Copy of Molecules to Medicine Unit 2_ Genetics - Sheet1 Flashcards
Proband
The affected member through whom a family with genetic disorder is first brought to the attention of the geneticist
alleles
alternative variants of a gene
Pleiotropic
a single abnormal gene or gene pair produces multiple diverse phenotypic events and determines which organ systems are involved, which particular signs and symptoms occur, and when they occur. Ex: Neurofibromatosis Type I
Homozygous
identical alleles encoded in nuclear DNA
Heterozygote or carrier
different alleles encoded in nuclear DNA
Hemizygous
A male has an abnormal allele for a gene located on the X chromosome and there is no other copy of the gene
Hemophilia A and B
X-linked recessive disease characterized by bleeding, hematomas, and hemathroses. Classically a male disease although females can be affected via rare skewed X chromosome inactivation.
Hemophilia A
Mutation to the F8 gene that causes deficiency or dysfunction of clotting factor VIII
Hemophilia B
Mutation to the F9 gene that causes deficiency or dysfunction of clotting factor IX
Risk for hemophilia if mother is carrier
each son has 50% risk of hemophilia. Each daughter has 50% risk of inheriting the F8 or F9 mutation (carrier). Since skewed X chromosome inactivation is rare daughters have a low risk of inheriting hemophilia.
Risk of Mother being carrier if she has a son with hemophilia
98% of mothers of a male with one of these hemophilia mutations are carriers due to a mutation in their father (affected male’s maternal grandfather). Point mutations and the common F8 inversions almost always arise in male meiosis, while deletion mutations usually arise during female meiosis.
Dominant
Phenotype expressed when only 1 chromosome of a pair carries the mutant allele and the other chromosome has a wild-type allele at that locus. Alleles which exert their effects over other alleles in the heterozygous state.
Recessive
Phenotype expressed only when both chromosome of a pair carry mutant alleles at that locus
Autosomal
chromosomal location of a gene locus on chromosomes 1-22
Sex-linked
On chromosome X or Y
Autosomal affect males and females ___________
equally
Recessive mutations usually result in ______ of function
Loss. They reduce of eliminate the function of the gene product. Many recessive diseases are caused by mutations that impair or eliminate the function of an enzyme. A heterozygote with only 1 pair of alleles functioning can make ~50% of the product made by wild-type homozygotes.
Codominant & provide example
both traits (alleles) are expressed in the heterozygote. Example: Blood type ABO.
Semi-dominant or incompletely dominant
Heterozygous phenotype is intermediate between the 2 homozygous phenotypes. And disorder is more severe in homozygote.
Mendelian Inheritance
disorders that are due to the predominant effects of a single mutant gene.
Mendel’s First Law: Law of segregation
At meiosis, alleles separate from each other such that each gamete (egg or sperm) receives one copy from each allele pair.
Mendel’s Second Law: Law of Independent Assortment
The segregation of each pair of alleles is independent. (physical linkages violate this law)
Genotype
Molecular sequence in an individual’s DNA
Phenotype
Observable expression (of a genotype) as a morphological, clinical, cellular, or biochemical trait
Penetrance
The probability that a gene will have any phenotypic expression at all. Fraction of individuals with a (disease) trait genotype who show manifestations of the disease. Analogous to a light switch– either On or Off. 100% Penetrance= all people with the mutation express the disease.
Reduced/Incomplete Penetrance
If some mutation carriers do NOT show signs of the trait. More commonly encountered.
Expressivity
The degree to which a trait is expressed in an individual; measure of severity. Analogous to a dimmer– brightness (expressivity) is on a spectrum of severity. Variation can be explained by sex influence, environmental factors, stochastic (chance) and modifier genes.
Neurofibromatosis (NF1)
Autosomal dominant disease. Common disorder of the nervous system, eye, and skin. Multiple benign fleshy tumors (neurofibromas) in the skin, flat irregular pigmented skin lesions (cafe au lait spots), small beningn tumors (hamartomas) Lisch nodules on the iris of the eye, and less frequently mental retardation, CNS tumors. Example of pleiotropic phenotype.
Achrondroplasia (short-limbed dwarfism)
Dominant disease that produces short height ~4’4’’ (in heterozygote). Mutation Gly380Arg. Normally do not encounter homozygous recessive because it is lethal.
Sex Influence/limitation
Sex Influence= gout more common in males than in premenopausal females. Sex limitation= if only one sex can express phenotype (uterus, prostate)
Human genome is record of human evolutionary history
reflects selections pressures (ancient environment) that have occurred over evolutionary time and shaped genome. Adaptive features have been retained.
Gene order on a chromosome: in order or out of order?
Normally genes are distributed on a chromosome in a non-linear fashion. Beta globin is an exception whose genes are ordered in a developmental way from fetus to adult. There are also large differences between genes in terms of size and distance of introns and exons.
Random variation is the fuel of evolution: what are the 2 outcomes and which is more common?
Random variation almost always results in deleterious consequences (rarely do good random mutations occur). Genetic disease is the price we pay for to continue to have a genome that can evolve and adapt to changing environments.
Genome dynamicity
~30 new mutations occur in each new individual. Results from meiotic recombination shuffling of regions. Average of 1 SNP every 1000 bp between any 2 randomly chosen unrelated people. 99.9% the same 3,000,000 differences. Can produce somatic as well as germ line DNA changes
Gene Rich chromosome
Chr19
Gene poor regions
Chr 13, 18, 21 (these are all viable trisomies)
Stable vs Unstable regions of the genome
Majority = stable. Unstable, dynamic regions = many are disease-associated SMA (Chr 5q13); DiGeorge syndrome (Chr22q); 12 diseases (1q21)
GC-rich vs. AT-rich regions
GC:38% AT:54% clustering of GC-rich and AT-rich regions is basis for chromosomal banding patterns
Chromosome size and gene #
The number of genes on a chromosome does not necessarily correspond to the size of the chromosome
Euchromatin
more relaxed regions of DNA. Focus of Human Genome Project
Heterochromatin
More condensed and repeat rich regions of DNA. Essentially unsequenced.
% of protein coding DNA
1.50%
Gene representation in genome including exons, introns, flanking sequences
20-25%
Single copy sequences
Compose 50% of genome
Repetitive DNA
40-50%
Tandem repeats or Satellite DNAs
ex: A-T-T-C-G-A-T-T-C-G-A-T-T-C-G. Some particular pentanucleotide sequences found as part of human-specific heterochromatic regions on long arms of 1, 9, 16 and Y. These are hot spots for human-specific evolutionary changes. alpha satellite repeats (171 bp repeat) found near centromeric region of all human chromosomes– may be important for chromosome segregation in mitosis and meiosis
Dispersed repetitve elements
May have short and long INterspersed repetitive elements. May facilitate aberrant recombination events between different copies of dispersed repeats —> disease (via Non-allelic homologous recombination.
