- Generations are assigned Roman numerals
- individuals within each generation are indicated by Arabic numerals.
- The arrow points at the proband, the person in whom the genetic disorder was first diagnosed.
- Autosomal recessive inheritance
- condition is expressed only in persons who have two copies of (ie, are homozygous for) the mutant allele
- often observed with enzyme deficiencies (MCQ)
- What is margin of safety effect.
- heterozygotes express 50% of normal activity. (MCQ)
- However, 50% of normal enzyme activity in these cases permits normal
- physiologic function because expression of enzyme from the normal allele is sufficient to provide for the needs of the cell.
- Both parents of an affected person must have one normal and one mutant allele, making them obligate carriers barring very rare new mutations.
- The likelihood of a person being homozygous for an autosomal recessive trait increases in consanguineous matings because of the existence of a common ancestor. (MCQ)
- Rare autosomal recessive diseases also occur with high frequency among genetically isolated populations due to inbreeding. (MCQ)
- Pedigree charts show the following:
- The disease phenotype is expressed by siblings but not by their parents or offspring. (MCQ)
- Equal occurrence in males and females. (MCQ)
- Recurrence risk for each sibling is 25%.(MCQ)
- Possible consanguinity. (MCQ)
Recessive inheritance is shown in pedigrees A and B.
- Autosomal dominant inheritance
- this condition is expressed even if a single mutant allele is present, ie, in the heterozygous state
- Following are four possible situations by which having one normal copy of a gene is insufficient to prevent disease, leading to a dominant
- Situation 1 :
- When the presence of 50% normal activity (ordinarily the margin of safety) is not generous enough to allow normal physiologic function, a condition called haploinsufficiency. (MCQ)
- Situation 2 :
- When the defective allele produces a malfunctioning protein product that binds to and interferes with function of the normal gene product—the dominant negative effect.
- Situation 4 :
- When the mutant protein has an enhanced function that overrides normal controls or is cytotoxic
- Situation 5 :
- When the phenotype appears as dominant inheritance even though the actual allele is recessive at the level of function in individual cells.
- Situation 1 :
- The homozygous mutant state usually produces a more severe clinical condition than the heterozygous condition in autosomal dominant diseases.
- Pedigree charts for an autosomal dominant disorder
- The disease phenotype appears in all generations, with each affected person having an affected parent. (MCQ)
- There is an equal occurrence in males and females, except in cases when ex- pression of the trait is influenced by the person’s sex (ie, sex-limited). (MCQ)
- Risk of transmission of the mutant allele is 50%, but because there usually are so few persons in a family, there may be deviations from this expectation. (MCQ)
- Potential for some cases to be due to a new mutation, which is more likely for a dominant condition because disease symptoms would be expressed in heterozygotes. (MCQ)
Dominant inheritance is shown in pedigree, in which every affected person has an affected parent.
- An autosomal dominant disorder exhibiting anticipation
- In pedigree , the age of onset, indicated next to the symbols for affected individuals, becomes progressively earlier with each generation.
- X-linked recessive inheritance pattern
- there can be no male-to-male transmission because the sex of male offspring is determined by contribution of a Y chromosome from the father. (MCQ)
- Because they have only one X chromosome, the sons of heterozygous mothers have a 50% chance of being affected. (MCQ)
- Pedigree charts
- Incidence of disease is higher in males than in females. (MCQ)
- Female heterozygotes are usually unaffected carriers. (MCQ)
- Affected men transmit the gene to all daughters, but never to sons. (MCQ)
- New mutations cause a significant number of isolated cases in males due to unopposed expression of the mutant allele. (MCQ)
- X-linked dominant diseases are relatively rare
- Such genes may be transmitted either to sons or daughters by an affected mother but only to daughters by an affected father.
