Genetic linkage
Encyclopedia
Genetic linkage is the tendency of certain loci
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...

 or alleles to be inherited together. Genetic loci that are physically close to one another on the same chromosome tend to stay together during meiosis
Meiosis
Meiosis is a special type of cell division necessary for sexual reproduction. The cells produced by meiosis are gametes or spores. The animals' gametes are called sperm and egg cells....

, and are thus genetically linked.

Background

At the beginning of normal meiosis
Meiosis
Meiosis is a special type of cell division necessary for sexual reproduction. The cells produced by meiosis are gametes or spores. The animals' gametes are called sperm and egg cells....

, a homologous chromosome pair (called a bivalent, made up of a chromosome from the mother and a chromosome from the father) intertwine and exchange sections or fragments of chromosome. The pair then breaks apart to form two chromosomes with a new combination of genes that differs from the combination supplied by the parents. Through this process of recombining genes, organisms can produce offspring with new combinations of maternal and paternal traits that may contribute to or enhance survival.

This recombination of genes, called the crossing over
Chromosomal crossover
Chromosomal crossover is an exchange of genetic material between homologous chromosomes. It is one of the final phases of genetic recombination, which occurs during prophase I of meiosis in a process called synapsis. Synapsis begins before the synaptonemal complex develops, and is not completed...

 of DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...

, can cause alleles previously on the same chromosome to be separated and end up in different daughter cells. The farther the two alleles are apart, the greater the chance that a cross-over event may occur between them, and the greater the chance that the alleles are separated.

The relative distance between two genes can be calculated by taking the offspring of an organism showing two linked genetic traits, and finding the percentage of the offspring where the two traits do not run together. The higher the percentage of descendants that do not show both traits, the farther apart on the chromosome the two genes are. Genes for which this percentage is lower than 50% are typically thought to be linked.

Genetic linkage can also be understood by looking at the relationships among phenotypes. Among individuals of an experimental population or species, some phenotypes or traits can occur randomly with respect to one another, or with some correlation with respect to one another.

The former is known as independent assortment. Today, scientists understand that independent assortment occurs when the genes affecting the phenotypes are found on different chromosomes or separated by a great enough distance on the same chromosome that recombination occurs at least half of the time.

The latter is known as genetic linkage. This occurs as an exception to independent assortment, and develops when genes appear near one another on the same chromosome. This phenomenon causes the genes to usually be inherited as a single unit. Genes inherited in this way are said to be linked, and are referred to as "linkage groups". For example, in fruit flies, the genes affecting eye color and wing length are inherited together because they appear on the same chromosome.

Discovery

Genetic linkage was first discovered by the British
United Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...

 geneticists William Bateson
William Bateson
William Bateson was an English geneticist and a Fellow of St. John's College, Cambridge...

 and Reginald Punnett
Reginald Punnett
Professor Reginald Crundall Punnett FRS was a British geneticist who co-founded, with William Bateson, the Journal of Genetics in 1910. Punnett is probably best remembered today as the creator of the Punnett square, a tool still used by biologists to predict the probability of possible genotypes...

 shortly after Mendel's laws
Mendelian inheritance
Mendelian inheritance is a scientific description of how hereditary characteristics are passed from parent organisms to their offspring; it underlies much of genetics...

 were rediscovered. The understanding of genetic linkage was expanded by the work of Thomas Hunt Morgan
Thomas Hunt Morgan
Thomas Hunt Morgan was an American evolutionary biologist, geneticist and embryologist and science author who won the Nobel Prize in Physiology or Medicine in 1933 for discoveries relating the role the chromosome plays in heredity.Morgan received his PhD from Johns Hopkins University in zoology...

. 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
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...

.

Alfred Sturtevant
Alfred Sturtevant
Alfred Henry Sturtevant was an American geneticist. Sturtevant constructed the first genetic map of a chromosome in 1913. Throughout his career he worked on the organism Drosophila melanogaster with Thomas Hunt Morgan...

, a student of Morgan's, first developed genetic maps, also known as linkage maps. Sturtevant proposed that the greater the distance between linked genes, the greater the chance that non-sister chromatids would cross over in the region between the genes. By working out the number of recombinants it is possible to obtain a measure for the distance between the genes. This distance is called a genetic map unit (m.u.), or a centimorgan
Centimorgan
In genetics, a centimorgan or map unit is a unit of recombinant frequency for measuring genetic linkage, defined as that distance between chromosome positions for which the expected average number of intervening chromosomal crossovers in a single generation is 0.01. It is often used to infer...

and is defined as the distance between genes for which one product of meiosis
Meiosis
Meiosis is a special type of cell division necessary for sexual reproduction. The cells produced by meiosis are gametes or spores. The animals' gametes are called sperm and egg cells....

