View source for Genetic linkage

{{Short description|Tendency of DNA sequences that are close together on a chromosome to be inherited together}}
{{Redirect-distinguish|Genetic map|Gene map}}

'''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 [[Genetic recombination|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.<ref name="Cooper">{{Cite journal |last1=Cooper |first1=DN |last2=Krawczak |first2=M |last3=Polychronakos |first3=C |last4=Tyler-Smith |first4=C |last5=Kehrer-Sawatzki |first5=H |date=October 2013 |title=Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease |journal=[[Human genetics]] |volume=132 |issue=10 |pages=1077–130 |doi=10.1007/s00439-013-1331-2 |pmc=3778950 |pmid=23820649}}</ref>

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.

==Discovery==
[[Gregor Mendel]]'s [[Law of Independent Assortment]] states that every trait is inherited independently of every other trait. But shortly after [[Gregor Mendel#Rediscovery of Mendel's work|Mendel's work was rediscovered]], exceptions to this rule were found. In 1905, the [[United Kingdom|British]] geneticists [[William Bateson]], [[Edith Rebecca Saunders]] and [[Reginald Punnett]] cross-bred pea plants in experiments similar to Mendel's.<ref>{{Cite web |last1=Lobo |first1=Ingrid |last2=Shaw |first2=Kenna |title=Discovery and Types of Genetic Linkage |url=http://www.nature.com/scitable/topicpage/discovery-and-types-of-genetic-linkage-500 |access-date=21 January 2017 |website=Scitable |publisher=[[Nature Education]]}}</ref><ref>{{Cite book |last1=Bateson |first1=W |author-link1=William Bateson |url=https://archive.org/details/RoyalSociety.ReportsToTheEvolutionCommittee.ReportIi.Experimental |title=Reports to the Evolution committee of the Royal Society |last2=Saunders |first2=ER |author-link2=Edith Rebecca Saunders |last3=Punnett |first3=RC |author-link3=Reginald Punnett |date=18 May 1904 |publisher=Harrison and Sons, Printers |location=London |access-date=21 January 2017}}</ref> 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.{{cn|date=December 2024}}

According to [[Mendelian inheritance|Mendelian genetics]], the expected [[phenotype]]s 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:{{cn|date=December 2024}}

{| class="wikitable"
|+'''Bateson, Saunders, and Punnett experiment'''
|-
!Phenotype and genotype||Observed||Expected from 9:3:3:1 ratio
|-
|Purple, long (''P_L_'')||284||216
|-
|Purple, round (''P_ll'')||21||72
|-
|Red, long (''ppL_'')||21||72
|-
|Red, round (''ppll'')||55||24
|}

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 [[Genetic recombination|recombination]] frequency is more difficult to compute in an F2 cross than a backcross,<ref name="Fisher">{{Cite journal |last1=Fisher |first1=RA |author-link1=Ronald Fisher |last2=Balmukand |first2=B |date=July 1928 |title=The estimation of linkage from the offspring of selfed heterozygotes |journal=[[Journal of Genetics]] |volume=20 |issue=1 |pages=79–92 |doi=10.1007/BF02983317 |s2cid=27688031}}</ref> 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.{{cn|date=December 2024}}

The understanding of linkage was expanded by the work of [[Thomas Hunt Morgan]]. Morgan's observation that the amount of [[Chromosomal crossover|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.{{cn|date=December 2024}}

==Linkage map==
[[File:Drosophila Gene Linkage Map.svg|thumb|500px|[[Thomas Hunt Morgan|Thomas Hunt Morgan's]] ''[[Drosophila melanogaster]]'' genetic linkage map. This was the first successful [[gene mapping]] work and provides important evidence for the [[chromosome theory of inheritance]]. The map shows the relative positions of [[alleles]] on the second ''Drosophila'' chromosome. The distances between the genes ([[centimorgans]]) are equal to the percentages of [[chromosomal crossover]] events that occur between different alleles.<ref>{{Cite book |last=Mader |first=Sylvia |title=Biology Ninth Edition |date=2007 |publisher=McGraw-Hill |isbn=978-0-07-325839-3 |location=New York |page=209}}</ref>]]
{{See also|Gene map}}

