POLYGENIC AND MULTIFACTORIAL INHERITANCE
POLYGENIC AND MULTIFACTORIAL INHERITANCE
Jan 14, 2023
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Microsoft PowerPoint - POLYGENIC AND MULTIFACTORIAL [Compatibility Mode]Polygenic and multifactorial inheritance
Many disorders demonstrate familial clustering that does not conform to any recognized pattern of Mendelian inheritance. Examples include several of the most common congenital malformations and many of the common acquired diseases of childhood and adult life.
It is likely that many factors – genetic and environmental – It is likely that many factors – genetic and environmental – are involved in causing these disorders they are showing multifactorial inheritance.
Concept of normal distribution generated by many genes, known as polygenes, each acting in an additive fashion, is plausible for physiological characteristics such as height and blood pressure.
However, for disease such as insulin-dependent diabetes mellitus research has shown that the genetic contribution is not straightforward and involves many loci, some of which play a much more important role than others.
Polygenic and multifactorial inheritance
Sequencing of the human genome has shown that the 3 billion bps are 99.9% identical in every person. This is also means that individuals are, on average, 0.1% different genetically from every other person on the different genetically from every other person on the planet.
Within this 0.1% lies the mystery of why some people are more susceptible to a particular illness, or more likely to be healthy, than other members of the population.
Disorders which show multifactorial inheritance
Congenital malformations
Cleft lip/palate
Congenital dislocation of the hip
Acquired diseases of childhood and adult life Acquired diseases of childhood and adult life
Asthma
What is known as polygenic or quantitative inheritance?
This involves the inheritance and expression of a phenotype being determined by many genes at different loci and each gene exerting a small additive effect.gene exerting a small additive effect.
Effects of the genes are cumulative , no one gene is dominant or recessive to another.
Several human characteristics show a continuous distribution in the population that closely resembles a normal distribution.
Approximately 68%, 95% and 99.7% of observations fall within the mean plus or minus one, two or three standard deviations respectively.
Human characteristics that show a continuous
normal distribution
Blood pressure
Head circumference
Height, Intelligence
Skin color
First-degree relatives share on average 50% of their genes. If a parameter such as height is polygenic, then genes. If a parameter such as height is polygenic, then the correlation between first-degree relatives such as siblings should be 0.5. Several studies have shown it.
Correlation is a statistical measure of the degree of association of variable phenomena.
In reality, characteristics such as height and intelligence are also influenced by environment., and possibly also by genes that are not additive in that they exert a dominant effect.
Degrees of relationship
-------------------------------------------------------------------- ----
Grandparents, grandchildren, half-siblings
Polygenic inheritance
It is possible to show that phenotype with a normal distribution in the general population can be generated by polygenic inheritance involving the action of many genes at different loci, each of which exerts an equal additive effect.
This can be illustrated by considering a trait such as height.
If height were to be determined by two equally frequent alleles, a (tall) and b (short), at a single locus, this would result in a discontinuous phenotype with three groups in a ratio of 1 (tall-aa) : 2 (average-ab/ab) : 1 (short-bb).
If the same trait were to be determined by two alleles at each of two loci interacting in a simple additive way, this would lead to a phenotypic distribution of five groups in a ratio of 1 (4 tall genes) : 4 (3 tall +1 short) : 6 (2 tall + 2 short) : 4 (1 tall+3 short) : 1 (4 short).
Multifactorial inheritance was first studied by Galton in the late 1900s.
Polygenic inheritance
In reality , human characteristics such as height and intelligence are also influenced by environment, and possibly also by genes that are not additive in that they exert a dominant effect.
These factors probably account for the observed tendency of These factors probably account for the observed tendency of offspring to show what is known as a “regression to the mean”.
This is demonstrated by tall or intelligent parents (the two are not mutually exclusive!) having children whose average height or intelligence is slightly lower than average or mid- parental value.
Similarly, parents who are very short or of low intelligence tend to have children whose average height or intelligence is lower than the general population average, but higher than the average value of the parents.
A representation of Galton's studies on the inheritance of height. If the son's
height were determined only by the father's height, the correlation should be
that of the solid line. The dashed line is what is observed. Galton called this
“regression to mediocrity”.
In cleft lip/palate the proportion of affected first-degree relatives (parents, siblings and
offspring) is 6% if the index patient has bilateral cleft lip and palate, but only 2% if the index
patient has an unilateral cleft lip.
