Genetics: Mendelian Genetics, Mutations, Disease Flashcards
Hardy-Weinberg Equilibrium
Determining allele frequency and heterozygote carrier frequency in a population for which the frequency of a phenotype is known. Used for clinical risk assessment.
Assumptions of Hardy-Weinberg Equilibrium
Random mating, no selection, no high frequency of new mutations, no migration
Consanguinity
Children produced by 2 related individuals. Can occur in isolated populations.
Founder effect
Selection caused by groups moving from one region to another. Causes different frequencies in different regions.
Genetic drift
Drift in frequencies from the original population in a particular region
Biological fitness example
Selection of malaria for mutation (HbS) that causes SCD - will have “protection” from malaria.
Haldane hypothesis
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.
LOF Mutations
Reduced or no protein function. Usually recessive except for dominant phenotypes resulting from haploinsufficiency.
GOF Mutation Types
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).
GOF Mutations are normally…
Dominant. Exception: SCD - GOF (sickled cells) leads to loss of function (anemia) so it is autosomal recessive.
Collagen
Most abundant protein in body. 60% of protein in bone and cartilage.
Collagen I structure
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).
Mosaicism
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.
Chimerism
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.
Anticipation
Occurrence of genetic disease at an earlier age of onset or with increasing severity in successive generations. In triplet repeat expansion diseases.
Triplet repeats
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.
Triplet repeats in coding sequence
Polyglutamine repeats form aggregates. Ex. SBMA, SCA, HD
Triple repeats in 5’-UTR can cause:
Fragile X Syndrome (FMR1 and FMR2)
Triple repeats in 3’-UTR can cause:
Myotonic dystrophy - expanded repeats sequester mRNA so cannot make necessary proteins.
Triple repeats in intron can cause:
Friedreich’s Ataxia (recessive)
Mitochondrial inheritance
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.
Heteroplasmy
Mixed population of normal and abnormal mitochondrial genomes within each cell. Influences disease expression.
Mitochondrial diseases have greatest effect on…
Highly aerobic tissues (nervous system, eyes, cardiac and skeletal muscles).
Most common disorders of mitochondrial inheritance:
Leber hereditary optic neuropathy, MERRF, MELAS.
(T/F) Disorders of mitochondria cannot be caused by mutations in nuclear genome.
False. Some can be caused by mutations in nuclear genome.
SMN2 vs. SMN1
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.
DMD gene
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.
Dystrophin
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.
Reasons for nonpenetrance
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).
Allelic Heterogeneity
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).
Locus Heterogeneity
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.
Clinical Heterogeneity
Some diseases have very different phenotypes but are caused by different mutations in the same gene. Ex. FGFR3, MECP2, RET, dystrophin.
What is one more complication of risk assessment for genetic diseases?
False paternity. Incidence unknown but estimated 1 - 30%. Need to perform paternity testing using polymorphisms.
