sgu genetics Flashcards

Terms Definitions
Huntington's Disease
Autosomal Dominant, triplet repeat expansion disorder in coding region, worse as more expanded (Anticipation), delayed onset at 40 years. CAG repeats. Polyglutamate.
Achondroplasia
Autosomal Dominant, FGFR3 gene, prone to germline mosaicism (gonadal mutation)
Retinoblastoma
Autosomal Dominant, 90% Penetrance, RB1 gene, Tumor suppressor gene, Two hit mutation to cause disease.
Familial Hypercholesterolemia
Autosomal Dominant, haploinsufficiency.
Myotonic Dystrophy
Autosomal Dominant, variable expression, triplet repeat expansion disorder in NON-coding region, worse as more expanded (Anticipation). CTG repeats.
Marfan Syndrome
Autosomal Dominant, variable expression, pleiotropy as well, fibrin mutation.
Osteogenesis Imperfecta
Autosomal Dominant, variable expression, (prone to gonadal mosaicism), blue sclera, multiple childhood fractures.
Neurofibromatosis Type 1
Autosomal Dominant, mutation in tumor suppressor gene Neurofibromin, small, soft, benign skin growths. 100% penetrance. Some cases of epilepsy and CNS tumors. 50% caused by new mutations.
Acute Intermittent Porphyria
Autosomal Dominant, heme synthesis enzyme mutation
Tuberous Sclerosis
Autosomal Dominant, Pleiotropy, causing several different problems.
Hereditary Hemochromatosis
Autosomal Recessive, incomplete penetrance, delayed onset
Cystic Fibrosis
Autosomal Recessive, CTFR gene for Chloride channel TM protein. Most cases are F508 mutation, can scan for this, but there are many many other mutations that can cause CF, long arm of Chromosome 7. (Displays Cholera resistance). Use ASO to scan for this.
Tay Sachs
Autosomal Recessive, Caused by frameshift mutation, insertion of 4 bases. Hexosaminidase A. more common among Ashkenazi Jews. 4 base insertion into Hexosaminidase A gene. Accumulation of gangliosides. Allelic Heterogeniety (several mutations can cause this, frameshift is most common).
Phenylketonuria (PKU)
Autosomal Recessive, more common in Irish and Scottish
Xeroderma Pigmentosum
Autosomal Recessive, defect in DNA nucleotide excision repair (NEC) mechanism. Suceptible to Melanoma. Light sensitive, skin rashes. there is a substitution in a base for the XPA gene (common with Japanese). In the USA, mutations in the XPC Helicase is more common. An increase in sister chromatid exchange is seen in these patients after UV exposure.
a-B-Thalassemia
Autosomal Recessive, Arab, Medeitteranean, Asian more common. (Plasmodium Falciparum Resistance) a-Thalassemia Can be splice site mutations. A) loss of splice site, intron added to protein. B) NEW splice site, part of exon lost from protein. Both non-functional.
Sickle Cell Anemia
Autosomal Recessive, HBB gene, (Plasmodium Falciparum Resistance) Missense mutation (Glutamine to a Valine). In B6 b-globulin gene. Causes Anemia and RBC clumping due to poor solubility of HbS. Causes infarctions widespread out the body, and Splenomegaly. Missense Mutation in b-globulin gene B6, causing Glu to a Val, causing poor solubility of the HbS protein. Causes Ishemia by RBC clumping and anemia due to destruction of RBCs in the spleen.
Bloom Syndrome (Congenital Telangiectasia)
Autosomal Recessive, Due to BLM Helicase gene mutation, due to lots of recombination. Growth deficiency, pigmentation, photosensitivity, erythema (skin telanglectasia), cancer suceptible.
Ataxia Telegiectaxia (ATM)
Autosomal Recessive. ATM initiates repair due to DS breaks. Related to ATR, which repsonds to Hypoxia, UV damage, replication damage. Causes increase in cancer susceptibility, due to lack of repair. Lympomas, tumors, sensitive to radiation.
