the woman who is the  most recent common matrilineal (female-lineage) ancestor  of all living humans.


Haplogroups can be used to define  genetic  populations and are often geographically oriented. For example, the following are common divisions for mtDNA haplogroups:


The mitochondrial haplogroups are divided into three main groups, which are designated by the sequential letters L, M, N.
Humanity first split within the L group between L0 and L1-6. L1-6 gave rise to other L groups, one of which, L3, split into the M and N group.


The M group comprises the first wave of human migration which is thought to have evolved outside of Africa, following an eastward route along southern coastal areas. Descendant lineages of haplogroup M are now found throughout Asia, the Americas, and Melanesia, as well as in parts of the Horn of Africa and North Africa; almost none have been found in Europe. The N haplogroup may represent another macrolineage that evolved outside of Africa, heading northward instead of eastward. Shortly after the migration, the large R group split off from the N.


Haplogroup R consists of two subgroups defined on the basis of their geographical distributions, one found in southeastern Asia and Oceania and the other containing almost all of the modern European populations. Haplogroup N(xR), i.e. mtDNA that belongs to the N group but not to its R subgroup, is typical of Australian aboriginal populations, while also being present at low frequencies among many populations of Eurasia and the Americas.


The L type  consists of nearly all Africans.


The M type  consists of:


M1 – Ethiopian, Somali and Indian populations. Likely due to much gene flow between the Horn of Africa and the Arabian Peninsula (Saudi Arabia, Yemen, Oman), separated only by a narrow strait between the Red Sea and the Gulf of Aden.


CZ – Many Siberians; branch C – Some Amerindian; branch Z – Many Saami, some Korean, some North Chinese, some Central Asian populations.


D – Some Amerindians, many Siberians and northern East Asians


E – Malay, Borneo, Philippines,  Taiwanese aborigines , Papua New Guinea


G – Many Northeast Siberians, northern East Asians, and Central Asians


Q – Melanesian, Polynesian, New Guinean populations


The N type  consists of:


A – Found in many Amerindians and some East Asians and Siberians


I – 10% frequency in Northern, Eastern Europe


S – Some Indigenous Australian (First Nations People of Australia)


W – Some Eastern Europeans, South Asians, and southern East Asians


X – Some Amerindians, Southern Siberians, Southwest Asians, and Southern Europeans


Y – Most  Nivkhs  and people of  Nias ; many Ainus,  Tungusic people , and  Austronesians ; also found with low frequency in some other populations of Siberia, East Asia, and Central Asia


R  – Large group found within the N type. Populations contained therein can be divided geographically into West Eurasia and East Eurasia. Almost all European populations and a large number of Middle-Eastern population today are contained within this branch. A smaller percentage is contained in other N type groups (See above). Below are  subclades of R :


B – Some Chinese, Tibetans, Mongolians, Central Asians, Koreans, Amerindians, South Siberians, Japanese, Austronesians


F – Mainly found in southeastern Asia, especially  Vietnam ; 8.3% in Hvar Island in Croatia. [ 11 ]


R0 – Found in Arabia and among Ethiopians and Somalis; branch HV (branch H; branch V) – Europe, Western Asia, North Africa;


Pre-JT – Arose in the Levant (modern Lebanon area), found in 25% frequency in Bedouin populations; branch JT (branch J; branch T) – North, Eastern Europe, Indus, Mediterranean


U – High frequency in West Eurasia, Indian sub-continent, and Algeria, found from India to the Mediterranean and to the rest of Europe; U5 in particular shows high frequency in Scandinavia and Baltic countries with the highest frequency in the  Sami people .


