Module 2

Mendelian/Monogenic Traits

depend on the alleles present at a single gene or locus

Mendel’s Law of Equal Segregation

each haploid gamete carries one allele for each gene/locus

Autosomal Dominant Inheritance

one copy of variant on an autosome causes disease

affected individuals are heterozygous

vertical pattern of inheritance with 50% risk for each child of an affected parent

both sexes transmit to both sexes

Vertical Inheritance Pattern

there is an affected family member in every generation

Horizontal Pattern of Inheritance

there is not an affected member in every generation

Haploinsufficiency

variant is a null allele or low-function allele

half is not enough

mechanism of autosomal dominant disorders

Dominant Negative

variant protein interferes with function of wild type protein

mechanism of autosomal dominant disorders

Gain of Function

variant leads to increased protein production or activity or variant generates toxic mRNA or new protein function/behavior that is deleterious

mechanism of autosomal dominant disorders

Autosomal Recessive Inheritance

two copies of variant on an autosome causes disease

affected individuals are homozygous or compound heterozygotes

horizontal pattern with 25% risk for each child of carrier parents

both sexes equally affected

may involve consanguinity

Loss of Function

variant is a null allele or low function allele

mechanism of autosomal recessive disorders

Toxic Gain of Function

variant protein has toxic properties but only in homozygous state

rare

mechanism of autosomal recessive disorders

X-Linked Dominant Inheritance

one copy of variant on X chromosome causes disease

affected individuals are heterozygous females or hemizygous males

vertical pattern: if affected mother, both sexes have 50% risk; if affected father, males have 0% risk and females have 100% risk

more affected females than males but affected females typically have milder phenotype

can have male lethality

X-Linked Recessive Inheritance

one (hemizygous male) or two (homozygous female) copies of variant on X chromosome cause disease

horizontal pattern: unaffected female is carrier, male offspring have 50% risk, no male-to-male transmission

Skewed X-Inactivation

if disease allele-expressing cells have a growth/survival disadvantage, wild type cells will be selected, resulting in an X-inactivation pattern that favors expression of wild type allele

if this happens, females are very unlikely to be symptomatic

Mitochondrial DNA

16,569 base pairs compact circular genome with 37 genes

Compound Heterozygote

person has two different mutated versions of the same gene

Mitochondrial Inheritance

affected (or unaffected) female transmits to male and female offspring with equal risk

no transmission from male

clinical manifestations depend on degree of representation of mutant allele

Heteroplasmy

each oocyte contains different amounts of mtDNA

Incomplete Penetrance

individuals with a disease genotype may show no phenotype due to modifier alleles and environmental factors

relevant to dominant and more rarely recessive disorders

Age-Related Penetrance

individual with a disease genotype may not show genotype until later in life

phenotype may require: accumulation of toxic materials and/or second hit

relevant to dominant and more rarely recessive diseases

Cell Autonomy of Protein Product

whether or not a protein product stays within a cell (autonomous) or is secreted (non-autonomous)

Variable Expressivity

individuals with the same mutant allele may demonstrate different clinical features and/or different severity of clinical features

most common in dominant diseases

New Mutation

variant arises during gametogenesis or early embryogenesis

most common in dominant or X-linked lethal diseases

Allelic Heterogeneity

different variants in a single gene cause the same disease

Locus/Genetic Heterogeneity

variants in different genes/loci may cause the same disease

Complementation

offspring of affected persons have no phenotype

can result from locus heterogeneity in recessive diseases

Pleiotropy

a single genetic variant can cause multiple phenotypic traits

Phenotypic Heterogeneity

different variants in a single gene cause different disorders

Forward Genetics

phenotype to genotype

used to find new genes that govern developmental or disease process of interest

done by performing random mutagenesis, identifying mutant phenotype, and finding mutation responsible for phenotype

Reverse Genetics

genotype to phenotype

used to determine the function of a gene of interest

done by manipulating gene in a targeted manner by knockout, knockdown, overexpression, allele replacements, etc.

Knock Down

reduce mRNA using RNAi or reduce translation, block splicing, or degrade mRNA with ASOs

Antisense Oligonucleotides (ASOs)

single-stranded DNA oligos (15-30 nt) that are complementary to target pre-mRNA or mature mRNA

modified backbones enhance stability, uptake, and potency

used in knockdown

mechanisms: splice blocking, transcript cleavage by RNase H, and translation blocking

Knock Out/Knock In

remove an essential part of a gene or a whole gene to assess its role in cell function, development, or disease or replace endogenous gene with reporter or variant

Precise Genome Editing

uses CRISPR/Cas9 or deactivated Cas9 (dCas9)

Adeno-Associated Virus (AAV) Gene Therapy

use viral delivery of cDNA to express a gene to compensate for a loss of function allele

Lentiviruses (LV)

retroviruses that stably integrate into genomic DNA