Lectures 7 & 8. Patterns of Inheritance: Mendelian & Beyond Flashcards
What are the goals of the Human Genome Project?
1) Discover the complete set of human genes
2) Make the information accessible for further biological study
3) Determine the complete sequence of DNA bases in the human genome
What is a Pedigree?
A specialized chart or family tree that uses a particular set of standardized symbols
Roman numerals (I, II, III) symbolize generations
Arabic numbers (1, 2, 3) symbolize birth order within each generation
Individuals within a pedigree can be identified by the combination of two numbers (i.e. II-3)
Names can also be included in a pedigree but numbers provide anonymity for patient privacy
Objective of a Pedigree
To show and analyze the history of inherited traits through generations in a family
a. Pedigrees provide concise and accurate records of families
b. Pedigrees are helpful in following and diagnosing heritable traits (e.g. diseases and medical conditions), by describing patterns or modes of inheritance
c. Pedigrees are useful in mapping (i.e. locating and isolating) genes that are responsible for certain traits
d. Pedigree can frequently rule out, but not necessarily prove, a certain mode of inheritance
What information must be included on a pedigree?
1) Proband
2) First name or initials of relatives (alternatively, generation-individual numbers (I-1, I-2, II-1) can be used to maintain confidentiality (HIPAA)
3) Affected status (person with the trait/disease) for each individual in the pedigree
4) Age of all family members or age at death (if individual deceased, then cause of death, if known, is indicated below the person’s symbol)
5) Adoption status
6) Pregnancy/abortion
7) Consanguinity (mating within close relatives)
8) Marriage/divorce
9) Race/ethnicity
10) Date pedigree obtained
11) Key to shading of symbols
Definition of proband
A person being studied; noted with an arrow and the box (male) or circle (female) shaded accordingly
Use “consultant” if relaying history
Consanguinity
Same ancestor/mating between individuals with same ancestor/connected by double straight lines
Degrees of consanguinity
First degree - between parents
Second degree- between siblings
Third degree - first cousins or aunts/uncles
Monozygotic twins
Twins that develop from a single fertilized egg, i.e., identical twins
Dizygotic twins
Twins that develop from simultaneous shedding of two oocytes and their subsequeny fertilization by two different sperms, i.e., fraternal twins
Locus
Specific location of a gene or DNA sequence on a chromosome
Homozygous
Carrying identical alleles for one or more genes
Heterozygous
Carrying two different alleles for one or more genes
Heterogeneity
Many genes responsible for one phenotype
Ex: deafness/hearing loss, blood clotting disorders, blindness
Ploidy
Number
Diploid cell
_The condition in which each chromosome is represented twice as a member of a homologous pair, one set from each parent
_Human somatic cells are diploid cells
Germ cells
_Cells from which a new organism can develop = egg and sperm
_Germ cells are haploid cells with half the number of chromosomes as the somatic cells
Aneuploidy
_Abnormal number of chromosomes
_Occurs during cell division when chromosomes do not separate equally between two daughter cells
Monosomy/monosomic condition
Only one copy of a chromosome is present instead of two; 2n - 1
Trisomy/trisomic condition
One extra copy of a chromosome; 2n + 1
Nullisomy/nullisomic condition
No chromosome of that chromosome pair is present; 2n - 2)
Name the most common aneuploidy
Trisomy 21, 18, and 13
Knockout mouse
A genetically engineered mouse with specific gene(s) artificially deleted or inactivated from its genome
Cellular homeostasis
The tendency of an organism/cell to regulate its internal conditions, such as the chemical composition of its body fluids, so as to maintain health and functioning, regardless of external conditions
Phenocopy
An environmentally caused trait that mimics a genetically determined trait
Examples of phenocopy
1) Thalidomide exposure: a phenocopy of chemotherapy
2) Hair loss from chemotherapy: a phenocopy of the genetic disorder alopecia
Pleiotropy
The diverse effects of one gene or gene pair on several organ systems and functions resulting in multiple phenotypic effects in the body
Example of Pleiotropy
Marfan’s syndrome (slide 28)
Classification of Genetic Disorders
1) By chromosomal abnormalities
a) Number of chromosome (monosomy, trisomy, etc)
b) Structure of chromosome
2) By single gene defect
a) Autosomal dominant
b) Autosomal recessive
c) X-linked dominant
d) X-linked recessive
e) Y-linked
3) By mitochondrial genetic defect
4) By multifactorial/polygenic defects
5) By environmental influences - generally spontaneous mutation
Subcentric or submetacentric
Centromere not at center; the chromosome arms’ lengths are unequal
Metacentric
Two arms of chromosome are roughly equal in length
Acrocentric
_P arm is so short that is hard to observe, but still present
_In humans, chromosomes 13, 14, 15, 21, 22, and Y are acrocentric
Telocentric
Centromere is located at the terminal end of the chromosome
Not present in humans
Holocentric
Entire length of the chromosome acts as the centromere
Found in worms (nematodes); not present in humans
True or false: chromosomal studies should be performed for any individual with multiple malformations and unknown overall diagnosis
True
True or false: chromosomal abnormalities have adverse effects on many parts of the body. Consequently, an individual with only two anomalies is unlikely to have a chromosomal abnormality
True
True or false: Most people with unbalance chromosomes have pre- or post-natal onset growth deficiencies and intellectual disability. Individuals with normal growth patterns, psychomotor development, and intelligence are not candidates for chromosomal abnormalities
True
What are the exceptions to the generalizations regarding chromosomal abnormalities?
