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.
Alu family
example of SINEs Short Interspersed repetitive elements. (dispersed repetitive elements) ~300 bp and 500,000 copies in genome
L1 family
example of LINEs Long INterspersed repetitive elements (dispersed repetitive elements) ~6 Kb and 100,000 in genome.
Duplication rich genome structure promotes non-allelic homologous recombination (an aberrant recombination mechanism).
Ex: segmental dynamic mutation–NAHR b/t blocks of segmental duplication during meiosis leads to microdeletion (No copy) and microduplication (double dose) of the unique region bracketed by duplications. If the region contains dosage sensitive genes then disease may result.
minisatellites
type of insertion-deletion polymorphism (indel) 10-100bp tandemly repeated DNA VNTR (variable number of tandem repeats)
Microsatellites
2,3,4 nucleotide repeats. >50000 per genome Short Tandem Repeat Polymorphisms (STRP)
Single Nucleotide Polymorphism (SNPs)
1 in 1000 bp. PCR-detectable. widely distributed.
Gene family & duplication
genes with high sequence similarity (>85-90%) that may carry out similar but distinct functions. Arise through gene duplication, a major mechanism of evolutionary change. Rationale: 1 copy can retain function while the duplicate is free to innovate. Usually at a disease locus.
Copy number variations
Variation in segments of genome from 200bp-2Mb. Can range from 1 additional copy to many. primary type of structural variation. May cover 12% of genome.
examples of Structural Variation
copy # variation. Insertion/deletion. Inversion. Duplication and translocation.
Segmental Duplications
segmental duplications usually occur right next to gaps. about 5% of genome is a segmental duplication. >10 Kb and >95% sequence similarity.
DUP1220 in 1q21
Variations in copy number of DUF1220 in 1q21. Deletions result in Microcephaly and associated with Schizophrenia. Duplications result in Macrocephaly and associated with Autism. We have more than double that of apes.
Missing heritability problem
Despite genome-wide association studies SNPs found only account for 1-2% of genetics. Maybe the heritability lies in the unexamined parts of the genome?
Mitosis Vs. Meiosis
1) Paternally and Maternally derived chromosomes line up at Meiosis (Prophase I). 2) Reciprocal recombination events between maternal and paternal sister chromatids generate chiasmata (crossing over/physical linkages) between homologs.
Describe the basic steps of Meiosis
Maternal and Paternal homologous chromosomes line up. 2) DNA replication creates sister chromatids 3) Crossing over and homologous chromosomes separate 4)Another meiotic division separates the sister chromatids into 4 gametes.
Meitotic Prophase I
Maternal and paternal homologs pair and synapse along entire length forming bivalents (tetrads) and forms a proteinaceous structure called a synaptonemal complex which promotes inter-homologue interactions.
Meiotic Recombination
Physical links known as chiasmata are formed between homologs. 2-3 crossovers on each chromosome. Synaptonemal complex disassembles at end of Prophase I then bivalents only held together by chiasmata
Trisomy 21 (47, XX, +21)
Down Syndrome: short stature, transverse palmar crease, clinodactyly, wide sandal gap, hypotonia, moderate intellectual abilities, congenital malformations (endocardial,gastrointestinal anomalies, Hirschprung diesease) Early onset alzheimers. ~1/900 incidence
Trisomy 18
Edwards syndrome. Intrauterine growth retardation, Hypertonicity (clenched hands,narrow hips) severe intellectual disabilities, characteristic hand position. Congenital malformaitons (valvular heart disease, posterior fossa CNS maldevelopment, diaphragmatic hernias, renal anomalies. 1/7500 incidence.
Trisomy 13
47 XY or XX +13 Patau syndrome. severe intellectual disabilities. Congential malformations- heart disease, holoprosencephaly, facial clefts, polydactyly, renal anomalies, omphalocele. 1/22,700 incidence
Klinefellter Syndrome
47,XXY. Tall stature, hypogonadism, elevated frequency of gynecomastia, high frequency of sterility, language impairment, underdeveloped secondary sexual characteristics. 1/1000 incidence. 1/2 of cases from paternal meiosis I errors= failure of recombination in pseudoautosomal regions. 15% of cases result from mosaicism 46, XY/47, XXY
47, XYY syndrome
Indistinguishable physically or mentally from XY males. Usually fertile. 1/1000 incidence. Error in paternal meiosis II. produce YY sperm. Increased risk for behavioral and educational problems, delayed speech and language skills.
Turner Syndrome
45 X. short stature,webbed neck, edema of hands and feet, broad shield-like chest, narrow hips, renal and cardiovascular anomalies, gonadal dysgenesis (failure of ovarian maintenance – sterile) >99% of 45, X fetuses abort spontaneously. 1/4000 incidence. 25% are mosaic.