In spina bifida, if one sibling is affected the risk to the next sibling (if folic acid is
not taken by the mother periconceptionally) is approximately 4% risk; if two
siblings are affected, the risk to a subsequent sibling is approximately 10%.
HERITABILITY
It is possible to estimate what proportion of the etiology can be ascribed to genetic factors as opposed to environmental factors.
This is referred to as heritability, which can be defined as the proportion of the total phenotypic variance of a condition which is caused by additive genetic variance.
Estimates of the heritability of a condition or trait provide an indication of the relative importance of genetic factors in its Estimates of the heritability of a condition or trait provide an indication of the relative importance of genetic factors in its causation, so that the greater the value for the heritability the greater the role of genetic factors.
Heritability is often depicted using the symbol h² and is expressed either as a proportion of 1 or as a percentage.
Alternatively, heritability can be calculated using data on the concordance rates in monozygotic and dizygotic twins.
The greater the value for the heritability, the greater the role of genetic factors.
Estimates of heritability for some common diseases
Disorder Frequency (%) Heritability
Cleft lip/palate 0.1 76
Club foot 0.1 68
Hypertension (essential) 5 62
Peptic ulcer 4 37
IDENTIFYING GENES THAT CAUSE
MULTIFACTORIAL DISORDERS
Multifactorial disorders are common and make a major contribution to human morbidity and mortality.
A number of strategies have been used to search for disease susceptibility genes.
Mapping multifactorial disorders is much more difficult than mapping single gene disorders for the following reasons:single gene disorders for the following reasons:
- it is extremely difficult mathematically to develop strategies for
detecting linkage of additive “polygenes’, each of which makes only a small contribution to the phenotype.
- many multifactorial diseases show a variable age of onset
- most families in which a multifactorial disease is, have only one or two
living affected members
involved in different subtypes.
Strategy to find disease susceptibility genes for 2 diabetes mellitus (T2DM).
Candidate genes may be selected from human models, knowledge of biology, positional cloning or
animal models. The candidate gene is screened to find variants, which are then tested for association
with T2DM by genotyping cohorts of subjects with T2DM and controls.
DISEASE MODELS FOR MULTIFACTORIAL
There are two main forms of diabetes mellitus:
Type 1 (IDDM) is the rarer juvenile onset insulin-dependent form which affect 0.4% of the population and shows a high which affect 0.4% of the population and shows a high incidence of potentially serious renal, retinal and vascular complications.
Type 2 is the more common, later-onset non-insulin-dependent form that affects up to 10% of the population.
Both type 1 and 2 show complex patterns of familial clustering which
led to diabetes being labeled as the “geneticist’s nightmare”.
TYPE 1 DIABETES MELLITUS
In type 1 diabetes, there is greater evidence for familial clustering. The concordance rates in monozygotic and dizygotic twins are around 50% and 12% respectively. These observations point to a multifactorial etiology with both environmental and genetic contributions. Known environmental factors include diet, viral exposure in early childhood and certain drugs. The disease process involves childhood and certain drugs. The disease process involves irreversible destruction of insulin-producing islet β-cells in the pancreas by the body’s own immune system, probably as a result of an interaction between infection and an abnormal genetically programmed immune response.
The first major breakthrough came with the recognition of strong associations with the HLA region. The next locus to be identified was the insulin gene on chromosome 11p15 where it was shown that variation in the number of tandem repeats of a 14bp sequence upstream to the gene influences disease susceptibility.
TYPE 1 DIABETES MELLITUS
The current understanding is that T1DM is indeed a multifactorial disorder with an underlying oligogenic or polygenic susceptibility consisting of one major locus and up to 20 minor loci.
The products of these loci are believed to interact in a complex and poorly understood way to confer susceptibility to environmental triggers of autoimmune pancreatic β-cell destruction.
This phenomenon of gene interaction is referred to as epistasis.
TYPE 2 DIABETES MELLITUS
The prevalence of T2DM is increasing and is predicted to reach 215 million affected worldwide by 2010. patients with T2DM are also prone to diabetic complications with corresponding excess morbidity and mortality.corresponding excess morbidity and mortality.
The later age of onset has made family studies difficult.
Large-scale association studies were performed and confirmed by meta-analysis of all published smaller studies.
The contribution of loci varies between populations, with some variants being population specific.
CONCLUSION
The term multifactorial has been coined to describe the pattern of inheritance displayed by a large number of common disorders that show familial clustering and which are probably caused by the interaction of genetic with environmental factors.
The genetic mechanisms underlying these disorders are not The genetic mechanisms underlying these disorders are not well understood.
