genetics exam2

3 causes of prader willi syndrome

- the inheritance of a deletion (15q13) from the father -uniparental disomy where both chromosome come from the mother - imprinting defects where the father imprints the region like the mother rather than like the father.

4 causes of angel man syndrome

- the inheritance of a deletion (15q13) from the mother, -uniparental disomy where both chromosome come from the father -imprinting defects where the mother imprints the region like the father rather than like the mother. -A few cases are caused by mutations in the UBE3A gene. angleMAN (father)

mitochondrial genome

1 circular chromosome , no non coding sequences with 37 genes packed into 16569 bas pairs

what are the three important features of mitochondrial inheritance

1. males and females are equally affected 2.only affected mothers pass the trait on to their children 3.all of their children are affected (only mother contributes to genotype) (the egg contributes the mitochondria)

the mitochondrial genome consists of 37 genes that encode for --- subunits of enzyme involved in oxidative phosphorylation as well as ribosomal RNA's and transfer RNA's required for translating the transcripts of the mitochondria encoded polypeptides

13

in the mitochondrial gene there are 37 genes ---- RNA genes encoding part of the translation machinery of mitochondria and --- individual proteins

24, 13

Mitochondrial function requires both mitochondrial and nuclear genes mitochondrial inheritance patterns is --- while mendelian inheritance patterns are ----

37 genes, >1000 genes

the rate of inheritance for an autosomal domination disease

50%

bottleneck effect

A change in allele frequency following a dramatic reduction in the size of a population

genetic drift

A change in the allele frequency of a population as a result of chance events rather than natural selection.

dominant negative mutation

A heterozygote produces a nonfunctional altered protein that also prevents the normal gene product from functioning

Hemophilia A

An X-linked recessive disorder in which blood fails to clot properly, leading to excessive bleeding if injured.

Lynch Syndrome (HNPCC)

Autosomal dominant non-polyposis syndrome with high risk of CRC

Pompe disease

Autosomal recessive glycogen storage disorder - deficiency in lysosomal enzyme GAA results in accumulation of glycogen in muscle tissue

Defects in the -----gene lead to the development of Cystic Fibrosis. But the symptoms experienced by the patient can be vastly different depending on the activities of modifier genes.

CFTR

Tumor suppressor genes (caretakers)

Caretakers: maintain the integrity of genome by assisting in DNA repair: BRAC1, BRAC2, MSH2, MLH-1, WT-1, NF-1

Beckwith-Wiedemann Syndrome (BWS)

Caused by IGF2 over expression due to a lack of imprinting that in turn is caused by improper epigenetic modifications which lead to a gain of methylation.

loss of function mutation

Causes the complete or partial absence of normal function.

is a measure of the loss of fitness and is defined as 1 −f, i.e., the proportion of deleterious alleles that are not passed on and are therefore lost as a result of selection.

Coefficient of selection (s)

Mosaicism

Condition in which regions of tissue within a single individual have different chromosome constitutions.

Methylation of DNA is catalyzed by

DNA methyltransferases (DNMTs) DNMT3A and DNMT3B (responsable for Lenovo synthesis) DNMT1( maintains existing methylation patterns)

CpG islands

DNA regions rich in C residues adjacent to G residues. Especially abundant in promoters, these regions are where methylation of cytosine usually occurs. (at least 200bp and GC percentage is greater than 50%)

Rett Syndrome *X-linked dominant

Defect in MECP2 (binds to methylated DNA) Develop normally then regress Microcephaly Hand-wringing Seizures Autistic Features

Beta Thalassemia

Disease in which insufficient beta-globin chains are produced and there is an excess of alpha chains

Alpha Thalassemia

Diseases in which there are insuffiecient alpha-globin chains due to gene deletions (expressed early in life causes more life than beta )

a dominantly inherited skeletal dysplasia with dispropriate short stature and deformity of the forearms (common more in females )

Dyschondrosteosis (pseudoautosomal inheritance)

what are the increased environmental factors for deep vein thrombosis

Factor V leiden allele and prothrombin allele

checkpoints throughout the cell cycle

G1 ,G2,M

Refers to any situation where a single actor influences a wide variety of downstream effects. Pleiotropic genes are single genes that influence multiple cellular pathways and therefore could result in several maladies or diseases that affect multiple organ systems of an individual.