Here is a list of Y-chromosome and MtDNA geographic haplogroup assignment proposed by Bekada et al. 2013. [ 12 ]


According to SNPS haplogroups which are the age of the first extinction event tend to be around 45–50 kya. Haplogroups of the second extinction event seemed to diverge 32–35 kya according to  Mal'ta . The ground zero extinction event appears to be Toba during which haplogroup CDEF* appeared to diverge into C, DE and F. C and F have almost nothing in common while D and E have plenty in common. Extinction event #1 according to current estimates occurred after Toba, although older ancient DNA could push the ground zero extinction event to long before Toba, and push the first extinction event here back to Toba. Haplogroups with extinction event notes by them have a dubious origin and this is because extinction events lead to severe bottlenecks, so all notes by these groups are just guesses. Note that the SNP counting of ancient DNA can be highly variable meaning that even though all these groups diverged around the same time no one knows when. [ 13 ] [ 14 ]


Y-Chromosome


Haplogroup I-BY316 , also known as  I-Y7626  or  I1a3a1a2a1b1  per the International Society of Genetic Genealogy ('ISOGG), is a  Y chromosome   haplogroup . It is correlated with a DYF406S1 value of 8 and a DYS617 value of 12. [ 1 ]


I-BY316 may be classed as a Nordic haplogroup and it is most common in Finland. [ citation needed ]  Its progenitor is assumed to have lived in Fenno-Scandinavia at around 300 BC. [ 2 ] [ 3 ]


On the basis of analysing samples of volunteers in  YDNA sequencing , the YDNA analysis company  YFull  estimated that I-BY316 formed 2,300 years ago ( 500 BC ) (95%  CI  3,100 <-> 1,950  ybp ) with a  TMRCA  (Time to Most Recent Common Ancestor) of 2,400 years (95%  CI  2,800 <-> 2,100  ybp ) before present. [ 4 ]


Geographically I-BY316 is believed to have arisen in or near what is now  Finland  (based in part on the current distribution of this haplogroup).The current distribution of I-BY316 shows that there is a very high concentration in the regions bordering the Baltic Sea. [ 3 ]  Due to the distinct distribution pattern around the Baltic sea it would appear that the progenitor of I-BY316 may have been immersed in a seafaring culture. In a historical context the distribution patterns fits well with the historical region of  Kvenland  and the associated tribe of the Kvens.


At the time when haplogroup I-BY316 came into existence, the Celts were beginning to expand from their traditional territory in southern Germany. The Germanic peoples were then presumed to be occupying a possible original homeland in southern Sweden and the Jutland peninsula (i.e. the presumed homeland of parent haplogroup  I-Z63 ). There were surrounded on three sides by Kvens. They appear to have gone through a period in which they were conquered by the western Celts and remained subject to them (especially in Jutland). Triggered by the Gallic invasion, the Germanic peoples began expanding south-westwards along the North Sea coast and eastwards along the shores of the Baltic Sea. The push eastward along the Baltic Sea deep into Kven territory is assumed to coincide with the migration pattern of I-BY316. Historical records from the time of haplogroup origin are extremely sparse. The mythological king  Fornjót  of the  Orkneyinga saga  was said to have ruled over  Kvenland  roughly around the time of haplogroup origin. Interestingly some academic sources transcribe the name  Fornjót  as "the old Jute" which is significant because of the suspected origin of parent haplogroup I-Z63 in Jutland. [ 5 ]   Fornjót  was eventually followed by the dynasty of " sea kings " starting with  Heiti Gorsson . Even though mythology may be very far removed from historical truth, it nevertheless paints a picture of a strong seafaring tradition in the area of interest and can therefore help to explain the subsequent expansion of the haplogroup. [ 6 ]


The earliest archeological sample of I-BY316 is CGG106524 at the Hestehavens Mose site near Hjørring in Denmark whereby C14 dating revealed the sample to be approximately 2,275 years old. The haplogroup was determined as I1a3a1a2a1b1a (PH3482/Y7627).  [ 7 ]  The PH3482 haplogroup is estimated to have formed 2,800 ybp by YFull [ 8 ]  and as 700 BCE by FamilyTreeDNA. [ 9 ]


I-BY316/I-Y7626 was also found in a late 6th Century cemetery in Collegno, Italy, near the city of Torino. [ 10 ]   The Collegno  burial site is associated with Gothic and  Lombard  remains and dated to the late 6th Century.  The remains of sample CL63 belong to subclade I-FT104588. [ 11 ]  Sample CL63 was also remarkable from an autosomal point of view because CL63 was an individual of predominant central/northern ancestry who did not genetically belong to the major kindred unit. This discovery adds another historical connection of I-Z63 to the Gothic migrations of the early Medieval Period. [ 12 ]


