Lectures 7 and 8 Flashcards
(131 cards)
1
Q
What was the human genome project?
A
1990 to 2003
18 countries participating
Primary goals were to discover the complete set of human genes, to make the information accessible for further biological study, and to determine the complete sequence of DNA bases in the human genome
2
Q
What is a pedigree?
A
A pedigree is a specialized chart or family tree that uses a particular set of standardized symbols
3
Q
How are individuals in a pedigree identified?
A
By a set of 2 numbers
Roman numerals (I, II, III…) symbolize generations
Arabic numerals (1, 2, 3…) symbolize birth order within each generation
4
Q
Can names also be used to identify someone in a pedigree?
A
Yes
5
Q
What is the objective of a pedigree?
A
To show and analyze the history of inherited traits through generations in a family
6
Q
Are pedigrees helpful in following and diagnosing heritable traits?
A
Yes
They do this by describing patterns or modes of inheritance
7
Q
Can pedigrees prove a certain mode of inheritance every time?
A
No, more often they are ruling out certain modes
8
Q
What does mode of inheritance mean?
A
Dominant, recessive, etc.
9
Q
What information must be included on a pedigree?
A
Proband
Race/ethnicity
First name or initials of relatives
Alternatively, generation-individual numbers (I-1, I-2, II-1) can be used to maintain confidentiality (HIPAA)
Affected status (person with the trait/disease) for each individual in the pedigree
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
Adoption status
Pregnancy/abortion
Consanguinity (mating within close relatives)
Marriage/divorce
Date pedigree obtained
Key to shading of symbols
10
Q
What is a proband?
A
The person we want to know about/study
11
Q
Where do male partners usually go on a pedigree?
A
To the left, and the female goes to the right
12
Q
Where does the oldest sibling go on a pedigree?
A
Oldest on the left, youngest on the right
Siblings are connected by
a horizontal line above the symbols
13
Q
How do you denote year of birth on a pedigree?
A
b. date
14
Q
How do you denote year or age at death?
A
d. date/82 y
15
Q
How do you denote a pregnancy on a pedigree?
A
Diamond with a P if sex is unspecified
Square (male) or circle (female) with P if gender is known
Gestational age written below the diamond/symbol
16
Q
How do you denote if someone is alive and well?
A
A.W.
17
Q
How is mating denoted in a pedigree?
A
Connected by a straight horizontal line
18
Q
How is consanguinity (same ancestor) denoted on a pedigree?
A
Double horizontal line connecting them
19
Q
What are the different degrees of consanguinity?
A
First degree = parents
Second degree = siblings
Third degree = first cousins/aunts and uncles
20
Q
Are we looking at social relationships in a pedigree?
A
No, just genetic ones
21
Q
What are monozygotic twins?
A
Twins that develop from a single fertilized egg, i.e., identical twins of the same gender
Occurs b/c of the splitting of the zygote at any stage of development, even as early as the two-cell stage
Both zygotes implant separately, and each has its own placenta and chorionic (gestational) sac
22
Q
What are dizygotic twins?
A
Develop from simultaneous shedding of two ooctyes, and their subsequent fertilization by two different sperms, i.e., fraternal twins of different genders
The individual twin off-springs are no more similar than siblings
23
Q
What is a locus?
A
Specific location of a gene or DNA sequence on a chromosome
24
Q
What is homozygous?
A
Carrying identical alleles for one or more genes
25
What is heterozygous?
Carrying two different alleles for one or more genes
26
What is heterogeneity?
Many genes with one phenotype
27
What are some examples of heterogeneity?
Deafness/hearing loss
Blood clotting disorders
Blindness
28
What is aneuploidy?
Abnormal number of chromosomes
Occurs during cell division when chromosomes do not separate equally between two daughter cells
A chromosomal abnormality resulting in genetic disorders because of extra or missing chromosomes
29
What happens as a result of aneuploidy?
