RL Lectures 43-44: Mendelian and Non-Mendelian Inheritance

Question 1

What is a gain of function mutation?

Answer 1

a mutation causing increased activity, a new activity, or a new pattern of gene expression

Question 2

What is a loss of function mutation?

Answer 2

a mutation causing decreased or lack of activity

Question 3

What is haploinsufficiency?

Answer 3

a single functional copy of a gene is insufficient for proper cell or tissue function or development

Question 4

Describe the dominant negative effect.

Answer 4

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

Question 5

What are compound heterozygous mutations?

Answer 5

causes of autosomal recessive disease where different mutations on each allele are identified

Question 6

Describe X inactivation.

Answer 6

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

Question 7

What factors affect genotype-phenotype correlation?

Answer 7

X-inactivation
penetrance
mosaicism
anticipation
variable expressivity
phenotypic heterogeneity
genetic or locus heterogeneity

Question 8

What is mosaicism?

Answer 8

the state in which different populations of cells in a person or part of the body have different genetic makeups

Question 9

How does mosaicism occur?

Answer 9

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

Question 10

List the two types of mosaicism.

Answer 10

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)

Question 11

Describe incomplete penetrance.

Answer 11

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

Question 12

Describe anticipation.

Answer 12

further expansion of repeats (which occur primarily during meiosis in males) in succeeding generations, increasing disease severity manifesting at an earlier age of onset

Question 13

What is variable expressivity?

Answer 13

severity of the disease differs from person to person despite having the same genotype

Question 14

What causes variable expressivity?

Answer 14

various multigenic factors or environmental modifiers

Question 15

What is a pleiotropic mutation?

Answer 15

when a genotype produces diverse and differing organ system involvements

Question 16

Describe phenotypic heterogeneity.

Answer 16

variants within the same gene that may predispose to milder or more severe disease
different variants can result in seemingly distinct disorders

Question 17

What is genetic (locus) heterogeneity?

Answer 17

a single clinical phenotype arising from a mutation in multiple distinct genes

Question 18

Describe the hallmarks of maternal transmission of mitochondrial genes.

Answer 18

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

Question 19

What is epigenetics?

Answer 19

gene regulation that is a heritable pattern of gene function in the absence of any nucleotide sequence change

Question 20

List examples of epigenetic mechanisms.

Answer 20

DNA methylation
histone modifications
regulation by non-coding RNA

Question 21

What are the two epigenetic phenomena observed in humans?

Answer 21

imprinting

environmental epigenetic effects

Question 22

Describe imprinting.

Answer 22

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

Question 23

Describe the pathway of maternally inherited imprinting.

Answer 23

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)

Question 24

Describe the pathway of paternally inherited imprinting.

Answer 24

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)

Question 25

Describe the possible causes of Prader-Willi syndrome.

Answer 25

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

Question 26

Describe the possible causes of Angelman syndrome.

Answer 26

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

Question 27

What is the most common mechanism of uniparental disomy?

Answer 27

trisomy rescue

Question 28

Provide examples of environmental factors that can contribute to epigenetic changes.

Answer 28

environmental exposures (toxins/chemicals)
stressors (child abuse, fasting/starvation, jobs)
well-being (diet, exercise, meditation)