8-25 Single Gene Inheritance

Question 0

Hemizygous

Answer 0

genotype with ONLY ONE Allele for a given chromosome segment

ex. Males only have 1 X and 1 Y

Question 1

1) Where do Genetic disorders orginiate from?
2) What is the differnce between onset of Chromosomal abnormalities and multifactorial genetic abnormalities?

3)Typically single gene mutations are most apparent in…?

Answer 1

1)Genetic Disorders originate from heritable DNA mutations
2)
-Chromosomal abnormalities ONSET before birth!
-Multifactorial problems show up later in life

3)Single gene mutations generally are most apparent in pediatric pts

Question 2

Compound heterozygote

Answer 2

genotype that has 2 different but both MUTANT alleles at one locus

Question 3

Locus

Answer 3

place where a gene is located on a chromosome

Question 4

Genotype

Answer 4

genetic constitution of an individual or specific chromosomal locus

Question 5

Polymorphism

Answer 5

when Alternate genotypes are present (greater than 1%) in a population

Opposite= Rare variant–> (less than 1% frequency in a population)

Question 6

Penetrance

Answer 6

Proportion of mutant individuals who actually manifest a disease

Question 7

Expressivity

Answer 7

THE EXTENT to which a mutant or mutation “expresses” a phenotype (qualitative)

Question 8

Heterozygote vs. Homozygote

Answer 8

Heterozygote=genotype with 2 different alleles at a given locus

HOMOzygote=genotype with 2 IDENTICAL alleles at a given locus

Question 9

1) What are single gene disorders?

2) How many estimated Human single gene disorders exist?

Answer 9

1) disorders caused by a single defective gene inherited in a Mendelian or unifactorial manner
2) 11,000 human single gene disorders exist

Question 10

What is the inheritance patterns for AUTOSOMAL RECESSIVE disease
[5]

Answer 10

-SKIPS GENERATIONS but both males and females are affected equally!

• Often displayed in a cluster amongst siblings BUT ABSENT IN ANCESTORS
• BOTH Parents are carriers & don’t have the dz
• Recurrence risk of A.Recessive for Siblings is 1 in 4 (25% siblings can get it)
• Unaffected sibs of the proband have a 2/3 chance of being a carrier

Question 11

The more rare the disease=___[greater/lower] the chances you’ll find BOTH mutant alleles for that disease in a single individual= ____[Greater/Lower] chances the mutant allele is just residing amongst more carriers.

Answer 11

INC rarity of disease=LOWER chance BOTH mutant alleles for that disease are in a single individual and = GREATER proportion of mutant alleles that just reside in carriers
-For every 1 person with Cystic fibrosis (2 mutant alleles) there are 69 CaRRiers (each with ONLY ONE MUTANT allele)

Question 12

Wht could cause Genetic heterogeneity? [2]

Answer 12

GH could occur from having different mutations at 1 locus (allelic)
OR
from having mutations at 2 completely different loci (locus)

Question 13

Describe Phenotypic heterogeneity

Answer 13

Occurs when the SAME mutation manifest itself differently in different people

Question 14

Haploinsufficiency

Answer 14

happens when the single NORMAL copy does not adequately produce enough of the normal gene product for tht organism–>MUTANT ALLELE IS THEN SAID TO BE THE DOMINANT one

Question 15

What is the typical Inheritance pattern for Autosomal Dominant? [2]

Answer 15

1) Appears in Every Generation

2) DADS do NOT ALWAYS Give dz to their daughters

Question 16

A mutant allele is dominant when: [4]

Answer 16

1) Haploinsufficiency=normal copy of gene is not sufficiently producing enough product
2) Dominant Negative Effect= inactive mutant gene Product interfers w/the function from normal
3) Simple gain of function=mutant product acquires new/enhanced unction
4) mutant allele is dominant when the affected gene was a tumor suppressor gene–>common cause of cancer

Question 17

• Co-Dominance

* example?

Answer 17

Situation in which BOTH alleles are equally strong and BOTH alleles are visible in the hybrid phenotype. Both expressed in heterozygous state

(ex. Blood types in Humans!)

Question 18

1) Degree of Relationship
2) Ex.?
3) How is this related to Coefficient of Inbreeding?