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]].{{cn|date=December 2024}}

A linkage map is a map based on the frequencies of [[homologous recombination|recombination]] between markers during [[chromosomal crossover|crossover]] of [[homologous chromosome]]s. 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 [[phenotype]]s (enzyme production, eye colour) derived from [[Coding DNA sequence|coding DNA]] sequences; eventually, confirmed or assumed [[noncoding DNA]] sequences such as [[Microsatellite (genetics)|microsatellites]] or those generating restriction fragment length polymorphisms ([[RFLP]]s) have been used.{{cn|date=December 2024}}

{{anchor|linkage group}}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.<ref>{{Cite book |last=Griffiths |first=AJF |url=https://www.ncbi.nlm.nih.gov/books/NBK21878/ |title=An Introduction to Genetic Analysis |date=2000 |publisher=W. H. Freeman |edition=7th}}</ref> For well-studied organisms the linkage groups correspond one-to-one with the chromosomes.{{cn|date=December 2024}}

A linkage map is '''not''' a physical map (such as a [[radiation reduced hybrid]] map) or [[gene map]].{{cn|date=December 2024}}

==Linkage analysis==
Linkage analysis is a genetic method that searches for chromosomal segments that [[Mendelian inheritance|cosegregate]] with the ailment phenotype through families.<ref name="Cantor2013">{{Citation |last=Cantor |first=Rita M. |title=Emery and Rimoin's Principles and Practice of Medical Genetics |date=2013 |pages=1–9 |editor-last=Rimoin |editor-first=David |editor-last2=Pyeritz |editor-first2=Reed |editor-last3=Korf |editor-first3=Bruce |chapter=Analysis of Genetic Linkage |edition=6th |publisher=Academic Press |doi=10.1016/b978-0-12-383834-6.00010-0 |isbn=978-0-12-383834-6 }}</ref> It can be used to map genes for both binary and quantitative traits.<ref name="Cantor2013" /> 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.{{cn|date=December 2024}}
[[File:Parametric Linkage Analysis.png|thumb|Pedigree illustrating Parametric Linkage Analysis]]

===Parametric linkage analysis===
The '''LOD score''' (logarithm (base 10) of odds), developed by [[Newton Morton]],<ref>{{Cite journal |last=Morton NE |date=1955 |title=Sequential tests for the detection of linkage |journal=American Journal of Human Genetics |volume=7 |issue=3 |pages=277–318 |pmc=1716611 |pmid=13258560}}</ref> 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 inheritance|Mendelian]] traits (or between a trait and a marker, or two markers).{{cn|date=December 2024}}

The method is described in greater detail by Strachan and Read.[https://www.ncbi.nlm.nih.gov/nlmcatalog/101523906] Briefly, it works as follows:{{cn|date=December 2024}}
# Establish a [[Pedigree chart|pedigree]]
# Make a number of estimates of recombination frequency
# Calculate a LOD score for each estimate
# The estimate with the highest LOD score will be considered the best estimate

The LOD score is calculated as follows:

: <math>
\text{LOD} = Z = \log_{10} \frac{
\text{probability of birth sequence with a given linkage value}
}{
\text{probability of birth sequence with no linkage}
} = \log_{10} \frac{(1-\theta)^{NR} \times \theta^R}{ 0.5^{NR + R} }
</math>

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''&nbsp;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 {{nowrap|''R'' / (''NR'' + ''R'')}}.{{cn|date=December 2024}}