Another archeological sample is sample Zeytinliada 14832 which is possibly tied to the Kievan Rus. It belongs to an 25 to 35 year old adult who lived between 600 and 1000 CE during the Medieval Age and was found in the region now known as Zeytinliada, Erdek, Turkey. The genetic profile of this individual does not resemble northern Europeans, so he might be the descendant of a northern European (e.g. part of the Varangian guard of Byzantium) who intermarried with the local population, although a more proximal origin is also possible, as this lineage was found also in Langobards from Hungary. The  Rus'  provided the earliest members of the Varangian Guard. They were in Byzantine service from as early as 874. [ 13 ] [ 14 ]


Based on the public YDNA database FTDNA in December 2019 the I-BY316 haplogroup is showing the following distribution: [ 3 ]


The breakdown by countries as above can be condensed into regions:


Haplogroup I-Z63 , also known as  I1a3  per the International Society of Genetic Genealogy ('ISOGG), is a  Y chromosome   haplogroup . It is correlated with a DYS456 value inferior to 15, but there are exceptions. [ citation needed ]  It is a subgroup of  Haplogroup I-M253 .


I-Z63 is most common in  England ,  Scotland ,  Germany ,  Fennoscandia [ citation needed ]  and  Poland . [ 1 ]  Its progenitor is assumed to have lived in  Jutland  at around 2500 BCE. The earliest archeological sample for I-Z63 is indeed connected to an individual from near Hjørring in Jutland, present Denmark. [ 2 ]  Within  Fennoscandia , I-Z63 has a particularly strong association with Finland. [ 3 ] [ 4 ]  To date, ancient I-Z63 has been found archeologically in historic  Jutland  (present Denmark and Germany) along with  Poland , Hungary, Turkey and  Italy . [ 5 ] [ 6 ]


On the basis of analysing samples of volunteers in  YDNA sequencing , the YDNA analysis company  YFull  estimated that I-Z63 formed 4,600 years ago ( 2600 BC ) (95%  CI  5,100 <-> 4,000  ybp ) with a  TMRCA  (Time to Most Recent Common Ancestor) of 4,400 years (95%  CI  4,900 <-> 3,900  ybp ) before present. [ 7 ]


The earliest archeological sample of I-Z63 is CGG106524, found in Jutland at the Hestehavens Mose site, near Hjørring in Denmark.  The sample is from the pre-roman iron age, between 400-220 BC, whereby C14 dating revealed an age of 2,275 years before present. The haplogroup was determined as I1a3a1a2a1b1a (PH3482/Y7627). [ 8 ]  This is a haplogroup situated in the  I-BY316  subclade of I-Z63. The PH3482 haplogroup is estimated to have formed 2,800 ybp by YFull. [ 9 ]


Geographically I-Z63 is believed to have arisen in or near what is now  Denmark  (based in part on the current distribution of this haplogroup). [ 10 ]  The current distribution of I-Z63 shows that there is a very high concentration of I-Z63 on the British Isles. [ 1 ]  At the same time, the archeological record presents a strong association of I-Z63 to the  Wielbark culture  and by extension with the  Goths . [ 5 ]  There is a proposed link between the Goths and British migration, the so-called "Jutish Hypothesis". [ 11 ]  The "Jutish hypothesis" claims that the Jutes may be synonymous with the  Geats  of southern  Sweden  or their neighbours, the  Gutes . The evidence adduced for this theory includes:


The Jutes invaded and settled in southern  Britain  in the late  4th century  during the  Age of Migrations , as part of a larger wave of Germanic settlement in the  British Isles . The Jutish migration to Britain may explain the high concentration of I-Z63 found in modern Britain. However, I-Z63 is notably sparse among modern volunteer testers from Denmark. This is surprising because, in a geographical sense, Denmark encompasses the ancient homeland of the Jutes. Foreign invaders displacing the Jutes from their ancient homeland may explain the relative lack of I-Z63 in Denmark. Even in the year  945 , the peoples of Jutland were threatened by foreign invaders (yet ironically were posing a threat to other groups elsewhere, such as in England). In 945  King Hacon  of Norway arrived in Jutland and slew many of the people there, sending the survivors “far up into the land”. [ 14 ]  The current distribution of I-Z63 clearly shows that while there is a near absence of I-Z63 in modern Denmark, sizable numbers of I-Z63 men live today in Finland, Norway, Sweden and Aland. [ 1 ]


Based on the combined evidence, the preferred current working hypothesis puts the progenitor of I-Z63 in ancient  Jutland  around the year  2000 BCE .