Monosomic condition (only one copy of a chromosome is present instead of two; 2n - 1)
Trisomic condition (one extra copy of a chromosome; 2n + 1)
Nullisomic condition (no chromosome of that chromosome pair is present; 2n -2) - generally a lethal condition
30
What are the most common aneuploidys?
Trisomy 21, 18, and 13
31
What is a knockout mouse?
A genetically engineered mouse with specific gene(s) artificially deleted or inactivated from its genome
Knock out mice have been used to study many human diseases including cancer and hearing loss
32
What is 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
33
What is a phenocopy?
An environmentally caused trait that mimics a genetically determined trait
The trait resembles symptoms of a Mendelian disorder or
It mimics inheritance by occurring in certain relatives
34
What is an example of a phenocopy?
Thalidomide exposure
A phenocopy of phocomelia
Hair loss from chemotherapy
A phenocopy of the genetic disorder alopecia
35
What is pleiotropy?
The diverse effects of one gene or gene pair on several organ systems and functions resulting in multiple phenotypic effects in the body
36
What is an example of a pleiotropy?
Marfan's syndrome
37
What is marfan's syndrome?
Autosomal dominant genetic disorder of connective tissue
Above average height
Tall, thin, long fingers (arachnodactyly)
Heart problems (aneurysm of the aorta, most serious)
Dislocated lenses of the eyes
Skeletal problems such as scoliosis, abnormal joint flexibility, and frontal bossing of the forehead
Speech disorders resulting from symptomatic high palate and small jaw
38
What famous person was suspected to have marfan's syndrome?
Abraham Lincoln
39
How do you classify chromosomal abnormalities?
Number and structure
40
What are the different types of single gene defects?
Autosomal dominant
Autosomal recessive
X-linked dominant
X-linked recessive
Y-linked
41
Are human chromosomes grouped together by size?
Yes
42
Are chromosomes also grouped together by where the centromere is?
Yes
43
What are all the different variations of centromere location?
Subcentric - p and q are unequal
Metacentric - p and q are roughly equal in length
Acrocentric - p arm is short (chromosomes 13, 14, 15, 21, 22, and Y)
Telocentric - centromere is located at the terminal end
Holocentric - Entire chromosome acts as a centromere
44
What two variations of centromere locations are not present in humans?
Telocentric and holocentric
45
What are the main two generalizations of chromosomal abnormalities?
They have adverse effects on many parts/structures of the body
Most people with unbalanced chromosomes have pre- or post- natal onset growth deficiencies and intellectual disability
46
What are some exceptions to these chromosomal generalizations?
Some sex chromosome disorders that may have few if any recognizable phenotypic anomalies
Very small deletions or duplications of chromosome material in any chromosome
47
What is mendelian or monogenetic inheritance?
The inheritance of conditions caused by a single gene mutation
48
What are the two important laws of mendelian inheritance?
Law of segregation and law of independent assortment
49
What is the law of segregation?
The idea that each parent passes on a randomly selected gene copy or allele to their offspring
Not passing both genes, only one from mom and one from dad
50
What is the law of independent assortment?
Separate genes for separate traits are passed from parents to offspring independently of one another
They have no influence on one another
51
What does the law of independent assortment only hold true for?
Genes that are not in close proximity to each other
Genes that are close can be affected by another gene
52
Are most cases of genetic deafness today recognized as monogenetic (caused by a mutation of a single gene)?
Yes
53
T/F: Proteins coded by genes related to hearing loss are involved in many functions in the ear
True
54
What are some examples of some of these proteins that are coded by genes related to hearing loss?
Cochlear fluid homeostasis
Ionic channels
Stereocilia morphology and function
Synaptic transmission
Gene regulation
55
What is autosomal dominant?
One gene in a gene pair is mutated
Dominates the normal gene and caused an abnormal phenotype
56
What are some characteristics for autosomal dominant inheritance?