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|''p''-value]] of approximately 0.05,<ref>{{Cite journal |last=Nyholt |first=Dale R |date=August 2000 |title=All LODs Are Not Created Equal |journal=[[American Journal of Human Genetics]] |volume=67 |issue=2 |pages=282–288 |doi=10.1086/303029 |pmc=1287176 |pmid=10884360}}</ref> and no [[multiple testing correction]] (e.g. [[Bonferroni correction]]) is required.<ref>{{Cite journal |last=Risch |first=Neil |date=June 1991 |title=A Note on Multiple Testing Procedures in Linkage Analysis |journal=[[American Journal of Human Genetics]] |volume=48 |issue=6 |pages=1058–1064 |pmc=1683115 |pmid=2035526}}</ref>

=== Limitations ===
Linkage analysis has a number of methodological and theoretical limitations that can significantly increase the [[Type I and type II errors|type-1 error]] rate and reduce the power to map human quantitative trait loci (QTL).<ref>{{Cite journal |last=Ferreira |first=Manuel A. R. |date=2004-10-01 |title=Linkage Analysis: Principles and Methods for the Analysis of Human Quantitative Traits |journal=Twin Research and Human Genetics |language=en |volume=7 |issue=5 |pages=513–530 |doi=10.1375/twin.7.5.513 |issn=2053-6003 |pmid=15527667 |s2cid=199001341}}</ref> While linkage analysis was successfully used to identify genetic variants that contribute to rare disorders such as [[Huntington's disease|Huntington disease]], it did not perform that well when applied to more common disorders such as [[Cardiovascular disease|heart disease]] or different forms of [[cancer]].<ref>{{Cite journal |last1=Gusella |first1=James F. |last2=Frontali |first2=Marina |last3=Wasmuth |first3=John J. |last4=Collins |first4=Francis S. |last5=Lehrach |first5=Hans |last6=Myers |first6=Richard |last7=Altherr |first7=Michael |last8=Allitto |first8=Bernice |last9=Taylor |first9=Sherry |date=1992-05-01 |title=The Huntington's disease candidate region exhibits many different haplotypes |journal=Nature Genetics |language=en |volume=1 |issue=2 |pages=99–103 |doi=10.1038/ng0592-99 |issn=1546-1718 |pmid=1302016 |s2cid=25472459}}</ref> An explanation for this is that the genetic mechanisms affecting common disorders are different from those causing some rare disorders.<ref>{{Cite journal |last1=Mark J. Daly |last2=Hirschhorn |first2=Joel N. |date=2005-02-01 |title=Genome-wide association studies for common diseases and complex traits |journal=Nature Reviews Genetics |language=en |volume=6 |issue=2 |pages=95–108 |doi=10.1038/nrg1521 |issn=1471-0064 |pmid=15716906 |s2cid=2813666}}</ref>

==Recombination frequency==
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 [[gene]]s 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.{{cn|date=December 2024}}

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.<ref>{{Cite book |last1=Meneely |first1=Philip Mark |title=Genetics: genes, genomes, and evolution |last2=Dawes Hoang |first2=Rachel |last3=Okeke |first3=Iruka N. |last4=Heston |first4=Katherine |date=2017 |publisher=Oxford University Press |isbn=978-0-19-879536-0 |location=Oxford |page=361 |oclc=951645141}}</ref>

During meiosis, chromosomes assort randomly into [[gamete]]s, such that the segregation of [[allele]]s of one gene is independent of alleles of another gene.  This is stated in [[Mendelian inheritance|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.{{cn|date=December 2024}}

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.{{cn|date=December 2024}}

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.{{cn|date=December 2024}}

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%.{{cn|date=December 2024}}

As an example of linkage, consider the classic experiment by [[William Bateson]] and [[Reginald Punnett]].<ref>{{Cite journal |last1=Punnett |first1=R. C. |last2=Bateson |first2=W. |date=1908-05-15 |title=The Heredity of Sex |journal=Science |volume=27 |issue=698 |pages=785–787 |bibcode=1908Sci....27..785P |doi=10.1126/science.27.698.785 |issn=0036-8075 |pmid=17791047}}</ref>  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 inheritance|Mendelian genetics]], the expected [[phenotype]]s 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).

