Patterns of inheritance Flashcards
what determines generations in pedigrees
Roman numerals (I, II, III…) symbolize generations
what determines birth order in a pedigree
Arabic numerals (1, 2, 3…) symbolize birth order within each generation
what is a pedigree?
A pedigree is a specialized chart or family tree that uses a particular set of standardized symbols
what is the goal of a pedigree
The object of a pedigree is to show and analyze the history of inherited traits through generations in a family
can pedigrees prove mode of inheritance ?
Pedigrees can frequently rule out, but not necessarily prove, a certain mode of inheritance
what must be included in a pedigree?
(11)
Proband
Race/ethnicity
First name or initials of relatives
people who have the disease
their age
age of death
Adoption status
Pregnancy/abortion
Consanguinity (mating within close relatives)
Marriage/divorce
Date pedigree obtained
what is a proband ?
the person being studied
it is the first affected family member seeking medical help for a possible genetic disorder
The person who is seeking the information
where to start on the pedigree
It is helpful to start in the middle of the page
how should mating be illustrated on pedigree?
Male partners to the left and female partners to the right connected by a single straight line
how should birth order be illustrated on pedigree?
Oldest to youngest with the oldest on the left and the youngest on the right
what is consanguinity?
mating with someone in the family (not siblings or parents)
what are monozygotic twins?
Twins that develop from a single fertilized egg
are monozygotic twins fraternal or identical?
identical (same sex)
How do monozygotic twins happen?
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
are dizygotic twins fraternal or identical
fraternal
how does dizygotic twins happen?
Develop from simultaneous shedding of two ooctyes, and fertilized by two different sperms, i.e., fraternal twins of different genders
look at pedigree symbols slide 14
what is locus
Specific location of a gene or DNA sequence on a chromosome
each gene is found in a specific place on the chromosome
what does Homozygous/homologous mean
same gene from each parent on each chromosome
what does Heterozygous mean
different gene from each parent on each chromosome
what does Heterogeneity mean
many genes are involved but the result (phenotype) will still be the same
Many genes but one phenotype
ex. hearing loss/ deafness
blood clotting disorders
blindness
P arm
short arm
q arm
long arm
what is region in terms of chromosomes address
Each arm subdivided into numbered regions, beginning from the centromere
what is band in terms of addressing a chromosome?
Within each region identified by numbers
how do you write a descriptive address for chromosomes?
chromosome number, arm, region, band
what does ploidy mean
number
what is a diploid cell?
Double the number of chromosomes found in a mature germ cell (46 chromosomes)
are human somatic cells haploid or diploid?
Human somatic cells are diploid cells with 23 pairs of chromosomes (46 individual chromosomes)
44 somatic and two germ chromosomes (XX or XY)
how many chromosomes are in haploid cells
23
what are germ cells
eggs and sperms (sex cells)
are germ cells haploid or diploid
Germ cells are haploid cells with half the number of chromosomes as the somatic cells
what is aneuploidy
Abnormal number of chromosomes
what causes aneuploidy to happen
Occurs during cell division when chromosomes do not separate equally between two daughter cells
what is the result of aneuploidy?
A chromosomal abnormality resulting in genetic disorders because of extra or missing chromosomes
-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
what is a knock out mouse
A genetically engineered mouse with specific gene(s) artificially deleted or inactivated from its genome
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
what are the most common aneuploidy?
trisomy 13, 18, 21
what is phenocopy
An environmentally caused trait that mimics a genetically determined trait
(it’s not inherited but it mimics it)
-The trait resembles symptoms of a Mendelian disorder or
-It mimics inheritance by occurring in certain relatives
what are examples of phenocopy
thalidomide exposure (a phenocopy of phocomelia)
hair loss from chemotherapy (a pheoncopy of the genetic disorder aloperca)
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
Pleiotropy occurs when one gene influences two or more seemingly unrelated phenotypic trait
onegene infulencing multiple phenotypics effect on the body
whats an example of pleiotropy and what symptoms would appear with someone with that condition?
