Quantitative trait locus
Encyclopedia
Quantitative traits refer to 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 (characteristics) that vary in degree and can be attributed to polygenic
Polygene
A polygene, multiple factor, multiple gene inheritance, or quantitative gene is a group of non-allelic genes that together influence a phenotypic trait. The loci or identities of the non-allelic genes are often unknown to biologist...

 effects, i.e., product of two or more 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...

, and their environment. Quantitative trait loci (QTLs) are stretches of DNA containing or linked to the genes that underlie a quantitative trait. Mapping regions of the genome that contain genes involved in specifying a quantitative trait is done using molecular tags such as AFLP
Amplified fragment length polymorphism
Amplified Fragment Length Polymorphism PCR is a PCR-based tool used in genetics research, DNA fingerprinting, and in the practice of genetic engineering. Developed in the early 1990s by Keygene, AFLP uses restriction enzymes to digest genomic DNA, followed by ligation of adaptors to the sticky...

 or, more commonly SNPs
Single nucleotide polymorphism
A single-nucleotide polymorphism is a DNA sequence variation occurring when a single nucleotide — A, T, C or G — in the genome differs between members of a biological species or paired chromosomes in an individual...

 . This is an early step in identifying and sequencing the actual genes underlying trait variation.

Quantitative traits

Polygenic inheritance, also known as quantitative or multifactorial inheritance refers to inheritance of a phenotypic
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...

 characteristic (trait) that is attributable to two or more 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 the interaction with the environment, or both. Unlike monogenic traits, polygenic traits do not follow patterns of Mendelian inheritance
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...

 (separated traits). Instead, their phenotypes typically vary along a continuous gradient depicted by a bell curve.

An example of a polygenic trait is human skin color. Many genes factor into determining a person's natural skin color, so modifying only one of those genes changes the color only slightly. Many disorders with genetic components
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....

 are polygenic, including autism
Autism
Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...

, cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

, diabetes and numerous others. Most phenotypic characteristics are the result of the interaction of multiple genes.

Examples of disease processes generally considered to be results of multifactorial etiology
Etiology
Etiology is the study of causation, or origination. The word is derived from the Greek , aitiologia, "giving a reason for" ....

:

Congenital malformation
  • Cleft palate
  • Congenital dislocation of the hip
    Hip dysplasia (human)
    Hip dysplasia, developmental dysplasia of the hip or congenital dysplasia of the hip is a congenital or acquired deformation or misalignment of the hip joint.-Terminology:...

  • Congenital heart defects
  • Neural tube defects
    Neural tube defects
    Neural tube defects are one of the most common birth defects, occurring in approximately one in 1,000 live births in the United States. An NTD is an opening in the spinal cord or brain that occurs very early in human development. In the 2nd week of pregnancy called gastrulation, specialized cells...

  • Pyloric stenosis
    Pyloric stenosis
    Pyloric stenosis is a condition that causes severe vomiting in the first few months of life. There is narrowing of the opening from the stomach to the intestines, due to enlargement of the muscle surrounding this opening , which spasms when the stomach empties...

  • Talipes

Adult onset diseases
  • Diabetes Mellitus
    Diabetes mellitus
    Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...

  • Cancer
    Cancer
    Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

  • Epilepsy
    Epilepsy
    Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...

  • Glaucoma
    Glaucoma
    Glaucoma is an eye disorder in which the optic nerve suffers damage, permanently damaging vision in the affected eye and progressing to complete blindness if untreated. It is often, but not always, associated with increased pressure of the fluid in the eye...

  • Hypertension
    Hypertension
    Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...

  • Ischaemic heart disease
    Ischaemic heart disease
    Ischaemic or ischemic heart disease , or myocardial ischaemia, is a disease characterized by ischaemia of the heart muscle, usually due to coronary artery disease...

  • Manic depression
  • Schizophrenia
    Schizophrenia
    Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...

  • Psoriasis
    Psoriasis
    Psoriasis is an autoimmune disease that appears on the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of...

  • Thyroid diseases


Multifactorially inherited diseases are said to constitute the majority of genetic disorders affecting humans which will result in hospitalization or special care of some kind.

Multifactorial traits in general

Generally, multifactorial traits outside of illness contribute to what we see as continuous characteristics in organisms, such as height, skin color, and body mass. All of these phenotypes are complicated by a great deal of interplay between genes and environment. The continuous distribution of traits such as height and skin colour described above reflects the action of genes that do not quite show typical patterns of dominance and recessiveness. Instead the contributions of each involved locus are thought to be additive. Writers have distinguished this kind of inheritance as polygenic, or quantitative inheritance.