Numerical abnormalities
Triploidy, Trisomy, Monosomy, Mosaicism
Structural abnormalities
Deletion, Inversion, Duplication, insertion, ring, marker
Metacentric
the centromere is located in the middle of the chromosome, such that the 2 chromosome arms are approximately equal in length
Submetacentric
the centromere is slightly removed from the center.
Acrocentric
the centromere is near one end of the chromosome
Maternal age effect
“two-hit” theory. 1st hit is diminished recombination, caused either by lack of chiasma or their mislocation, resulting in a chromosome more susceptible to possible nondisjunction. 2nd hit is diminished ability of oocytes over time to successfully complete chromosome segregation in the presence of recombination events (deterioration in cellular machinery that segregates homologous chromosomes). Another Theory is that cohesion degrades between sister chromatids over ~40 years
Most frequent mutational mechanism in humans
chromosome non-disjunction in maternal meiosis I (most error-prone step)
Genetic consequences of meiosis
1) diploid–> haploid 2) random segregation of Mom and Dad Homologs = 2^23 possibilities 3) Random shuffling of genetic material due to crossover events increase in gnetic variability
occurs in somatic cells and germ line precursor cells prior to meiosis
Mitosis
Type of cell division that occurs only in the germ line
Meiosis
Banding patterns
result from the differential staining of various chromosomal regions ex: high G-C or high A-T, heterochromatin via dyes (ex: Giemsa) allows for exact ID of chromosome
p
short arm of chromosome (petite)
q
long arm of chromosome
How is a chromosome numbered?
Numbered outward from centromere
69XXX, 69 XXY, 69 XYY
Incompatible with life. Generally sponateonous miscarried.
Mechanisms of non-disjunction
1) Chiasmata too near or too far from centromere. Centromere distal exchanges –> poor spindle attachment and separation of paired homologs. Centromere-proximal or excessive exchanges =entanglement 2) Reduced or absent recombination increases likelihood of non-disjunction
Mosaicism
2 genetically different cells in tissue from single zygote or person. Common Cause: nondisjunction in early postzygotic mitotic division. 47, XX +21/46, XX (mosaic down syndrome); 46, XX/46, XY (true hermaphroditism)
Germ line mosaicism
somatic mutation in early development and generates a mutant sub-population of germ cells
2 Types of Structural abnormalities
1) Balanced – normal complement of genetic material. No loss of genetic material. 2) Unbalanced – additional or missing chromosomal material
Inversion
double strand break then intervening sequence is inverted prior to rejoining.
Paracentric Inversion
Inversion that excludes centromere
Pericentric Inversion
Inversion that includes the centromere
Carriers of a paracentric inversion ________
Produce abnormal gametes. During pairing of homologs in meiosis a loop must be introduced so that the homologous regions match up. If crossover occurs within the inverted region of a paracentric region dicentric or acentric chromosomes can be made which are highly unstable and contain deletions.
Carriers of a pericentric inversion ________
Produce abnormal gametes. During pairing of homologs in meiosis a loop must be introduced so that the homologous regions match up. If crossover occurs within the inverted region of a pericentric region chromosomes are made that contain deletions/duplications.
Reciprocal Translocation
breakage and rejoining of non-homologous chromosomes, reciprocally exchanging the broken segments
Reciprocal Translocation pairing and segregation at Meiosis 1
form a quadrivalent figure in which the homologous regions from the unaffected and translocated chromosomes match up. Then they can segregate in 1 of 3 ways. 1) Alternate segregation (most common) produces gametes with normal chromosomal complement or 2 reciprocal chromosomes that are balanced. 2) Adjacent segregation 1 and 2 lead to unbalanced gametes (partial monosomy/partial trisomy)
Reciprocal Translocation disease example?
Reciprocal translocation between 9 and 22 results in BCR (breakpoint cluster region) and abl (proto-oncogene kinase) fusion which upregulates cell division and leads to Chronic Myelogenous Leukemia. Philidelphia chromosome. 46, XX t(9;22) (q34;q11.2)
Robertsonian Translocation
fusion of 2 acrocentric chromosomes resulting in loss of the short (p) arms (containing rDNA repeats). Result in reduction of chromosome # but are balanced b/c loss of some rDNA repeats not deleterious. Carrier=phenotypically normal. Offspring =monosomy/trisomy; 50% gametes unviable. Meiotic translocation forms a Trivalent (1 fusion + 2 normal Chr.). Can give rise to Trisomy 21. 46, XX der(14;21) (q10;q10) +21 Most common in 14 and 21 45, XX or XY der(14q;21q)
Deletion
loss of genetic info (haploinsufficiency) via simple chromosome breakage and rejoining, unequal crossing over between misaligned homologous chromosomes or sister chromatids, abnormal segregation of balances translocation or inversion.
