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Karyotype color chromosomes white background

Image: “Karyotype color chromosomes white background.” License: Public Domain


Definitions

A phenotype is an individual feature or characteristic that can be weighed, recorded, or noticed, such as hair or eye color.

A genotype is a part of the feature, or phenotype, that is found in the progeny. It is formed by alleles or genes on different loci. It is impossible to record/measure or notice a genotype.

Polygenic inheritance is a mode of inheriting phenotypic traits, occurring when several gene pairs on different loci have an additive effect, leading to an individual’s particular trait or characteristic, such as fingertip ridges.

Multifactorial inheritance is another mode of inheritance. It is polygenic, but it also occurs due to the influence of other genes and the individual’s ante and post-natal environments, such as height and skin color.

Types of Phenotype Traits

Quantitative-traits

“Continuous Quantitative traits are measurable” Image created by Lecturio

Quantitative traits occur as a result of continuous variation, which is the sum total of small effects caused by a gene. Usually, several genes, or a group of genes, control quantitative traits. A polygenic trait refers to multiple genes’ influencing a trait, such as height, human intelligence, and skin color. Height,  considered the best example of a quantitative trait, occurs in a range of values.

Qualitative traits are “yes or no traits” and can be classified into categories, which may not be in any particular order. This type of trait has a monogenetic inheritance pattern. The trait is only influenced by a single gene, and the environment does not affect the development of this trait.

Qualitative-Traits

“Discrete Qualitative traits are either present or absent” Image created by Lecturio

Inherited disorders are caused by a single gene mutation, such as ABO blood groups. With a few rare exceptions, most humans have one of the following four categories of blood types: A, B, AB, or O. Since the ABO blood group can be classified neatly into any of the four categories, it is considered a good example of a qualitative trait.

Threshold traits are inherited quantitatively but are expressed qualitatively. As several genes form a threshold trait, it is considered a quantitative trait in practice. Threshold traits occur in families, but their exact segregation ratio cannot be predicted, unlike inherited diseases, according to the Mendelian pattern.

Qualitative Traits: Risk Assessment

The risk of qualitative traits can be assessed using familial aggregation studies, such as relative risk ratios and case-control studies.

Relative risk ratios

Λr = presence of a disease in relatives/presence of a disease in the population.

If an allele increases the chance of developing a disease, then one would expect the affected individual to have a greater-than-expected number of affected relatives.

r) = 1 means there is little or no genetic impact.

r) > 1 means there is a possible genetic predisposition.

Disease Relationship Λs
Schizophrenia Siblings 12
Autism Siblings 150
Bipolar disorder Siblings 7
NIDDM (type I DM) Siblings 35
Crohn’s disease Siblings 25
Multiple sclerosis Siblings 24

Case-control studies are another risk calculation method. The genetic contribution is evaluated by comparing an affected individual to an unrelated control, such as a spouse who has shared the same environment.

Approximately 3.5% of the first degree relatives of patients with multiple sclerosis (MS) is also reported to suffer from the disease, indicating a genetic component. This can be compared to an incidence of only 0.2% of first degree relatives of matched controls (married couples) who suffer from MS.

Considering the incidence of 3.5% and 0.2%, we can calculate that the incidence of MS would be 18 times greater among siblings than unrelated individuals.

Quantitative Traits: Risk Assessment

The risk for quantitative traits can be assessed using correlation and heritability studies.

Correlation studies: The coefficient of correlation (r) is a measure of similarities among relatives. A positive correlation is represented by an upward slope, while the negative correlation is represented by a straight line or downward slope.

Heritability studies (H2): Measures the extent of variation in a phenotypic trait attributable to a genetic variation (not environmental) among individuals of a population.

H2 = 1 (heritability equals one,  meaning all variations are attributable to genetics)

H2 = 0 (none of the heritability is attributable to genetics)

Twin studies

Twin-Studies

“Identical. Monozygotic twins share 100% of their genetic information (theoretically)” Image created by Lecturio

Theoretically, identical or monozygotic twins share almost 100% of their genetic information. Epigenetic studies provide more detailed information.

Fraternal or dizygotic twins share approximately 50% of their genetic information, depending on whether they inherited maternal or paternal traits.