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
what famous president could have marfans syndrome
Abraham Lincoln
what are classifications of genetic disorders
By chromosomal abnormalities
-Number
-Structure
By single gene defect
-Autosomal dominant
-Autosomal recessive
-X-linked dominant
-X-linked recessive
-Y-linked
By mitochondrial genetic defect
By multifactorial/polygenic defects
By environmental influences – generally spontaneous mutation
What do chromosomal abnormalities affect?
-Size
-Centromere location
-subcentric/ submetacentric
-metacentric
-acrocentric
-telocentric
holocentric
what does subcentric/submetacentric mean?
The chromosome’s p & q arms’ lengths are unequal
located a bit above on the center of the centromere
what does metacentric mean?
The two arms of chromosome are roughly equal in length
it’s located in the middle
what does acrocentric mean
P arm is so short that is hard to observe, but still present
almost at the end of the centromere
what chromosomes in humans are acrocentric ?
13, 14, 15, 21, 22, & Y
what does telocentric mean
Centromere is located at the end of the chromosome
are telocentric present in humans ?
no
what does holocentric mean?
Entire length of the chromosome acts as the centromere
are holocentric present in humans
no. but they’re present in worms
when should chromosomal abnormalities be studied
Chromosomal studies should be performed for any individual with multiple malformations and unknown overall diagnosis
what are generalizations regarding chromosomal abnormalities that can recognize conditions?
how do you know if it’s a chomosomal abnormality or not ?
1)chromosomal abnormalities have adverse effects on many parts/structures of the body
-nevertheless someone with 2 anomalies are unlikely to have chromosomal abnormalities
2)most people with unbalance chromosomes have pre- or post-natal onset growth deficiencies and intellectual disability
-someone with normal growth patterns, and intelligence, and psychomotor development are not a candidate for chromosome abnormalities
what are some exceptions to generalizations about chromosomal abnormalities
-sex chromosomes
-Very small deletions or duplications of chromosome material in any chromosome
what is the first law of mendelian/ monogenetic inheritance
it’s called the law of segregation
what it is:
-Every individual has a pair of alleles for every particular trait, which segregate or separate during cell division
-Each parent passes a randomly selected gene copy or an allele to his or her offspring
(whatever gene we get is random)
-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
(one gene from mom and dad in EVERYTHING)
what is mendelian/monogenetic inheritance?
It is the inheritance of conditions caused by mutation of a single gene
(only one gene is affected)
What is the second law of Mendelian/monogenetic inheritance
it’s called the law of independent assortment
what it is:
-It states that separate genes for separate traits are passed from parents to offspring independently of one another
-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
most genetic deafness recognized today by…
1)monogenic disorders caused by mutation of a single gene and broadly classified by the mode of inheritance (autosomal dominant, autosomal recessive, x linked, and mitochondrial)
2) and by the presence of phenotypic feature
ex. syndromic (something w/ hl) and non-syndromic (hl is the only problem)
When does the second law of mendelian/monogenetic inheritance apply
it only applies for genes that are not linked to one another
(genes that are not in close proximity to one another on the same chromosome )
Proteins coded by genes related to hearing loss are involved in what functions in the ear?
Cochlear fluid homeostasis
Ionic channels
Stereocilia morphology and function
Synaptic transmission
Gene regulation
What is autosomal dominant (AD)?
One gene in a gene pair is mutated but this change dominates the normal gene and causes an abnormal phenotype
-Affected individuals are heterozygotes (can come from mom or dad, it doesn’t matter)
what are characteristics of AD inheritance
-Vertical transmission
-50% risk to offspring per pregnancy
-Unaffected individuals cannot transmit the disease
-Males and females equally affected
-Variable expressivity and penetrance
what does expressivity mean?
refers to the severity of the genetic condition apparent for the affected individual
what does penetrance mean?
refers to frequency of occurrence, usually expressed as a percentage
why might some AD gene mutations appear later in life?
because of the presence of environmental factors or modifier genes
D
dominant allele for deafness
d
allele for hearing
How many AD inheritance are there?