Interstitial deletion
Either deletes acentric fragment (rest of chromosome survives) or centric fragment (leaves all pieces unstable). These fragments can circularize into a ring chromosome.
Cri-du-chat syndrome
46, XY, del (5)(p15). microcephaly, characteristic cry, seizures and intellectual disabilities.
Isochromosome
a chromosome in which one arm is missing and the other arm is duplicated in a mirror-like fashion. Most common involves long arm of X chromosome. Small percentage of Down syndrome have 46, XX i(21)(21q21q) 100% of offspring from this phenotypically normal carrier will be abnormal.
Mechanisms that lead to Down Syndrome (5)
1) 95% of Down’s = Meiosis I nondisjunction. 2) 4%=Robertsonian translocation 3) Isochromosome 4) Mosaic Down Syndrome 5) Very rare= Partial trisomy only portion of 21 duplicated
Contiguous Gene Syndrome
Abnormal phenotypes caused by over-expression or loss (haploinsufficiency) of neighboring genes. Caused by Non-allelic homologous recombination when 2 repetitive sequences cross over and lead to unequal crossing over (deletion or duplication).
Charcot-Marie-Tooth disease
Autosomal dominant duplication of 17p11.2 containing gene for peripheral myelin protein-22. One of most common inherited neurological disorders (1/2500). Foot and lower leg muscle weakness. Foot deformities, hammertoes, weakness and muscle atrophy of the hands later in disease.
Hereditary neuropathy with predisposition to pressure palsy (HNPP)
deletion of peripheral myelin protein 22
Velocardiofacial syndrome
microdeletion of 22q11. Autosomal dominant. Cleft palate, lateral nasal buildup, cardiac septal defects
DiGeorge syndrome
microdeletion of 22q11. Autosomal dominant. absent or hypoplastic thymus and parathyroids, congenital heart disease, characteristic facies.
Epigenetics
mitotically and meiotically heritable variations of gene expression not caused by changes in DNA sequence. ex: post-translational modifcations of histones, DNA methylation=altered chromatin structure. Affect gene expression.
Genetic imprinting
Allele-specific methylation of CpG dinucleotides in the promoters of imprinted genes, established in one of the 2 germs lines in gametogenesis. The methylation recruits methyl CpG binding proteins that transcriptionally silence those genes. Genes inherited in a transcriptionally active or inactive state from both mom and dad.
Characteristics of Imprinted genes (3)
1) clustered, not distributed equally among all 23 Chr. 2) Contain both materally and paternally imprinted genes. 3) Imprinted genes encode both proteins and non-coding regions. ~1% of genes are imprinted.
Characteristics of the Epigenetic mark (methylation)
1) must be established in gamete 2) must be stably maintained in somatic cells after fertilization 3) must be reversible so it can be reset in gametogenesis to transmit appropriate sex-specific imprint to progeny.
Maintenance Methyltransferase
Propagates the epigenetic mark (methylation) in somatic cells. When DNA replicates (semi-conservative) the half-methylated DNA requires re-methylation which maintenance methyltransferases do.
How are sex-specific patterns of methylation established during gametogenesis
1) fertilization of a paternally imprinted Chr 15 with maternally imprinted Chr 15. 2) Conception: somatic cells of embryo are coded with maternal and paternal imprints 3) Erasure (demethylation) of embryo’s gamete chromosomes and conversion to all female or all male (se-specific) imprinting patterns depending on sex of embryo.
Chromosomal mutations on imprinted loci
Parent of origin effects based on which parent’s homolog has been deleted or duplicated
Prader-Willi Syndrome
obesity, hyperphagia, short stature, small hands & feet, hypogonadism, intellectual abilities. Deletion of long arm on Chr. 15 from Paternal homolog. (15q11-q13). Normal maternal homolog is imprinted. defects in SNORD116 snoRNA- alternative splicing.
Angelman Syndrome
unusual facial appearance, short stature, severe intellectual disabilities, spasticity, seizures. Deletion on maternal Chr. 15 homolog. paternal Chr. is imprinted. Defects in expression of UBE3A= ubiquitin ligase involves in early brain development.
Uniparental disomy
Occurs via reduction of trisomy 15 to normal 46 chromosomal complement by loss of (ex:) paternal homolog. This is essentially a “rescue” from a trisomic fetus resulting from maternal non-disjunction. In this example Prader Willi would result.
In which disease is Uniparental Disomy more common, Angelman or Prader-Willi?
Prader Willi results from UPD 25% of the time compared with Angelman which occurs from UPD only
