Understanding Genetics & Epigenetics: Genotype, Phenotype, Mutations, & Gene Expression, Exams of Advanced Education

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MMSC491 Exam 2-with 100% verified solutions phenotype the set of observable characteristics of an individual resulting from the interaction of its genotype genotype the genetic constitution of an individual organism homozygous having two identical alleles of a particular gene or genes heterozygous having two different alleles of a particular gene or genes compound heterozygote The presence of two different mutated alleles at a particular gene locus example of compound heterozygote Tay-Sachs disease, GM2-gangliosidosis, AB variant, and Sandhoff disease might easily have been defined together as a single disease, because the three disorders are associated with failure of the same enzyme and have the same outcome dominant dominance is the phenomenon of one variant of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome example of dominance V-shaped hairline, Almond-shaped eyes, Right handedness, Detached earlobes, Dark hair Brown eyes, baldness recessive Refers to a trait that is expressed only when genotype is homozygous; a trait that tends to be masked by other inherited traits, yet persists in a population among heterozygous genotypes examples of recessive Cleft chin, dimples, freckles, Straight hairline, Round eyes, Left handedness, Attached earlobes, Blond hair, red hair, Blue eye co-dominant refers to a type of inheritance in which two versions (alleles) of the same gene are expressed separately to yield different traits in an individual example of co-dominance blood type. People with the AB blood type have one A allele and one B allele. Because both alleles are expressed at the same time, their blood type is AB. pedigree a diagram that shows the occurrence and appearance of phenotypes of a particular gene or organism and its ancestors from one generation to the next sib sibling male square female circle sex unstated diamond autosomal dominant Autosomal dominant inheritance is a way a genetic trait or condition can be passed down from parent to child. One copy of a mutated (changed) gene from one parent can cause the genetic condition. A child who has a parent with the mutated gene has a 50% chance of inheriting that mutated gene. example of autosomal dominant Huntington's disease Many different mutations in one gene can have the same effect and produce similar phenotypes examples of allelic and phenotypic heterogeneity For example, β-thalassemia results from a deficiency of β-globin and can arise by any number of different mutations in the hemoglobin β chain (HBB) gene. Different mutations in a single gene can also often result in different phenotypes. That can arise in two ways: either different types of mutation somehow have different effects on how the underlying gene works—which we consider here—or some factors outside the disease locus have varying effects on the phenotype (described below)., Ex. Duchenne and Becker muscular dystrophies (OMIM 310200 and 300376, respectively) represent severe and mild forms of the same type of muscular dystrophy and are both examples of dystrophinopathies penetrance the probability that a person who has a mutant allele will express the disease phenotype non-penetrance the disorder can sometimes appear to skip a generation so that a person who must have inherited the disease allele is unaffected age-related penetrance In some disorders, there is a late age at onset so that the penetrance is initially very low but then increases with age. Age-related penetrance means a late onset of symptoms, and quite often the disease first manifests in adults. example of age-related penetrance Huntington disease (PMID 20301482) is a classic example of a late-onset single-gene disorder. Age-at-onset curve: In Huntington disease an unaffected person who has an affected parent will have a 50% a priori risk that decreases with age (see Figure 5.13); if one is still free of symptoms by age 60, for example, the chance of developing the disease falls to less than 20%. imprinting The parent-of-origin effects are due to an epigenetic mechanism known as imprinting. The mutant allele that is not expressed is often described as the imprinted allele. example of imprinting Beckwith-Wiedemann syndrome is said to be paternally imprinted, because paternally inherited alleles are not expressed. anticipation expressed at an earlier age and become increasingly severe with each generation example of anticipation fragile X mental retardation syndrome, myotonic dystrophy, and Huntington disease are caused by unstable mutations (often called dynamic mutations) whose characteristics can change after they undergo DNA replication cis-acting elements regions of non-coding DNA which regulate the transcription of neighboring genes, limited to a single DNA molecule on which is resides Ex. operator in the lac operon trans-acting factor regulate gene transcription by binding directly or through an intermediate protein to the gene at a particular DNA sequence, called a cis-regulatory region, free to migrate by diffusion so as to recognize and bind specific short target nucleic acid sequences, Ex. RNA polymerase, repressor, TATA Binding Protein, TFIIB, CAP, tryptophan epigenetic event heritable changes in gene expression that are, unlike mutations, not attributable to alterations in DNA sequence. Two predominant epigenetic mechanisms are DNA methylation and histone modification promoter a region of DNA upstream of a gene where relevant proteins (such as RNA polymerase and transcription factors) bind to initiate transcription of that gene enhancers cis-acting DNA sequences that can increase the transcription of genes silencer regulatory DNA elements that reduce transcription from their target promoters; they are the repressive counterparts of enhancers insulator a type of cis-regulatory element known as a long-range regulatory element, can block inappropriate interactions between enhancers and promoters notably the CTCF regulator DNA looping occurs when a protein or a complex of proteins simultaneously binds to two different sites on DNA with looping out of the intervening DNA, allows directy physical interactions between proteins bound to a distant cis-actin element that regulates a fene with some o fhte many proteins bound to the gene's promoter zinc finger motif involves the binding of Zn2+ ion by four conserves amino acids so as to form a loop leucine zipper a helical stretch of amino acids rich in hydrophobic leucine residues, aligned on one side of the helix, Facilitates the dimerization of the protein by interdigitation of two leucine- containing helices on different molecules combinatorial effects