 in 100 is recombinant. A recombinant frequency (RF) of 1 % is equivalent to 1 m.u. But this equivalence is only a good approximate for small percentages; the largest percentage of recombinants cannot exceed 50%, which would be the situation where the two genes are at the extreme opposite ends of the same chromosomes. In this situation, any crossover events would result in an exchange of genes, but only an odd number of crossover events (a 50-50 chance between even and odd number of crossover events) would result in a recombinant product of meiotic crossover. A statistical interpretation of this is through the Haldane mapping function
or the Kosambi mapping function, among others. A linkage map is created by finding the map distances between a number of traits that are present on the same chromosome, ideally avoiding having significant gaps between traits to avoid the inaccuracies that will occur due to the possibility of multiple recombination events.

Linkage map

A linkage map is a genetic map of a species or experimental population that shows the position of its known genes
Gênes
Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...

 or genetic markers relative to each other in terms of recombination frequency, rather than as specific physical distance along each chromosome. Linkage mapping is critical for identifying the location of genes that cause genetic diseases.

A genetic map is a map based on the frequencies of recombination
Homologous recombination
Homologous recombination is a type of genetic recombination in which nucleotide sequences are exchanged between two similar or identical molecules of DNA. It is most widely used by cells to accurately repair harmful breaks that occur on both strands of DNA, known as double-strand breaks...

 between markers during crossover
Chromosomal crossover
Chromosomal crossover is an exchange of genetic material between homologous chromosomes. It is one of the final phases of genetic recombination, which occurs during prophase I of meiosis in a process called synapsis. Synapsis begins before the synaptonemal complex develops, and is not completed...

 of homologous chromosome
Homologous chromosome
Homologous chromosomes are chromosome pairs of approximately the same length, centromere position, and staining pattern, with genes for the same characteristics at corresponding loci. One homologous chromosome is inherited from the organism's mother; the other from the organism's father...

s. The greater the frequency of recombination (segregation) between two genetic markers, the farther 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
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...

s (enzyme production, eye color) derived from coding DNA sequences; eventually, confirmed or assumed noncoding DNA
Noncoding DNA
In genetics, noncoding DNA describes components of an organism's DNA sequences that do not encode for protein sequences. In many eukaryotes, a large percentage of an organism's total genome size is noncoding DNA, although the amount of noncoding DNA, and the proportion of coding versus noncoding...

 sequences such as microsatellites or those generating restriction fragment length polymorphisms (RFLPs) have been used.

Genetic maps help researchers to locate other markers, such as other genes by testing for genetic linkage of the already known markers.

A genetic map is not a physical map (such as a radiation reduced hybrid
Radiation reduced hybrid
Radiation reduced hybrid is procedure in discovering the location of genetic markers relative to one another. The relative location of these markers can be combined into a physical map or a genetic map...

 map) or gene map
Gene map
A gene map is the descriptive representation of the structure of a single gene. It includes the DNA sequence of a gene with introns and exons, 3' or 5' transcribed-untranslated regions, termination signal, regulatory elements such as promoters, enhancers and it may include known mutations defining...

.

LOD score method for estimating recombination frequency

The LOD score (logarithm (base 10) of odds), developed by Newton E. Morton, 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 favor the presence of linkage, whereas negative LOD scores indicate that linkage is less likely. Computerized LOD score analysis is a simple way to analyze complex family pedigrees in order to determine the linkage between Mendelian traits (or between a trait and a marker, or two markers).

The method is described in greater detail by Strachan and Read http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hmg.section.1412. Briefly, it works as follows:
  1. Establish a pedigree
    Pedigree chart
    A pedigree chart is a diagram that shows the occurrence and appearance or phenotypes of a particular gene or organism and its ancestors from one generation to the next, most commonly humans, show dogs, and race horses....

  2. Make a number of estimates of recombination frequency
  3. Calculate a LOD score for each estimate
  4. The estimate with the highest LOD score will be considered the best estimate


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.

Theta is the recombinant fraction, it is equal to R / (NR + R)

In practice, LOD scores are looked up in a table which lists LOD scores for various standard pedigrees and various values of recombination frequency.

By convention, a LOD score greater than 3.0 is considered evidence for linkage. A LOD score of +3 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 the LOD scores. It is important to keep in mind that this traditional cutoff of LOD>+3 is an arbitrary one and that the difference between certain types of linkage studies, particularly analyses of complex genetic traits with hundreds of markers, these criteria should probably be modified to a somewhat higher cutoff.

