X-Inactivation, Fam Hx, Pattern Gene Inheritance

Front 1

Lyonization

Back 1

process by which all X chromosomes in excess of one are made genetically inactive and heterochromatic

Front 2

4 Key Features of X inactivation

Back 2

1) Occurs during blastocyst stage

2) It's a random process. As a result, females are a "mosaic" of maternal and paternal X chromosomes.

3) Clonal stability. Once an X is inactivated, all of the mitotic products have that same X inactivated. Thought to be achieved via particular methylation pattern

4) X Chromosome regions subject to inactivation. X-inactivation center (XIC). XIST thought to control the inactivation process - it's expressed from the inactivated chromosome!! (Some genes escape inactivation)

Front 3

X-inactivation center/X-Inactive Specific Transcript

Back 3

Area/gene product on the "inactivated" X chromosome. Call this because several individuals who had deletions here had problems deactivating their X chromosomes.

XIST is a gene thought to control this process. It's ON THE INACTIVATED X CHROMOSOME.

Some genes on the "inactivated" x chromosome actually escape the inactivation. These genes seem to have <b> homologous sequences on the Y chromosome </b>, reflecting importance of gene dosage.

Front 4

Pseudoautosomal region

Back 4

homologous sequences of nucleotides on the X and Y chromosomes. You're getting <b> two </b> doses of these genes, and they do recombine. They undergo reciprocal exchange by crossing over and do not show strict sex-linked inheritance.

The pseudoautosomal regions get their name because any genes located within them (so far at least 29 have been found)are inherited just like any autosomal genes.

So, females can inherit an allele originally present on the Y chromosome of their father and males can inherit an allele originally present on the X chromosome of their father.

Front 5

Exceptions to X-inactivation randomness

Back 5

If a translocation occurs between X chromosome and autosome, the normal X chromosome is preferentially inactivated (thus inactivation doesn't spread to the X-autosome because that would have more serious consequences)

Has been observed in women who express disease genes located on the X chromosome.

Front 6

Klinefelter Syndrome

Back 6

47,XXY

Tall eunuchoid habitus, intellectual develop generally ok, infertile

Front 7

XYY

Back 7

1 in 1000 (same as Klinefelter)

Tall stature, intellectual development decent, normal fertility, no increase in children with chromosomal changes interestingly

Could possibly be slightly overrepresented in prison population.

Slight increase in behavior problems.

Front 8

Turner Syndrome

Back 8

45,X

only viable human monosomy

Small stature Intellectual development good, possible coarctation of aorta

Front 9

Isochromosome

Back 9

a chromosome that has lost one of its arms and replaced it with an exact copy of the other arm. This is sometimes seen in some females with Turner syndrome

Front 10

Cytogenetic Heterogeneity: What does it mean for Turner syndrome?

Back 10

Not all ppl with Turner have monosomy X. Other kinds are isochromosome Xq, deletions of X, mosaicism, ring X chromosome (more severe developmental delay) or other anomolies

Front 11

Structural chromosome abnormality resulting in deletion of XIST gene in Turner: what happens?

Back 11

More severe phenotype, including mental retardation

Especially ring chromosome

Front 12

Trisomy X

Back 12

47, XXX

Normal appearance, kind of tall. In the pseudoautosomal region, there may be genes regulating height (b.c Turner women are short)

Normal fertility

Front 13

Individuals having >3 sex chromosomes, eg. XXXX. What is their phenotype like?

Back 13

Tends to be more severe with both growth and mental problems present

Front 14

Sex Determination

Back 14

Processes that determine what sex an embryo will be

Front 15

Sexual Differentiation

Back 15

After Sex Determination, it's the actual cellular/morphogenetic changes that take place that distinguish one sex from another.

Front 16

Barr bodies

Back 16

An area of dark stain (heterochromatin) that is the inactivated X chromosome. Corresponds to the number of X chromosomes minus one.

(Y chromosomes are not inactivated, even if they're extra)

Front 17

SRY genes

Back 17

Sex determining region of the Y Chromosome.

