Ms1 Biochem Winter Test 1

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Genotype

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represents the genetic constitution of an organism. It is the summation of the entire DNA within the cell or organism

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Mutations

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Alter a genotype, Mutations can be from replication errors. Mutations are random

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Phenotype

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Also called trait, is the observable characteristics of cell or organism

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More about phenotypes

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A given phenotype arises from a genotype that develops within a particular environment. Both genotype and environment influence phenotype

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Types of mutations - based on molecular nature of the change

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Point mutations
Small insertions and deletions
Large insertions and deletions

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Point mutations

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Correspond to a singe base pair changing in the sequence of DNA

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Types of point mutations

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Transitions - purine for purine
Transversions - purine for pyrimadine

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Consequences of point mutations

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Missense - occurs in coding regions, can change a single amino acid
Silent - Change in the third base of a codon, no AA change
Nonsense - creation of a stop codon

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Point mutations that affect phenotype are usually . . .

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Missense or nonsense but not necessarily restricted to coding region

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Hemophilia B

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Point mutation - deficiency in coagulation Factor IX. It is found in the 5' untranslated region of the gene. it is an A to G transition

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Tay-Sachs (variant)

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Lysosomal storage disorder resulting in a deficiency of the lysosomal hexosaminidase-A protein from the hexA gene. GM2 buildup in neurons. A point mutation that alters mRNA splicing

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Sickle cell disease

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a missense mutation from a different amino acid in the B-globin peptide. a transversion A to T.

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Neurofibromatosis Type 1 (NF1)

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Variety of symptoms, cafe-au-lait spots, neurofibromas, scoliosis, learning disability. It is a nonsense mutation the indroduces a stop codon

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B-thalassemia

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decrease in the production of B-globin. Point mutations that affect transcription, splicing, coding, protein stability

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Frameshift mutations

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Small insertions or deletions that are not multiples of three.

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Tay-Sachs (most common variant)

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a 4 base insertions in the hexA gene. alters the reading frame (frameshift)

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Cystic Fibrosis (CF)

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the gene for CF is CFTR, the most common mutation is a three nucleotide deletion. Causes the loss of a single amino acid. CFTR is a chloride channel.

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Large insertion and deletions

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Large deletions or insertions are often the result of aberrant recombination between highly similar DNA sequences

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Red Green color blindness

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result of a large deletion.

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α-thalassemia

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three genes on the loci α1 α2 and ψα1. They are all very similar so mistakes are made during recombination. The mistake is called aberrant recombination.

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Charcot-Marie-Tooth disease (CMT)

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most common neurological disorder. Peripheral nervous system disease. Insertion of genetic material. The critical gene is PMP22 which encodes a peripheral myelin protein. Additional expression cases demyelination

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Mutations based on their effect on a phenotype

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Lethal
Conditional
Loss-of-Function
Gain-of-Function
Dominant
Haploinsufficiency
Epigenetic Changes

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Lethal mutations

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cause organisms to die. This often occurs during development resulting in miscarriage. Many dominant diseases are lethal in homozygous state

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Conditional mutations

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Depend upon enviromental conditions for manifestation.

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Loss of Function mutations

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this type of mutation results in a loss of activity of a gene product. It is not usually a total loss but a reduction in activity. common to recessive genes

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Gain of Function mutations

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result in an increase of protein activity or protein in a novel location. Common of cancers

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Dominant negative mutations

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it blocks normal gene activity. They affect genes which products must function as multimers. this is common of congenital malformations

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Haploinsufficiency

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it occurs when a loss of function mutation produces a phenotype in both the homozygote and heterozygote. 50% normal enzyme activity but not enough for normal phenotype. Homozygous is more severe than heterozygous

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Epigenetic changes

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not true mutations. represent alterations in phenotype without true genotype alterations. Methylation is an example. causes normally expressed genes to be silent. it is not a mutation and thus cannot be inherited

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Polymorphisms vs. Mutations

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Mutations are infrequent in the population and potentially harmful (less than 1%) Polymorphisms are DNA variations that are common in the population and usually not harmful (more than 1 %)

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Type of polymorphisms
(number of bases not number of repeats of bases)

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SNP - a single base
STRP - 2-5 base repeats (microsatellites)
VNTR - 14-500 base repeats (minisatellites)
CNV - millions of base pairs

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RFLP

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Analysis of polymorphism that can be used as a genetic fingerprint. CODIS is 15 VNTR's that can identify a persion. with few VNTR's it is better at excluding than including

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monogenic or Mendelian trait

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is defined as one produced by a single gene.Unifactorial inheritance or mendelian inheritance refers to traits resulting from a single gene.