GENETIC PLEIOTROPY

p2+2pq+q2=1

Hardy-Weinberg equation

Li-Fraumeni Syndrome (LFS)

Inherited TP53 mutations: 70% patients have p53 mutations A hereditary cancer predisposition syndrome

Mitochondrial Encephalopathy, Lactic Acidosis, and stroke-like episodes (MELAS)

MELAS caused by the point mutation in MT-TL1 occurs later in life and the symptoms are milder than other mitochondrial diseases. This occurs when the mutation is present in a relatively low heteroplasmy threshold.At a higher hetoroplasmy percentage the same mutation produces the symptoms of Leigh syndrome. caused by mtDNA mutations

Leigh Syndrome

Mitochondrial disease caused by defects in themitochondrial respiratory chain complexes. This is a heterogeneous disease that can be caused by mutations in 75 different genes(some show mendelian inheritance.Some show mitochondrial inheritance) There are 5 mitochondrial respiratory complexes with defects noted in each one:mitochondrial complex I-most commonly affected complex accounting for 33% of the cases, mutations in NDUFA12 (nuclear gene) just one of 25 different genes that could be affected.

do Y linked diseases skip generations?

No (all males affected)

factors that can disturb hardy weinberg principle

Non-random mating (example1 - the aa genotype is not capable of reproduction) (example 2 - red heads marry only red heads) 2. New Mutations (less or more viable genotype produced) (think how a new gene starts in a population) 3. Selection (Most colorful bugs get eaten) (An individual doesn't live long enough to reproduce) 4. Population shifts (change in population size can lead to genetic drift) 5. Gene flow (migration) into or out of the population.

incomplete penetrance

Not all individuals with a mutant genotype show the mutant phenotype (treacher -collins syndrome) TCOF 1 (autosomal dominant)

uniparental disomy

Offspring receives 2 copies of a chromosome from 1 parent and no copies from the other parent.

Heteroplasmy

Presence of both normal and mutated mtDNA, resulting in variable expression in mitochondrial inherited disease

TNM Staging System: most widely used (exception: brain & spinal cord tumors, blood cancers)

Primary Tumor (T) = refers to the size and extent of the main tumor Regional Lymph Nodes (N) = refers to # of nearby lymph nodes w./ cancer Distant Metastasis (M) = presence & extent of metastasis or spread

Circular double-stranded DNA One origin of replication and only two promotersAlmost all coding sequence Overlapping transcripts and some overlapping genes Multiple genes per transcriptNo splicing, but the RNA is processed Genetic code is different:AUA specifies methionine not isoleucine UGA encodes tryptophan not a stop codon AGA and AGG are stop-codons not arginine Reduced recombination Several copies of the genome per organelle.

Properties of the Mitochondrial Genome

Skewed X inactivation

Rare instance in which a female displays symptoms of an x-linked recessive disease because by chance, the working allele has been deactivated where it matters (duchenne muscular dystrophy)

MECP2 gene

Rette syndrome X-linked, binding protein binds to methylated CpG island

is and autosomal recessive disease that can be caused by mutations in different genes. It is possible to have this pedigree.

Sensorineural Deafness

Autosomal Recessive Inheritance

Skips generations, usually seen in only 1 generation. 25% of offsprings from 2 carrier parents affected. Often due to enzyme deficiencies, more severe than dominant disorders; symptoms presents in childhood.

cancer stages

Stage 0:Abnormal cells present but have NOT spread (may also be called "in-situ")Not "cancer", but may become cancerous Stage I - III:Cells are cancerous.The higher the classification, the larger the tumor and the more invasive Stage IV:Cancer has metastasized to distant sites

is defined as the rate at which new mutations occur per generation and the mutation/selection balance is were the number of alleles lost due to selection is offset by the introduction of alleles due to mutations. [μ = sq]

The mutation rate(μ)

Heritability

The proportion of variation among individuals that we can attribute to genes. The heritability of a trait may vary, depending on the range of populations and environments studied.