A person can have one of 3 patterns
Genotype Phenotype
DD = homozygote deaf
Dd = heterozygote deaf
dd = homozygote hearing
Summary of characteristics of AD traits
-Only one copy of the gene is needed to produce the phenotype; affected individuals are heterozygotes
-Chance of occurrence per pregnancy is ½ (50%)
-Vertical family pattern
-Persons with the trait have a parent with the trait unless they represent a spontaneous mutation
-If the line is broken it stays broken
Incomplete penetrance
-Variable expressivity
-Male : female = 1:1
What is an example of variable expression of the phenotype
waardenburg syndrome
Dd means?
Heterozygote
dd
homozygote
look at risks of calculating AD inheritance
For autosomal dominant, if the person had the trait, what are the chances they pass it to their kids?
50%
For autosomal dominant, if the person didn’t have the trait, what are the chances they pass it to their kids?
0% because he never had it
do carrier types exist for autosomal dominant?
no, only for recessive
a vertical transmission is seen in?
autosomal dominant
a horizontal gene is seen in?
autosomal recessive
What is the percentage a child might get the trait in recessive?
25%
what is the chances the kid could get the trait in dominant
50%
How do recessive genes work?
Two identical copies of the gene are required
(homozygous offspring)
Which generation is affected in recessive?
Family members of the same generation are affected but not in other generations
Is consanguinity common for recessive inheritance ?
yes
Who is more likely to get affected in recessive inheritance?
Males and females are equally affected
what is the founder effect
Shared genetic ancestry/limited gene pool resulting in genetic conditions seen far more commonly in certain ethnic groups
where is the founder effect mainly seen?
in recessive inheritance
What can recessive inheritance patterns look like?
Genotype Phenotype
RR = homozygous hearing
Rr = heterozygous hearing, carrier
rr = homozygous deaf
what might the genes for a carrier look like ?
Rr (heterozygous)
What are risk factors of autosomal recessive inheritance?
Consanguinity
What are obligate carriers
Both parents have to have the gene in order for their offspring to inherit the trait
Can the trait still pass down the gene, even tho they have different deaf genes?
no, it has to be the same identical gene in order to manifest
What is the difference between carriers and obligate carriers?
obligate carriers, the parents offspring come out with the condition. Carriers, they carrier the gene but the kids don’t manifest with the gene
how to calculate risk of inheritance in recessive
Complementary mating
Non-complementary mating
Risk for unaffected sibling to be a carrier
Pseudo-dominance
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
where is Pseudo-dominance seen?
X linked recessive inheritance of male offspring
x linked from dad
an example of complementary mating is when
If the parents had different forms of autosomal recessive deafness, all of their children would be hearing. kids would be carriers for 2 different affected genes
what is an example of non-complementary mating?
the parents have the same recessive form of deafness, all of their children will be deaf
How are x linked inheritance divided into?
x linked recessive or x linked dominant
How do you determine if it’s x linked recessive or x linked dominant if it’s from mom?
-if the mom is a carrier and she shows no sign of the disease, it’s X linked recessive
-if mom is a carrier and does show signs of a disease, it is X linked dominant
Who is more affected in x linked disorders?
men because they don’t have a X balancing chromosome
If the trait is recessive in affected males, how are their daughters going to be affected?
daughters will be carriers
if the male has a dominant X linked gene, how will the daughter be affected?
She will manifest the trait
how do you define an X linked chromosome?
Traits controlled by genes on the X chromosome are defined as dominant or recessive by the phenotype of the females
(by the phenotype of mom)
are two copies of the same gene necessary for X LINKED RECESSIVE
no, because Men only have a single X chromosome, so they have only one copy of any gene on the X chromosome
Men are ___ for all genes on the X chromosome
hemizygous (each chromosome is different)
Will X linked recessive diseases affect men?
yes because they only have one X.
there is no corresponding paired X chromosome with a good gene to balance the bad gene making males affected making it psuedo-dominance
will an an X linked recessive disease affect women?
no. because they have 2 X chromosomes. one good x gene to balance the bad gene. That’s why females are always carriers
What are characteristics of X linked recessive inheritance ?
