Inheritance of quantitative traits or polygenic inheritance refers to the inheritance of a phenotypic A phenotype is any observable characteristic or trait of an organism: such as its morphology, development, biochemical or physiological properties, or behavior. Phenotypes result from the expression of an organism's genes as well as the influence of environmental factors and possible interactions between the two characteristic that varies in degree and can be attributed to the interactions between two or more genes A gene is the basic unit of heredity in a living organism. All living things depend on genes. Genes hold the information to build and maintain an organism's cells and pass genetic traits to offspring. A modern working definition of a gene is "a locatable region of genomic sequence, corresponding to a unit of inheritance, which is associated and their environment. Though not necessarily genes A gene is the basic unit of heredity in a living organism. All living things depend on genes. Genes hold the information to build and maintain an organism's cells and pass genetic traits to offspring. A modern working definition of a gene is "a locatable region of genomic sequence, corresponding to a unit of inheritance, which is associated themselves, quantitative trait loci (QTLs) are stretches of DNA that are closely linked to the genes that underlie the trait in question. QTLs can be molecularly identified (for example, with AFLP 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 1990’s by Keygene, AFLP uses restriction enzymes to cut genomic DNA, followed by ligation of adaptors to the sticky ends of the restriction fragments. A subset of the) to help map regions of the genome that contain genes involved in specifying a quantitative trait. This can be an early step in identifying and sequencing these genes.

Contents

Quantitative traits

Polygenic inheritance, also known as quantitative or multifactorial inheritance refers to inheritance of a phenotypic A phenotype is any observable characteristic or trait of an organism: such as its morphology, development, biochemical or physiological properties, or behavior. Phenotypes result from the expression of an organism's genes as well as the influence of environmental factors and possible interactions between the two characteristic (trait) that is attributable to two or more genes A gene is the basic unit of heredity in a living organism. All living things depend on genes. Genes hold the information to build and maintain an organism's cells and pass genetic traits to offspring. A modern working definition of a gene is "a locatable region of genomic sequence, corresponding to a unit of inheritance, which is associated and their interaction with the environment. Unlike monogenic traits, polygenic traits do not follow patterns of Mendelian inheritance Mendelian inheritance is a set of primary tenets relating to the transmission of hereditary characteristics from parent organisms to their offspring; it underlies much of genetics. They were initially derived from the work of Gregor Mendel published in 1865 and 1866 which was "re-discovered" in 1900, and were initially very controversial (qualitative traits). Instead, their phenotypes typically vary along a continuous gradient depicted by a bell curve In probability theory and statistics, the normal distribution or Gaussian distribution is a continuous probability distribution that describes data that cluster around the mean. The graph of the associated probability density function is bell-shaped, with a peak at the mean, and is known as the Gaussian function or bell curve. The Gaussian.[1]

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 A genetic disorder is an illness caused by abnormalities in genes or chromosomes. While some diseases, such as cancer, are due in part to a genetic disorders, they can also be caused by environmental factors. Most disorders are quite rare and affect one person in every several thousands or millions. Some types of recessive gene disorders confer an are polygenic, including autism Autism is a disorder of neural development that is 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 involves many parts of the brain; how this occurs is not well understood. The two other autism spectrum disorders are Asperger, cancer Cancer /ˈkænsə/ ( listen) (medical term: malignant neoplasm) is a class of diseases in which a group of cells display uncontrolled growth (division beyond the normal limits), invasion (intrusion on and destruction of adjacent tissues), and sometimes metastasis (spread to other locations in the body via lymph or blood). These three malignant, diabetes Diabetes mellitus —often referred to as diabetes—is a condition in which the body either does not produce enough, or does not properly respond to, insulin, a hormone produced in the pancreas. Insulin enables cells to absorb glucose in order to turn it into energy. This causes glucose to accumulate in the blood (hyperglycemia), leading to 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 is the study of causation, or origination. The word is derived from the Greek αἰτιολογία, aitiologia, "giving a reason for" (αἰτία, aitia, "cause"; and -λογία, -logia):

Congenital malformation

Adult onset diseases

Multifactorially inherited diseases are said to constitute the majority of all genetic disorders affecting humans which will result in hospitalization or special care of some kind[5] [6].

Multifactorial traits in general

Generally, multifactorial traits outside of illness contribute to what we see as continuous characteristics in organisms, such as height[5], skin color, and body mass[7]. All of these phenotypes are complicated by a great deal of interplay between genes and environment[5]. While some authors[5] [7] include intelligence in the same vein, and it is tempting to do so, the problem with intelligence is that it is so ill-defined. Indeed, the entry on intelligence Intelligence is an umbrella term used to describe a property of the mind that encompasses many related abilities, such as the capacities to reason, to plan, to solve problems, to think abstractly, to comprehend ideas, to use language, and to learn. There are several ways to define intelligence. In some cases, intelligence may include traits such offers so many definitions, that the point is easily made that there is no single, agreed-upon entity that one could say amounts to a definable cluster of heritable traits.