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autosomal trait

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is one wherein the gene is localized to chromosome 1-22 (autosomes) rather than sex-linked (X or Y chromosomes) or mitochondrial.

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Gene

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is a DNA sequence that codes for the amino acid sequence of one or more polypeptide chains. It specifies an inherited trait.

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Locus

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is the location in the chromosome of a particular gene.

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Allele

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refers to one or more alternative forms that a gene may have in the population

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Principle of Segregation (First Law):

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Sexually reproducing organisms possess genes in pairs, and only one of each pair is transThe principle also states that genes remain intact and distinct in the next generation.mitted to a particular offspring.

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Principle of Independent Assortment (Second Law):

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Genes that reside at different loci are transmitted independently.
o The principle dictates that an allele transmitted at one locus has no influence on which allele is transmitted at another locus (i.e. it is all chance).
o Later, it would be shown that this law applies only to genes on different chromosomes or very far apart in the same chromosome.

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dominant

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the allele that determines how the trait will appear in an organism

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recessive

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the allele that is present in the genome but phenotypically masked by the dominant allele when present together.

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Homozygous

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indicates that two identical alleles are present for a given gene

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heterozygous

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indicates that both alleles for a given gene are different

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Punnett square

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is a table that allows us to predict the outcome of a particular breeding experiment.

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Probabilities

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Probability is defined as the proportion of times a specific outcome occurs in a given number of events.They are routinely used to provide couples with an understanding of the risks of producing a child with a genetic disorder.

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principle of independence

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Each event is independent of every other. The outcome of each event has no effects on subsequent outcomes.

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Multiplication rule (AND)

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In two independent trials, the probability of obtaining a given outcome in both trials is the product of their independent probabilities.

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Addition rule (OR)

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If we want to know the probability of one outcome or the other, we add the probabilities together.

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Gene frequency (i.e. allele frequency)

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is defined as the proportion of chromosomes that contain a specific gene in a population. Allele refers to the different forms, or DNA sequences, that a gene may have in a population.

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Genotype frequency

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is how often a given genotype occurs in the population.For example, in African-American population, approximately 1/500 newborns is

affected by sickle cell anemia (genotype ss).

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Population gene frequency vs. Individual gene frequency

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Utilizing estimates of gene frequencies, we can estimate an individual’s risk of
passing on a disease gene given their status in the population. We do NOT know if
they carry the mutated allele. in contrast, if D. L. is known to have a Cystic Fibrosis mutation, the frequency of this mutation in his offspring will be ~50% since he has a 50% chance of passing the gene with each child.

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Hardy-Weinberg principle

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p2 + 2pq + q2 = 1

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Proband or propositus

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is the first person in a pedigree to be identified clinically as having the disease in question.

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The hallmark of an autosomal dominant disease

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it requires only one disease allele for manifestation of the disease phenotype.

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most diseases that are inherited in a dominant fashion

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the result of genes whose products are nonenzymatic structural proteins

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Characteristics of autosomal dominant diseases

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1. Two sexes exhibit the trait in approximately equal proportions and both sexes are
equally likely to transmit the trait to their offspring. 2. There is no skipping of generations, in general. For example, if a child exhibits
polydactyly, then one of his parents must also have had the disease. This produces a vertical transmission pattern where the phenotype is seen in one generation after another.
3. Father-to-son transmission of the disease gene is observed. The presence of at least one father-to-son transmission excludes X-linked inheritance.
4. Affected individuals transmit the trait to approximately half of his or her offspring. Unaffected couples do not transmit the trait to their children.

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Huntington disease (HD)

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autosomal dominant. HD is a trinucleotide repeat expansion disease. The gene involved is HD (also named huntingtin), but the function of the protein encoded is unknown.

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Occurrence risk

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is the risk of producing an affected child when no children have yet been produced.

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Recurrence risk

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is the risk of producing another affected child when one or more children with the disease have already been produced.

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Achondroplasia

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autosomal dominant. Achondroplasia is produced by a point mutation in the 380th codon of the FGFR-3 gene. missense mutation results in a glycine to arginine substitution in the resulting protein. It is thought to be a gain-of-function mutation. Approximately 90% cases are the result of new mutations

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Achondroplasia is characterized by

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a short- limbed dwarfism.

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Neurofibromatosis Type 1

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autosomal dominant

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Marfan syndrome

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autosomal dominant. Disorder caused by mutations in the FBN1 gene that encodes fibrillin, a glycoprotein of the fibrous connective tissue.Marfan syndrome is characterized by disproportionate tall stature, arachnodactyly. Approximately 25% of cases are
the result of new mutations.