Duchenne Muscular Dystrophy (DMD)
X-linked Recessive, DMD gene, can be mild symptoms in females due to uneven X-inactivation (lyonization)
Fragile X Syndrome
X-linked Dominant, Anticipation (repeat expansion in the mother). CGG repeat causes Methylation of the FMR-1 Gene
Hemophelia A/B
X-linked Recessive, FVIII gene, lyonization
G6P Deficiency
X-linked Recessive, malarial resistence, Plasmodium Falciparum Resistance (Malaria)
Incontinetia Pigmenti
X-linked Dominant, so all sons have it and only mothers pass it. Females will get it with mosaicism.
Vitamin D resistent Ricketts
X-linked Dominant
Charcot Marie Tooth Diesease
.
SRY Gene, H-Y hisocompatibility antigen
Y-linked
Night Blindness
Heterogenetity, Autosomal Recessivity. Need Both genes, ROM1 and Peripherin degenerate rods to get this.
Mitochondrial Diseases
Passed by the mother's Gametocytes via mitosis, will appear in every child from that affected mother. Variability, Penetrance, Plieotropy.
LHON (Leber's Hereditary Optic Neuropathy)
ND4 gene, blindness, Mitochondrial Mutation
MELAS
Mutation in Mitochondrial DNA, Mitochondrial Enchepalopathy, Lactic Acidosis, and Stroke-Episodes. Ragged Red Fibers in muscle. tRNA leuUUR gene is responsible. Several point mutations. May be due to heteroplasmy, explaining variability in individuals. Also takes some time to develop enough mutant mitochondria, so develops later.
Angelman's
Imprinting, Methylation of the Chromosome 15q11-q13 in the Father, Mutation in the Maternal UBE3A Genes.
Prader Willi
Imprinting, Methylation of the Chromosome 15q11-q13 in the Mother, Mutation in the Paternal SNRPN Genes
Down Syndrome (47, XX, +21)
Wide, slanting forehead (brachycephaly), single simeon crease on hands (Clinodactyly), GI abnormalities, Mental Retardation, Brushfield spots on iris, adult cataracts. Trisomy 21, Nondisjunction in Meiosis I or II, OR ADJACENT 14-21 Robertsonian Reciprocal Translocation, two satellite chromoesomes join together. Translocation can end up with 3 copies of chromosome 21. (47, XX, +21)
Patau Syndrome (47, XX, +13)
Trisomy 13. Cleft Lip, polydactyly, Microthalmia, mental retardation, lethal heart defects, fatal. Can detect Polydactytly on Ultrasound.
Edward's Syndrome (47, XX, +18)
Trisomy 18. Rockerbottom Feet, Clinched hands, Congenital heart defects, Fatal. Can see Rockerbottom feet on ultrasound, clinched hands, also Exomphalos.
Klinefelter's Syndrome (47, XXY)
XXY, girly, trisomy, velvet breasts, tall, osteoporosis, testicular atrophy, extra X is inactivated, but causes symptoms since not all genes are inactivated. Low sperm count. There is a bar body in these Males!!!
Turner's Syndrome (45, X0), may be Mosaic (46, XX), 47(XXX)
X, monosomy. Webbed neck, short. Overweight, wide nipples, broad chest, infertile. Ammenorhea (no menstruation). No bar body in females in (45, X) cells with Turners!!
Cru du Chat Syndrome
difficulty, swallowing, mental retardation, microcephaly, high pitched catlike cry, caused by DELETION on Chromosome 5p15.2
Familial Breast/ovarian cancer
Mutations in BRCA1 and BRCA2 cause breast cancer susception, causing faulty HRR. Has delayed onset
Colorectal Cancer
MYH Polyposis (colon cancer) disrupts Base excision repair, and HNPCC due to mutations in MLH1 on Chromosome 2, or MSH2 on Chromosome 3. Disrupts MMR (mismatch repair)
Diabetes Mellitus Type 1
Mutigenic in 99% of cases. Less than 100% concordance in twins. Environmental AND genetic. More than 20 genes involved.