Answer 18

1)Measures Consanguinity (inbreeding) by determining the proportion of alleles two related individuals will have in common

2) Ex. when 2 related people mate, there is a probably that there child will receive BOTH alleles for a specific gene from the same grandpa/grandma (one of grandpas thru the mom and the other of grandpa thru the Dad)
3) That probability = Coefficient of inbreeding [F]

Question 19

Coefficient of inbreeding [F] {{3}}

Answer 19

1) Probability that a child has received BOTH of his alleles for a gene from the same grandparent/ancestor (vs. different unrelated grandparents) because mom and dad are related [Consanguineous]

2)Amount of exactly homozygous genetic material that two relatives share from a common ancestor
3)Proportion of loci at which a person is homozygous by descent
(AKA identical by descent)

Question 20

1)What is the Equation Formula for the [Coefficient of Inbreeding?]/[F]

Answer 20

1/2 x Coefficient of Relationship
OR
[1/2 x (1/2)^n] —- where n= degree of relationship

Question 21

Degree of relationship (n) for:

• Brother-half sister
• Uncle-niece/aunt-nephew
• FIRST cousins
• Half First cousins
• First cousins once removed
• Second cousins

Answer 21

Degree of relationship (n) for:

• Bro and half sis= 2nd [1/4 alleles in common]
• Uncle-niece/aunt-nephew= 2nd

*FIRST cousins= 3rd[1/8 alleles in common]

• Half First cousins = 4th [1/16 alleles in common]
• First cousins once removed= 4th

*Second Cousins = 5th [ 1/32 alleles in common]

Question 22

• What does a pedigree symbol (square or circle) with a line going thur it indicate?
• Square/Circle with (dot in the middle)

Answer 22

Person has genotype that indicates they SHOULD have the dz but that person doesn’t display sx of the dz
*Square/Circle(dot in middle)= Carrier/will not manifest disease

Question 23

What is a clinical example of Recessive inheritance?

Answer 23

Sickle Cell Anemia in which both parents can be carriers but the child= SC disease

Question 24

What's the difference between Coefficient of Relationship (n) and Coefficient of Inbreeding??

Answer 24

COR= proportion of genes 2 people related have in common COi=meausres the increased chance to which two alleles are more likely to be HOMOzyGous (AA or aa) rather than heterozygous (Aa) in a child, solely because the parents are related to each other/inbreeding

Question 25

How do you determine "Degree of Relationship" of a probands parents by looking at a pedigree?

Answer 25

Count the amount of uninterrupted lines which connect the two parents of the proband

Question 26

How do you calculate the odds a child will have a certain homozygous recessive disease? 2 ways -->DRAW IT OUT

Answer 26

FIRST WAY: 1)find Degree of relationship (n) --> 2) use degree to calculate coefficient of relationship [1/2^n] 3) Use COR to find COi (1/2 x [1/2^n]=COi) 4) Multiply COi x overall chance of getting that gene SECOND WAY: 1)Find probability each parent is a carrier (Prob. of getting gene from ancestor^# of generations inbetween) 2)Multiply carrier probability x chance of giving to child -->*1/2* FOR EACH PARENT altogether

Question 27

A higher Coefficient of Inbreeding [F] indicates what for populations....

Answer 27

HIGHER COi=There's MORE homozygous genetic material in common w/the ancestors solely as a result of parents being related

Question 28

Incomplete Dominance

Answer 28

Situation where 2 DIFFERENT alleles both have an effect on the hybrid both but the hybrid doesn't look like either of the 2 alleles (i.e. Pink Flower Rr<----White rr + Red RR )

Question 29

1) Phenotype for Osteogenesis Imperfecta is __[better/worst] for a Point mutation than it is for a null mutation. This is because... 2) What is this called?

Answer 29

Phenotype for OI is MUCH WORST for a point mutation or proteins that work as a part of a large complex than it is for a null mutation because a point mutation in the allele will cause proteins chains to misfold all over the place while null mutation will still allow the other normal allele to make some normal chains = Dominate Negative Effect!