Progress has been slow, and probably awaits the development of more sophisticated methods.
The future strategies are envisaged:
- haplotype mapping
- sequence-based mapping
Many disorders demonstrate familial clustering that does not conform to any recognized pattern of Mendelian inheritance. Examples include several of the most common congenital malformations and many of the common acquired diseases of childhood and adult life.
It is likely that many factors – genetic and environmental – It is likely that many factors – genetic and environmental – are involved in causing these disorders they are showing multifactorial inheritance.
Concept of normal distribution generated by many genes, known as polygenes, each acting in an additive fashion, is plausible for physiological characteristics such as height and blood pressure.
However, for disease such as insulin-dependent diabetes mellitus research has shown that the genetic contribution is not straightforward and involves many loci, some of which play a much more important role than others.
Polygenic and multifactorial inheritance
Sequencing of the human genome has shown that the 3 billion bps are 99.9% identical in every person. This is also means that individuals are, on average, 0.1% different genetically from every other person on the different genetically from every other person on the planet.
Within this 0.1% lies the mystery of why some people are more susceptible to a particular illness, or more likely to be healthy, than other members of the population.
Disorders which show multifactorial inheritance
Congenital malformations
Cleft lip/palate
Congenital dislocation of the hip
Acquired diseases of childhood and adult life Acquired diseases of childhood and adult life
Asthma
What is known as polygenic or quantitative inheritance?
This involves the inheritance and expression of a phenotype being determined by many genes at different loci and each gene exerting a small additive effect.gene exerting a small additive effect.
Effects of the genes are cumulative , no one gene is dominant or recessive to another.
Several human characteristics show a continuous distribution in the population that closely resembles a normal distribution.
Approximately 68%, 95% and 99.7% of observations fall within the mean plus or minus one, two or three standard deviations respectively.
Human characteristics that show a continuous
normal distribution
Blood pressure
Head circumference
Height, Intelligence
Skin color
First-degree relatives share on average 50% of their genes. If a parameter such as height is polygenic, then genes. If a parameter such as height is polygenic, then the correlation between first-degree relatives such as siblings should be 0.5. Several studies have shown it.
Correlation is a statistical measure of the degree of association of variable phenomena.
In reality, characteristics such as height and intelligence are also influenced by environment., and possibly also by genes that are not additive in that they exert a dominant effect.
Degrees of relationship
-------------------------------------------------------------------- ----
Grandparents, grandchildren, half-siblings
Polygenic inheritance
It is possible to show that phenotype with a normal distribution in the general population can be generated by polygenic inheritance involving the action of many genes at different loci, each of which exerts an equal additive effect.
This can be illustrated by considering a trait such as height.
If height were to be determined by two equally frequent alleles, a (tall) and b (short), at a single locus, this would result in a discontinuous phenotype with three groups in a ratio of 1 (tall-aa) : 2 (average-ab/ab) : 1 (short-bb).
If the same trait were to be determined by two alleles at each of two loci interacting in a simple additive way, this would lead to a phenotypic distribution of five groups in a ratio of 1 (4 tall genes) : 4 (3 tall +1 short) : 6 (2 tall + 2 short) : 4 (1 tall+3 short) : 1 (4 short).
Multifactorial inheritance was first studied by Galton in the late 1900s.
Polygenic inheritance
In reality , human characteristics such as height and intelligence are also influenced by environment, and possibly also by genes that are not additive in that they exert a dominant effect.
These factors probably account for the observed tendency of These factors probably account for the observed tendency of offspring to show what is known as a “regression to the mean”.
This is demonstrated by tall or intelligent parents (the two are not mutually exclusive!) having children whose average height or intelligence is slightly lower than average or mid- parental value.
Similarly, parents who are very short or of low intelligence tend to have children whose average height or intelligence is lower than the general population average, but higher than the average value of the parents.
A representation of Galton's studies on the inheritance of height. If the son's
height were determined only by the father's height, the correlation should be
that of the solid line. The dashed line is what is observed. Galton called this
“regression to mediocrity”.
In cleft lip/palate the proportion of affected first-degree relatives (parents, siblings and
offspring) is 6% if the index patient has bilateral cleft lip and palate, but only 2% if the index
patient has an unilateral cleft lip.
In spina bifida, if one sibling is affected the risk to the next sibling (if folic acid is
not taken by the mother periconceptionally) is approximately 4% risk; if two
siblings are affected, the risk to a subsequent sibling is approximately 10%.