An individual (sample CGG106524) with the subclade I1a3a1a2a1b1a (PH3482/Y7627)  was found near Hjørring in Jutland, Denmark with C14 dating placing the sample at 2,275 ybp, i.e. the pre-roman Iron Age. [ 2 ]


An individual with the subclade of  I-Y21381  was found just south of Denmark in the Schleswig Rathausmarkt excavation [ 15 ]  in  Schleswig, Schleswig-Holstein , Germany. This city on the  Jutland peninsula  is the successor to the important Viking settlement of  Hedeby , which was destroyed in 1066. Sample SWG007 was obtained from grave 179 and dated to 1070-1140 CE. [ 16 ]


The I-S2077 subclade of haplogroup I-Z63 was sampled on an elite warrior buried in  Bodzia Cemetery  in a rich burial from ca. 1010-1020 AD. [ 17 ] [ 18 ]  All artefacts there indicate a strong relation to the  Kievian Rus  ruling elite, so this man who probably succumbed to combat wounds, was in a close relationship with the Kievian Prince,  Sviatopolk the Accursed  (son of  Vladimir the Great ), married to a daughter of the Polish king  Boleslaw the Great  (Burisleifr from the Scandinavian sagas). The cemetery in Bodzia is exceptional in terms of Scandinavian and  Kievian Rus  links. The Bodzia man (sample VK157, or burial E864/I) was not a simple warrior from the princely retinue, but he belonged to the princely family himself. His burial is the richest one in the whole cemetery, moreover, Strontium analysis of his teeth enamel shows he was not local. It is assumed that he came to Poland with the Prince of Kiev,  Sviatopolk the Accursed , and met a violent death in combat. This corresponds to the events of 1018 AD when Sviatopolk himself disappeared after having retreated from Kiev to Poland. It cannot be excluded that the Bodzia man was  Sviatopolk  himself, as the genealogy of the  Rurikids  at this period is extremely sketchy and the dates of birth of many princes of this dynasty may be quite approximative. [ 19 ] [ 20 ]


Another archeological sample possibly tied to the Kievan Rus is sample Zeytinliada 14832, which belongs to an 25 to 35 year old adult who lived between 600 and 1000 CE during the Medieval Age and was found in the region now known as Zeytinliada,  Erdek , Turkey. This sample has been tied to subclade I-Y3979. [ 21 ]  The genetic profile of this individual does not resemble northern Europeans, so he might be the descendant of a northern European (e.g. part of the Varangian guard of Byzantium) who intermarried with the local population, although a more proximal origin is also possible, as this lineage was found also in Langobards from Hungary. The  Rus'  provided the earliest members of the  Varangian Guard . They were in  Byzantine  service from as early as 874. Hence it appears plausible that sample Bodzia 157 and Zeytinliada 148 are both connected to the  Kievan Rus . [ 22 ]


I-Z63 has been traced to the  Kowalewko  burial site in Poland which dates to the  Roman Iron Age . In 2017 Polish researchers could successfully assign YDNA haplogroups to 16 individuals who were buried at the site. Out of these 16 individuals three belonged to haplogroup I-Z63, and in particular  subclade   I-L1237 . [ 5 ]  The  Kowalewko  archeological site has been associated with the  Wielbark culture . The  Wielbark culture  in turn has been associated with the  Goths . Therefore the subclade I-L1237 of I-Z63 may be seen somewhat as a genetic indicator of the  Gothic  tribe of  late antiquity . [ 23 ]  There is an academic theory that the Gothic tribe is connected to British migration through the so-called "Jutish Hypothesis", which would explain why I-L1237 is so strongly associated both with British migration and with Gothic migration patterns. [ 11 ]


I-Z63 was found in a late 6th Century cemetery in  Collegno , Italy, near the city of Torino. [ 6 ]   The Collegno  burial site is associated with Gothic and  Lombard  remains and dated to the late 6th Century. This discovery adds another historical connection of I-Z63 to the Gothic migrations of the early Medieval Period.