Thus, due to the nature of polygenic traits, inheritance will not follow the same pattern as a simple monohybrid
Monohybrid cross
Monohybrid Cross is a method of determining the inheritance pattern of a trait between two single organisms. A monohybrid cross is a cross between parents who are heterozygous at one locus; for example, Bb x Bb . Example: B = brown. b = blue. BB = Dark Brown. Bb = Brown . bb = Blue.Monohybrid...

 or dihybrid cross
Dihybrid cross
A dihybrid cross is a cross between F1 offspring of two individuals that differ in two traits of particular interest. For example: RRyy/rrYY or RRYY/rryy parents result in F1 offspring that are heterozygous for both R and Y ....

. Polygenic inheritance can be explained as Mendelian inheritance at many loci, resulting in a trait which is normally-distributed. If n is the number of involved loci, then the coefficients of the binomial expansion of (a + b)2n will give the frequency of distribution of all n allele combinations. For a sufficiently high n, this binomial distribution will begin to resemble a normal distribution. From this viewpoint, a disease state will become apparent at one of the tails of the distribution, past some threshold value. Disease states of increasing severity will be expected the further one goes past the threshold and away from the mean.

Heritable disease and multifactorial inheritance

A mutation resulting in a disease state is often recessive, so both alleles must be mutant in order for the disease to be expressed phenotypically. A disease or syndrome may also be the result of the expression of mutant alleles at more than one locus. When more than one gene is involved with or without the presence of environmental triggers, we say that the disease is the result of multifactorial inheritance.

The more genes involved in the cross, the more the distribution of the genotypes will resemble a normal, or Gaussian distribution. This shows that multifactorial inheritance is polygenic, and genetic frequencies can be predicted by way of a polyhybrid Mendelian
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...

 cross. Phenotypic frequencies are a different matter, especially if they are complicated by environmental factors.

The paradigm of polygenic inheritance as being used to define multifactorial disease has encountered much disagreement. Turnpenny (2004) discusses how simple polygenic inheritance cannot explain some diseases such as the onset of Type I diabetes mellitus, and that in cases such as these, not all genes are thought to make an equal contribution.

The assumption of polygenic inheritance is that all involved loci make an equal contribution to the symptoms of the disease. This should result in a normal curve distribution of genotypes. When it does not, the idea of polygenetic inheritance cannot be supported for that illness.

A cursory look at some examples

Examples of such diseases are not new to medicine. The above examples are well-known examples of diseases having both genetic and environmental components. Other examples involve atopic diseases such as eczema or dermatitis
Atopic dermatitis
Atopic dermatitis is an inflammatory, chronically relapsing, non-contagious and pruritic skin disorder...

; also spina bifida
Spina bifida
Spina bifida is a developmental congenital disorder caused by the incomplete closing of the embryonic neural tube. Some vertebrae overlying the spinal cord are not fully formed and remain unfused and open. If the opening is large enough, this allows a portion of the spinal cord to protrude through...

 (open spine) and anencephaly
Anencephaly
Anencephaly is a cephalic disorder that results from a neural tube defect that occurs when the cephalic end of the neural tube fails to close, usually between the 23rd and 26th day of pregnancy, resulting in the absence of a major portion of the brain, skull, and scalp...

 (open skull) are other examples

While schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...

 is widely believed to be multifactorially genetic by biopsychiatrists, no characteristic genetic markers have been determined with any certainty.

Is it multifactorially heritable?

It is difficult to ascertain if any particular disease is multifactorially genetic. If a pedigree chart
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....

 is taken of the patient's family and relations, and it is shown that the brothers and sisters of the patient have the disease, then there is a strong chance that the disease is genetic and that the patient will also be a genetic carrier. But this is not quite enough. It also needs to be proven that the pattern of inheritance is non-Mendelian. This would require studying dozens, even hundreds of different family pedigrees before a conclusion of multifactorial inheritance is drawn. This often takes several years.

If multifactorial inheritance is indeed the case, then the chance of the patient contracting the disease is reduced if only cousins and more distant relatives have the disease. It must be stated that while multifactorially-inherited diseases tend to run in families, inheritance will not follow the same pattern as a simple monohybrid
Monohybrid cross
Monohybrid Cross is a method of determining the inheritance pattern of a trait between two single organisms. A monohybrid cross is a cross between parents who are heterozygous at one locus; for example, Bb x Bb . Example: B = brown. b = blue. BB = Dark Brown. Bb = Brown . bb = Blue.Monohybrid...

 or dihybrid cross
Dihybrid cross
A dihybrid cross is a cross between F1 offspring of two individuals that differ in two traits of particular interest. For example: RRyy/rrYY or RRYY/rryy parents result in F1 offspring that are heterozygous for both R and Y ....

.