LOD score

The ratio of probabilities that two genes are linked to the probability that they are not linked, expressed as a log10. Scores of 3.0 or higher are taken as establishing linkage.

Mitochondrial Depletion Syndromes:

There are mutations in several genes that lead to the syndromes listed above. However, the main gene affected is usually DNA polymerase gamma (POLG). This is a nuclear encoded gene that has functions in both the nucleus and the mitochondria. An A467T mutation is the most common mutation and some forms are caused by a (CAG)n repeat also found at the 5' end of POLG. For all of these syndromes the net result is a loss of mitochondrial genomes rather than a mutation in the mitochondrial genome.

Chimerism

Two or more genetically different cell lines within a single individual derived from different zygotes

X-linked recessive

What pattern of genetic transmission affects only M and has no M-to-M transmission, and mother is usually an unaffected carrier. mom usually passes on gene to half the kids when father has the disease only the daughters will be carriers . if the mom also is a carrier the daughters will get the disease skips a generation

Beckwith-Wiedemann

Wilms tumor, macroglossia, organomegaly, hemihypertrophy (WT2 mutation)

X-linked hypophosphatemia

X linked dominant

Rett Syndrome

X linked dominant, lethal in males, results from a mutation in the X-linked gene methyl-cytosine binding protein (MeCP2), symptoms include loss of speech and acquired hand skills, seizures, and irregular breathing and motor control problems

•The trait is common in a pedigree •Trait does not skip generations •Fathers pass the trait on to all of their daughters but cannot pass them on to their sons •Males and females affected nearly equally. males die in utero affects half the females

X-linked dominant

red-green color blindness

X-linked recessive

TDF/SRY

Y linked genes

oncogene

a gene that in certain circumstances can transform a cell into a tumor cell.

homeoplasy

a similar structure or molecular sequence that has evolved independently in two species

p53 gene

a tumor-suppressor gene that codes for a specific transcription factor that promotes the synthesis of proteins that inhibit the cell cycle

p+q=1

allele frequency

Wilms tumor (nephroblastoma)

linked to a loss of imprinting on chromosome 11

in the context of genetic disease refers to the phenomenon whereby symptoms become apparent at an earlier age with each generation and in many cases, increase in severity with each generation.

anticipation

Achondroplasia brachydactyly huntingtons disease

autosomal dominant

Neurofibromatosis

autosomal dominant

Affected children usually have at least one affected parent .•Two affected parents can produce an unaffected child (if both are heterozygous). •Two unaffected parents will not have affected children. •Both males and females are affected at equal frequency .•Heterozygotes are affected (if zygosity is known) •Fathers can pass trait on to sons and daughters. •Mothers can pass traits on to sons and daughters. •The incidence rate among children approaches 50%

autosomal dominant inheritance features

Tay-Sachs disease (deficiency in HexA enzyme) •Phenylketonuria (PKU, deficiency in the phenylalanine hydroxylase enzyme metabolizing phenylalanine into tyrosine) •Cartilage-hair hypoplasia dwarfism (CHH)

autosomal recessive disorder

sickle cell disease

autosomal recessive disorder change in the beta subunit causes glutamic acid to be replaced by valine casing HbS. (caused by point mutation in the gene for hemoglobin beta) SOB, tachycardia, pallor, nail bed deformities, lethargy. lab- sickledex (detect presence of HbS) and Hgb electrophoresis determines if trait.

•Most Affected children have unaffected parents .•Two unaffected parents can produce an affected child .•Matings between an affected parent and an unaffected parent can produce unaffected children. (in other words, the disease can skip a generation) •The disease frequency is low (1 in 4 at most) in most pedigrees, but with enough information one finds that males and females are affected at equal frequency. •Heterozygotes are unaffected (if zygosity is known)•Matings between affected mothers and affected fathers produce all affected children .•Matings between one affected and one unaffected parent may yield no affected children or half of the children are affected .•Affected fathers may not pass trait on to sons and daughters, but can pass them on to the children of their children. •Affected mothers may not pass trait on to sons and daughters, but can pass them on to the children of their children.