Another I-Z63 archeological find at the  Crypta Balbi  site in Rome was dated to Late Antiquity (400-600 CE) and reported to be Y-DNA haplogroup  I-Y7234 . Interestingly,  Lombard -associated ornaments have been excavated at this site, pointing to connections with central Europe. Additionally, five of the seven individuals from this site, including the I-Z63 individual, were classified by ChromoPainter [ 24 ]  into a cluster with more haplotype sharing with central/northern Europeans. [ 25 ]


Excavated in Hungary, Tiszafüred 798 was a man, associated with the Late  Avar  cultural group, who lived between 700 and 800 CE during the Medieval Age and was found in the region now known as Majoros-halom,  Tiszafüred . Likewise Tiszafüred 509 was a man who lived between 800 and 830 CE. Both were matched to haplogroup  I-S10360 . [ 26 ]  Avars, under the rule of a  khagan  called Bayan, 565 AD, allied with the  Longobards  and defeated the Germanic  Gepides  in the  Danube  Plains. In 7th c. AD they continued raiding Western Europe. They helped the lombard king  Grimoald  to vanquish a rebellion in  Frioul , 663 AD. Hence a plausible explanation exists how a haplogroup which is strongly associated with the  Gothic  migrations is also attached to the Avar cultural group. [ 27 ]  Also found in Hungary  was Magyarhomorog 88 who belongs to subclade  Y2245/PR683 , he was a man who lived between 1000 and 1100 CE during the Medieval Age  and was found in the region now known as Kónyadomb,  Magyarhomorog , Hungary. [ 26 ]


The genetic analysis of sample VK157 from the  Bodzia Cemetery  presents a compelling case for a connection to  Sviatopolk I of Kiev . Although this link is highly probable based on current data, the assertion that VK157 was  Sviatopolk  himself remains hypothetical  as of now, there is no definitive evidence confirming this. From a genetic standpoint, VK157 has been identified as possessing SNP 300756, which is unique to the  I-Y45113  branch (subclade of haplogroup I-Z63). This specific genetic marker classifies VK157 within this branch, contributing to the broader narrative of the population's genetic history in the region. However, interpretations of VK157's historical identity remain speculative and should be cautiously considered, aligning with scholarly caution. [ 17 ] [ 19 ] [ 28 ] [ 29 ]


The Hamilton DNA Project, involving hundreds of participants including a close relative of the current  Duke of Abercorn , has made significant contributions to understanding the genetic lineage of  Clan Hamilton , a prominent  Lowland Scottish  clan. The clan, tracing its roots back to Walter fitz Gilbert of Hambledon in 14th-century  Lanarkshire , has a rich history, with its chiefs ascending to various noble titles over the centuries. One branch of the clan acquired titles including Laird of Cadzow, Lord Hamilton,  Earl of Arran , Marquess of Hamilton, and  Duke of Hamilton , with the dukedom passing to  Clan Douglas  in 1895 after the 12th Duke of Hamilton died without a male heir. Another branch ascended to the titles of  Lords Paisley , Earls of Abercorn, Marquesses of Abercorn, and Dukes of Abercorn, a title that continues to this day. The genetic research conducted by the Hamilton DNA Project has demonstrated that all Hamilton branches descending from Sir James Hamilton, 5th Laird of Cadzow, who is the progenitor of both the mentioned branches, belong to the I1-Z63. This finding suggests a most recent common ancestor for these branches who lived about 750 years ago. [ 30 ] [ 31 ]


One of the prominent members of this haplogroup is the 21st president of the United States,  Chester A. Arthur  (1829-1886). His lineage is believed to belong to haplogroup  I1-Z63 > BY151 > BY351  based on results from the Arthur family DNA project. [ 32 ]


Another notable member is Richard Bradberry (ca 1775-ca 1826) of  King William County , Virginia. He is considered the common ancestor of a cluster of individuals belonging to haplogroup I-Z63. [ 33 ]


