RL Lectures 43-44: Mendelian and Non-Mendelian Inheritance Flashcards
What is a gain of function mutation?
a mutation causing increased activity, a new activity, or a new pattern of gene expression
What is a loss of function mutation?
a mutation causing decreased or lack of activity
What is haploinsufficiency?
a single functional copy of a gene is insufficient for proper cell or tissue function or development
Describe the dominant negative effect.
encoded mutant protein is part of a multi-protein complex that includes the wild-type protein and the presence of the mutant protein in the complex disrupts wild-type protein function
What are compound heterozygous mutations?
causes of autosomal recessive disease where different mutations on each allele are identified
Describe X inactivation.
only one of the two X chromosome copies in cells of females is active in any given cell, the other copy is inactivated by an epigenetic mechanism involving the long non-coding RNA XIST
it may be apparent in those cells in which the allele has been inactivated
What factors affect genotype-phenotype correlation?
X-inactivation penetrance mosaicism anticipation variable expressivity phenotypic heterogeneity genetic or locus heterogeneity
What is mosaicism?
the state in which different populations of cells in a person or part of the body have different genetic makeups
How does mosaicism occur?
spontaneous mutations arise after fertilization, limiting the change to one cell of many in the early embryo that is perpetuated through mitosis of mutated cells
List the two types of mosaicism.
somatic (occurring in the non-gonadal cells; cannot be inheritance)
gonadal (occurring only in the germline cells; not expressed in the individual; can be inherited)
Describe incomplete penetrance.
known mutations that do not always lead to disease due to a number of multigenic factors and modifiers or due to age/sex of patient
Describe anticipation.
further expansion of repeats (which occur primarily during meiosis in males) in succeeding generations, increasing disease severity manifesting at an earlier age of onset
What is variable expressivity?
severity of the disease differs from person to person despite having the same genotype
What causes variable expressivity?
various multigenic factors or environmental modifiers
What is a pleiotropic mutation?
when a genotype produces diverse and differing organ system involvements
Describe phenotypic heterogeneity.
variants within the same gene that may predispose to milder or more severe disease
different variants can result in seemingly distinct disorders
What is genetic (locus) heterogeneity?
a single clinical phenotype arising from a mutation in multiple distinct genes
Describe the hallmarks of maternal transmission of mitochondrial genes.
all affected females are transmitting the disease to all males and female offspring
none of the males are transmitting disease to either male or female offspring
however, due to heteroplasmy, the threshold effect quantifies whether disease will be expressed in those cells
What is epigenetics?
gene regulation that is a heritable pattern of gene function in the absence of any nucleotide sequence change
List examples of epigenetic mechanisms.
DNA methylation
histone modifications
regulation by non-coding RNA
What are the two epigenetic phenomena observed in humans?
imprinting
environmental epigenetic effects
Describe imprinting.
act of suppressing gene expression, not allowing for biallelic expression of the gene but preferentially allowing for only mono-allelic expression depends on parent of origin
mediated by DNA methylation and histone modification under control of imprinting centers
Describe the pathway of maternally inherited imprinting.
adult somatic cells will carry maternally inherited imprinted cells in both sexes
during creation of the germline, imprinting “erased”
once gametes are created, the genes in each gamete are imprinted in accordance with their sex (both egg cells will contain only imprinted copies of the gene whereas both sperm cells will contain the gene in its non-imprinted form)
Describe the pathway of paternally inherited imprinting.
adult somatic cells will carry paternally inherited imprinted cells in both sexes
during creation of the germline, imprinting is “erased”
once gametes are created, the genes in each gamete are imprinted in accordance with their sex (both egg cells will contain only un-imprinted copies of the gene in its imprinted form)
Describe the possible causes of Prader-Willi syndrome.
Maternally imprinted gene mutation in the paternal copy will result in no active copy producing phenotype uniparental disomy where both copies of the gene come from the mother would result in no active copies of the gene
Describe the possible causes of Angelman syndrome.
Paternally imprinted gene mutation in the maternal copy will result in no active copy producing phenotype uniparental disomy where both copies of the gene come from the father would result in no active copies of the gene
What is the most common mechanism of uniparental disomy?
trisomy rescue
Provide examples of environmental factors that can contribute to epigenetic changes.
environmental exposures (toxins/chemicals)
stressors (child abuse, fasting/starvation, jobs)
well-being (diet, exercise, meditation)
