A quantitative trait locus (QTL) is a
locus (section of
DNA) that correlates with variation of a
quantitative trait in the
phenotype
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological prop ...
of a
population
Population typically refers to the number of people in a single area, whether it be a city or town, region, country, continent, or the world. Governments typically quantify the size of the resident population within their jurisdiction using ...
of
organism
In biology, an organism () is any life, living system that functions as an individual entity. All organisms are composed of cells (cell theory). Organisms are classified by taxonomy (biology), taxonomy into groups such as Multicellular o ...
s. QTLs are mapped by identifying which molecular markers (such as
SNPs or
AFLPs) correlate with an observed trait. This is often an early step in identifying the actual
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
s that cause the trait variation.
Definition
A quantitative trait locus (QTL) is a region of
DNA which is associated with a particular
phenotypic trait, which varies in degree and which can be attributed to
polygenic
A polygene is a member of a group of non- epistatic genes that interact additively to influence a phenotypic trait, thus contributing to multiple-gene inheritance (polygenic inheritance, multigenic inheritance, quantitative inheritance), a type o ...
effects, i.e., the product of two or more
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
s, and their environment.
[
.] These QTLs are often found on different
chromosomes. The number of QTLs which explain variation in the phenotypic trait indicates the
genetic architecture of a trait. It may indicate that plant height is controlled by many genes of small effect, or by a few genes of large effect.
Typically, QTLs underlie continuous
traits (those traits which 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 in his experiments).
Moreover, a single
phenotypic trait is usually determined by many genes. Consequently, many QTLs are associated with a single trait.
Another use of QTLs is to identify
candidate genes underlying a trait. 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, this task being fundamental for marker-assisted crop improvement.
History
Mendelian inheritance was rediscovered at the beginning of the 20th century. As
Mendel's ideas spread, geneticists began to connect Mendel's rules of inheritance of single factors to
Darwinian evolution. For early geneticists, it was not immediately clear that the smooth variation in traits like body size (i.e.,
Incomplete Dominance) was caused by the inheritance of single genetic factors. Although
Darwin
Darwin may refer to:
Common meanings
* Charles Darwin (1809–1882), English naturalist and writer, best known as the originator of the theory of biological evolution by natural selection
* Darwin, Northern Territory, a territorial capital city i ...
himself observed that inbred features of fancy pigeons were inherited in accordance with Mendel's laws (although Darwin didn't actually know about Mendel's ideas when he made the observation), it was not obvious that these features selected by fancy pigeon breeders can similarly explain quantitative variation in nature.
An early attempt by
William Ernest Castle to unify the laws of Mendelian inheritance with Darwin's theory of speciation invoked the idea that species become distinct from one another as one species or the other acquires a novel Mendelian factor.
Castle's conclusion was based on the observation that novel traits that could be studied in the lab and that show Mendelian inheritance patterns reflect a large deviation from the wild type, and Castle believed that acquisition of such features is the basis of "discontinuous variation" that characterizes speciation.
Darwin discussed the inheritance of similar mutant features but did not invoke them as a requirement of speciation.
Instead Darwin used the emergence of such features in breeding populations as evidence that mutation can occur at random within breeding populations, which is a central premise of his model of selection in nature.
Later in his career, Castle would refine his model for speciation to allow for small variation to contribute to speciation over time. He also was able to demonstrate this point by selectively breeding laboratory populations of rats to obtain a hooded phenotype over several generations.
Castle's was perhaps the first attempt made in the scientific literature to direct evolution by artificial selection of a trait with continuous underlying variation, however the practice had previously been widely employed in the development of
agriculture
Agriculture or farming is the practice of cultivating plants and livestock. Agriculture was the key development in the rise of sedentary human civilization, whereby farming of domesticated species created food surpluses that enabled peop ...
to obtain livestock or plants with favorable features from populations that show quantitative variation in traits like body size or grain yield.
Castle's work was among the first to attempt to unify the recently rediscovered laws of Mendelian inheritance with Darwin's theory of evolution. Still, it would be almost thirty years until the theoretical framework for evolution of
complex traits would be widely formalized.
In an early summary of the theory of evolution of continuous variation,
Sewall Wright
Sewall Green Wright FRS(For) Honorary FRSE (December 21, 1889March 3, 1988) was an American geneticist known for his influential work on evolutionary theory and also for his work on path analysis. He was a founder of population genetics alon ...
, a graduate student who trained under Castle, summarized contemporary thinking about the genetic basis of quantitative natural variation: "As genetic studies continued, ever smaller differences were found to mendelize, and any character, sufficiently investigated, turned out to be affected by many factors."
Wright and others formalized population genetics theory that had been worked out over the preceding 30 years explaining how such traits can be inherited and create stably breeding populations with unique characteristics. Quantitative trait genetics today leverages Wright's observations about the statistical relationship between genotype and phenotype in families and populations to understand how certain genetic features can affect variation in natural and derived populations.