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[8].

Thus, due to the nature of polygenic traits, inheritance will not follow the same pattern as a simple monohybrid 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 (not blue). bb = Blue or 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 & Y[6]. Polygenic inheritance can be explained as Mendelian inheritance at many loci[5], 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[8].

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 In probability theory and statistics, the normal distribution or Gaussian distribution is a continuous probability distribution that describes data that cluster around the mean. The graph of the associated probability density function is bell-shaped, with a peak at the mean, and is known as the Gaussian function or bell curve. The Gaussian distribution[5]. This shows that multifactorial inheritance is polygenic, and genetic frequencies can be predicted by way of a polyhybrid Mendelian Mendelian inheritance is a set of primary tenets relating to the transmission of hereditary characteristics from parent organisms to their offspring; it underlies much of genetics. They were initially derived from the work of Gregor Mendel published in 1865 and 1866 which was "re-discovered" in 1900, and were initially very controversial 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[8].

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, then 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 Atopic dermatitis (a type of eczema) is an inflammatory, chronically relapsing, non-contagious and pruritic skin disease. It has been given names like "prurigo Besnier," "neurodermitis," "endogenous eczema," "flexural eczema," "infantile eczema," and "prurigo diathsique" or dermatitis Atopic dermatitis (a type of eczema) is an inflammatory, chronically relapsing, non-contagious and pruritic skin disease. It has been given names like "prurigo Besnier," "neurodermitis," "endogenous eczema," "flexural eczema," "infantile eczema," and "prurigo diathsique"[5]; also spina bifida Spina bifida is a developmental birth defect caused by the incomplete closure 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 stick out through the opening in the bones. There may or may not be a (open spine) and 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. Children with this disorder are born without a forebrain, the largest part of (open skull) are other examples[2]

While schizophrenia Schizophrenia , from the Greek roots skhizein (σχίζειν, "to split") and phrēn, phren- (φρήν, φρεν-; "mind") is a psychiatric diagnosis that describes a mental disorder characterized by abnormalities in the perception or expression of reality. It most commonly manifests as auditory hallucinations, paranoid or is widely believed to be multifactorially genetic by biopsychiatrists Biological psychiatry, or biopsychiatry is an approach to psychiatry that aims to understand mental disorder in terms of the biological function of the nervous system. It is interdisciplinary in its approach and draws on sciences such as neuroscience, psychopharmacology, biochemistry, genetics and physiology to investigate the biological bases of, 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 A pedigree chart is a chart that shows all of the known phenotypes for an organism and its ancestors, most commonly humans, show dogs, and race horses. The word pedigree is a corruption of the French "pied de grue" or crane's foot, because the typical lines and split lines resemble the thin leg and foot of a crane 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[2]. It must be stated that while multifactorially-inherited disease tends to run in families, inheritance will not follow the same pattern as a simple monohybrid 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 (not blue). bb = Blue or 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 & Y[6].

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 some people still don't express the disease. 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.

Psychiatry has determined, often without sufficient evidence, that mental illness follows this pattern. The problem with mental illness itself is that most diagnoses are largely subjective, and even the nosologies in DSM-IV are not widely agreed upon. The example most often cited as an example of a multifactorial mental illness is schizophrenia Schizophrenia , from the Greek roots skhizein (σχίζειν, "to split") and phrēn, phren- (φρήν, φρεν-; "mind") is a psychiatric diagnosis that describes a mental disorder characterized by abnormalities in the perception or expression of reality. It most commonly manifests as auditory hallucinations, paranoid or, however, no genes have been isolated to date. It has been said that genetic causes of mental illness are being emphasised at the expense of paying sufficient attention to environmental factors, especially in the field of biopsychiatry Biological psychiatry, or biopsychiatry is an approach to psychiatry that aims to understand mental disorder in terms of the biological function of the nervous system. It is interdisciplinary in its approach and draws on sciences such as neuroscience, psychopharmacology, biochemistry, genetics and physiology to investigate the biological bases of.[9]

More often than not, investigators will hypothesise that a disease is multifactorially heritable, along with a cluster of other hypotheses when it is not known what causes the disease.

Quantitative trait locus

A QTL for osteoporosis Osteoporosis is a disease of bone that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is disrupted, and the amount and variety of proteins in bone is altered. Osteoporosis is defined by the World Health Organization (WHO) in women as a bone mineral density 2.5 standard deviations on the human chromosome 20

Typically, QTLs underlie continuous traits A trait is a distinct variant of a phenotypic character of an organism that may be inherited, environmentally determined or somewhere in between. For example, eye color is a character or abstraction of an attribute, while blue, brown and hazel are 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 Johann Mendel was an Augustinian priest and scientist, who gained posthumous fame as the figurehead of the new science of genetics for his study of the inheritance of certain traits in pea plants. Mendel showed that the inheritance of these traits follows particular laws, which were later named after him. The significance of Mendel's work in his experiments).