autosomal recessive inheritance

gain of function mutation

causes the appearance of a new trait or function or causes the appearance of a trait in inappropriate tissue or at an inappropriate time

founder effect

change in allele frequencies as a result of the migration of a small subgroup of a population

mitocndiral chromosome

circular piece of DNA similar to bacteria

Lever hereditary optic neuropathy

develops in young adult with painless, bilateral subacute visual failure males 5X more likely than females to be affectedfemales with the disease may go on to develop an MS-like illness Diagnosis is based on the findings of visual impairment (legally blind), which presents a significant impact on quality of life. Most LHON patients (90%) have one of 3 identified point mutations in the mtDNAm. 3460G>A, m. 11778G>A or m.14484T>Cmutations affect different respiratory chain complex I subunit genes Management: largely supportive, provision of visual aids, occupational therapy. Families with known risk: members should be encouraged to avoid alcohol and smoking or other environmental exposures that might exacerbate disease

Heritability (Zero)

environment is totally responsible for the phenotypic variance

refers to the proportion of signs and symptoms that an individual with a genetic disorder may exhibit

expressivity

p=

frequency of dominant allele

2pq=

frequency of heterozygous genotype(Aa)

p2=

frequency of homozygous dominant genotype (AA)

q2=

frequency of homozygous recessives (aa0

q=

frequency of recessive allele

hertibability of 1

genes are totally responsible for the phenotypic variant

is the phenomenon wherein mutations in different genes or different locations of the same gene can produce the same disease.

genetic heterogenity

are genes that may increase or reduce the penetrance, expressivity, age of disease onset, rate of progression, and severity of a phenotype. They are not the primary cause of the disease, but modify the observed phenotype.

genetic modifiers

Russel-Silver Syndrome

growth retardation, small triangular shaped face, 1/3 caused by imprinting abnormality that eventually lead to diminished growth, 10% of cases from a maternal uniparental disomy. (due to lack of methylation)

the condition where an individual possesses only one copy of a gene

hemizygous

sickle cell anemia shows ---- against malaria

heterozygote advantage

in autosomal dominance most individuals are ---

heterozygous

Lyon hypothesis

in females with XX genotype, one X is inactivated after zygote formed during embryonic development

Barr bodies

inactivated X chromosomes found only in females

concordance rate

indicates the percentage of twin pairs or other pairs of relatives who exhibit the same disorder

tumor suppressor genes (gate keepers)

inhibit cell proliferation/promote apoptosis of cells with DNA damage: p53, RB1, APC, p16

Charcot-Marie-Tooth (CMT)

is a disease that impairs nerves to the hands and feet and causes muscle weakness. It is the most common inherited neurological disorder. It can be caused by genetic mutations in any of 39 genes. CMT1A results from a duplication of the PMP22 gene on chromosome 17 that carries instructions for producing the peripheral myelin protenin-22. This gene has an autosomal dominant form of inheritance. Mutations in SH3TC2 result in the autosomal recessive Charcot-Marie-Tooth disease type 4C. This gene is on chromosome 5. CMTX2 and CMTX3 are located on the X chromosome and can carry X-linked dominant disease mutations.

Imprinting

is an epigenetic phenomenon involving DNA methylation of specific regions of the genome so that certain genes can be expressed in a parent -of -origin- specific manner (associated with the methylation of CpG islands near certain genes)

Mutations in ------gene that cause a form of Emery-Dreifuss muscular dystrophy

lamin A

imprinting control region (ICR)

located near the imprinted gene, contains binding sites for one or more proteins that regulate the transcription of the imprinted gene

polycistronic

mRNA codes for more than one protein. Found mainly in Prokaryotes.

consanguinity

mating between related individuals

metabolites are produced in the --- and used not he nucleus

mitochondria

Lever hereditary optic neuropathy

mitochondrial

Kearns-Sayre Syndrome

mitochondrial DNA defect causing mutations in complex II of the ETC -people present with short stature, complete external ophthalmoplegia, pigmentary retinopathy, ataxia, and cardiac conduction defects) The most common deletion removes 4,997 nucleotides, which includes twelve mitochondrial genes.

