Somatic Cells
Cells that are not gametes. Contain 2 copies of each chromosome (1-22) and either XX or XY
Autosome
Any chromosome not considered a sex chromosome (1-22)
Allosome (Gonosome)
Sex chromosomes (X and Y)
Gametes
Ova and sperm cells. Contain 1 copy of each chromosome (1-22) and either X or Y.
Haploid
Having one copy of each chromosome.
Diploid
Having 2 copies of each chromosome.
Homologous Chromosomes
The two chromosomes in a diploid pair. Contain the same genes but one is paternal origin and one is of maternal origin.
Gene
A sequence of DNA that encodes a specific protein or RNA
Allele
One of several alternative forms of a gene sequence at a locus.
Polymorphism
When a locus has multiples alleles present in a population. A genetic variant with at least two alleles and occurs in at least 1% of the population.
Locus
A specific chromosomal location.
Wild-Type
Allele present in the majority of individuals. Not deleterious.
Mutant
Allele that differs from the wild-type due to mutation.
Genotype
Set of alleles an individual possesses.
Phenotype
Expression of the alleles. Protein present in clinical manifestation.
Homozygous
Two alleles at a particular locus are identical.
Heterozygous
Two alleles at a particular locus are different.
Hemizygous
X-linked genes in males.
Pleiotropism
A single mutant gene may result in many phenotypic variants.
Oculodentodigital Dysplasia
Example of Pleiotropism. A connexion mutation. Clinical Features: Thin nose, microcephaly, microphthalmia, microcornea, microdontia, partial adontia, hand and foot abnormalities.
Mendelian Inheritance
Single Gene (20%). Two categories of single-gene inheritance; autosomal and gonosomal.
Complex Inheritance/Multigenic
Unsure of specific mode. Complex. 50%
Environmental teratogen
Environmental factor. 5%
Chromosomal Imbalance
25%
Dominant
Allele that is always expressed, even if another allele is present.
Incompletely dominant
Expression of two different alleles results in an intermediate phenotype. For example: A red rose is crossed with a white rose. Offspring are pink roses.
Codominant
Each allele results in an observable phenotype. For example: Blood type.
Recessive
Requires the presence of two identical alleles to express an observable phenotype.
Loss-of-function
Reduced production of a gene product or inactive protein. Most common.
Gain-of-function
Gene product gains new function. Most often toxic properties. Sometimes increased activity (for example receptor activation). Note: Not necessarily a good gain.
Recurrence Risk
The probability that the offspring of a couple will express a genetic disease.
Autosomal Dominant Disorders
- Disorder is manifested in the heterozygous state
- Both males and females affected
- Most often affects enzymes, receptors, feedback inhibitors, and structural protein
Dominant Negative Allele
Mutant allele negatively affects a normal allele. Multimeric proteins
Autosomal Dominant Pedigree
- Disease typically observed over multiple generations.
- Skipped generations unlikely to be seen.
- Males and Females equally affected.
Haploinsufficiency
Normal physiology requires more than half of the fully functioning gene product. Can be sporadic, resulting from a new mutation.
Penetrance
The frequency (%) in which the allele expresses itself phenotypically.
Incomplete Penetrance
An individual inherits the allele but is phenotypically normal.
Variably Expressed
All individuals express the phenotype but to different degrees.
Autosomal Recessive Disorder
- Parents of affected usually unaffected.
- Usually completely penetrant.
- Onset is usually early in life.
- Usually not a new mutuation.
Margin of Safety
Heterozygous individuals with half the normal content function normally.
Autosomal Recessive Pedigree
- Typically only seen in one generation
2. Males and Females equally affected.
Consanguinity
The mating of related individuals Individuals who share common ancestors are more likely to carry the same recessive allele.
X-Linked disorders
Those affecting gonosomes. Most Y-linked disorders cause infertility so this is generally not considered a pattern of inheritance.
X-linked recessive disorders
Almost all X-linked disorders are recessive. All affected males will be hemizygosity. Heterozygous females usually don’t express the full phenotypic change.
X-Linked dominant disorders
Few Exist.
X-linked recessive pedigree
Males are more commonly affected. Skipped generations are common. Male to male transmission not seen.
X-linked dominant pedigree
Male to male transmission not seen. Heterozygous females are affected so expressed twice as often in females. Skipped generations unusual. No sons but all daughters of an affected male will express the disease.
X-Inactivation/Dosage Compensation (General Overview)
- Inactivates copy of the X chromosome in all somatic cells of females.
- Begins during blastocyte formation
- Condensed into heterochromatin
- Gene regions methylated.
- Barr Body
Barr Body
Highly condensed chromosome visible in the nuclei of interphase cells.
X-Inactivation/Dosage Compensation (Rules)
- Random: 50% chance in each cell that either the maternal or paternal X chromosome is inactivated. Genetic Mosaicism.
- Fixed: Once inactivated, every descendent of the cell will have the same X chromosome inactivated.
- Incomplete: Some regions not inactivated. Manifesting heterozygotes.
Genetic Mosaicism
Condition in which cells with different genotypes or chromosome constitutions are present in the same individual.
Manifesting heterozygotes
Some females will express an X-linked recessive mutation due to X-inactivation.
Myotonic Dystrophy
Autosomal dominant condition with variable expression in clinical severity and age at onset. Manifests as bilateral cataracts, moderate facial weakness and ptosis, myotonia.
SHH Mutation (Sonic Hedgehog)
Variable expressivity.Caused by a missense mutation. For example: Mother has a single central upper incisor. Daughter is severely affected with microcephaly, abnormal brain development, hyp-telorism, and cleft palate.
Expressivity
The severity of expression of the phenotype among individuals with the genotype.
Allelic Heterogeneity
Different mutations can be responsible for more or less severe expression. Usually not within a family.
Pleiotropy
A single disease causing mutation affects multiple organ systems.
Locus Heterogeneity
A single disorder is caused by mutations at different chromosomal loci.
Point Mutations
Replace one nucleotide with another.
Missense mutation
Alters the meaning of the sequence such that it encodes a different amino acid. May or may not affect the overall protein structure.
Nonsense Mutation
Alters the meaning of the sequence to a STOP codon. Protein is truncated. (Stop this nonsense!)
Frameshift Mutations
Insertion or Deletion into a sequence. If not a multiple of three, entire message is changed in the sequence following it. If a multiple of three, subsequent protein will lose or gain an AA.
Trinucleotide Repeat Mutations
Amplification of a sequence usually containing Cs and Gs. Dynamic or continually changing during cell division.