_Some sex chromosome disorders that may have few if any recognizable phenotypic anomalies
_Very small deletions or duplications of chromosome material in any chromosome material in any chromosome
True or false: It is the inheritance of conditions caused by mutation of several genes
False: it is the inheritance of conditions caused by mutation of a SINGLE gene
What is the first law of Mendelian inheritance?
Law of segregation
What is the law of segregation in the context of Mendelian inheritance?
1) Every individual has a pair of alleles for every particular trait, which segregate or separate during cell division
2) Each parent passes a randomly selected gene copy or an allele to his or her offspring
3) The offspring then receives his or her own pair of alleles of that gene for that trait by inheriting sets of homologous chromosomes from the parent organisms
What is the second Mendelian law?
Law of independent assortment
What does the law of independent assortment state?
1) It states that separate genes for separate traits are passed from parents to offspring independently of one another
2) More precisely, the law states that the biological selection of a particular gene in the gene pair for one trait that is passed to the offspring has nothing to do with the selection of the gene for any other trait
**This law holds true only for genes that are not linked to one another. i.e. genes that are not in close proximity to one another on the same chromosome
Most cases of genetic deafness recognized today are _____ disorders caused by mutation of ____ single gene(s) and broadly classified by __________
1 ) Monogenic
2) Single
3) Mode of inheritance
What are some functions of the proteins encoded by genes that are related to hearing loss?
1) Cochlear fluid homeostasis
2) Ionic channels
3) Stereocilia morphology and function
4) Synaptic transmission
5) Gene regulation
Definition of Autosomal Dominant (AD)
One gene in a gene pair is mutated but this change dominates the normal gene and causes an abnormal phenotype
Characteristics of Autosomal Dominant
1) Affected individuals are heterozygotes
2) Vertical transmission
3) 50% risk to offspring per pregnancy
4) Unaffected individuals cannot transmit the disease
5) Males and females equally affected
6) Variable expressivity and penetrance
7) Persons with the trait have a parent with the trait unless they represent a spontaneous mutation
8) If the line stays broken it stays broken
What is expressivity?
Refers to the severity of the genetic condition apparent for the affected individuals
What is penetrance?
Refers to frequency of occurrence, usually expressed as a percentage
Characteristics of Autosomal Recessive
1) Two copies of the gene are required
2) 25% chance of occurrence per pregnancy
3) Obligate carrier (heterozygous) parents
4) Horizontal family pattern
5) Family members of the same generation are affected but not in other generations
6) Males and females are equally affected
7) Consanguinity is common
8) Founder effect
a) Shared genetic ancestry/limited gene pool resulting in genetic conditions seen far more commonly in certain ethnic groups
b) Example: Tay Sach’s disease, a lethal neurodegenerative disease seen ~1:31 for the general population vs Ashkenazi Jews
What are some risk factors of autosomal recessive inheritance?
1) Consanguinity (same blood)
a. Mates related to each other by blood
b. Not just 1st cousins but 2nd and 3rd too
c. More commonly seen in pedigrees involving rare genetic traits
2) Obligate carriers
a. Both parents have be carriers in order for the offspring to inherit the trait
What is pseudo-dominance?
A situation in which inheritance of an autosomal recessive trait mimics an autosomal dominant pattern; one recessive allele could cause expression of the trait
What is non-complementary AR mating?
When both parents have the same recessive form of the disease/disorder/syndrome
What is a complementary autosomal recessive mating?
When the parents have different alleles for the disorder/syndrome/disease
What is the difference between X-linked recessive and X-linked dominant
If females are carriers with no sign of disease - X-linked recessive
If females manifest some signs of the disorder - X-linked dominant
True or False: females are more severely affected than males in X-linked disorders
False
True or False: No male-to-male transmission because males don’t give their sons the X, they give them the Y
True
What is it called when a gene error in the X chromosome will cause disease in men because there is no corresponding paired X chromosome with a good geme to balance the bad gene making males affected?
Pseudo-dominance
What is called when men only have a single X chromosome so they have only one copy of any gene on the X chromosome?