Question 30

How is it 2 children could acquire OI or Ectrodactyly [autosomal DOMINANT disorder] and no parents show the sx at all? [2]

Answer 30

1) One of the parents must have had a point DNA mutation in their GERM LINE which would affect their gametes but not they themselves [OI] 2) Reduced Penetrance=even though the parent HAS the genotype for a dz, they do NOT manifest the disease. -->Can still pass it on to progeny though :-/ "found in Ectrodactyly"

Question 31

What is the inheritance pattern for Sex-linked (X-linked) RECESSIVE disorders? [4]

Answer 31

1. SKIPS GENERATIONS but ONLY males affected 2. Affected Fathers ALWAYS make carrier daughters and NEVER be able to give it to their son 3. Affected Males express the disease and Affected females are carriers with 50% chance of giving it to child **4.Affected fathers gives dz to grandsons {thru their daughters}

Question 32

Phenotypic Variability

Answer 32

Disorders that affect multiple organs and have the same genotype but produce different sx in different people within a family due to effect of environment or outside genes

Question 33

Inheritance pattern for X-linked dominant inheritance (more rare) [4]

Answer 33

1-Appears in Every Generation 2-FATHER ALWAYS GIVES DZ TO DAUGHTERS 3-More Females affected than males (females have a "masking" [X] from Mom) 4-Father consistently gives dz to Grandson thru daughter 5-Females pass on trait to kids REGARDLESS of their sex!

Question 34

Mosaicism

Answer 34

Some cells affected but NOT ALL of the cells = mosaic-likeif occurs in the germ line then CHILDREN of that person will be non-mosaic and have ALL CELLS mutated vs. some

Question 35

What is the primary basis for Imprinting?

Answer 35

Some genes can ONLY BE PASSED TO CHILDREN when they're in EGGS OR SPERM specifically. (ex. If a gene is Sperm Imprint Active then Dad w/defective allele can pass it to children and children WILL have active imprint=express dz) (For that same gene, if Mom has the defective allele and passes it then her children will still have defective allele BUT WON'T SHOW IT because it is inactive when passed thru eggs/oocyte)

Question 36

Prader-Willi gene is a ____[Sperm/Egg] Imprint Active gene which means ___________. If a deletion occurs in the Prader-Willi/Angelman chromosomal region from DAD what will this mean?

Answer 36

PW gene is a SPERM IMPRINT ACTIVE GENE which means although it can be passed to the kids from Mom, it will only be passed as an ACTIVE gene when passed from DAD/in SPERM! If deletion of this area [which houses both PW and angelman genes] occurs in Dad, then Angelman prevention will still be fine since Mom passes that active imprint. PW Active genes come from Dad and deletion--> No Active PW Gene-->Prader-Willi syndrome

Question 37

What does Dz of anticipation refer to?

Answer 37

Dz (like Huntington) which only get WORST and earlier onset with each generation!-->triplet repeat disorders are found even more abundant with every generation

Question 38

Mitochondrial DNA are _____ meaning....... 2) Mitochondrial DNA is inherited from ______only and will undergo ____segregation through___________. 3) How is mitochondria passed onto offspring? 4) What's a trademark pedigree sign for mitochondrial inheritance?

Answer 38

1) Mitochondrial DNA are HETEROPLASMIC=more than 1 type of mitochondrial DNA can be present in cells within a single person 2) Mitochondrial DNA is inherited from THE MOM ONLY and undergoes RANDOM embryogenesis segregation thru multiple rounds of mitosis 3) passed to kids when a small/random sample of mitochon DNA is selected to b included in the progeny eggs during oogenesis 4) THe pedigree WILL STOP WITH AN AFFECTED DAD!

Question 39

What are the 4 general features of Mitochondrial DNA disorders?

Answer 39

1. MATERNAL inheritance ONLY 2. Reduced penetrance=person may carry the gene for a dz but may not actually DISPLAY SX of that dz 3. Variable Expressivity =varies in level of severity from pt to pt 4. Pleiotrophy= can be problematic in 1 part of the body but may be just fine in the other body parts/organs[One gene can affect multiple organs/traits or only one and not the others]

Question 41

1) What is the most common mode of inheritance for REDUCED PENETRANCE situations? 2) What is Reduced Penetrance?

Answer 41

1) Most Commn for Reduced Penetrance=AUTOSOMAL DOMINANT! 2) Situation in which some people express a phenotype while others don't even though THEY ALL HAVE THE SAME GENOTYPE FOR THAT DZ

Question 42

What are the 3 viable Trisomy Dz?

Answer 42

PED Patel = Trisomy 13 Edwards = Trisomy 18 DownSyndrome= Trisomy 21

Question 43

If a Pedigree shows a dz in EVERY Generation and the Age of Onset is DEC each and every time, what Mode of Inheritance is this?

Answer 43

Autosomal Dominant-Dz of Anticipation!