Quantitative traits
Polygenic inheritance refers to inheritance of a
phenotypic characteristic (trait) that is attributable to two or more
genes and can be measured quantitatively. Multifactorial inheritance refers to polygenic inheritance that also includes interactions with the environment. Unlike
monogenic traits, polygenic traits do not follow patterns of
Mendelian inheritance
Mendelian inheritance (also known as Mendelism) is a type of biological inheritance following the principles originally proposed by Gregor Mendel in 1865 and 1866, re-discovered in 1900 by Hugo de Vries and Carl Correns, and later populari ...
(discrete categories). Instead, their phenotypes typically vary along a continuous gradient depicted by a
bell curve.
An example of a polygenic trait is
human skin color
Human skin color ranges from the Dark skin, darkest brown to the Light skin, lightest hues. Differences in skin color among individuals is caused by variation in pigmentation, which is the result of genetics (inherited from one's biological pa ...
variation. Several genes factor into determining a person's natural skin color, so modifying only one of those genes can change skin color slightly or in some cases, such as for
SLC24A5, moderately. Many disorders with
genetic components are polygenic, including
autism
The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental condition (or conditions) characterized by difficulti ...
,
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bl ...
,
diabetes
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level (hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...
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 many contributing factors:
Congenital malformation
*
Cleft palate[
][
]
*
Congenital dislocation of the hip
*
Congenital heart defects
*
Neural tube defects
*
Pyloric stenosis
Pyloric stenosis is a narrowing of the opening from the stomach to the first part of the small intestine (the pylorus). Symptoms include projectile vomiting without the presence of bile. This most often occurs after the baby is fed. The typical ...
*
Talipes
Adult onset diseases
*
Diabetes Mellitus
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level (hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...
*
Cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bl ...
*
Glaucoma
Glaucoma is a group of eye diseases that result in damage to the optic nerve (or retina) and cause vision loss. The most common type is open-angle (wide angle, chronic simple) glaucoma, in which the drainage angle for fluid within the eye re ...
*
Hypertension
*
Ischaemic heart disease
*
Bipolar disorder
Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...
*
Schizophrenia
Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social wi ...
*
Psoriasis
*
Thyroid diseases
*
Alzheimer's disease
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
Traits controlled both by the environment and by genetic factors are called multifactorial.
Usually, multifactorial traits outside of illness result in what we see as continuous characteristics in organisms, especially human organisms such as: height,
skin color, and body mass.
[
] All of these phenotypes are complicated by a great deal of give-and-take between genes and environmental effects.
The continuous distribution of traits such as height and skin color described above, reflects the action of genes that do not manifest 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 or
dihybrid cross.
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 sufficiently high values of ''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
There are several kinds of mean in mathematics, especially in statistics. Each mean serves to summarize a given group of data, often to better understand the overall value ( magnitude and sign) of a given data set.
For a data set, the '' ari ...
.
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
genotype
The genotype of an organism is its complete set of genetic material. Genotype can also be used to refer to the alleles or variants an individual carries in a particular gene or genetic location. The number of alleles an individual can have in a ...
s 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 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 (Gaussian) distribution of genotypes. When it does not, the idea of polygenetic inheritance cannot be supported for that illness.
Examples
The above are well-known examples of diseases having both genetic and environmental components. Other examples involve atopic diseases such as
eczema or
dermatitis
Dermatitis is inflammation of the skin, typically characterized by itchiness, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become thickened. The area of skin involved can ...
;
spina bifida
Spina bifida (Latin for 'split spine'; SB) is a birth defect in which there is incomplete closing of the spine and the membranes around the spinal cord during early development in pregnancy. There are three main types: spina bifida occulta, m ...
(open spine), and
anencephaly (open skull).
While
schizophrenia
Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social wi ...
is widely believed to be multifactorially genetic by
biopsychiatrists, no characteristic genetic markers have been determined with any certainty.
If 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. This is not quite enough as 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 only if 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 or
dihybrid cross.
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.
QTL mapping
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, 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. It is often not the actual gene underlying the phenotypic trait, but rather a region of DNA that is closely linked with the gene
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.
In a recent development, classical QTL analyses were combined with gene expression profiling i.e. by
DNA microarray
A DNA microarray (also commonly known as DNA chip or biochip) 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 ...
s. Such
expression QTLs (eQTLs) describe
cis- and
trans
Trans- is a Latin prefix meaning "across", "beyond", or "on the other side of".
Used alone, trans may refer to:
Arts, entertainment, and media
* Trans (festival), a former festival in Belfast, Northern Ireland, United Kingdom
* ''Trans'' (fil ...
-controlling elements for the expression of often disease-associated genes. Observed
epistatic effects have been found beneficial to identify the gene responsible by a cross-validation of genes within the interacting loci with
metabolic pathway
In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence of chemical ...
- and
scientific literature
: ''For a broader class of literature, see Academic publishing.''
Scientific literature comprises scholarly publications that report original empirical and theoretical work in the natural and social sciences. Within an academic field, sci ...
databases.