Diabetes Mellitus Type 2
early onset cases had 50% condordance in twins before age 45, and no diabetic parents. highly environmental. 100% concordance after age 45, with half having a diabetic parent. So 100% genetic for delayed onset.
Alzheimer's Disease
Can be a Promoter mutation, increaing the amyloid precursor protein synthesis. Causes plaques. Dementia, B-amyloid protein mis folding and aggregation due to insolubility. Familial and Sporadic. Familial is < 10%. ALL are early onset <65years. Dominant inheritance. Sporadic, associates with APOE4 Gene on Chr. 19, 25% population is heterozygoing for mutant gene (4X increased risk, 10X in homozygous (2% pop)). Aluminum exposure supposed increase in likelyhood.
Hemophelia B
clotting factor 9 mutation, promoter mutation, severe deficiency in IX until pubery, when androgens upregulate the synthesis.
Retinoblastoma
RB1 gene is a tumor suppressor gene. TWO HIT hypothesis. Both copies of the gene must be mutated for a phenotypic mutation.
X-inactivation
XIST Gene involved in this process. In female, or kleinfelter's males, where more than one X chromosome exists, during Embryo development, X-inactivation occurs, where one X-chromosome is mostly, but not completely inactivated. It can be seen in cells as a Bar Body remnant. It can be mosiac in which X is inactivated.
Heteroplasmy
Mixed mitochondrial genes, some mutant, some normal. Explains variability in mitochondrial diseases.
Homoplasmy
Either both normal, or both mutated genes.
Anupliody
Single genes are altered
Euploidy
Whole chromosomes are altered, added or deleted
Polyploidy
Whole genome altered, (ex. 3 copies of every chromosome).
Digynic Polyploidy
Non-Molar placenta. Two sets of maternal chromosomes. ("Di-gina, two ginas.")
Diandric Polyploidy
Molar. Two sets of Paternal chromosomes. ("Di-andy, two Andy's")
Trisomy, Tetrasomy, Monosomy, Disomy
3 copies of a chromosome, 4 copies, 1 copy, 2 copies (normal)
Heterodysomy
Nondysjunction in Meiosis I, causing germline mosaicism. Causes 2 haploid cells with no copies, and 2 with 2 copies of the chromosome.
Homodysomy
Nondysjunction in Meiosis II, causing germline mosaicism. Causes 1 empty haploid cell and one with 2 copies of a chromosome, + 2 normal ones.
Anticipation
Refers to the repeat expansion diseases, huntingtons, myotonic dystrophy… the more expanded, the younger, and more severe the disease.
Germline (gonadal) Mosaicism
refers to mutations in the gamete cells by the parents, resulting in and explaining abnormal and variable diseases.
Translocation
The breakage and re-joining of parts of chromosomes. Can be balanced (functional), or unbalanced (dysfunctional)
Robertsionian Translocation
The long arms of two chromosomes join around a centromere, in place of small, satellite arms. Can result in 14/21 Downsyndrome, normal, or fatality.
Alternate Segregation
Robersonian translocation that results in BALANCED chromosomes, nonviable. Will result in Normal gametes.
Adjacent Segregation
Robersonian translocation that results in UNBALANCED chromosomes, nonviable, Carrier, or Down syndrome in the case of 14/21 R.trans
Deletion
Can result in Cru Du Chat syndrome, Ch5p15.2 DELETION. loss of genes.
Inversions
Removed, inverted, re-inserted genes. Can be pericentric or paracentric.
Pericentric Inversion
Balanced and unbalanced. Revolves around the centromere (included). Always has a centromere on the chromatids.
Paracentric Inversion
Balanced and unbalanced. WORSE. End up with two centromeres on a chromatid, and one with none, cell cant handle this.