Vertical transmission
50% risk to offspring per pregnancy
Unaffected individuals cannot transmit the disease
Males and females equally affected
Variable expressivity and penetrance
57
Are individuals with autosomal dominance heterozygotes or homozygotes?
Heterozygotes
58
What is expressivity?
The severity of the genetic condition apparent for the affected individual
Mild to moderate to severe
Dimmer switch
59
What is penetrance?
The frequency of occurrence usually expressed as a percentage
You either show it or you don't
On/off switch
60
Can autosomal dominant conditions appear as though they skip a generation?
Yes
You can carry a gene without expressing it
Some manifest later in life in the presence of environmental factors or modifier genes
61
Do people with autosomal dominant traits need to have a parent with the trait?
Yes, unless it occurred by spontaneous mutation
62
What is an example of variable expression of phenotype?
Waardenburg syndrome
63
What are some characteristics of autosomal recessive traits?
Two identical copies of the gene are required
25% chance of occurrence per pregnancy
Obligate carrier (heterozygous) parents
Horizontal family pattern
Family members of the same generation are affected but not in other generations
Males and females are equally affected
Consanguinity is common
Founder effect
64
What is the founder effect?
Shared genetic ancestry/limited gene pool resulting in genetic conditions seen far more commonly in certain ethnic groups
65
What are obligate carriers?
When a child has an autosomal recessive trait, both parents have to be carriers
66
What is complementary mating?
Different recessive deafness gene in each parent
Every child will be hearing
67
What is non-complementary mating?
Each parent has the same recessive deafness gene
Every child they have will be deaf
68
What is x-linked inheritance?
Inheritance passed down by the X chromosome
69
Can x-linked inheritance be dominant or recessive?
Yes
Based on whether or not a female manifests signs of diseases or is only a carrier*
If females are carriers with no sign of disease – X-linked recessive
If females manifest some signs of the disorder – X-linked dominant
70
Are males more severely effected by x-linked disorders?
Yes
71
If the trait is recessive (x-linked), will the daughter have it?
No, she will only be a carrier
72
If the trait is dominant (x-linked), will the daughter have it?
Yes
73
Is there male to male transmission for x-linked traits?
No
The dads only give the Y to their sons
74
Since males only have one X, what do they call all the genes of the X?
Hemizygous
75
Will a gene error on the X in males cause a disease?
Yes
Because there is no corresponding paired X chromosome with a good gene to balance the bad gene making males affected - psuedo-dominance
76
What is pseudo-dominance?
Males only have one X, so any recessive trait on the X becomes dominant
77
What is the difference between heterozygous and hemizygous?
Heterozygous – same chromosomes, different genes
Hemizygous – different chromosomes
78
Do females have pseudo-dominance?
No, they have two X's
If they have one bad one, it's balanced out by a good one
79
What are some characteristics of x-linked recessive traits?
No father to son transmission
Transmission from unaffected (normal phenotype) female carriers to males
All daughters of a male with the trait will be carriers
Carrier females will have a
50% chance to have sons with the abnormal trait
50% chance to have carrier daughters
50% chance of having a normal offspring
The abnormal trait may be transmitted through a series of carrier females
80
What are some examples of x-linked recessive inheritance?
Color blindness
Hemophilia
X-linked hearing loss with stapes gusher
Muscular dystrophy
81
Is x-linked dominant inheritance rare?
Yes
82
Will a female with an X-linked dominant trait manifest the disease?
Yes
They will have it regardless of what the other X chromosome is
83
What is the probability of sons and daughters to inherit the condition from their father with an x-linked dominant trait?
50%
The daughter can be affected if the father is affected and not just be a carrier
But the son is unaffected even if the father is affected
84
How do you differentiate an X-linked recessive hearing loss from an X-linked dominant one?