1) no father to son transmission
2)Transmission from unaffected (normal phenotype) female carriers to males (carrier women give it to son)
3)All daughters of a male with the trait will be carriers
4)The abnormal trait may be transmitted through a series of carrier females
Carrier females of x linked recessive traits will have :
-50% chance to have a son with the abnormal trait
-50% chance to have daughters who are carriers
-50% chance of having a normal off spring
This all depends if they give their child the bad or good x chromosome
what are x linked recessive patterns we can see in genes ?
Genotype Phenotype
XX = homozygote hearing female
Xx = heterozygote hearing female
XY = hemizygote hearing male
xY = hemizygote deaf male
What are examples of x linked recessive inheritance ?
Color blindness
Hemophilia
X-linked hearing loss with stapes gusher
Muscular dystrophy (Duchenne-type)
is x linked dominant common?
no, it’s rare
how will x linked dominant chromosome manifest?
The female with the abnormal gene on one X chromosome will manifest the disease condition regardless of what is on the other X chromosome
-therefore, both son and daughter have a 50% chance of inheriting the conditions from the mother
how do you tell apart x linked recessive and x linked dominant if it’s from dad?
-LOOK AT THE FATHER TO SON TRANSMISSION
(the son should have normal transmission because he only gets a y chromosome from dad)
-LOOK AT DAUGHTER TRANSMISSION
(if he has it then the daughter will have it, she won’t be a carrier anymore)
-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
what are transmission traits in x linked dominant inheritance?
-both genders are affected if it’s coming from mom
-if dad is affected then the daughter will be too (she’s getting his only good X)
-father can not pass it down to son (cause he’s giving him his y)
what is an example of x link dominant trait
alport’s syndrome
does y linked patterns exist ?
rare, but yes
how is y linked chromosome trasmitted?
father to son
why are y linked traits only expressed in male offspring?
-All males are hemizygous for all genes on the Y chromosome
-No balancing of the mutant Y gene by X or another Y gene on the Y chromosome
what are nontraditional modes of inhertiance?
1)Multifactorial
2)Polygenic
what are multifactorial traits ?
Traits resulting from the interplay of multiple environmental factors with multiple genes
what are multifactorial traits most commonly associated?
with sporadic (spontaneous) gene mutations
what is an example of multifactorial traits?
Oculo-Auricular-Vertebral (OAV) spectrum disorder
what are polygenic traits?
-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
what is an example of polygenic traits?
cleft lip/ palate
spina bifida
does Mitochondrial inheritance obey the rules of classic Mendelian transmission
no
how is mitochondrial cells transmitted?
-During meiosis, mitochondria are passed only from the mother to the oocyte
-Because sperms do not contribute cytoplasm during fertilization and mitochondria are found only in cytoplasm
HOW are mitochondrial traits passed down thru?
they’re passed down thru the mom’s eve gene
-dad can’t pass it down
-both sexes from mom are affected
what is the risk factor of mom passing down mitochondrial traits?
100 because we have mitochondria in everything
What has a higher spontaneous mutation rate, mitochondrial dna or DNA in nuclear genes? and why?
-Mitochondrial DNA (mtDNA) has a higher spontaneous mutation rate than DNA in nuclear genes
-because mtDNA evolves 5 to 10 times more rapidly than genomic DNA
why do syndromes occur in mitochondrial syndromes?
Syndromes occur as a result of the affected mitochondria being unable to meet the metabolic demands of the tissues
where are mitochondrial disorders prominent?
Mitochondrial disorders are predominant in tissues with high energy demands such as muscles but can affect multiple unrelated systems of the body
what is an example of a mitochondrial disorder?