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Familial Hypercholesterolemia

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autosomal dominant. FH is caused by a loss-of-function mutation in the LDL receptor gene. It exhibits haploinsufficiency.

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hallmark of an autosomal recessive disease

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that it requires both disease alleles for manifestation of the disease phenotype.

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Autosomal recessive mutations

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Most autosomal diseases characterized to date have been mutations in genes that encode enzymes.

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Most genetic defects in metabolism are

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inherited in a recessive fashion.

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Characteristics of autosomal recessive inheritance

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1. Disease is usually seen in one or more siblings, but not in earlier generations.
There is usually no prior family history of the disease. Most affected individuals
are children of phenotypically normal parents. 2. Males and females are equally likely to be affected. 3. On average, 1/4 of the offspring of matings between two heterozygous carriers
will be affected. 4. Consanguinity is present more often in pedigrees involving autosomal recessive
diseases, especially rare autosomal diseases.

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Autosomal recessive pedigree

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A typical pedigree for an autosomal recessive disease shows how the disease
appears suddenly in a family and just suddenly leaves.

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Hurler syndrome

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autosomal recessive. is a type of mucopolysaccharidosis, a lysosomal storage disease.
o It is the result of a defect in the gene that codes for -L-iduronidase. Hurler syndrome is characterized by skeletal abnormalities, short
stature, mental retardation, corneal clouding and course facial features.

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Hereditary Hemochromatosis (HH)

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autosomal recessive. HH is a disorder of iron overload, as a result of a mutation in the HFE gene. Most cases of HH are produced by a single missense mutation.

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Complications to Patterns of Inheritance

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New (or de novo) mutations
Germline mosaicism
Delayed Age of Onset
Reduced Penetrance
Variable expression
Pleiotropy and Heterogeneity
Genomic Imprinting

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New (or de novo) mutations

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All the remaining germ cells in the parent are likely normal for this gene, so the recurrence risk in other siblings is low. However, the occurrence risk for the affected child’s offspring would be high (50%). Many observed cases of autosomal dominant diseases turn out to be new mutations. o Achondroplasia: ~ 90% new mutations
o NF1: ~ 50% new mutations

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Germline mosaicism

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When two or more offspring present with an autosomal dominant disease and there is no family history of the disease, then germline mosaicism must be considered.During development of the parent, a mutation occurred that affected all or some of the germ cells, but not enough of the somatic tissue to produce a phenotype. osteogenesis imperfecti (OI)

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The recurrence risk in a case of OI with germline mosaicism is higher/same/lower than the recurrence risk in a case of achondroplasia produced by a new mutation.

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higher

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Delayed Age of Onset

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Huntington disease or hemochromatosis are well-known examples of delayed age
of onset.

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Penetrance

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indicates the proportion of individuals carrying a particular genotype that also express the associated phenotype.

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reduced penetrance

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An individual who has the genotype for a disease but does not exhibit the disease phenotype. This person can still transmit the disease to later generations.

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Variable expression concerns the severity

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is independent of penetrance. The penetrance is complete, but the severity of the disease can vary greatly.

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pleiotropy

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a single gene exerts its effects on multiple aspects of physiology or anatomy. Cystic fibrosis, Marfan syndrome, von Gierke disease and diabetes are good examples of pleiotropic diseases.

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heterogeneous disease

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is one where mutations at different gene loci can produce the same phenotype. More than one gene can be responsible for the disease, but it is only one deficient in each person. Osteogenesis imperfecti

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Genomic imprinting

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refers to the differential activation of genes, depending on the parent from which they are inherited. The transcriptionally inactive genes are said to be imprinted.

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Angelman syndrome

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(UBE3A) encodes a protein involved
in ubiquitin-mediated protein degradation, which is strongly expressed in the brain. The lack of expression of this gene produces the phenotype in Angelman syndrome.

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Prader-Willi syndrome

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one of them is SNRPN, a small nuclear riboprotein expressed in the brain. The lack of expression of SNRPN or any of the other genes involved in Prader-Willi syndrome produces the phenotype.

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Anticipation

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A genetic disease that displays an earlier onset and/or more severe expression in more recent generations of a pedigree exhibits anticipation.

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Studies on myotonic dystrophy, fragile X syndrome and Huntington disease have identified the molecular explanation for this anticipation.

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DMPK (myotonic dystrophy protein kinase) revealed that the disease is caused by an expansion of a trinucleotide repeat

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Trinucleotide repeat expansion

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The number of repeats often increases in succeeding generations, thus explaining the earlier onset and/or severity and the phenomena of anticipation. It is believed that slippage by DNA polymerase during DNA replication is the cause.

