Genetics: Mendelian Genetics, Mutations, Disease

Question 1

Hardy-Weinberg Equilibrium

Answer 1

Determining allele frequency and heterozygote carrier frequency in a population for which the frequency of a phenotype is known. Used for clinical risk assessment.

Question 2

Assumptions of Hardy-Weinberg Equilibrium

Answer 2

Random mating, no selection, no high frequency of new mutations, no migration

Question 3

Consanguinity

Answer 3

Children produced by 2 related individuals. Can occur in isolated populations.

Question 4

Founder effect

Answer 4

Selection caused by groups moving from one region to another. Causes different frequencies in different regions.

Question 5

Genetic drift

Answer 5

Drift in frequencies from the original population in a particular region

Question 6

Biological fitness example

Answer 6

Selection of malaria for mutation (HbS) that causes SCD - will have “protection” from malaria.

Question 7

Haldane hypothesis

Answer 7

1/3 of mutant alleles are lost each generation in an X-linked lethal disease. If disease frequency is constant over time, then 1/3 must be new mutations.

Question 8

LOF Mutations

Answer 8

Reduced or no protein function. Usually recessive except for dominant phenotypes resulting from haploinsufficiency.

Question 9

GOF Mutation Types

Answer 9

1) Additional or unregulated function in same pathway of protein produced (ex. achondroplasia). 2) Novel function unrelated to function of normal protein (ex. poly Q aggregates in HD).

Question 10

GOF Mutations are normally…

Answer 10

Dominant. Exception: SCD - GOF (sickled cells) leads to loss of function (anemia) so it is autosomal recessive.

Question 11

Collagen

Answer 11

Most abundant protein in body. 60% of protein in bone and cartilage.

Question 12

Collagen I structure

Answer 12

2 alpha 1 (I) chains, 1 alpha 2 (I) chain. Triple helical structure; > 300 Gly-XY repeats (X often proline to cause bend, Y often hydroxyproline or hydroxylysine).

Question 13

Mosaicism

Answer 13

Single egg fertilized by single sperm to make one zygote. As zygote starts dividing, a mutation occurs in one cell, which divides and eventually distributes in body.

Question 14

Chimerism

Answer 14

2 individual eggs fertilized by 2 individual sperm to make 2 zygotes. At some point the zygotes fuse - leading to half normal cells and half mutant cells in body.

Question 15

Anticipation

Answer 15

Occurrence of genetic disease at an earlier age of onset or with increasing severity in successive generations. In triplet repeat expansion diseases.

Question 16

Triplet repeats

Answer 16

Triplet repeats of 3 nucleotides anywhere in gene. Expand each generation in male or female germline (anticipation) and cause expansion diseases. Most cause neurological diseases (neurons more sensitive); unknown why.

Question 17

Triplet repeats in coding sequence

Answer 17

Polyglutamine repeats form aggregates. Ex. SBMA, SCA, HD

Question 18

Triple repeats in 5’-UTR can cause:

Answer 18

Fragile X Syndrome (FMR1 and FMR2)

Question 19

Triple repeats in 3’-UTR can cause:

Answer 19

Myotonic dystrophy - expanded repeats sequester mRNA so cannot make necessary proteins.

Question 20

Triple repeats in intron can cause:

Answer 20

Friedreich’s Ataxia (recessive)

Question 21

Mitochondrial inheritance

Answer 21

May resemble X-linked dominant but it’s not! Maternal transmission only (sperm have only a tiny nucleus, no mitochondria). Affected males do not transmit to daughters. Complicated by heteroplasmy. Disease expression influenced by dosage of abnormal genomes within cell or tissue.

Question 22

Heteroplasmy

Answer 22

Mixed population of normal and abnormal mitochondrial genomes within each cell. Influences disease expression.

Question 23

Mitochondrial diseases have greatest effect on…

Answer 23

Highly aerobic tissues (nervous system, eyes, cardiac and skeletal muscles).

Question 24

Most common disorders of mitochondrial inheritance:

Answer 24

Leber hereditary optic neuropathy, MERRF, MELAS.

Question 25

(T/F) Disorders of mitochondria cannot be caused by mutations in nuclear genome.

Answer 25

False. Some can be caused by mutations in nuclear genome.

Question 26

SMN2 vs. SMN1

Answer 26

SMN2 has single base change in splicing site from SMN1 that 90% of the time prevents incorporation of exon 7 required for normal protein function. Other 10% it produces normal protein.

Question 27

DMD gene

Answer 27

Largest known human gene characterized to date; 2.5 Mb on Xp21 - prone to mutations. 79 exons in a 14 kb full-length transcript. Dystrophin absent in DMD, truncated in BMD.

Question 28

Dystrophin

Answer 28

Protein that protects striated muscle membranes from damage by links F-actin submembraneous cytoskeleton to ECM via dystrophin-associated protein complex (DAPC, DGC). Acts like force transducer to transfer force to ECM instead of muscle membrane. 430 dystrophin protein localized to cytoplasmic face of plasma membrane in skeletal and cardiac muscle.

Question 29

Reasons for nonpenetrance

Answer 29

Some genes expressed primarily by individuals of one sex (ex. hereditary breast/ovarian cancer). Adult or later age onset (age-dependent penetrance) - ex. HD. Environmental trigger (adult-onset diabetes or lung cancer). Influenced by modifier genes and polymorphisms (complex diseases, SMA).

Question 30

Allelic Heterogeneity

Answer 30

Most disorders caused by multiple different mutations in the same allele. Each family may have own unique mutation. Exception: SCD (only single mutation causes in African Americans).

Question 31

Locus Heterogeneity

Answer 31

Same disease caused by mutations in more than one gene (frequently different genes in same pathway). Ex. hereditary breast/ovarian cancer, Fancomi anemia, xeroderma pigmentosum, Lynch syndrome.

Question 32

Clinical Heterogeneity

Answer 32

Some diseases have very different phenotypes but are caused by different mutations in the same gene. Ex. FGFR3, MECP2, RET, dystrophin.

Question 33

What is one more complication of risk assessment for genetic diseases?

Answer 33

False paternity. Incidence unknown but estimated 1 - 30%. Need to perform paternity testing using polymorphisms.