G banding
detects 5Mb mutations
FISH
Detects 1.5Mb mutations, understand which mutations will be visible on the karyotype, and which need FISH. Needed for Williams Syndrome, Prader Willi, Angelman, Velocardiofacial Syndrome/Di George's
Amniocentesis
Amnoitic Fluid aspirated guided by Ultrasound, screened for a-fetoprotein. Can increase miscarraige by 1%. Can be done at 16 weeks.
Chorionic Villus Sampling
Remove fetal cells by aspiration from inner surface of placenta, increases possibility of misscarraige. Can be done at 11-12 weeks, sooner than amniocen.
Polymorphisms
mutations that do not cause a deleterious phenotype. Examples are G6P variants, a-1antitrypsin variants, ABO blood groups,
SNP's (single nucleotide Polymorphisms)
Often associated with adverse drug reactions
STR's or VTNR's (Short Tandem Repeats)
Very good marker for DNA fingerprinting using PCR, sequencing, restriction enzymes, Southern Blot Probing. Very variable between individuals, used for forensic fingerprinting. IMPORTANT: Can prove NOT the father with one loci better than is the father. Must use multiple loci to do this.
Structural Variants
Deletions, Inversion, dupilications. Most associated with human variability.
Tautaumerism
The incorporation of a wrong base
Oxidative Damage to DNA
Causes transversion, tautaumerism, damaged G's pair with A's, instead of C.
DNA Pol
Has 3'-5' exonuclease Proof Reading ability.
Single Base Excision Repair
ROS, Alkylation, Deamination, Abasic (depurination/pyrimidization), or single strand breaks due to energy. DNA glycosylates remove the wrong base. Example would be MYH Polyposis.
XPA, XPF, XPG
XPA is a helicase and holds nucleotide excision repair open, the others indicate snip sites to remove wrong nucleotide string. In Xeroderma Pigmentosum, there is a substitution in a base for the XPA gene (common with Japanese). In the USA, mutations in the XPC Helicase is more common.
MMR (Mismatch Repair)
Important post replication mechanism to fix Expansion repeats. MSH proteins recognize, MLH1/PMS2 recruit exonuclease. DNA Pol, adds bases which were removed.
Hereditary Non-Polyposis Colorectal Cancer (HNPCC)
Autosomal Dominant. Mutation in gene's for MLH1 on Chromosome 3, or MSH2 on Chromosome 2. (90%). Genetic Predisposition for cancer. Screen with colonscopy starting at age 25. Look for Microsatellite expansions, which will accumulate in those with this mutation. Mutation in MMR (mismatch repair)
BLM Helicase
Resolves Holiday junctions in Double strand Break, non-homologous end joining repair. (DSB, NHEJ). Also inhibits crossing of of sister chromatids.
Bloom Syndrome (Congenital Telangiectasia)
Autosomal Recessive, DNA Ligase mutation. Due to BLM Helicase gene mutation, due to lots of recombination. Growth deficiency, pigmentation, photosensitivity, erythema (skin telanglectasia), cancer suceptible.
HRR (Homologous Recombination Repair)
BRCA1promotes HR, and BRCA2 stimulates it. BLM helicase resolves the holiday junctions between adjacent chromatids. DNA pol fills in gaps. Uses
Ataxia Telegiectaxia (ATM)
Autosomal Recessive. Mutation in Topoisomerase ATM initiates repair due to DS breaks. Related to ATR, which repsonds to Hypoxia, UV damage, replication damage. Causes increase in cancer susceptibility, due to lack of repair. Lympomas, tumors, sensitive to radiation.
MMR (Mismatch Repair)
HNPCC (colon cancer, MLH1 or MSH2 genes)
NHEJ, HRR (non-homologous end joining, homologous recombination repair)
corrects double strand breaks, like Breast Cancer (BRCA1/2), or Bloom Syndrome (BLM)
BER (Base excision repair)
MYH Polyposis (colon cancer)
NER (Nucleotide excision repair)
Xeroderma Pigmentosum (XPA in japanese, XPC in USA).