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Consanguinity

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Consanguinity is mating between related individuals. It is rare in Western populations, but still common in many parts of the world.

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genetic load

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It has been shown that matings between related individuals produce a high frequency of mortality.
It is estimated that each person carries five recessive genes in heterozygous form that would result in a lethal phenotype if they were present in a homozygous state.

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Phases of the cell cycle

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G1, S, G2, M

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PhasesofMitosis

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Prophase Prometaphase Metaphase Anaphase Telophase

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Entrance into the cell cycle is stimulated by

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the exposure of cells to mitogens (signaling molecules that stimulate cell division).

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A cell that is not proliferating is said to be

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“arrested” in the phase G0.

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G1 phase

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In G1, the cell begins to replicate its non-chromosomal contents (enzymes, metabolites, etc.) so that each daughter cell will have the appropriate supply of cellular components necessary for its survival.The cell also begins making proteins that will be needed for DNA replication

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S phase

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Each of the 46 chromosomes is duplicated by the cell, with each daughter chromosome remaining attached to the parental chromosome from which it was replicated.
Remember that the DNA is still loosely arranged at this point to allow access by the replication machinery.

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G2 phase

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Proteins needed for mitosis are also made during this phase.
The cell also double-checks duplicated chromosomes for errors, making any needed repairs.

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interphase

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The cell division phases in which the cell components are not actively being separated from each other (G1, S, G2)

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G1 and G2 phases are referred to as

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“gap” phases where the cell is not actively replicating DNA or physically dividing.

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M phase

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As a result of the events in mitosis, a cell with 2x the normal amount of cellular contents divides to become two daughter cells.

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mitotic spindle

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Centrosomes at separate poles of the cell create several types of microtubule protein networks that are collectively referred to as the mitotic spindle.

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kinetochore

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is a protein complex that connects each chromatid to the mitotic spindle

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centromere

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is the region of DNA within each chromatid that joins sister chromatids together, and contains special sequences of DNA that attach to
DNA proteins of the kinetochore.

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Prophase

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The cell is considered to be in prophase when individual chromosomes have condensed to the point of being visible as discrete objects in the light microscope.

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Prometaphase

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The onset of prometaphase is defined as the point in which the membrane of the nuclear envelope begins to break down.

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Metaphase

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A cell is in metaphase when the chromosomes, which are now maximally condensed, align at the metaphase plate.

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Anaphase

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At the beginning of anaphase, the two sister chromatids begin to separate.
The microtubules within the spindle get shorter and shorter, pulling sister chromatids (via their kinetochore “handles”) toward opposite poles of the cell.

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Telophase

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The chromosomes begin to decondense, and a nuclear envelope reforms around each group of daughter chromosomes.

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Cytokinesis

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Cytokinesis divides the cytoplasm in two, completing the process of cell division.
Cytokinesis begins during anaphase and is usually completed in telophase.
Cleavage depends on a belt-like bundle of actin microfilaments called the contractile ring

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Chromosome Number In Mitosis

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These cells are referred to as 2n, a notation which reflects the number of copies of homologous chromosomes present in the cellWhen the cell goes through S phase, each of the 46 chromosomes is duplicated by the cell (now 4n)..

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synapsis

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The close pairing of maternal and paternal duplicated chromosomes during meiosis I

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Meiosis Vs. Mitosis

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In Mitosis, all duplicate chromosomes line up at the metaphase plate.
In Meiosis I, homologous sister chromatids derived from both parents line up side by side with each other (4 chromatids side-by-side). Each set of homologous chromosomes then lines up end-to-end along the metaphase plate.

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Meiosis I

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Meiosis is always preceded by DNA replication of a diploid cell (2N4N). The cell begins Meiosis I with 46 duplicated chromosomes (ie 46 “X”-
shaped molecules), 23 maternal and 23 paternal.

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Meiosis II

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At the end of meiosis I, two daughter cells have formed, each of which has 23 pairs of sister chromatids (i.e. 23 “X”s).
The two daughter cells then undergo a second phase, meiosis II, which is very similar to mitosis.

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Lyon hypothesis

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suggests that one of the two X chromosomes of females is randomly inactivated in every somatic cell.

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dosage compensation

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Without it, females would have
twice the product for almost any gene residing on the X chromosome.

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X inactivation

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is random. is permanent. Females have two distinct populations of cells, with either the paternal or the maternal X chromosome inactivated. Females are mosaics for the X chromosome.

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hemizygous

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Males have only one copy of the X chromosome, and are not mosaics but hemizygous for the X chromosome (“hemi” means “half”).