Different transcription factors work in concert by binding to adjacent recognition sequences cis-acting sequences that regulate RNA splicing the 5 splice site, the 3 splice site, as well as the branchpoint sequence, which conform to ′ ′ partially conserved motifs that are recognized by cognate trans-acting factors, also splice enhancers sequences and splice suppressor sequences splice donor contains an invariant GU dinucleotide, 5' splice acceptor contains an invariant AG dinucleotide, 3' branch site located every close to the splice acceptor; it contains an invariant A nucleotide and is responsible for initiating the splicing reaction alternative splicing When primary transcripts of a single gene are spliced in different ways compromise the mother's health and future reproductive success, Insulin-like growth factor gene IDF2 is maternally imprinted, UBE3A gene (angelman syndrome) is paternally imprinted Describe how X-chromosome inactivation occurs at a DNA level Early in embryonic development in females, one of the two X chromosomes is randomly and permanently inactivated in cells other than egg cells. This phenomenon is called X- inactivation or lyonization. X-inactivation ensures that females, like males, have one functional copy of the X chromosome in each body cell., Initiate at an X-inactivation center (XIC), XIST gene encodes ncRNA, centrally involved in spreading heterochromatinization outward from teh XIC: both XIST ENA and the polycomb proteins that ir recruits seem to spread along the inactive X sex differences in gene dosage A gene dosage compensation mechanism equalizes X-chromosome gene expression in male and female cells (causing one of the two X chromosomes in females to be heterochromatinized), Y-specific genes are rare and largely devoted to male-specific functions, X-chromosome has more than 800 protein-coding genes genetic basis of the calico cat Heterozygous at an X-linked coat color locus. One allele specifies a black coat color, the other orange. The different color patches reflect clones in which different X chromosomes are inactivated. The white patches are the result of an unrelated coat color gene. They are always female, except for occasional XXY males, The X chromosome carries a gene that determines fur color, and there are two different versions (or alleles) of this gene in calico cats. One allele produces orange fur, and the other produces black fur. Calico cats are predominantly female because they're coloring is related to the X chromosome. I'll try not to put you to sleep with a complicated genetics lesson, so here's a quick overview: Two X chromosomes are needed for a cat to have that distinctive tri-color coat. If a cat has an XX pair, she will be female uniparental disomy occurs when a person receives two copies of a chromosome, or part of a chromosome, from one parent and no copies from the other parent. UPD can occur as a random event during the formation of egg or sperm cells or may happen in early fetal development Describe the two broad ways in which genetic variation can cause disease First: it may cause a change in the sequence of the gene product, Second: by changing the amount of gene product made Describe the various classes of mutations that cause disease by altering the amount of gene product Some small-scale pathogenic mutations in protein-coding genes result in unstable mRNAs and failure to make the normal gene product. Other mutations can result in altered gene copy number or adversely affect regulatory sequences controlling gene expression so that too little or too much product is made. Although most pathogenic mutations affect individual genes, some mutations (and chromosome abnormalities) can simultaneously affect multiple genes. synonymous (or silent) substitution no change in amino acid, no change in phenotype might be expected. nonsynonymous substitution There are different classes (Table 7.1), but the predominant one causes one amino acid to be replaced by another, a missense mutation. Missense mutations can sometimes have minimal effects on the phenotype, but they sometimes have adverse effects as described below. Describe the outcomes of single nucleotide substitutions within coding sequences can lead in terms of pathogenic consequences synonymous and non synonymous substitutions silent occur when the change of a single DNA nucleotide within a protein-coding portion of a gene does not affect the sequence of amino acids that make up the gene's protein nonsense a mutation in which a sense codon that corresponds to one of the twenty amino acids specified by the genetic code is changed to a chain-terminating codon missense an amino-acid specifying coding is replaced by a codon for a different amino acid frameshift the insertion or deletion of nucleotide bases in numbers that are not multiples of three, may indirectly lead to a premature termination codon. conservative substitution A nucleotide substitution that replaces one amino acid by another of the same chemical class non-conservative substitution Replacing one amino acid by another belonging to a different chemical class may be expected to have more significant consequences. factors of non-conservative substitution One factor is whether the individual amino acid has an important role in the function of the protein, Additional factors include the potential effects on protein folding and protein structure, Some amino acids are not tolerated in certain structural elements exon skipping That can result in abnormal splicing patterns such as omission of an exon, Point mutations in these sequences often have marked effects on RNA splicing, especially if they change highly conserved nucleotides, such as in GT (GU in RNA) and AG dinucleotides at the extreme 5ʹ end and 3ʹ end, respectively, of an intron intron retention failure to splice out an intron activation of a cryptic splice site sometimes a sequence may be almost identical to a genuine splice donor or splice acceptor site (a latent or cryptic splice site), and changing a single nucleotide can cause it to become a novel splice site. Activation of cryptic splice sites produces truncated or extended exons miRNA disorder autosomal deafness, type 50 (MIR96 and MIR184 genes) snRNA disorder microcephalic osteodysplastic primordial dwarfism type 1 (RNU4ATAC gene) long ncRNA disorder type 1 autosomal dominant dyskeratosis congenital, susceptibility to anapestic anemia (TERC gene) Describe pathogenic mutations that are triggered by repetitive DNA Genes that have multiple large introns (which usually contain diverse types of repeats) are more prone to intragenic deletions. Quite often, large-scale pathogenic mutations are caused by exchanges between low-copy- number repeats that have very similar sequences (homologous repeats).