If a genetic cause is suspected and little else is known about the illness, then it remains to be seen exactly how many genes are involved in the phenotypic expression of the disease. Once that is determined, the question must be answered: if two people have the required genes, why are there differences in expression between them? Generally, what makes the two individuals different are likely to be environmental factors. Due to the involved nature of genetic investigations needed to determine such inheritance patterns, this is not usually the first avenue of investigation one would choose to determine etiology.

Quantitative trait locus

Typically, QTLs underlie continuous traits (those traits that vary continuously, e.g. height) as opposed to discrete traits (traits that have two or several character values, e.g. red hair in humans, a recessive trait, or smooth vs. wrinkled peas used by Mendel
Gregor Mendel
Gregor Johann Mendel was an Austrian scientist and Augustinian friar who gained posthumous fame as the founder of the new science of genetics. Mendel demonstrated that the inheritance of certain traits in pea plants follows particular patterns, now referred to as the laws of Mendelian inheritance...

 in his experiments).

Moreover, a single phenotypic
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...

 trait is usually determined by many genes. Consequently, many QTLs are associated with a single trait.

A quantitative trait locus (QTL) is a region 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...

 that is associated with a particular phenotypic
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...

 trait - these QTLs are often found on different chromosomes. Knowing the number of QTLs that explains variation in the phenotypic trait tells us about the genetic architecture
Genetic architecture
Genetic architecture refers to the underlying genetic basis of a phenotypic trait. A synonymous term is the 'genotype-phenotype map', the way that genotypes map to the phenotypes....

 of a trait. It may tell us that plant height is controlled by many genes of small effect, or by a few genes of large effect.

Another use of QTLs is to identify candidate gene
Candidate gene
A candidate gene is a gene, located in a chromosome region suspected of being involved in the expression of a trait such as a disease, whose protein product suggests that it could be the gene in question...

s underlying a trait. Once a region of DNA is identified as contributing to a phenotype, it can be sequenced. The DNA sequence of any genes in this region can then be compared to a database of DNA for genes whose function is already known.

In a recent development, classical QTL analyses are combined with gene expression profiling i.e. by DNA microarray
DNA microarray
A DNA microarray is a collection of microscopic DNA spots attached to a solid surface. Scientists use DNA microarrays to measure the expression levels of large numbers of genes simultaneously or to genotype multiple regions of a genome...

s. Such expression QTLs (eQTLs)
Expression quantitative trait loci
Expression quantitative trait loci are genomic loci that regulate expression levels of mRNAs or proteins. Expression traits differ from most other classical complex traits in one important respect—the measured mRNA or protein trait almost always is the product of a single gene with a specific...

 describe cis- and trans
Trans-acting
In the field of molecular biology, trans-acting , in general, means "acting from a different molecule"...

-controlling elements for the expression of often disease-associated genes. Observed epistatic effects
Epistasis
In genetics, epistasis is the phenomenon where the effects of one gene are modified by one or several other genes, which are sometimes called modifier genes. The gene whose phenotype is expressed is called epistatic, while the phenotype altered or suppressed is called hypostatic...

 have been found beneficial to identify the gene responsible by a cross-validation of genes within the interacting loci with metabolic pathway
Metabolic pathway
In biochemistry, metabolic pathways are series of chemical reactions occurring within a cell. In each pathway, a principal chemical is modified by a series of chemical reactions. Enzymes catalyze these reactions, and often require dietary minerals, vitamins, and other cofactors in order to function...

- and scientific literature
Scientific literature
Scientific literature comprises scientific publications that report original empirical and theoretical work in the natural and social sciences, and within a scientific field is often abbreviated as the literature. Academic publishing is the process of placing the results of one's research into the...

 databases.

QTL mapping

QTL mapping is the statistical study of the alleles that occur at a locus and the phenotypes (physical forms or traits) that they produce. Because most traits of interest are governed by more than one gene, defining and studying the entire locus of genes related to a trait gives hope of understanding what effect the genotype of an individual might have in the real world.

Statistical analysis is required to demonstrate that different genes interact with one another and to determine whether they produce a significant effect on the phenotype. QTLs identify a particular region of the genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....

 as containing a gene that is associated with the trait being assayed or measured. They are shown as intervals across a 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...

, where the probability of association is plotted for each marker used in the mapping experiment.

The QTL techniques were developed in the late 1980s and can be performed on inbred strains of any species.

To begin, a set of genetic markers
Genetic marker
A genetic marker is a gene or DNA sequence with a known location on a chromosome that can be used to identify cells, individuals or species. It can be described as a variation that can be observed...

 must be developed for the species in question. A marker is an identifiable region of variable DNA. Biologists are interested in understanding the genetic basis of 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 (physical traits). The aim is to find a marker that is significantly more likely to co-occur with the trait than expected by chance, that is, a marker that has a statistical association with the trait. Ideally, they would be able to find the specific 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...

 or genes in question, but this is a long and difficult undertaking. Instead, they can more readily find regions of DNA that are very close to the genes in question. When a QTL is found, it is often not the actual gene underlying the phenotypic trait, but rather a region of DNA that is closely linked with the gene.