If the mother is affected, each offspring has a 50% chance of being affected
Look carefully at the hearing of male offspring of the father
The son should have normal hearing because he inherits the normal Y chromosome from the father
If the father has an X-linked dominant gene passed on to his female offspring, she will have a hearing impairment
The daughter can be affected if the father is affected and not just be a carrier
But the son is unaffected even if the father is affected
85
What are the different transmission traits for x-linked dominance?
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)
86
What is an example of x-linked dominant traits?
Alport’s syndrome
Collagen gene mutation
Affects BM of the cochlea - hearing loss
Affects BM of kidneys - glomerulonephritis, kidney failure
May also affect eyes
87
Are there y-linked inheritance patterns?
Yes
They are very rare
88
Are Y-linked traits only passed to boys?
Yes
Traits encoded by genes on the Y chromosome are passed directly from father to son
No father to daughter transmission
89
Is there a specific region on the Y chromosome that determines gender?
Yes
It is the SRY region
90
What are many of these Y-transmitted traits involved in?
Abnormal male sexual development
May be infertile
So, it doesn’t pass onto future generations
That is why it is so rare
Not all infertile, but a lot are infertile or have low fertility
91
What is multifactorial inheritance?
Traits resulting from the interplay of multiple environmental factors with multiple genes
Most commonly associated with sporadic gene mutations
92
What is an example of multifactorial inheritance?
Oculo-Auricular-Vertebral (OAV) spectrum disorder
Consists of three rare disorders that may be intimately related to each other
It maybe a range of severity of the same disorder
Rarely maybe inherited as an AD or AR disorder
93
What is polygenic inheritance?
Traits or diseases caused by the impact of many different genes
Each gene has only a small individual impact on the phenotype
Traits are quantitative rather than qualitative i.e., the more severe the manifestation, the more predisposing genes are involved
94
What is an example of polygenic inheritance?
Cleft lip/palate
Spina bifida
95
Who were the ancestors of present-day mitochondria?
Free-living bacteria that adapted to living inside of primitive eukaryotic cells
96
What is the mitochondria like today?
Over time most genes carried on the bacterial chromosomes were lost
But mitochondria today still carry DNA molecules that encode information for ~37 mitochondrial genes
Of those 37 genes, 13 genes still encode proteins that function in energy production
97
Is the diagnosis of mitochondrial disorders difficult?
Yes, it is hard to isolate these genetic conditions
A wide variety of dysfunction in multiple organ systems should raise suspicions of a mitochondrial disorder
98
Does mitochondrial inheritance obey the rules of classic Mendelian transmission?
No
During meiosis, mitochondria are passed only from the mother to the oocyte
99
Why does mitochondrial inheritance only come from mom?
Sperm sheds its cytoplasm and mitochondria are only found in the cytoplasm
100
What is another phrase for a mitochondrial trait?
Eve gene
101
What is the likelihood of a child inheriting a mitochondrial condition from their mother?
100% of all children being affected
102
Does mitochondrial DNA have a higher spontaneous mutation rate than DNA in nuclear genes?
Yes
103
Why does mitochondrial DNA have a higher spontaneous mutation rate than DNA in nuclear genes?
Maybe because mtDNA evolves 5 to 10 times more rapidly than genomic DNA
104
Why do syndromes occur when the mitochondria is affected?
Syndromes occur as a result of the affected mitochondria being unable to meet the metabolic demands of the tissues
105
What kinds of tissues does mitochondrial disorders affect?
Predominant in tissues with high energy demands such as muscles but can affect multiple unrelated systems of the body
Initially mitochondrial transmission was thought to cause only neuromuscular disorders but now known that it can present with many different phenotypes
106
What happens when division happens faster?
It is more likely there are mistakes
107
What is Leber's hereditary optic neuropathy an example of?
Mitochondrial inheritance
108
What happens in Leber’s hereditary optic neuropathy?