HERITABILITY
It is possible to estimate what proportion of the etiology can be ascribed to genetic factors as opposed to environmental factors.
This is referred to as heritability, which can be defined as the proportion of the total phenotypic variance of a condition which is caused by additive genetic variance.
Estimates of the heritability of a condition or trait provide an indication of the relative importance of genetic factors in its Estimates of the heritability of a condition or trait provide an indication of the relative importance of genetic factors in its causation, so that the greater the value for the heritability the greater the role of genetic factors.
Heritability is often depicted using the symbol h² and is expressed either as a proportion of 1 or as a percentage.
Alternatively, heritability can be calculated using data on the concordance rates in monozygotic and dizygotic twins.
The greater the value for the heritability, the greater the role of genetic factors.
Estimates of heritability for some common diseases
Disorder Frequency (%) Heritability
Cleft lip/palate 0.1 76
Club foot 0.1 68
Hypertension (essential) 5 62
Peptic ulcer 4 37
IDENTIFYING GENES THAT CAUSE
MULTIFACTORIAL DISORDERS
Multifactorial disorders are common and make a major contribution to human morbidity and mortality.
A number of strategies have been used to search for disease susceptibility genes.
Mapping multifactorial disorders is much more difficult than mapping single gene disorders for the following reasons:single gene disorders for the following reasons:
- it is extremely difficult mathematically to develop strategies for
detecting linkage of additive “polygenes’, each of which makes only a small contribution to the phenotype.
- many multifactorial diseases show a variable age of onset
- most families in which a multifactorial disease is, have only one or two
living affected members
involved in different subtypes.
Strategy to find disease susceptibility genes for 2 diabetes mellitus (T2DM).
Candidate genes may be selected from human models, knowledge of biology, positional cloning or
animal models. The candidate gene is screened to find variants, which are then tested for association
with T2DM by genotyping cohorts of subjects with T2DM and controls.
DISEASE MODELS FOR MULTIFACTORIAL
There are two main forms of diabetes mellitus:
Type 1 (IDDM) is the rarer juvenile onset insulin-dependent form which affect 0.4% of the population and shows a high which affect 0.4% of the population and shows a high incidence of potentially serious renal, retinal and vascular complications.
Type 2 is the more common, later-onset non-insulin-dependent form that affects up to 10% of the population.
Both type 1 and 2 show complex patterns of familial clustering which
led to diabetes being labeled as the “geneticist’s nightmare”.
TYPE 1 DIABETES MELLITUS
In type 1 diabetes, there is greater evidence for familial clustering. The concordance rates in monozygotic and dizygotic twins are around 50% and 12% respectively. These observations point to a multifactorial etiology with both environmental and genetic contributions. Known environmental factors include diet, viral exposure in early childhood and certain drugs. The disease process involves childhood and certain drugs. The disease process involves irreversible destruction of insulin-producing islet β-cells in the pancreas by the body’s own immune system, probably as a result of an interaction between infection and an abnormal genetically programmed immune response.
The first major breakthrough came with the recognition of strong associations with the HLA region. The next locus to be identified was the insulin gene on chromosome 11p15 where it was shown that variation in the number of tandem repeats of a 14bp sequence upstream to the gene influences disease susceptibility.
TYPE 1 DIABETES MELLITUS
The current understanding is that T1DM is indeed a multifactorial disorder with an underlying oligogenic or polygenic susceptibility consisting of one major locus and up to 20 minor loci.
The products of these loci are believed to interact in a complex and poorly understood way to confer susceptibility to environmental triggers of autoimmune pancreatic β-cell destruction.
This phenomenon of gene interaction is referred to as epistasis.
TYPE 2 DIABETES MELLITUS
The prevalence of T2DM is increasing and is predicted to reach 215 million affected worldwide by 2010. patients with T2DM are also prone to diabetic complications with corresponding excess morbidity and mortality.corresponding excess morbidity and mortality.
The later age of onset has made family studies difficult.
Large-scale association studies were performed and confirmed by meta-analysis of all published smaller studies.
The contribution of loci varies between populations, with some variants being population specific.
CONCLUSION
The term multifactorial has been coined to describe the pattern of inheritance displayed by a large number of common disorders that show familial clustering and which are probably caused by the interaction of genetic with environmental factors.
The genetic mechanisms underlying these disorders are not The genetic mechanisms underlying these disorders are not well understood.
Progress has been slow, and probably awaits the development of more sophisticated methods.
The future strategies are envisaged:
- haplotype mapping
- sequence-based mapping
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