Myoclonic epilepsy with ragged red fibers (MERRF)

mitochondrial disease, mutation in tRNA gene, affects neurons and muscle cells (that require large amounts of ATP), heteroplasmy -produces multiple deficiencies of enzyme complexes on the respiratory chain1. NADH-CoQ reductase (complex 1)2. cytochrome c oxidase (COX) (complex IV)

Von Willebrand Disease

most common inherited bleeding disorder autosomal dominant

gene flow

movement of alleles from one population to another

Neuropathy, ataxia and retinitis pigmentosa (NARP)

mtDNA gene = ATP6 (one subunit of ATP synthase) Symptoms appear when 70-90% of the mitochondria carry the mutation-makes a protein essential for mitochondrial functioN

Adrenoleukodystrophy

mutation in ABCD1 gene X linked disorder affecting males disrupts metabolism of VLCFA which build up in the nervous sytem tests and adrenal gland

digenic inheritance

mutation on two genes interacting to cause a genetic phenotype or disease

nuclear genome is composed of 23 linear chromosomes , 2 copies per nucleus , many non coding elements and one coding gene per 100000 base pairs

nuclear genome

human genome =

nuclear genome + mitochondrial genome

is where the amount of increase between generations is different depending on whether the diseased allele is inherited from the mother or the father.

parental bias

refers to the proportion of people with a particular genetic change such as a mutation in a specific gene ) whole exhibit signs and symptoms of the genetic disorder

penetrance

a certain number of alleles for the trait must be present before it appears phenotypically

polygenic threshold traits

Imprinting

primarily shuts down gene expression at imprinted (methylated) CpG islands. It is one of the ways that uniparental disomy causes disease. Another is the inheritance of two recessive genes from the same parent. Imprinting has large affects during fetal growth, but it also influences gene expression in adulthood. In some cases a gene might be suppressed during fetal development but expressed specifically in the adult tissue. This is also why D is the correct answer. The actual imprinting is de novo methylation, which is carried out by DNMT3A and DNMT3B.

Hardy-Weinberg Principle

principle that allele frequencies in a population will remain constant unless one or more factors cause the frequencies to change (mating are random)

Methylation of CpG islands

shuts down gene expression

subgroups within a population that remain genetically distinct but geographically co-localized.

stratification Stratification can lead to increases in distinctly different minor allele frequencies in the separate populations.

Proto-oncogenes

the corresponding normal cellular genes that are responsible for normal cell growth and division

pseudoautosomal inheritance

the inheritance pattern of genes that are found on both the X and Y chromosomes. Even though such genes are located physically on the sex chromosomes, their pattern of inheritance is identical to that of autosomal genes

population genetics

the qualitative description of genetic variation in a a population and how gene frequencies and genotypes are maintained or changed

assertive mating

theory stating that people find partners based on their similarity to each other

Mitochondrial Neurogastrointestinal Encephalopathy Syndrome (MNGIE):-also known as POLIP Syndrome

this specific syndrome is caused by mutation in TYMP (thymidine phosphorylase), which is located on chromosome 22. -Gastrointestinal tract -poor mobility, pseudo-obstruction with peristalsisleads to malabsorption-weight loss - Neurologicalperipheral neuropathy and myopathyThe speculation is that the excess thymidine may somehow increase the mutation rate of mtDNA, which affects rapidly growing cells more than slowly growing cells.

Pseudoautomal regions

tips of X and Y chromosome that carry same genes

The methylation of DNA is catalyzed by DNA methyltransferases (DNMTs). There are three active DNMTs in eukaryotes: DNMT3A and DNMT3B, which are responsible for de novo methylation, and DNMT1, which maintains existing methylation patterns.

true

true or false tumor suppressor genes are recessive

true

Duchenne muscular dystrophy

x linked recessive trait manifesting in only male offspring while female offspring become carriers. waddling gait, prox muscle weakness, toe walking, pseudohypertrophy of calf and difficulty climbing stairs. rapid progression of this disease with inability to ambulate by ten to 12 yrs of age with death occurring as teenager or less frequently in the 20's.

X-linked dominant

• Both males and females are affected; often more females than males are affected • Does not skip generations. • Affected sons must have an affected mother; • affected daughters must have either an affected mother or an affected father • Affected fathers will pass the trait on to all their daughters • Affected mothers if heterozygous will pass the trait on to 1/2 of their sons and 1/2 of their daughters