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
In statistics, the ''t''-statistic is the ratio of the departure of the estimated value of a parameter from its hypothesized value to its standard error. It is used in hypothesis testing via Student's ''t''-test. The ''t''-statistic is used i ...
to compare the averages of the two marker
genotype
The genotype of an organism is its complete set of genetic material. Genotype can also be used to refer to the alleles or variants an individual carries in a particular gene or genetic location. The number of alleles an individual can have in a ...
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. 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 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. In interval mapping, each locus is considered one at a time and the logarithm of the odds ratio (
LOD score) is calculated for the model that the given locus is a true QTL. The odds ratio is related to the
Pearson correlation coefficient
In statistics, the Pearson correlation coefficient (PCC, pronounced ) ― also known as Pearson's ''r'', the Pearson product-moment correlation coefficient (PPMCC), the bivariate correlation, or colloquially simply as the correlation coefficien ...
between the phenotype and the marker genotype for each individual in the experimental cross.
The term 'interval mapping' is used for estimating the position of a QTL within two markers (often indicated as 'marker-bracket'). Interval mapping is originally based on the maximum likelihood but there are also very good approximations possible with simple regression.
The principle for QTL mapping is:
1) The Likelihood can be calculated for a given set of parameters (particularly QTL effect and QTL position) given the observed data on phenotypes and marker genotypes.
2) The estimates for the parameters are those where the likelihood is highest.
3) A significance threshold can be established by permutation testing.
Conventional methods for the detection of quantitative trait loci (QTLs) are based on a comparison of single QTL models with a model assuming no QTL. For instance in the "interval mapping" method the likelihood for a single putative QTL is assessed at each location on the genome. However, QTLs located elsewhere on the genome can have an interfering effect. As a consequence, the power of detection may be compromised, and the estimates of locations and effects of QTLs may be biased (Lander and Botstein 1989; Knapp 1991). Even nonexisting so-called "ghost" QTLs may appear (Haley and Knott 1992; Martinez and Curnow 1992). Therefore, multiple QTLs could be mapped more efficiently and more accurately by using multiple QTL models.
[http://www.genetics.org/content/135/1/205.full.pdf ] One popular approach to handle QTL mapping where multiple QTL contribute to a trait is to iteratively scan the genome and add known QTL to the regression model as QTLs are identified. This method, termed
composite interval mapping
Composite or compositing may refer to:
Materials
* Composite material, a material that is made from several different substances
** Metal matrix composite, composed of metal and other parts
** Cermet, a composite of ceramic and metallic materials
...
determine both the location and effects size of QTL more accurately than single-QTL approaches, especially in small mapping populations where the effect of correlation between genotypes in the mapping population may be problematic.
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
Family based QTL mapping, or Family-pedigree based mapping (Linkage and
association mapping), involves multiple families instead of a single family. Family based QTL mapping has been the only way for mapping of genes where experimental crosses are difficult to make. However, due to some advantages, now 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
*
Association Mapping
*
Family based QTL mapping
*
Epistasis
*
Dominance (genetics)
*
Expression quantitative trait loci (eQTL)
*
Genetic predisposition
*
Nested Association Mapping Nested association mapping (NAM) is a technique designed by the labs of Edward BucklerJames Holland anfor identifying and dissecting the genetic architecture of complex traits in corn ('' Zea mays''). It is important to note that nested associatio ...
*
Oncogene
*
Genetic susceptibility
References
* Bink MCAM, Boer MP, ter Braak CJF, Jansen J, Voorrips RE, van de Weg WE: Bayesian analysis of complex traits in pedigreed plant populations.
Euphytica 2008, 161:85–96.
* Rosyara U.R., J.L. Gonzalez-Hernandez, K.D. Glover, K.R. Gedye and J.M. Stein. 2009. Family-based mapping of quantitative trait loci in plant breeding populations with resistance to Fusarium head blight in wheat as an illustratio
Theoretical Applied Genetics 118:1617–1631* Garnier, Sophie, Truong, Vinh, Genome-Wide Haplotype Analysis of Cis Expression Quantitative Trait Loci in Monocyte
External links
Plant Breeding and Genomics on eXtension.orgINTERSNP– a software for genome-wide interaction analysis (GWIA) of case-control SNP data and analysis of quantitative traits
Precision Mapping of Quantitative Trait LociQTL CartographerComplex Trait ConsortiumA Statistical Framework for Quantitative Trait MappingGeneNetworkGridQTLQTL discussion forumA list of computer programs for genetic analysis including QTL analysisQuantitative Trait Locus (QTL) Analysis@
Scitable
Mapping Quantitative Trait LociWhat are Quantitative Trait Loci?–
University of Warwick
, mottoeng = Mind moves matter
, established =
, type = Public research university
, endowment = £7.0 million (2021)
, budget = £698.2 million (202 ...
{{DEFAULTSORT:Quantitative Trait Locus
Classical genetics
Statistical genetics
Quantitative trait loci
Genetic epidemiology
Quantitative genetics