- disorders with X linked dominant inheritance
- Xg blood group
- vitamin D–resistant rickets. (MCQ)
- Rett syndrome
- Most cases of Alport syndrome
- Incontinentia pigmenti
- Charcot–Marie–Tooth disease(MCQ)
- Pedigree charts
- All daughters of affected men are affected but never their sons, which may lead to prevalence of affected females over affected males. (MCQ)
- Recurrence risk is 50% for both male and female offspring of an affected female. (MCQ)
- Absence of affected males in several generations may suggest prenatal lethality for the hemizygous state. (MCQ)
Pedigrees illustrating X-linked recessive (A) and dominant (B) inheri- tance patterns. Note the absence of male-to-male transmission in both pedigrees and the predominance of affected males over females in the X-linked recessive pedigree.
- Incompletely dominant disorders
- occur in cases where the heterozygous genotype produces a different phenotype from that seen in the homozygous genotype.
- The effect is often of intermediate severity between the unaffected and fully affected phenotypes.
- For example, in sickle cell anemia, the normal allele is incompletely dominant in heterozygotes. (MCQ)
- Mitochondrial disorders
- The mitochondrial chromosome (mtDNA) is a 16.5 kb circular plasmid.
- The mtDNA bears 37 genes encoding rRNAs, tRNAs, and some genes for
- proteins involved in oxidative phosphorylation. (MCQ)
- are maternally transmitted because the ovum provides all mitochondria to the fertilized embryo
- What is heteroplasmy(MCQ)
- In these disorders, affected cells usually have a mixture of mitochondria, some with mutant mtDNA and others with wild-type mtDNA, a condition called heteroplasmy.
- Segregation of mitochondria during cell division is not as tightly controlled as for nuclear chromosomes, leading to random distribution of mitochondria carrying normal and mutant mtDNA to ova.
- This contributes to variable expression and reduced penetrance of the phenotype among persons within kindreds with mitochondrial disorders.
inheritance of a mitochondrial disorder . note the similarity to the X-linked dominant inheritance pattern but incomplete penetrance as exemplified by individuals II-4 and III-4.
- Major Concepts in Human Genetics
- When similar phenotypes or disease conditions can be caused by different geno- types, this may produce heterogeneity.
- Allelic heterogeneity (MCQ)
- occurs when different alleles of the same gene produce clinically similar conditions.
- Allelic heterogeneity may account for phenotypic variability in some families with genetic disease.
- Locus heterogeneity (MCQ)
- refers to the condition when mutations of more than one gene or locus can produce similar disease states.
- This genotypic variability is responsible for different inheritance patterns of some disorders.
- For example, Ehlers-Danlos syndrome may be caused by mutations at more than 10 known loci, producing inheritance patterns ranging from autosomal recessive or dominant to X-linked. (MCQ)
- Variable expression
- arises when the nature and severity of the phenotype for a genetic condition varies from one person to another.
- refers to a condition in which a mutant allele may have different phenotypic effects in various organ systems in an affected person.
- Genomic imprinting
- expression of an allele differs depending on whether it is inherited from the mother or the father.
- A gene that is shut off when inherited from the mother is maternally imprinted. (MCQ)
- A gene that is silenced when inherited from the father is paternally imprinted. (MCQ)
- Imprinting involves an epigenetic mechanism, ie, an alteration in phenotype that does not result from a change in the genotype. (MCQ)
- Expression of the imprinted genes is silenced or shut off by methylation of certain chromatin regions after DNA replication during gametogenesis.
- The imprint is reversible upon passage through gametogenesis in the next￼generation.
- Genetic Anticipation
- Certain inherited disorders exhibit increased severity of phenotype or decreased age of onset as the disease gene is passed from one generation to the next, an effect known as anticipation
- Examples of genetic diseases that show anticipation are Huntington disease, Fragile X syndrome(MCQ)
- disorders that arise from trinucleotide repeat expansion show Genetic anticipation(MCQ)
- Disease symptoms occur only when the length of the trinucleotide repeat region exceeds a threshold.
- It is defined as the presence of cells in the body that are genetically different.
- Somatic mosaicism
- mutation of a gene occurs in a non-germline (somatic) cell at some point during early development of the person, and all cells descendent from that progenitor are genetically distinct.