{| class="wikitable"
|+'''Bateson and Punnett experiment'''
|-
!Phenotype and genotype||Observed||Expected from 9:3:3:1 ratio
|-
|Purple, long (''P_L_'')||284||216
|-
|Purple, round (''P_ll'')||21||72
|-
|Red, long (''ppL_'')||21||72
|-
|Red, round (''ppll'')||55||24
|}
[[File:Unlinked vs. Linked Genes.svg|thumb|Unlinked Genes vs. Linked Genes]]
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,<ref name="Fisher" /> but the lack of fit between observed and expected numbers of progeny in the above table indicate it is less than 50%.{{cn|date=December 2024}}

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.{{cn|date=December 2024}}

The two possible arrangements, cis and trans, of alleles in a double heterozygote are referred to as [[gametic phase]]s, and ''phasing'' is the process of determining which of the two is present in a given individual.{{cn|date=December 2024}}

When two genes are located on the same chromosome, the chance of a [[chromosomal crossover|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'''.{{cn|date=December 2024}}

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 [[Genetic map function|Kosambi and Haldane transformations]] attempt to correct for multiple crossovers.<ref>{{Cite book |last1=Griffiths |first1=AJF |title=An Introduction to Genetic Analysis |last2=Miller |first2=JH |last3=Suzuki |first3=DT |date=2000 |publisher=[[W. H. Freeman]] |isbn=978-0-7167-3520-5 |edition=7th |location=New York |chapter=Accurate calculation of large map distances, Figure 6-4 |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK21819/#A1115}} Graph of mapping function from compared to idealised 1-1 equivalence of recombination frequency percentage (RF%) to map units.</ref>

===Linkage of genetic sites within a gene===

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 [[T4 rII system|rII]] mutants of [[Escherichia virus T4|bacteriophage T4]].  He found that, on the basis of recombination tests, the sites of [[mutation]] could be mapped in a linear order.<ref>Benzer S. Fine structure of a genetic region in bacteriophage.  Proc Natl Acad Sci U S A. 1955;41(6):344-354. doi:10.1073/pnas.41.6.344</ref><ref>Benzer S. On the topology of the genetic fine structure. Proc Natl Acad Sci U S A. 1959;45(11):1607-1620. doi:10.1073/pnas.45.11.1607</ref> 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.{{cn|date=December 2024}}

Edgar et al.<ref>{{cite journal | pmc=1210321 | date=1962 | last1=Edgar | first1=R. S. | last2=Feynman | first2=R. P. | last3=Klein | first3=S. | last4=Lielausis | first4=I. | last5=Steinberg | first5=C. M. | title=Mapping Experiments with R Mutants of Bacteriophage T4d | journal=Genetics | volume=47 | issue=2 | pages=179–186 | doi=10.1093/genetics/47.2.179 | pmid=13889186 }}</ref> 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<ref>{{cite journal | pmc=1210971 | date=1965 | last1=Fisher | first1=K. M. | last2=Bernstein | first2=H. | title=The Additivity of Intervals in the rIIA Cistron of Phage T4d | journal=Genetics | volume=52 | issue=6 | pages=1127–1136 | doi=10.1093/genetics/52.6.1127 | pmid=5882191 }}</ref> that likely reflects the underlying molecular mechanism of [[genetic recombination]].

==Variation of recombination frequency==
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.<ref>{{Cite journal |last=McKee |first=Bruce D. |date=2004-03-15 |title=Homologous pairing and chromosome dynamics in meiosis and mitosis |journal=Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression |volume=1677 |issue=1–3 |pages=165–180 |doi=10.1016/j.bbaexp.2003.11.017 |issn=0006-3002 |pmid=15020057}}</ref>

