Health Care
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Introduction
Chromosomes, found in the cell's nucleus, contain 30-35,000 genes that provide the information to make proteins. They are made out of DNA.
It is important to understand mitosis and meiosis to make sense of chromosomes and what can go wrong with them.
A good introduction to genetic biology has been written by the National Coalition for Health Professional Education in Genetics.
Genes are referred to as the fundamental units of heredity, and functionally are the reproducible template for RNA synthesis. Most of these RNAs are mRNAs that code proteins.
The synthesis of RNA from DNA is called transcription, while the synthesis of proteins from mRNA is called translation.
Genes, originally identified as the 'fundamental unit of heredity', represent the stretch of DNA needed to produce a functional product, which is in most cases a protein.
The specific location of a gene on a chromosome is called its 'locus'. Most genes, with the exception of those located on the X and Y chromosomes, are present twice, on two 'alleles'.
The 'genotype' of a person is their total genetic composition, and alo refers to the specific allele found at a given locus. The phenotype, on the other hand, is the observed expression of the gene, as determined both by the genetic sequence and the effect of the environment on biochemical, physiological, and morphological processes.
A person is called 'homozygous' if the alleles are identical, and heterozygous if they are different.
A 'dominant' trait is phenoytpically expressed in heterozygotes and homozygotes, while a 'recessive' trait is only seen in homozygotes. Patterns of phenotypic expression are determined by a gene's dominant or recessive chracteristics.
Allele inheritance is affected by Medelian laws
Genome
The human genome has approximately 3 billion base pairs and between 20-30 thousand genes. This is compared with 4.6 million bp for E. coli, 160 million bp for fruit flies, and approximately 3 billion bp for mice.
Genomics allows for pwerful diagnostic and tailored therapeutic opportunities in medicine.
DNA microarray analysis allows for widespread screening of genes.
Analysis of single nucleotide polymorphisms (SNPs) allows for prediction of disease susceptibility, drug response, and drug metabolism.
Perhaps 1500-2000 genes are now known to contribute to disease.
Mitochondrial Genome
- tRNA, rRNA, 13 proteins
- all mitochondrial DNA is inherited by the mother
Genetic Isolates
- populations where one population is isolated from neighbours by geographic, religious, cultural, or linguistic barriers
- founder effect and genetic drift increases the frequency of certain alleles over time
Principles of Inheritance
DNA is inherited and shared, therefore, with members of one's family.
| relationship | % DNA shared |
| MZ twins | 100 |
| DZ twins | 50 |
| 1st degree relative | 50 |
| 2nd degree relative (uncle, grandfather) | 25 |
| 3rd degree relative (ie cousins) | 12.5 |
Pedigree
ask a lot of questions to produce a graphic representation of family history.
standard symbols
first degree relatives: parents, siblings, offpring
second degree relative: grandparents, grandchildren, aunts and uncles
third degree relative: first cousins
fourth degree relative: first cousins once removed
Mendelian Genetics
Mendel's Principles
- genes are inherited as discrete characters
- acquired characteristics are not inherited
- the two alleles separate and segregate to different gametes
- loci in the haploid set of genes assort independenly unless they are tightly linked to one another
Hardy-Weinburg Equation
p2 + 2pq + q2 = 1
p + q = 1
Patterns of Inheritance
- Principles of inheritance goes through the basics of Mendelian genetics and other introductory information.
- Inherited patterns of phenotype, such as autosomal dominant or recessive, are important.
- Multifactorial inheritance describes outcomes affected by more than one gene.
- Population genetics discusses specific genetic patterns and mutations affecting cultural groups.
- Pedigrees, or family trees, provide graphic representation of patterns of inheritance and predict risks of carrying certain alleles.
- Linkage analysis provides a measure of how alleles segregate with markers.
Modifying Factors
Pleiotropy
a single mutant allele cna have widespread effects in different tissues of the body
Variable Expressivity
- how and to what degree individuals show manifestations; variability can be tremendous, especially in autosomal dominant conditions
- can be intrafamilial or interfamilial
Penetrance
- proportion of indivuduals with a genotype that express the phenotype
- if it is anything below 100%, it is 'incomplete'
- accounts for 'skipped' generations
Genetic Heterogeniety
- The same or similar phenotype can be produced by different phenotypes
- locus heterogeniety: a phenotype can be caused by mutations in more than one locus
- allelic heterogeniety: a phenotype can be caused by different mutations in the same locus
Sex Influence
X Inactivation and other Epigenetic Effects
Non-Paternity
Gonadal Mosaicism
Patterns of Inheritance
DOminant: bicycle analogy: need both wheels
recessive: two-slot toaster
- autosomal
dominant - autosomal
recessive - X-linked
recessive - X-linked
dominant
Autosomal Dominant
- successive generations of vertical transmission
- any affected person has an affected parent, unless it is a new mutation
- affected people are usually homozygous
- every child of an affected person has a 50% chance of inheriting the abnormal gene
- unaffected individuals do not transmit
- two sexes are affected at equal rates
- male-male transmission
examples of autosomal domiant conditions:
- NF1
- achondroplasia
- Huntington's Disease
- Marfan syndrome
- familial adenopolyposis
Autosomal Recessive
- in a pedigree, a single generation tends to be affected, ie siblings; horizontal pattern
- both parents are heterozygous
- each sibling has a 25% chance of being affected
- sexes affected in equal numbers
- consanguinity increases chances of autosomal recessive conditions
- chance of an unaffected sibling being a carrier of an autosomal recessive alelle: 2/3
examples of autosomal recessive conditions:
- PKU
- cyctic fibrosis
- albinism
- sickle cell
- thalassemia
- tay sachs disease
X-Linked Recessive
- no male to male transmission
- generally, only males affected (hemizygote)
- all daughters of affected males are carriers
- all the affected males are related to each other through females - diagonal pedigree
- one half of sons of carrier females affected
- can occur in females due to:
- non-random X-inactivation
- XO karyotpye
- X chromosome deletion
- homozygote
examples X-linked recessive conditions:
- Duchenne muscular dystrophy
- Fabry disease
- Hemophelia A
- red green color blindness
X-Linked Dominant
- females more affected than males but typically have a milder phenotype
- affected males with normal mates have no affected males and no unaffected females
- affected females have half of offspring affected
- vertical transmission, with successive generations affected
Multifactorial Inheritance
- monogenic vs polygenic inheritance
- threshold traits
- quantitative traits
- role of the environment
- genes versus the environment
- recurrence risks
- genetic mapping of complex traits
- multifactorial diseases
Multifactorial inheritance describes a trait whose manifestations are determined by two or more genes, accompanied by environmental factors. This is different from genetic heterogeneity, which is the capacity of various genes to cause the same trait independently. With genetic heterogeniety, if you know the information you can predict the trait. This isn't possible with multifactorial inheritance.