Governor William Bradford ,  Mayflower  passenger and leader of the  Plymouth Colony . At least two reported descendants have tested under I-Z63 to  I-Y21381  > Y21371 > Y21370 > Y21372 > FGC72882. [ 34 ]


A  haplotype  ( haploid   genotype ) is a group of  alleles  in an  organism  that are inherited together from a single parent. [ 1 ] [ 2 ]


Many organisms contain genetic material ( DNA ) which is inherited from two parents. Normally these organisms have their DNA organized in two sets of pairwise similar  chromosomes . The offspring gets one chromosome in each pair from each parent. A set of pairs of chromosomes is called  diploid  and a set of only one half of each pair is called haploid. The haploid genotype (haplotype) is a genotype that considers the singular chromosomes rather than the pairs of chromosomes. It can be all the chromosomes from one of the parents or a minor part of a chromosome, for example a sequence of 9000  base pairs  or a small set of alleles.


Specific contiguous parts of the chromosome are likely to be inherited together and not be split by  chromosomal crossover , a phenomenon called  genetic linkage . [ 3 ] [ 4 ]  As a result, identifying these statistical associations and a few alleles of a specific haplotype sequence can facilitate identifying  all other such  polymorphic sites that are nearby on the chromosome ( imputation ). [ 5 ]  Such information is critical for investigating the genetics of common  diseases ; which have been investigated in humans by the  International HapMap Project . [ 6 ] [ 7 ]


Other parts of the genome are almost always haploid and do not undergo crossover: for example, human  mitochondrial DNA  is passed down through the maternal line and the  Y chromosome  is passed down the paternal line. In these cases, the entire sequence can be grouped into a simple evolutionary tree, with each branch founded by a  unique-event polymorphism  mutation (often, but not always, a  single-nucleotide polymorphism  (SNP)). Each  clade  under a branch, containing haplotypes with a single shared ancestor, is called a  haplogroup . [ 8 ] [ 9 ] [ 10 ]


An organism's  genotype  may not define its haplotype uniquely.  For example, consider a  diploid  organism and two bi-allelic  loci  (such as  SNPs ) on the same chromosome.  Assume the first locus has alleles  A  or  T  and the second locus  G  or  C . Both loci, then, have three possible  genotypes : ( AA ,  AT , and  TT ) and ( GG ,  GC , and  CC ), respectively.  For a given individual, there are nine possible configurations (haplotypes) at these two loci (shown in the  Punnett square  below).  For individuals who are homozygous at one or both loci, the haplotypes are unambiguous - meaning that there is not any differentiation of haplotype T1T2 vs haplotype T2T1; where T1 and T2 are labeled to show that they are the same locus, but labeled as such to show it does not matter which order you consider them in, the end result is two T loci. For individuals  heterozygous  at both loci, the  gametic phase  is  ambiguous  - in these cases, an observer does not know which haplotype the individual has, e.g., TA vs AT.


The only unequivocal method of resolving phase ambiguity is by  sequencing .  However, it is possible to estimate the probability of a particular haplotype when phase is ambiguous using a sample of individuals.


Given the genotypes for a number of individuals, the haplotypes can be inferred by haplotype resolution or  haplotype phasing  techniques. These methods work by applying the observation that certain haplotypes are common in certain genomic regions. Therefore, given a set of possible haplotype resolutions, these methods choose those that use fewer different haplotypes overall. The specifics of these methods vary - some are based on combinatorial approaches (e.g.,  parsimony ), whereas others use likelihood functions based on different models and assumptions such as the  Hardy–Weinberg principle , the  coalescent theory  model, or perfect phylogeny. The parameters in these models are then estimated using algorithms such as the  expectation-maximization algorithm  (EM),  Markov chain Monte Carlo  (MCMC), or  hidden Markov models  (HMM).


Microfluidic whole genome haplotyping  is a technique for the physical separation of individual chromosomes from a  metaphase  cell followed by direct resolution of the haplotype for each allele.