For organisms whose genomes are known, one might now try to exclude genes in the identified region whose function is known with some certainty not to be connected with the trait in question. If the genome is not available, it may be an option to sequence the identified region and determine the putative functions of genes by their similarity to genes with known function, usually in other genomes. This can be done using BLAST
BLAST
In bioinformatics, Basic Local Alignment Search Tool, or BLAST, is an algorithm for comparing primary biological sequence information, such as the amino-acid sequences of different proteins or the nucleotides of DNA sequences...

, an online tool that allows users to enter a primary sequence and search for similar sequences within the BLAST database of genes from various organisms.

Another interest of statistical geneticists using QTL mapping is to determine the complexity of the genetic architecture underlying a phenotypic trait. For example, they may be interested in knowing whether a phenotype is shaped by many independent loci, or by a few loci, and do those loci interact. This can provide information on how the phenotype may be evolving.

Analysis of variance

The simplest method for QTL mapping is analysis of variance (ANOVA, sometimes called "marker regression") at the marker loci. In this method, in a backcross, one may calculate a t-statistic to compare the averages of the two marker 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...

 groups. For other types of
crosses (such as the intercross), where there are more than two possible genotypes, one uses a more general form of ANOVA, which provides a so-called F-statistic
F-statistics
In population genetics, F-statistics describe the level of heterozygosity in a population; more specifically the degree of a reduction in heterozygosity when compared to Hardy–Weinberg expectation...

. The ANOVA approach for QTL mapping has three important weaknesses. First, we do not receive separate estimates of QTL location and QTL effect. QTL location is indicated only by looking at which markers give the greatest differences between genotype group averages, and the apparent QTL effect at a marker will be smaller than the true QTL effect as a result of recombination
Genetic recombination
Genetic recombination is a process by which a molecule of nucleic acid is broken and then joined to a different one. Recombination can occur between similar molecules of DNA, as in homologous recombination, or dissimilar molecules, as in non-homologous end joining. Recombination is a common method...

 between the marker and the QTL. Second, we must discard individuals whose genotypes are missing at the marker. Third, when the markers are widely spaced, the QTL may be quite far from all markers, and so the power for QTL detection will decrease.

Interval mapping

Lander and Botstein developed interval mapping, which overcomes the three disadvantages of analysis of variance at marker loci. Interval mapping is currently the most popular approach for QTL mapping in experimental crosses. The method makes use of a genetic map of the typed markers, and, like analysis of variance, assumes the presence of a single QTL. Each location in the genome is posited, one at a time, as the location of the putative QTL....

Composite interval mapping (CIM)

In this method, one performs interval mapping using a subset of marker loci as covariates. These markers serve as proxies for other QTLs to increase the resolution of interval mapping, by accounting for linked QTLs and reducing the residual variation. The key problem with CIM concerns the choice of suitable marker loci to serve as covariates; once these have been chosen, CIM turns the model selection problem into a single-dimensional scan. The choice
of marker covariates has not been solved, however. Not surprisingly, the appropriate markers are those closest to the true QTLs, and so if one could find these, the QTL mapping problem
would be complete anyway.

Family-pedigree based mapping in plants

Plant geneticists are attempting to incorporate some of the methods pioneered in human genetics. Using family-pedigree based approach has been discussed (Bink et al. 2008). Family-based linkage and association has been successfully implemented (Rosyara et al. 2009)

See also

  • Epistasis
    Epistasis
    In genetics, epistasis is the phenomenon where the effects of one gene are modified by one or several other genes, which are sometimes called modifier genes. The gene whose phenotype is expressed is called epistatic, while the phenotype altered or suppressed is called hypostatic...

  • Dominance (genetics)
  • Expression quantitative trait loci (eQTL)
    Expression quantitative trait loci
    Expression quantitative trait loci are genomic loci that regulate expression levels of mRNAs or proteins. Expression traits differ from most other classical complex traits in one important respect—the measured mRNA or protein trait almost always is the product of a single gene with a specific...

  • Association Mapping
    Association mapping
    Association mapping, also known as "linkage disequilibrium mapping", is a method of mapping quantitative trait loci that takes advantage of historic linkage disequilibrium to link phenotypes to genotypes .-Theory:Association mapping is based on the idea that traits that have entered a population...

  • Nested Association Mapping
    Nested association mapping
    Nested association mapping is a technique designed by the labs of , , and for identifying and dissecting the genetic architecture of complex traits in corn...


External links

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