Monogenic vs Polygenic Inheritance
With monogenic traits, there is generally a limited number of outcomes which are usually discrete.
Mendelian traits are the exception, rather than the rule.
With multiple independent loci, each gene tends to cause a small variation that sum to creat a net effect.
Alternatively, mutiple modifier genes can act on a limited number of primary loci.
With increasing numbers of loci, the possible number of different outcomes increases exponentially. This creates a continuous distribution for the trait.
Theshold Traits
Threshold traits, in contrast to quantitiative traits, are either present or absent.
The liability of inheriting the trait is distributed normally in the population, and is both intrinsic (genetic factors) and extrinsic (the environment). Individuals thereofre only extress the trait once the sum of these liabilities crosses the threshold.
As family members share genes, they also share intrisic liability and therefore the risk of recurrence.
Quantitative Traits
A continuously variable trait that can be measured numerically and usually follows a normal distribution. Genes that contribute to quantitiative traits are termed quantitative trait loci (QTLs).
The existence of a range of values has led to (often arbitrary) cut-offs used to define normal from abnormal. There need not be a pathological basis for the differentiation, which is frequently set at 2 SDs away from the population mean.
If an individal shows a markedly increased or decreased value, it can be assumed genetic libaility is increased, assuming the environment is not extreme.
Role of the Environment
Environmental influences have a profound effect on genetic conditions, and this is especially true for complex polygenic traits. The environment can be mislead people to believe that a disease has a genetic contribution.
The measure of the genetic contribution in multifactorial inheritance is called heritability, in comparison to environmental liability.
As twins should theoretically have very similar environments, concordance rates for monozygotic vs dizygotic twins should reflext the heritability.
Heritability (h2) = (variation in DZ pairs - variation in MZ pairs ) / variation in DZ pairs
Recurrence Risks
As so many factors are required for a trait to occur, recurrence risk for a polygenic condition is much lower than would be expected in a single gene disorder.
At a given locus, 25% of siblings share 2 alleles, 50% share 1, and 25% share none.
Recurrence rates in first degree relatives is generally equal to the square root of the condition's frequency in a population
Emperic Risks are used for common conditions
Modifiers of Recurrence Risk
- Recurrence risk is correlated with severity of the condition, as it is a manifestation of increased genetic liability
- another reflection of high genetic liability is when the multifactorial condition occurs in an individual at lower risk for the condition
- ie, for conditions where incidence differs according to the sex of the individual, when the opposite sex acquires the condition, this really increases the recurrence risk
Genetic Mapping of Complex Traits
Association
The association method assumes that the frequency of a given allele is increased in frequency in affected vs unaffected individuals. This means that individuals, not families, are needed, facilitating study recruitment. Odds ratios are drawn up to predict the likelihood of an association between an allele and a trait.
Results can imply linkage, causation, or coincidence, and it can be difficult to distinguish them.
Affected Pedigree
This type of linkage analysis depends on whole genome scans using polymorphic markers to calculate proportions of alleles shared at given loci. An allele in concordant sibling pairs that occur more often than is normally predicted (ie 50%) implies it plays a role in modifying the trait.
However, a given locus is frequently not generalizable to the general population, as each locus usually has only a small effect in the context of a large number of contributing genes.
Multifactorial Diseases
Diseases with multifactorial inheritance are very common, including 9 of the 10 leading causes of mortality.
Threats to Genetic Integrity
Due to the immense complexity of DNA, both structurally and functionally, problems can occur. This can be during meiosis, mitosis, or involve random mutations.
Chromosome abnormalities affect large areas of genetic code.
Sun-chromosomal abnormalities
Genetic Disorders
Genetic disorders are diseases and conditions that result, in whole or in part, due to mutations or other changes in the DNA of a cell. They can be inherited from parents or result from new mutations.
Genetic disorders account for almost 50% of first trimester spontaneous abortions, 5% of all newborn births, and 40% of infant mortality.
Perhaps 10-12% of the population have enzyme deficiencies that make them hypersensitive to certain drugs.
Types of genetic disorders:
Chromosomal disorders are present in about 1:250 livebirths.
Single gene disorders, of which over 5000 have been identified, sre present in about 2% of livebirths.
Multifactorial, or polygenic, disorders, are present in about 2.5% of liveborn infants.
Environmental disorders can be caused by teratogens, carcinogens, or mutagens.
People often think that if you're born with it, you're stuck with it. Now, that's not so true anymore. Can have enzyme replacement therapy and other technologies.
Resources and References
GeneTests - gene reviews
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