Patterns of single gene inheritance Flashcards
Allele
one of both versions of a gene or DNA sequence at a given locus.
Locus
position occupied by a gene on a chromosome
Homozygote
genotype with identical alleles at a given locus
Heterozygote
genotype with different alleles at a given locus
Hemizygous
genotype with a single allele for a given chromosome segment
Compoud heterozygote
genotype with 2 different mutant alleles at one locus
Genotype
genetic constitution of an individual or locus
Phenotype
appearence or characteristics of an individual or gene
Polymorphism
alternate genotypes present in a population at >1%
Penetrance
the proportion of mutant individuals manifesting disease
Expressivity
The extent to which a mutation exhibits a phenotype
Single Gene disorders
With some exceptions, disorders due to a single defective gene are inherited in a Mendelian or unifactorial manner. An estimated 11,000 human single gene disorders exist
Autosomal recessive
inheritance- A trait is recessive if it is only displayed among homozygotes. Recessive disorders often display a clustering of the disease among siblings and is absent among ancestors, although consanguinity may be present. Parents are carriers. The recurrence risk for sublings is 1/4. Unaffected sibs of the proband hace a 2/3 chance of being a carrier.
Male
Female
Sex unspecified
Number of children of sex indicated
affected
Nonparent carrier, May manifest the disease
Obligate carrier, will not manifest the disease
Proband
Deceased
Stillbirth
Adopted into family
Adopted out of family
Arrow indicates consultant seeking counseling
Spontaneous abortion
marriage or union
divorced
Consanquinity
monozygotic twins
Dizygotic twins
Twins of unknown zygosity
Pedigree with generations and individuals numbered
Miscarriage
No offspring
Multiple unions
pregnancy with information on dates if available
Termination of pregnancy
Autosomal dominant
is phenotypically expressed in heterozygotes. if the disease is not lethal it will be seen in every generation. A child of an affected parent has a 1/2 risk of inheriting the disease trait. Unaffected family members are unlikely to pass the disease to their offspring. males and females are usually equally affected.
Codominant alleles
Are both expressed in the heterozygous state
Haploinsufficiency
When one normal allele is insufficient to compensate for loss of function of the other
List attributes of autosomal recessive inheritance
Appears in more than one sibling of the proband, but not in parents, offspring or other relatives.
Parents are asymptomatic carriers
Parents may be consanguinous
The risk to each siblings of the proband is 25%
Carriers
have a single mutant allele that is obscured by a normal copy. The rarer the disease the more unlikely that 2 mutant alleles are found in a single individual, therefore the greater the proportion of mutant alleles that resides among carriers.
Genetic heterogeneity
Can result from different mutations at one locus (allelic heterogeneity)) or from mutations at different loci (locus heterogeneity)
Phenotypic heterogeneity
occurs when the same mutation manifests itself differently among individuals
consanguinity
the relationship that results from common ancestry. Consanguinity increases the chance that both parents are carriers of the same mutant allele from a common ancestor.
Degree of relationship
corresponds to the number of uninterrupted line segments connecting two blood relatives in a pedigree chart
measurement of consanguinity
proportion of alelles two related individuals have in common. is calculated from their degree of relationship.
F(coefficient of inbreeding) = ½ • (½)<em>n</em>
where (½)<em>n</em>= coefficient of relationship
degree of relationship, proportion of alleles in common, and coefficient of inbreeding of child (F) for: parent-child
1st
1/2
1/4 (.25)
degree of relationship, proportion of alleles in common, and coefficient of inbreeding of child (F) for:
brother-sister
1st
1/2
1/4 (25)
degree of relationship, proportion of alleles in common, and coefficient of inbreeding of child (F) for:
brother-half sister
2nd
1/4
1/8 (.125)
degree of relationship, proportion of alleles in common, and coefficient of inbreeding of child (F) for:
uncle-neice/ aunt-nephew
2nd
1/4
1/8 (.125)
*degree of relationship, proportion of alleles in common, and coefficient of inbreeding of child (F) for:
first cousins
3rd
1/8
1/16 (.0625)
degree of relationship, proportion of alleles in common, and coefficient of inbreeding of child (F) for:
half first cousins
4th
1/16
1/32 (.031)
degree of relationship, proportion of alleles in common, and coefficient of inbreeding of child (F) for:
First cousins once removed
4th
1/16
1/32 (.031)
degree of relationship, proportion of alleles in common, and coefficient of inbreeding of child (F) for:
second cousins
5th
1/32
1/64 (.016)
A mutant allele is dominant when:
1) the single normal copy produces an insufficient quantity of the normal gene product for the requirements of the organism (haploinsufficiency)
2) The product of the inactive mutant gene interferes with the function of the normal gene product (dominant negative effect)
3) the product of the mutant gene acquires a new or enhanced function (simple gain of function)
4) The affected gene is a tumoir supressor resulting in a predisposition to cancer that is inherited as a dominant trait because even a single cell losing the function of the other allele by mutation is enough to cause cancer (which is bound to happen during the lifetime)
describe familial hypercholersteremia
dominant disorder resulting from haploinsufficiency. In the heterozygous state, the remaining normal allele produces a functional LDL recepter so that the level of the receptor is 50% normal. This level is not enough to maintain blood cholersterol leverls in the normal range.