Moreover, a single phenotypic A phenotype is any observable characteristic or trait of an organism: such as its morphology, development, biochemical or physiological properties, or behavior. Phenotypes result from the expression of an organism's genes as well as the influence of environmental factors and possible interactions between the two 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 Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms and some viruses. The main role of DNA molecules is the long-term storage of information. DNA is often compared to a set of blueprints or a recipe, or a code, since it contains the instructions needed that is associated with a particular phenotypic A phenotype is any observable characteristic or trait of an organism: such as its morphology, development, biochemical or physiological properties, or behavior. Phenotypes result from the expression of an organism's genes as well as the influence of environmental factors and possible interactions between the two trait A trait is a distinct variant of a phenotypic character of an organism that may be inherited, environmentally determined or somewhere in between. For example, eye color is a character or abstraction of an attribute, while blue, brown and hazel are traits - these QTLs are often found on different chromosomes A chromosome is an organized structure of DNA and protein that is 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. The word chromosome comes from the Greek χρῶμα. Knowing the number of QTLs that explains variation in the phenotypic trait tells us about the 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 genes 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 microarrays. Such expression QTLs (eQTLs) describe cis- and trans-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- and scientific literature databases.

QTL mapping

Example of a genome-wide scan for QTL of osteoporosis

QTL mapping is the statistical study of the alleles that occur in 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 as containing a gene that is associated with the trait being assayed or measured. They are shown as intervals across a chromosome, 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 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 phenotypes (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 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, 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 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. 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.

Non-traditional methods: Family-pedigree based mapping

Plant geneticists are attempting to incorporate some of the methods pioneered in human genetics.[10] There are some successful attempts to do so. One of quick method of QTL mapping was recently discussed.[11]

See Also

References

  1. ^ Ricki Lewis (2003), Multifactorial Traits, McGraw-Hill Higher Education, http://highered.mcgraw-hill.com/sites/007246268x/student_view0/chapter7/
  2. ^ a b c "Medical Genetics: Multifactorial Inheritance". Children's Hospital of the King's Daughters. 31 December 2005. http://www.chkd.org/HealthLibrary/Content.aspx?pageid=P02134. Retrieved 2007-01-06.
  3. ^ a b c "Multifactorial Inheritance". Pregnancy and Newborn Health Education Centre. The March of Dimes. http://www.marchofdimes.com/pnhec/4439_4138.asp. Retrieved 2007-01-06.
  4. ^ Emery's Elements of Medical Genetics
  5. ^ a b c d e f g Tissot, Robert. "Human Genetics for 1st Year Students: Multifactorial Inheritance". http://www.uic.edu/classes/bms/bms655/lesson11.html. Retrieved 2007-01-06.
  6. ^ a b c "Multifactorial Inheritance". Clinical Genetics: A Self-Study Guide for Health Care Providers. University of South Dakota School of Medicine. http://www.usd.edu/med/som/genetics/curriculum/1GMULTI5.htm. Retrieved 2007-01-06.
  7. ^ a b "Definition of Multifactorial inheritance". MedicineNet.com MedTerms Dictionary. MedicineNet.com. http://www.medterms.com/script/main/art.asp?articlekey=4453. Retrieved 2007-01-06.
  8. ^ a b c Turnpenny, Peter (2004). "Emery's Elements of Medical Genetics, 12th Edition, Chapter 9" (PDF). Elsevier. http://www.fleshandbones.com/readingroom/viewchapter.cfm?ID=1041. Retrieved 2007-01-06.
  9. ^ Douthit, Kathryn. "Preserving the Role of Counseling in the Age of Biopsychiatry: Critical Reflections on the DSM-IV-TR". VISTAS Online. http://counselingoutfitters.com/Douthit2.htm. Retrieved 2007-08-27.
  10. ^ Jannink, J; Bink, Mc; Jansen, Rc (Aug 2001). "Using complex plant pedigrees to map valuable genes". Trends in plant science 6 (8): 337–42. ISSN 1360-1385. PMID 11495765.
  11. ^ Rosyara, U. R.; Maxson-stein, K.L.; Glover, K.D.; Stein, J.M.; Gonzalez-hernandez, J.L. (2007), "Family-based mapping of FHB resistance QTLs in hexaploid wheat", Proceedings of National Fusarium head blight forum

External links

Genetics: Quantitative genetics
Concepts in Quantitative Genetics Heritability · Quantitative trait locus · Candidate gene · Effective population size
Related Topics Population genetics · Genomics · Evolutionary biology · Heredity

Categories: Classical genetics | Genetics | Statistical genetics

<<Table of Contents | Show All>>

 

The above information uses material from Wikipedia and is licensed under the GNU Free Documentation License.
Some facts may not have been fully verified for accuracy. [Disclaimers]
This page was last archived by our server on Sun Jan 10 19:26:01 2010. [ refresh local cache ]
Displaying this page or its contents does not use any Wikimedia Foundation's resources.
The owners of this site proudly support the Wikimedia Foundation.

[Hide]▼
[Hide]▲