Principle of Genetic Inheritance Flashcards
Lyonization
x-inactivation; choice of which x chromosome to be inactivated is random
-males can get by with just one
Mosaicism
condition in which cells from patient have different genotypes (and karyotypes); if enough cells have this, it will display this phenotype
- Down Syndrome: some 46XX, some 47XX +21
- Klinefelter Syndrome: some 46XY, some 46XXY
- Turner Syndrome: some 46XX, some 45XO
Non-disjunction
failure of homologous chromosomes or sister chromatids to separate normally during nuclear division leading to abnormal distribution (trisomy or monosomy)
Robertsonian Translocation
- translocations= non-homologous chromosomes exchange genetic material
- long arm of two acrocentric chromosomes combined, short arm typically lost
example: Down Syndrome –> 46, xx (14:21)(q10;q10)+21
Turner Syndrome
45 XO karyotype
- monosomy
- short stature, ovarian hypofunction/premature ovarian failure, lack of puberty without hormone therapy, infertility, webbed neck, low hairline on neck, CV, normal intelligence
Klinefelter Syndrome
47XXY
- trisomy
- some with no/limited symptoms
- varying degrees of cognitive social behavioral and learning difficulties
- hypogonadism (low T)
- small/undescended testes; gynecoomastia, tall stature, infertility, mosaic; variability in x numbers can increase
Trisomy 13, 18, 21
13: Pataeu Syndrome (47XX+13)
- severe developmental abnormalities; death within 1 week of birth
18: Edwards Syndrome (47XX+18)
- abnormal development; death within 1 year
21: Downs Syndrome (47XX+21)
- most common; increased risk with maternal age; translocation (5%)
Genomic Imprinting
- some human genes have alleles that are transcriptionally inactive (no mRNA produced)
- gene silencing: through methylation of 5’ region of gene; chromatin condesnation
- at least 100 genes known to be imprinted (30 paternally, 70 maternally)
- epigenetic imprints remain throughout lifespan of individual in somatic cells
- in germ cells, epigenetic imprints reset at each generation
- during meiosis, imprints are erased and new ones are reset
Prader-Willi Syndrome
paternally deleted- deletion of PWS gene on chromosome 15 while maternal gene methylated
-leading to short stature, hypotonia, small hands/feet, obesity, mild to moderate intellectual disability
Angelman Syndrome
maternally deleted- deletion of AS gene on chromosome 15 and maternal gene methylated
-leading to severe intellectual disability, seizures, ataxic gait
Uniparental Disomy
related to non-disjunction and genomic imprinting
-if two chromosomes are inherited from same parent, they will have parent-specific imprinting (no gene product)
Pleiotropy
individuals with same genotype can have multiple phenotypes (ex. PKU)
Autosomal Dominant
-one copy of mutant allele needed in one of 22 autosomes (non-sex determining chromosomes) and other is normal; it affects males and females equally and any offspring have 50% chance of inheriting mutant allele
A. trait expected in every generation
B. Example: Postaxial Polydactyly
Autosomal Recessive
manifests when individual has two copies of mutant allele; if one mutant allele is present, individual is carrier of mutation; males and females affected equally; if two carriers procreate, child will have 25% chance of being affected and unaffected; 50% unaffected carrier
A. occurrence more likely among individuals who share genes (consanguinity- first cousin mating)
B. skips generation
C. Example: Tyrosinase-negative albinism
X-linked recessive
do not manifest in presence of normal copy of gene; always expressed in males bc they only have one copy of X chromosome; women rarely affected; but can be if they have two copies of the mutation or random x-inacivation during development
A. no father-to-son transmission but there may be transmission from father to daughter, or it can be from mother to daughter or to son
B. disease allele on x in males= “hemizygous”
C. all daughters of affected males and 50% of sons and 50% of daughters from female carriers
D. Example: Duchenne Muscular Dystrophy
X-linked dominant
where mutation is in fathers x chromosome, all of his daughters will express the condition; father to son transmission not possible
A. children of carrier mom will have 50% chance of inheriting mutant allele
B. Example: Hypophosphatemia
Reduced Penetrance
frequency of a gene manifestation
a. some cases have 100% of individuals inheriting a genetic defect that shows the clinical presentation (phenotype) of disease penetrance; other cases <100%
b. Example: Retinoblastoma
Variable Expressivity
term used to describe the range of phenotypes that vary between individuals with a specific genotype (different degree of symptoms and degree of expression)
a. Example: Neurofibromatosis
- -> develop tumor like growths called neurofibromas and cafe-au-lait spots (spots differ)
locus heterogeneity
Single disorder, trait, or pattern of traits caused by mutations in genes at different chromosomal loci a. Example: Osteogenesis Imperfecta (brittle bone disease) --> Mutations in collagen genes (two loci: chromosome 7 and 17), either mutation exhibits the same phenotype
Gene frequencies vs. Genotype frequencies
-Gene Frequencies specify the proportions of each allele
in a population
-Genotype Frequencies specify the proportions of each
genotype in a population
The Hardy-Weinberg Principle specifies relationship
Hardy-Weinberg Principle
p2+2pq+q2= 1
P+q=1 (allele frequencies)
Multifactorial Inheritance
- traits in which variations are thought to be caused by combined effects of multiple genes= POLYGENIC
- when environmental factors cause variation in the trait= MULTIFACTORIAL
Threshold Model
- because traits are caused by many genetic and environmental factors, they tend to follow a normal, or bell-shaped distribution in populations
- for diseases that do not follow bell-curve distribution there is an underlying liability distribution
- for multifactorial diseases that are either present or absent, it is thought that threshold of liability must be crossed before the disease is expressed
A. below threshold–> the person appears normal
B. above threshold–> person is affected by disease
Heteroplasmy (orange box)
- presence of more than one type of mtDNA within cell or organism
- symptoms usually don’t develop until adulthood bc these mutant mitochondrial alleles must undergo many cell divisions before sufficient amount are present to cause symptoms (LHON, visual problems not expected until adulthood)
Recurrent Risk and Transmission Patterns of Multifactorial Inheritance
Recurrent risk:
a. risk for multifactorial diseases can change substantially from one population to another; this is bc gene frequencies as well as environmental factors can differ among populations
b. recurrence risk is higher if more than one family member affected
c. if expression of disease in probing is more severe–> recurrence risk higher
d. if probing is of less commonly affected sex–> recurrence risk is higher
e. recurrence risk decreases rapidly in more remotely related relatives
transmission patterns
a. Multifactorial disease- caused by simultaneous influence of multiple genetic and environmental factors
b. in some cases, trait may be influenced by combination of both a single gene with large effects and a multifactorial background in which additional genes and environmental factors have small individual effects