- Germline mosaicism
- a mutation that occurred in the parent’s gonadal make-up is transmitted through some gametes, but not all.
- All females are technically mosaic for the genes of their X chromosomes due to inactivation of one or the other X chromosomes early in development, a phenomenon termed the Lyon hypothesis or lyonization. (MCQ)
- Because X inactivation is random, this phenomenon accounts for variable expression of some X-linked disorders, depending on whether the diseaseallele or wild-type allele was inactivated. (MCQ)
- Distribution of cells from the early embryo to the tissues may be imbalanced, so that expression of the disease phenotype is not uniform among the organs.
- Up to 25% of patients with Turner syndrome exhibit a mosaic karyotype, in which only some cells have the 45,X karyotype classically associated with the condition. (MCQ)
- Uniparental disomy
- Applied Aspects :
- Variable expression in neurofibromatosis type
- The biochemical defect involves loss-of-function mutations of the NF1 tumor suppressor gene.(MCQ)
- variability of expression in kindreds makes genetic counseling very difficult.
- Disorders that exhibit imprinting
- Two clinically distinguishable conditions arise from deletion of the same region of chromosome 15 (15q11–q13) .(MCQ)
- Prader-Willi syndrome
- Arises when deleted chromosome 15 is paternally inherited. .(MCQ)
- exhibit .(MCQ)
- failure to thrive and short stature initially
- converts to a tendency toward excessive eating, obesity
- mild-to-moderate mental retardation, hypogonadism
- characteristic facial dysmorphology.
- Angelman syndrome
- occurs when chromosome 15 with the deletion is maternally inherited. .(MCQ)
- involve paternal imprinting of UBE3A, encoding a ubiquitin-protein ligase so that this gene product must be produced from the maternal chromosome. .(MCQ)
- it is a devastating neurologic disorder featuring
- severe mental retardation
- a “happy puppet” demeanor
- seizures, ataxic gait, and aphasia.
- Uniparental disomy in Beckwith-wiedemann syndrome
- They show an .(MCQ)
- overgrowth condition from birth
- macroglossia (enlarged tongue).
- severe hypoglycemia that may become life-threatening
- en hanced tendency to develop cancers of the liver, kidney, and adrenal glands.
- The mapped to chromosome 11 (11p15), a region encompassing the gene for insulin-like growth factor II (IGF2), which is maternally imprinted and thus is expressed only when paternally inherited. .(MCQ)
- Uniparental disomy may contribute to BWS in that excess paternal or decreased maternal contributions of chromosome 11 have been observed in some patients.
- They show an .(MCQ)
Human Inheritance Patterns
Determining Inheritance Patterns in Humans
Heredity: Crash Course Biology #9
Hank and his brother John discuss heredity via the gross example of relative ear wax moistness.
Pedigrees, Patterns of Genetic Inheritance, Autosomal Dominant Recessive X-Linked Mitocondrial
Pedigrees are graphical representations of ancestry with respect to one or more disease(s). Males are represented with a square while females are represented with a circle. The shape is black/filled in if the individual is affected by the disease. The shape is empty/white if the individual is not affected by the disease (may be unaffected or carrier). Usually each generation (row) is labeled with a roman numeral while each individual is labeled with a number.
Introduction to Patterns of Inheritance
Introduction to Patterns of Inheritance:
First Video Podcast.
Handwriting a little sloppy, not using a stylus…
First attempt at flipped classroom.
Biology 07-4 Patterns of Inheritance 1
This video introduces the basic patterns of inheritance, as discovered by Gregor Mendel, using simple mono- and dihybrid crosses.
Complex Patterns of Inheritance
Instructional video covering Mendel’s Laws and seven Complex Patterns of Inheritance (Linked Genes, Intermediate Inheritance, Codominance, Sex-Linked Traits, Epistasis, Multiple Alleles, Polygenic Traits) – Created for usage in the KU/NSF Social Media and Scientific Argumentation Research Grant