Sudden loss of central vision
Optic nerve damaged at ~20 years of age
Predisposition to deafness from increased susceptibility to aminoglycoside ototoxicity
Also associated with maternally transmitted disorders such as diabetes
Degeneration of cochlear neural elements
Degeneration of portion of CN VIII in the cochlea
109
What is aminoglycoside ototoxicity?
Aminoglycosides are antibiotics
With this mutation, one dose runs the risk of a severe to profound loss
Most of the time, dose and duration will determine the ototoxic loss
The larger the dose for a longer period of time = more of a loss
110
Does aminoglycoside ototoxicity
affect DNA?
No
Mutation happens on ribosomal RNA
Those code for proteins
This is the result
Gene mutation; deletion of adenine with substitution of guanine - A to G of the ribosomal RNA gene
Gene mutation; deletion of thymine with substitution of cytosine - T to C of the ribosomal RNA gene
111
What is genomic imprinting?
A process in which the phenotype differs depending upon which parent transmits a particular allele or chromosome
112
What are examples of genomic imprinting?
Prader Willi syndrome and Angelman syndrome
113
What is Prader Willi syndrome?
Deletion of chromosome 15 (del 15q11-13) of paternal origin
Small, floppy infants with small hands and feet
Intellectual disability
Obesity and uncontrollable eating and food cravings
Child does not enter puberty because the sex glands produce little or no hormones - cannot reproduce
Orthopedic issues later in life
Can have a normal life span if eating and associated obesity and diseases (e.g., diabetes) are controlled
114
How is Prader Willi syndrome inherited?
Typically starts as a spontaneous mutation that is passed down
But cannot continue to be passed down because they cannot reproduce
115
What is Angelman syndrome?
Deletion of chromosome 15 (del 15q11-13) of maternal origin
Intellectual disability
Developmental delay
Seizures
Happy demeanor
Laughs uncontrollably and excessively
Poor muscle coordination
Gait ataxia
116
What is genetic anticipation?
The worsening of symptoms of a genetic disease from one generation to the next
117
What is allelic expansion?
Increase in gene size
Caused by an increase in the number of the trinucleotide base sequences
As the number of these genes increase, the severity gets worse and worse
118
Is anticipation caused by allelic expansion?
Yes
119
What are some examples of genetic anticipation and allelic expansion?
Myotonic dystrophy
Huntington's disease
Tay Sachs
Fragile X syndrome
120
What is myotonic dystrophy?
Autosomal dominant
Expansion of the gene on chromosome 19
Repeat of base triplets CTG
Normal = 5 to 37 copies of CTG
Affected = 50 to 72,000 copies of CTG
121
What are some signs and symptoms of myotonic dystrophy?
Drooping eyelids
Facial weakness
Mild to severe muscle weakness
122
What is Huntington's disease?
Autosomal dominant
Gene on the tip of chromosome 4p
Repeat of base triplets CAG
Normal = 6 to 37 copies of CAG
Affected = 35 to 121 copies of CAG
123
What are some signs and symptoms of Huntington's disease?
Adult onset
Loss of muscle coordination and control
Deterioration of intellectual function
Generally early death
124
What is Fragile X syndrome?
X-linked dominant pattern with variable expressivity
Females and males are both affected
Caused by mutations in the FMR1 gene
FMR1 gene provides instructions for making a protein called fragile X mental retardation 1 protein (FMRP)
Tip of the X chromosome has a fragile site
Triplet repeat of CGG
Normal = 5 to 40 repeats
Fragile X = > 200 repeats
125
Is fragile X the most common form of inherited intellectual disability in boys?
Yes
Males can be normal or mild to severally affected
Intellectual disability is less common in females
126
Do people with fragile X typically have delayed development of speech and language?
Yes
127
Do people with fragile X may have ADHD as well?
Yes
128
What are some physical features of fragile X?
Long jaw
Big head
Large ears
129
Is hearing loss typically associated with fragile X?
No
130
If there are carriers involved, what kind of pattern is it not?
AD
131
Is consanguinity an issue with AD transmission?
No