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
Chromosomal crossover
Chromosomal crossover is an exchange of genetic material between homologous chromosomes. It is one of the final phases of genetic recombination, which occurs during prophase I of meiosis in a process called synapsis. Synapsis begins before the synaptonemal complex develops, and is not completed...

 will take place between two gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

s during meiosis
Meiosis
Meiosis is a special type of cell division necessary for sexual reproduction. The cells produced by meiosis are gametes or spores. The animals' gametes are called sperm and egg cells....

. A centimorgan
Centimorgan
In genetics, a centimorgan or map unit is a unit of recombinant frequency for measuring genetic linkage, defined as that distance between chromosome positions for which the expected average number of intervening chromosomal crossovers in a single generation is 0.01. It is often used to infer...

 (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 we systematically underestimate the genetic distance between two loci.

During meiosis, chromosomes assort randomly into gamete
Gamete
A gamete is a cell that fuses with another cell during fertilization in organisms that reproduce sexually...

s, such that the segregation of allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...

s of one gene is independent of alleles of another gene. This is stated in Mendel's Second Law
Mendelian inheritance
Mendelian inheritance is a scientific description of how hereditary characteristics are passed from parent organisms to their offspring; it underlies much of genetics...

 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.

As an example of independent assortment, consider the crossing of the pure-bred homozygote parental strain with genotype
Genotype
The genotype is the genetic makeup of a cell, an organism, or an individual usually with reference to a specific character under consideration...

 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 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.

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.

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%.

As an example of linkage, consider the classic experiment by William Bateson
William Bateson
William Bateson was an English geneticist and a Fellow of St. John's College, Cambridge...

 and Reginald Punnett
Reginald Punnett
Professor Reginald Crundall Punnett FRS was a British geneticist who co-founded, with William Bateson, the Journal of Genetics in 1910. Punnett is probably best remembered today as the creator of the Punnett square, a tool still used by biologists to predict the probability of possible genotypes...

. 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
Mendelian inheritance
Mendelian inheritance is a scientific description of how hereditary characteristics are passed from parent organisms to their offspring; it underlies much of genetics...

, the expected phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...

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).
Bateson and Punnett experiment
Phenotype and genotype Observed Expected from 9:3:3:1 ratio
Purple, long (PpLl) 284 216
Purple, round (Ppll) 21 72
Red, long (ppLl) 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 with p occurring together with l is greater than that of the recombinant Pl and pL. The recombination frequency cannot be computed directly from this experiment, but intuitively it is less than 50%.

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, unfavorable repulsion linkages do appear when breeding for disease resistance in some crops.

When two genes are located on the same chromosome, the chance of a crossover
Chromosomal crossover
Chromosomal crossover is an exchange of genetic material between homologous chromosomes. It is one of the final phases of genetic recombination, which occurs during prophase I of meiosis in a process called synapsis. Synapsis begins before the synaptonemal complex develops, and is not completed...

 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.

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.

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 and quantify 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 and phenotypes.

See also

  • Chromosomal crossover
    Chromosomal crossover
    Chromosomal crossover is an exchange of genetic material between homologous chromosomes. It is one of the final phases of genetic recombination, which occurs during prophase I of meiosis in a process called synapsis. Synapsis begins before the synaptonemal complex develops, and is not completed...

  • Genetic association
    Genetic association
    Genetic association is the occurrence, more often than can be readily explained by chance, of two or more traits in a population of individuals, of which at least one trait is known to be genetic....

  • Genetic epidemiology
    Genetic epidemiology
    Genetic epidemiology is the study of the role of genetic factors in determining health and disease in families and in populations, and the interplay of such genetic factors with environmental factors...

  • Genome-wide association study
    Genome-wide association study
    In genetic epidemiology, a genome-wide association study , also known as whole genome association study , is an examination of many common genetic variants in different individuals to see if any variant is associated with a trait...

  • Lander–Green algorithm
    Lander–Green algorithm
    The Lander–Green algorithm is an algorithm, due to Eric Lander and Philip Green for computing the likelihood of observed genotype data given a pedigree. It is appropriate for relatively small pedigrees and a large number of markers. It is used in the analysis of genetic linkage....

  • Linkage disequilibrium
    Linkage disequilibrium
    In population genetics, linkage disequilibrium is the non-random association of alleles at two or more loci, not necessarily on the same chromosome. It is also referred to as to as gametic phase disequilibrium , or simply gametic disequilibrium...

  • Quantitative trait locus
    Quantitative trait locus
    Quantitative traits refer to phenotypes that vary in degree and can be attributed to polygenic effects, i.e., product of two or more genes, and their environment. Quantitative trait loci are stretches of DNA containing or linked to the genes that underlie a quantitative trait...


External links

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