Haploinsufficiency
Familiar Hypercholesterolemia, one mutation in LDL receptor, other gene cannot make up for it.
Dominant-negative loss
Osteogenesis Imperfecta, collagen 1A1 or 1A2, affects dimer/multimer protein, or protein interferes with normal proteins
Gain of function
Huntington's disease, overexpression of CNS proteins, neurological degeneration, usually dominant mutations.
Silent Mutations
Will not change Amino Acids (redundancy), BUT can add splice sites or affect splice enhancers!!
Neutral Mutation
Changes the amino acid, but same type (non-polar ex.) so no effect on protein.
Missense Mutation
Changes crucial amino acid in protein function. Can be complete loss, partial loss (hypomorph), gain in function (hypermorph), or change in function (neomorph). Sickle Cell Anemia (Glutamine to a Valine). In B6 b-globulin gene
Nonsense Mutation
mutation causes a Stop Codon.
Frameshift
insertion or deletion of bases, that arent multiples of 3. Tay Sach's disease caused by insertion of 4 bases.
Genetic Testing Bad Idea
Could onset after death, penetrance, allele heterogeneity (could be caused by other mutations), locus heterogeneity, (cant test for all mutations)
Linkage Analaysis
Testing for RFLP or SNP or VNTR nearby the mutation, which are commonly associated with the mutation, since it is in such close proximity. There IS a chance that recomination could separate the allele marker and the mutation, but the closer they are, the smaller this chance. Cystic Fibrosis uses this, theres 2 markers 10kb away from the mutation. this is an indirect method.
ASO (Allele specific oligonucleotide Probes)
Used for point mutations or short aberations
Southern Blots
Used for larger aberations. Fragile X is tested with this. You CAN test for CF (3 base deletion). Triplet repeats, like Fragile X and Huntington's needs this.
FISH
NEVER use FISH for CF. Used for chromosomal changes and large insertions, deletions.
Proto-oncogenes
molar. Two sets of Paternal chromosomes. ("Di-andy, two Andy's")
Oncogenes
a mutated proto-oncogene, V-onc is a viral oncogene, causing host cell to become cancerous, and C-onc, a cellular mutation, causing cancer. INCREASE in function genes. DOMINANT mutations.
Myeloid Leukemia
Translocation of ABL oncogene from Ch. 9 to Chr. 22. Causes a fusion of BRC and ABL proteins, which is permanenely active, overexpressive. Inhibits DNA repair and increases cell cycle.
Burkitt Lymphoma
Translocation of c-MYC gene from Chr.8 to Chr. 14. (90% of cases). Codes for Enhancer boxes, and recruiting histone acetyltransferases. (HAT's and E-boxes). MYC genes related to Cancer, as well as Growth Factors.
Tumor Suppressor Genes
creaetes a nucleus with 92 chromosomes, instead of 45. Can re-create cancer when cells lose chromosomes. Will not cause cancer, but will aide in worsening the cancer once it starts. LOSS of function genes. RECESSIVE mutation.Neurofibromatosis, Retinoblastoma RB1, P53 are examples.
Retinoblastoma
RB1 gene is a tumor suppressor gene. TWO HIT hypothesis. Both copies of the gene must be mutated for a phenotypic mutation.
Familial Adenomatous Polyposis (FAP)
APC gene on Chr. 5, tumor suppressor gene. Inherited Autosomal Dominant, alike to HNPCC. Requires a second hit mutation/deletion to cause the cancer.