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Barr body

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The inactive X chromosome can be detected cytologically as a dense staining chromatin mass in interphase somatic cells

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Mechanism of X inactivation

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X inactivation starts at the X inactivation center (XIC), which contains the gene XIST XIST RNA coats the inactive X chromosome, which could be a signal leading to other aspects of X inactivation.
 X inactivation is also associated with high methylation

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About 15% of genes on the X chromosome escape inactivation

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Genes located on the pseudoautosomal regions (PAR1 and PAR2)

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Sex-linked inheritance

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Sex-linked genes are those that are located on either the X or the Y chromosome. Since relatively few genes (~255) are known to be located on the human Y chromosome, all discussion of sex-linked diseases will focus on the X chromosome.

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X-linked recessive inheritance

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Males are therefore much more likely to manifest an X-linked recessive disease.

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Characteristics of X-linked recessive inheritance

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1. The trait is much more frequent in males than in females 2. There is NOT father-to-son transmission of the disease gene. The presence of
father-to-son transmission excludes X-linked inheritance. 3. The disease can skip generations by being passed to carrier females.

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X-linked recessive diseases

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Some notable X-linked recessive diseases include:
oHemophiliaA:defectinfactorVII o HemophiliaB:defectinfactorIX o Lesch-Nyhansyndrome
o Duchennemusculardystrophy o Red-greencolorblindness
oSeverecombinedimmunodeficiency
o Ornithinetranscarbamylase

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Red-green color blindness

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However,
color blindness is rare among females.In most cases, color blindness is the result of aberrant recombination of the opsin
genes

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Hemophilia

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Caused by mutations on the coagulation factor VIII (hemophilia A) or factor IX
(hemophilia B). Hemophilia A is 5 times more common than hemophilia B.

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Duchenne muscular dystrophy (DMD)

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Muscular dystrophy is characterized by a progressive weakness and loss
of muscle, and it can present in many different forms. The most common and most debilitating form is DMD, caused by mutations in the dystrophin gene.

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Most mutations leading to DMD

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are deletions that cause frameshifts resulting in complete absence of dystrophin protein.

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Other mutations in the dystrophin gene lead to other types of muscular dystrophy.

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Becker muscular dystrophy is usually the result of in-frame deletions that allow for partial protein function.

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X-linked dominant inheritance

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Fragile X syndrome. It is characterized by mental retardation, distinctive facial appearance (large ears, long face). It is caused by a trinucleotide repeat expansion (see lecture #3) in a gene called FMR1: the number of repeats increases in succeeding generations, which explains the phenomena of anticipation.

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Characteristics of X-linked dominant diseases.

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1. Affected males cannot transmit the disease to their sons, but they transmit the disease to 100% of their daughters. 2. Females are twice as likely to be affected as males. However, the expression is less severe in female heterozygotes than in affected males. 3. Typical mating would be between a normal male and a heterozygous female. 4. Vertical transmission pattern 5. There is NOT father-to-son transmission of the disease.

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sex-influenced traits.

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Some autosomal traits are expressed more frequently in one sex than in another

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Male pattern baldness

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Sex-influenced traits are modified by the sex of the individual possessing the trait, which explains the higher expression in one sex than another.

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sex-limited trait

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In the extreme, when only one sex is affected, it is referred to as sex-limited trait. It is generally due to anatomical differences, but not to genetic differences.

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Unusual features of mitochondria

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Replicative segregation o There is no tight control of mtDNA segregation, as opposed to chromosomal DNA. o The multiple copies of mtDNA in each mitochondrion in a cell replicate and sort
randomly among newly synthesized mitochondria.

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heteroplasmy

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When a daughter cell received a mixture of mitochondria, some with the
mutation and some without the mutation

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homoplasmy

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When a cell, by chance, received mitochondria that contain only a pure
population of either normal mtDNA or mutated mtDNA

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Maternal inheritance

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Therefore, all mtDNA is inherited from the mother.

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Mitochondrial inheritance

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For diseases caused by mutations in mtDNA, only females can transmit the diseases to their offspring. Since mitochondrial inheritance has a very unique pattern of inheritance, it is called non-mendelian inheritance.

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Mitochondrial diseases

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Since the primary function of mitochondria is ATP production, mtDNA mutations will especially affect those cell types most dependent on a continuous supply of ATP: muscle and central nervous system are the most affected tissues.

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Some examples of mitochondrial diseases include:

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o CPEO (Chronic Progressive External Ophthalmoplegia) o Kearns-Sayre syndrome o Leigh syndrome o LHON: Leber Hereditary Optic Neuropathy o MELAS: Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like
episodes. o MERRF: Myoclonic Epilepsy with Ragged Red Fibers o Pearson syndrome