In  genetics , a  gametic phase  represents the original allelic combinations that a  diploid  individual inherits from both parents. [ 11 ]  It is therefore a particular association of  alleles  at different loci on the same  chromosome .  Gametic phase is influenced by  genetic linkage . [ 12 ]


Unlike other chromosomes, Y chromosomes generally do not come in pairs. Every human male (excepting those with  XYY syndrome ) has only one copy of that chromosome.  This means that there is not any chance variation of which copy is inherited, and also (for most of the chromosome) not any shuffling between copies by  recombination ; so, unlike  autosomal  haplotypes, there is effectively not any randomisation of the Y-chromosome haplotype between generations.  A human male should largely share the same Y chromosome as his father, give or take a few mutations; thus Y chromosomes tend to pass largely intact from father to son,
with a small but accumulating number of mutations that can serve to differentiate male lineages.
In particular, the Y-DNA represented as the numbered results of a  Y-DNA genealogical DNA test  should match, except for mutations.


Unique-event polymorphisms  (UEPs) such as SNPs represent  haplogroups . STRs represent haplotypes. The results that comprise the full Y-DNA haplotype from the Y chromosome DNA test can be divided into two parts: the results for UEPs, sometimes loosely called the SNP results as most UEPs are  single-nucleotide polymorphisms , and the results for  microsatellite   short tandem repeat  sequences ( Y-STRs ).


The UEP results represent the inheritance of events it is believed can be assumed to have happened only once in all human history.  These can be used to identify the individual's  Y-DNA haplogroup , his place in the "family tree" of the whole of humanity.  Different Y-DNA haplogroups identify genetic populations that are often distinctly associated with particular geographic regions; their appearance in more recent populations located in different regions represents the migrations tens of thousands of years ago of the direct  patrilineal  ancestors of current individuals.


Genetic results also include the  Y-STR haplotype , the set of results from the Y-STR markers tested.


Unlike the UEPs, the Y-STRs mutate much more easily, which allows them to be used to distinguish recent genealogy.  But it also means that, rather than the population of descendants of a genetic event all sharing the  same  result, the Y-STR haplotypes are likely to have spread apart, to form a  cluster  of more or less similar results.  Typically, this cluster will have a definite most probable center, the  modal haplotype  (presumably similar to the haplotype of the original founding event), and also a  haplotype diversity  — the degree to which it has become spread out.  The further in the past the defining event occurred, and the more that subsequent population growth occurred early, the greater the haplotype diversity will be for a particular number of descendants.  However, if the haplotype diversity is smaller for a particular number of descendants, this may indicate a more recent common ancestor, or a recent population expansion.


It is important to note that, unlike for UEPs, two individuals with a similar Y-STR haplotype may not necessarily share a similar ancestry.  Y-STR events are not unique.  Instead, the clusters of Y-STR haplotype results inherited from different events and different histories tend to overlap.


In most cases, it is a long time since the haplogroups' defining events, so typically the cluster of Y-STR haplotype results associated with descendants of that event has become rather broad.  These results will tend to significantly overlap the (similarly broad) clusters of Y-STR haplotypes associated with other haplogroups.  This makes it impossible for researchers to predict with absolute certainty to which Y-DNA haplogroup a Y-STR haplotype would point.  If the UEPs are not tested, the Y-STRs may be used only to predict probabilities for haplogroup ancestry, but not certainties.


A similar scenario exists in trying to evaluate whether shared surnames indicate shared genetic ancestry.  A cluster of similar Y-STR haplotypes may indicate a shared common ancestor, with an identifiable modal haplotype, but only if the cluster is sufficiently distinct from what may have happened by chance from different individuals who historically adopted the same name independently. Many names were adopted from common occupations, for instance, or were associated with habitation of particular sites.  More extensive haplotype typing is needed to establish genetic genealogy.  Commercial DNA-testing companies now offer their customers testing of more numerous sets of markers to improve definition of their genetic ancestry. The number of sets of markers tested has increased from 12 during the early years to 111 more recently.


Establishing plausible relatedness between different surnames data-mined from a database is significantly more difficult.  The researcher must establish that the  very nearest  member of the population in question, chosen purposely from the population for that reason, would be unlikely to match by accident.  This is more than establishing that a  randomly selected  member of the population is unlikely to have such a close match by accident.  Because of the difficulty, establishing relatedness between different surnames as in such a scenario is likely to be impossible, except in special cases where there is specific information to drastically limit the size of the population of candidates under consideration.