Multifactorial Diseases
Genes at multiple loci, polygenic diseases. Cleft Lip, Diabetes, Autism, Schitzophrenia, Neural tube defects, depression, hypertension, cardiac defects. Alzheimerz, Diabetes, Obesity
Liability Curves for Mutifactorial Disorder
Way of explaining inheritance. Multiple factors, graph has a Threshold. The more factors contributing to possible inheritance (people affected, closeness, environmental, etc), the graph is shifted to the right towards the threshold. Above the threshold, the disease is seen in the dividual. Can be faulty, is predicative, not Absolute.
Parents/Siblings
share 1/2 of genes, also those with a carrier sibling has a 1/2 chance of being a carrier themselves.
Grandparents, half siblings, cousins
share 1/4 of genes
1st cousins, Third degree family
share 1/8 of genes
2nd cousins
share 1/32 of genes
Sex Predisposition
A particular sex may be more susceptible to a particular disorder, due to being more polygenic or other factors.
Multifactorial Inheritance
The square root of the population incidence of a multifactorial disease = risk of siblings/offspring of having the disease.
Dizygotic Twins (DZ)
Ferternal twins, share 50% of genes.
Monozygotic Twins (MZ)
Identical twins, share 100% of their genes. Nearing 100% concordance if disease is completely genetic, but less so if environmental factors are involved. Should be the same concordance with DZ if completely environmental disorder.
Concondance
The percentage that twins have the same disease. Testing Monozygotic concordance measures the genetics of the disease, testing the Dizygotic concordance measures the enviromental influence. Whichever percentage Is higher shows which factor contributes to the disease.
Discordance
Percentage that twins don't have the same disease.
Heriditability
Heritability = (Variance in DZ - Variance in MZ) / Variance in DZ . The proportion of variayion caused by genetic, rather than environmental factors. For a completeley genetic disorder. Should be variance - 1/variance. So, proportion of
Relative Risk (RR)
measures relative risk of getting a disease. The frequency that the individual may contract the disease if the individual has a particular marker for it. Taking in account environment, can predict increase in Risk for particular persons. Percentage of those with a predisposition (allele w/risk /total) : to those without the predisposition (alleles/total). Example was smoker/cancer : non-smoker/cancer = 5.8X more likely.
Odds Ratio (OR)
compares relative odds of occurance. Tells you how much more likely you are of having a disease if you have the allele, vs not having it. Disease w/allele / no disease : disease w/o allele / no disease.
Modifier Genes
Genes which, do not cause a disease, but once a disease is present, make the condition much worse/better.
Idiopathic Chronic Pancreatitis
10-40% have 2 mutations in the CFTR gene, but don't have Cystic Fibrosis, however These are modifier genes, since those with CF get a much more severe case because of this.
Association Studies
like Linkage analysis for multigenic diseases. Can find a common SNP or marker that is common amongst most combinations of the disease, but still is not a great tool for measuring heredity.
Genotype Frequency
P2, 2PQ, Q2
Allele Frequency
The number of alleles, out of total. Homozygous counts for two.
Disease Incidence
In an autosomal recesssive disorder, the disease incidence is q^2 (square root = allele frequency, then use p2 +2pq +q2). In X-linked Recessive, q=disease incidence in males. Female heterozygocity = q2
MSS, a-fetoprotein
16 weeks, high a-FP signifies neural tube defects example, spina bifida. Low a-FP signifies Down's syndrome.
Triple Test (a-FP, un-estroil down, Gonadotropin UP
16 weeks
Ultrasound Timing
18weeks, can see trisomy defects
Amniocentesis Timing
16 weeks
Chorionic Villus Sampling Timing
10-12 weeks
Chronic Myelogenous Leukemia
9-22 translocation. ABL - know this gene, Philidelphia Chromosome, proto-oncogene
Burkit Lymphoma
8-14 Translocation. c-MYC gene, BEC Polyposis
FAP (Familial Acute Polyposis)
APC gene on Chr. 5, tumor suppressor gene. Inherited Autosomal Dominant, alike to HNPCC. Requires a second hit mutation/deletion to cause the cancer.
RAS Gene
Oncogene, GTP signalling, causes cancer if mutated.
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