Concordance values: If one twin has a trait, then the concordance value estimates the frequency of the other twin having it, too. Greater concordance in monozygotic twins versus dizygotic twins provides evidence that there is a genetic component to the disease. From the concordance values in the following list, one can discern that there is a likelihood of a genetic component in these conditions:

Disorder Monozygotic twins Dizygotic twins
Multiple sclerosis 18 2
Schizophrenia 46 15
Bipolar disorder 62 8
Rheumatoid arthritis 12 3
Cleft lip w/wo cleft palate 30 2
Systemic lupus erythematosus 22 0

Multifactorial Gene Disorders

Multifactorial gene disorders include genetic and environmental factors, which lead to small variations in the inherited genes. There is a different “threshold” of expression so that one gender is more adversely affected than the other. For example, congenital hip dysplasia is more common among females than males.

The probability of a multifactorial trait occurring in a family depends upon how close the relationship is between the family member with the trait and the rest of the family. For example, the incidence is higher if a sibling has the trait, as opposed to a first cousin since family members share a specific percentage of the genes based on the relationship.

Relationship degree Percentage of common genes Examples
1st degree relative 50% Parents, children, siblings
2nd degree relative 25% Aunts, uncles, nieces, nephews & grandchildren
3rd degree relative 12.5% First cousins

Examples of Multifactorial Gene Disorders

Multifactorial disorders without a clear genetic component

Multifactorial disorders without a clear genetic component are, for example, congenital heart disorders (ventricular septal defect, patent ductus arteriosus, atrial septal defect, and aortic stenosis), neuropsychiatric disorders, and coronary artery disease. Although the exact genes responsible for the disorders remain unknown, genome studies are likely to reveal them in the near future.

Congenital heart disorders:

Defect Incidence in the population Frequency in

siblings in %

Λr
Ventricular septal defect 0.17 4.3 25
Patent ductus arteriosus 0.083 3.2 38
Atrial septal defect 0.060 3.2 48
Aortic stenosis 0.044 2.6 59

Table: Congenital heart disorders

The high relative risk ratio (lambda value) in the above table indicates a probable genetic component.

Schizophrenia: This is a neuropsychiatric disorder, affecting approximately 1% of the population, with a concordance value of 40 – 60% in monozygotic twins and 10 – 16% in dizygotic twins. The prevalence suggests there is a strong genetic component to the disorder.

Bipolar disorder: This disorder affects approximately 0.8% of the population. Twin and family aggregation studies indicate a strong genetic component.

Coronary artery disease (CAD): Concordance rates in monozygotic twin studies indicate a strong genetic component in CAD, although non-genetic and environmental components (diet, physical activities, and smoking) can influence the development of this condition, too.

Neural tube defects (NTD): The incidence of NTDs, such as spina bifida and anencephaly, are approximately 1 to 2 cases per 1,000 live births. Females are more likely to be affected than males. NTDs occur because of genes inherited from both parents combined with environmental factors, such as uncontrolled maternal diabetes, anti-epileptic medications prescribed to the mother, etc.

A couple who have a child with an NTD has a 3 – 5% probability of having another child with the same disorder, although the type of NTD may be different. For example, the first child may have anencephaly, while the second may have spina bifida.

Congenital hip dysplasia (CHD): As mentioned earlier, this is more common among females than males. Maternal hormones are the environmental factor contributing to CHD development. A couple who have a child with CHD have a 6% probability of having another child with CHD.

Multifactorial disorders with a likely genetic contribution

Venous thrombosis: There are three factors involved in developing idiopathic cerebral thrombosis – two genetic factors and one environmental factor (oral contraceptive pill). However, the genetic factors contributing to lower limb thrombosis remain known.

Other examples include factor V mutation, which increases the incidence of thrombosis, and a prothrombin mutation, which leads to accelerated clot formation. Environmental factors, like oral contraceptive pills and smoking, increase the individual risk of thrombosis and, when combined with the genetic factors, can lead to an exponential increase in the incidence of thrombosis.

Hirschsprung disease: This is a developmental abnormality associated with an absence of enteric ganglia, leading to symptoms of constipation and intestinal obstruction. Causes of this condition include RET gene mutation as well as mutations in the non-coding regulatory regions near the RET locus.

Type I diabetes: It is now known to be an autoimmune disorder, with complex inheritance, associated with Major Histocompatibility Complex (MHC) genes on chromosome 6. Twin studies have reported a 40% concordance rate among monozygotic twins.

Alzheimer’s disease: With increasing lifespans, the incidence of this condition is currently reported to be 1 – 2% of the elderly. There are several forms of Alzheimer’s disease. Three autosomal dominant forms result in the late onset of Alzheimer’s (>60 years of age). Twin studies indicate concordance values of 50% in monozygotic twins. Genetic studies have found that individuals with two copies of the E 4 allele for Apolipoprotein E have an early-onset form of Alzheimer’s disease.

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