===Genes affecting recombination frequency===

[[Mutation]]s in [[gene]]s that encode proteins involved in the processing of DNA often affect [[genetic recombination|recombination]] frequency.  In [[Escherichia virus T4|bacteriophage T4]], mutations that reduce expression of the replicative [[DNA polymerase]] [gene product 43 (gp43)] increase recombination (decrease linkage) several fold.<ref name="Bernstein1967">Bernstein H. The effect on recombination of mutational defects in the DNA-polymerase and deoxycytidylate hydroxymethylase of phage T4D. Genetics. 1967;56(4):755-769</ref><ref name="Berger1969">Berger H, Warren AJ, Fry KE. Variations in genetic recombination due to amber mutations in T4D bacteriophage. J Virol. 1969;3(2):171-175. doi:10.1128/JVI.3.2.171-175.1969</ref>  The increase in recombination may be due to [[DNA replication|replication]] errors by the defective DNA polymerase that are themselves recombination events such as template switches, i.e. copy choice recombination events.<ref>Bernstein H. On the mechanism of intragenic recombination. I. The rII region of bacteriophage T4. (1962)  Journal of Theoretical Biology. 1962; 3, 335-353. https://doi.org/10.1016/S0022-5193(62)80030-7</ref> Recombination is also increased by mutations that reduce the expression of [[DNA ligase]] (gp30)<ref name="Bernstein1968">Bernstein H. Repair and recombination in phage T4. I. Genes affecting recombination. Cold Spring Harb Symp Quant Biol. 1968;33:325-331. doi:10.1101/sqb.1968.033.01.037</ref><ref name = Berger1969/> and dCMP hydroxymethylase (gp42),<ref name = Bernstein1967/><ref name = Berger1969/> two enzymes employed in [[DNA synthesis]].

Recombination is reduced (linkage increased) by mutations in genes that encode proteins with [[nuclease]] functions (gp46 and gp47)<ref name = Bernstein1968/><ref name = Berger1969/> and a [[DNA-binding protein]] (gp32)<ref name = Berger1969/>  Mutation in the bacteriophage uvsX gene also substantially reduces recombination.<ref>Hamlett NV, Berger H. Mutations altering genetic recombination and repair of DNA in bacteriophage T4. Virology. 1975;63(2):539-567. doi:10.1016/0042-6822(75)90326-8</ref>  The uvsX gene is analogous to the well studied ''[[recA]]'' gene of ''[[Escherichia coli]]'' that plays a central role in recombination.<ref>Fujisawa H, Yonesaki T, Minagawa T. Sequence of the T4 recombination gene, uvsX, and its comparison with that of the recA gene of Escherichia coli. Nucleic Acids Res. 1985;13(20):7473-7481. doi:10.1093/nar/13.20.7473</ref>

==Meiosis indicators==
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.{{cn|date=December 2024}}

==See also==
{{col div|colwidth=30em}}
* [[Centimorgan]]
* [[Genetic association]]
* [[Genetic epidemiology]]
* [[Genome-wide association study]]
* [[Identity by descent]]
* [[Lander–Green algorithm]]
* [[Linkage disequilibrium]]
* [[Structural motif]]
{{Div col end}}

==References==
{{Reflist|2}}

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 |lcheading=Gene mapping
 |label=Gene mapping}}
* {{Cite book |last1=Griffiths AJF |url=https://archive.org/details/introductiontog000grif |title=An Introduction to Genetic Analysis |last2=Miller JH |last3=Suzuki DT |last4=Lewontin RC |last5=Gelbart WM |date=1993 |publisher=W.H. Freeman and Company |isbn=978-0-7167-2285-4 |edition=5th |location=New York |chapter=Chapter 5 |display-authors=4 |chapter-url=https://archive.org/details/introductiontog000grif |url-access=registration |chapter-url-access=registration}}
* {{Cite book |last1=Poehlman JM |title=Breeding Field Crops |last2=Sleper DA |date=1995 |publisher=Iowa State Press |isbn=978-0-8138-2427-7 |edition=4th |location=Iowa |chapter=Chapter 3}}

{{Population genetics}}
{{Personal genomics}}
{{Authority control}}

[[Category:Classical genetics]]
[[Category:Population genetics]]