Osteogenesis imperfecta
null mutation in the procollagen alpha gene results in half the normal mount of normal collagen. This is not enough to prevent disease. inheritance is dominant due to haploinsufficiency. mutations that work work as part of a large complex produce a dominant negative effect.
X-linked inheritance
incidence of the trait is much higher in males than in females. heterozygous females are usually unaffected. The trait is usually transmitted from an affected male to 50% of hos grandsons through his daughters. Males never transmit the disease to males. Females are phenotypically normal.
X-linked dominant inheritance
Affected mothers have a 50% change of transmitting the disorder to sons and daughters. Affected fathers have affected daughters but no affected sons. Affected females have a milder expression of the phenotype. EX: DMD
somatic mosaicism
When a mutation occurs in the course of development, only that part of the body derived from the mutant cell may ultimately be affected
germline mosaicism
when a mutation affects germ cells the parents may be negligibly affected but multiple offspring may exhibit severe and uniform disease
Genomic imprinting
disease expression is dependent on the parent transmitting the disease (because of inherited expressivity of the gene copy in question). Different phenotypes result depending on the parental source of the mutation.
Complications to the pedigree patterns that may impact diagnosis or counseling
new mutation- especially for autosomal dominant disorders
Genomic imprinting- different phenotypes depend on the parental sourve of the mutation
Reduced penetance- not all patients with the disease phenotype express symtptons
Variable expressivity- the severity of the disease differs in patients with the same genotype
Phenotypic variability- disorders that affect multiple organs can produce different symptoms in related family members (pleiotropy) due to effects of environment or other genes
Delayed onset- triplet repeat disorders
Small family size- limited pedigree information on which to base counseling recomendations
mosiaciasm
A mutation that occurs during cell proliferation, in somatic cells or during gametogeneis, leads to a proportion of cells carrying the mutation.
Repeat disorders
Some genes contain several repeats of three nucleotides. The number of triplet repeats in a given gene can increase and expand from generation to generation. Beyond a certain locus-dependent threshold abnormalities in gene function can result tha worsen in subsequent generations (anticipation)
Anticipation
worsoning of symptoms from generation to generation
Mitochondrial inheritance
mitochondrial DNA is maternally inherited. genes inherited in this pattern can only be passed from mother to child, and no through the father.
replicative selection
refers to the distribution of cytoplasmic products in daughter cells. with relationship to mitochondrial inheritance it refers to the proportion of diseased mitochondria that end up in the daughter gametes after meiosis.
Factors defining inheritance of mitochondrial DNA
1) mitochondrial DNA can be heteroplasmic: more than one type of mitochondrial DNA can be present in cells from a single individual.
2) Mitochondrial DNA is inherited maternally. A small and random sampling of mitochondrial DNA is selected for inclusion in the oocyte
3) Mitochondrial DNa undergoes random segregation through multiple rounds of mitosis during embryogenesis.
General features of mitochondrial inheritance
1) reduced penetrance- phenotype may or may not be expressed depending on threshold copy number
2) variable expression- extend of phenotype varies with proportion to mutant mitochondria in the cell above threshol for disease.
3) plieotropy- copy number above threshold varies in different tissues affected by the mutation
4) mosaicism- mutation present in some tissues but not in others.
mitochondrial bottleneck
profound reduction in the mitochondrial DNA molecules within early oocytes, followed by a large increase during subsequent oocyte maturation. So only a small RANDOM sample of the mitochondrial DNA present in the original germ cell is represented in mature oocytes. Different offspring inherit different random dose of mutant mitochondrial DNA from their mother.