Hemizygous for all genes on the X Chromosome because they are neither heterozygous nor homozygous for the X chromosome
Characteristics of X-linked recessive inheritance
1) No father to son transmission: the mutant gene is on the X chromosome
2) Transmission from unaffected (normal phenotype) female carriers to male offspring
3) All daughters of a male with the trait will be carriers
4) Carrier females will have
a) 50% chance to have sons with the abnormal trait
b) 50% chance to have carrier daughters
c) 50% of chance of having a normal offspring
5) The abnormal trait may be transmitted through a series of carrier females
What are some examples of X-linked recessive inheritance?
1) Color blindness
2) Hemophilia
3) X-linked hearing loss with stapes gusher
4) Muscular dystrophy (Duchenne-type)
True or false: X-linked dominant is very common
False
True or false: both sons and daughters have a 50% chance of inheriting the condition from the mother in a X-linked dominant inheritance
True
In an X-linked dominant inheritance, what happens to the son if the father is affected?
The son should be unaffected because he inherits the normal Y chromosome from the father
In a X-linked dominant inheritance, what happens to the daughter(s) if the father is affected
The daughter will be affected
What happens to all the children in an X-linked dominant inheritance if the mother is affected?
Each offspring has a 50% chance of being affected
What are the transmission traits in an X-linked dominant inheritance?
Chance of transmission from mother to son and daughter: both genders will be affected
Transmission from affected father to daughter
NO transmission from affected father to son (normal Y chromosome)
What is an example of X-linked dominant inheritance?
Alport’s syndrome
a) Collagen gene mutation
b) Affects basilar membrane of the cochea
c) Affects basement membrane of kidneys - glomerulonephritis, kidney failure
d) May also affect eyes
True or false: in a Y-linked pattern of inheritance, father to daughter transmission is possible
FALSE
Why are Y-linked traits only expressed to male offspring?
1) All males are hemizygous for all genes on the Y chromosome
2) No balancing of the mutant Y gene by X or another Y gene on the Y chromosome
What does multifactorial inheritance mean?
Traits resulting from the interplay of multiple environmental factors with multiple genes
Most commonly associated with sporadic gene mutations
What is an example of a multifactorial inheritance?
Oculo-Auricular-Vertebral (OAV) spectrum disorder
What is polygenic inheritance?
1) Traits or diseases caused by the impact of many different genes
2) Each gene has only a small individual impact on the phenotype
3) Traits are quantitative rather than qualitative i.e., the more severe the manifestation, the more predisposing genes are involved
Example of polygenic inheritance
Cleft lip/palate
Spina bifida
When should we suspect a mitochondrial disorder?
A wide variety of dysfunction in multiple organ systems should raise suspicions of a mitochondrial disorder
What are some characteristics of mitochondrial inheritance?
1) Mitochondrial traits are passed through the maternal line only
2) No children of fathers with the trait will inherit the trait
3) All offspring of both sexes of affected mothers are affected
True or false: mitochondrial DNA (mtDNA) has a slower spontaneous mutation rate than DNA in nuclear genes
FALSE: it is higher because mtDNA evolves 5 to 10 times more rapidly than genomic DNA
Examples of mitochondrial inheritance
1) Leber’s hereditary optic neuropathy (sudden loss of central vision)
2) Predisposition to deafness from increased susceptibility to AMINOGLYCOSIDE OTOTOXICITY
3) The exact malfunction causing hearing loss due to mitochondrial mutation is not known but
a) Degeneration of cochlear neural elements
b) Degeneration of portions of CN VIII in the cochlea
What is genomic imprinting?
A process in which the phenotype differs depending upon which parent transmits a particular allele or chromosome
What is an example of genomic imprinting?
Prader Willi syndrome and Angelman syndrome. Both result from the deletion of chromosome 15 (del 15q11-13), but PW is from paternal origin while Angelman is from maternal origin
What is genetic anticipation?
The worsening of symptoms of a genetic disease from one generation to the next
What is allelic expansion?
Increase in gene size; caused by an increase in the number of trinucleotide base sequences
Examples of genetic anticipation and allelic expansion
Myotonic dystrophy
Huntington’s disease
Fragile X syndrome
Signs and symptoms of myotonic dystrophy
Drooping eyelids
Facial weakness
Mild to severe muscle weakness
(Autosomal dominant)
Signs and symptoms of Huntington’s disease
Adult onset Loss of muscle coordination and control Deterioration of intellectual function Generally early death (autosomal dominant)
Characteristics of Fragile X syndrome
1) Females and males are both affected
2) Males can be normal or mild to severely affected
3) Intellectual disability is less common in females
4) Delayed development of speech and language
5) May have ADHD
6) Physical features
a. Long jaw
b. Big head
c. Large ears