Leber’s hereditary optic neuropathy:
-Sudden loss of central vision
-Optic nerve damaged at ~20 years of age
why do mitochondrial disorders concern us
because Histopathologic studies show degeneration of cochlear neural elements and degeneration of portions of cn 8 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
-Angelman syndrome
how does prader willi syndrome occur?
Deletion of chromosome 15 (del 15q11-13) of PATERNAL origin
what are some characteristics of prader willi syndrome disorder?
-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
how does Angelman syndrome occur?
Deletion of chromosome 15 (del 15q11-13) of MATERNAL origin
what are some characteristics of Angelman syndrome?
-Intellectual disability
-Developmental delay
-Seizures
-Happy demeanor
-Laughs uncontrollably and excessively
-Poor muscle coordination
-Gait ataxia
what is genetic anticipation
The worsening of symptoms of a genetic disease from one generation to the next
what is allelic expansion
-it’s caused by an increase in the number of trinucleotide base sequence (increase in a gene)
- as the gene increases in number, the more severe the disorder becomes as the generations occur
what is an example of anticipations and allelic expansions?
huntingtins disease, myotonic dystrophy, fragile x syndrome
is myotonic dystrophy dominant or recessive?
dominant and is an expansion of the gene on chromosome 19
what are symptoms of someone with myotonic dystrophy
-Drooping eyelids
-Facial weakness
-Mild to severe muscle weakness
Is Huntington’s disease dominant or recessive
dominant and is a Gene on the tip of chromosome 4p
what are signs of huntington’s disease?
-Adult onset
-Loss of muscle coordination and control
-Deterioration of intellectual function
-Generally early death
who is affected in fragile x syndrome?
mom has a 50% chance to giving it to both sexes
dad doesn’t give it to son, but he does give it to daughter.
(girls affected either way) follows x linked dominant patterns
what is mutated in the fragile x syndrome
the FMR1 gene
is fragile x more common in boys and girls, and what doe we typically see present ?
Most common form of inherited intellectual disability in boys
-intellectual disability is less in girls
what id fragile X in charge of doing
FMR1 gene provides instructions for making a protein called fragile X mental retardation 1 protein (FMRP)
what are other symptoms seen in fragil x syndrome?
-Delayed development of speech and -language
-May have ADHD
-Physical features
-Long jaw
-Big head
-Large ears
is consanguinity an issue in autosomal transmission
NOOOOOOOOOOO
summary of mitochondrial inheritance (eve gene)
-Fathers cannot pass on the trait to his children because the sperm loses cytoplasm prior to fertilization
-All children, male and female, of affected mothers have a 100% risk of being affected
are carriers seen in autosomal dominant patterns of inheritance?
NOOOOOOO
x linked dominant inheritance summary
-If father is affected, each female off springs has a 100% risk of being affected (father has only one X to donate)
-If mother is affected, each offspring (male & female) has a 50% chance of being affected (mother has two Xs and can donate either the normal or mutated X – 50% chance)
summary of x linked recessive FATHER
All daughters are at a 100% risk of being carriers because father contributes an X chromosome to daughters
x linked recessive summary MOTHER
-50% chance of carrier daughters (mother has one normal and one affected X chromosome
-But if sons inherit the bad X, then 100% affected even though it’s a recessive trait – Pseudo dominance – no balancing good X in males, who are hemizygous, so the recessive trait behaves as a dominant trait in sons
can father pass an x linked disorder to son?
-No father-to-son (male-to-male) transmission for X-linked (recessive or dominant) patterns of inheritance
-Because father does not contribute an X chromosome to his son!
what is complementary mating
-autosomal recessive
-Commonly seen with deafness/hard-of-hearing phenotype
-Both parents are deaf, but children are not because each parent’s deafness is due to different genes
-Recessive traits require identical genes from each parent to manifest the phenotype
-All children will be 100% carriers of two different deafness genes
what is non-complementary mating
(autosomal recessive trait)
Both parents are affected and so are all children
Because both parents carry the same deafness genes