Important in sexual development. There's no homologous sequence on the X chromosome, and the gene is expression

Front 18

Errors in the pseudosomal region: What happens?

Back 18

Genes that are typically found only on the Y chromosome could be relocated onto an X chromosome (and vice versa), resulting in 1) a male with two X chromosomes that appear normal using microscopy but contain Y-specific sequences or 2) A female with an X and a Y chromosome that appear normal using microscopy but contain no Y-specific sex determining sequences.

Example, In the presence of SRY, there will be a switch to male

Front 19

Regions on the Y chromosome that play role in Sex Determination and Differentiation

Back 19

SRY

SOX9

DAX1:thought to interact with SRY and play role in sex differentiation cascade

Front 20

SOX9

Back 20

Region on chromosome 17q thought to be target for SRY and is impt early factor for sex determination cascade.

Mutations of this gene result in campomelic dysplasia (large head, short trunk, bone problems).

Front 21

Campomelic Dysplasia

Back 21

Rare, autosomal dominant condition caused by mutation of the SOC 9 gene. Results in phenotypic female with male chromosomal complement.

Large head, short trunk, bowed limbs, other bone problems.

Front 22

Androgen insensitivity syndrome

Back 22

"Testicular feminization"

Defect in androgen receptor results in failure of response to testosterone. XY individual develops as female. Testes are present but never descend. Little pubic hair, blind vagina

Gender assignment not an issue...psychosexual and sexual development are that of a normal (but infertile) female.

Front 23

Thorough family history includes

Back 23

Biological and medical information about family members.

Info about patient's psychological experience.

Info about patients' social structure and support system.

Front 24

SCREEN for family disease

Back 24

SC - some concern
R- Reproduction; problems in pregnancy, birth defencts in family, infertility in family
E - early disease, death, or disability
E - Ethnicity
N - Non-genetic: any other risk factors or non-medical conditions that run in the family (e.g., smoking)

Front 25

Proband

Back 25

Affected individual coming to medical attention independently of other family members. Designated with an arrow in the pedigree.

Front 26

Characteristics of autosomal dominant

Back 26

1) Vertical transmission

2) Gene product is usually structural (non-enzymatic) protein

3) Both sexes are affected equally

4) Both sexes can transmit

Front 27

Characteristics of autosomal recessive

Back 27

1) Horizontal inheritance

2) Both sexes affected equally

3) Both sexes equally capable of transmitting affected allele

4) Gene product is usually enzymatic protein (where half dose is enough)

Front 28

Characteristics of X-linked recessive

Back 28

1) Males affected much more than females

2) No male-to-male transmission

3) Diagonal inheritance - affected males are related thru females in maternal line

4) No or occasional mild expression in females due to X inactivation

Front 29

Characteristics of X-linked dominant

Back 29

Very rare

1) Twice as many females with the disorder than males (because they have 2x as many X chromosomes!)

2) No male-to-male transmission (no males pass X chr. to other males)

3) Females usually have milder expression due to X-linked inactivation

4) <b> Can distinguish between X-linked dominant and autosomal dominant by looking at female offspring of males. All will have it. </b>

Front 30

Penetrance

Back 30

What percent of people with the mutant allele is the trait expressed at all?

E.g., Retinoblastoma: 10% are not affected. Penetrance is 90%

Front 31

Expressivity

Back 31

The degree to which a trait is expressed. Can't talk about expressivity unless it is penetrant.

Front 32

Variable age of onset

Back 32

Variation in the time to phenotypic expression of a mutant gene.

Front 33

Pleiotropic

Back 33

Produces effects in multiple body systems

Ex. Marfan syndrome affects skeletal, cardiovascular, and ocular systems

Front 34

Locus heterogeneity

Back 34

Mutations at two different genetic loci result in similar phenotypes (ex., several genes can result in congenital deafness because several genes control ability to hear)

Front 35

Allelic heterogeneity

Back 35

Two or more different mutant alleles at the same genetic locus

Ex., >1500 mutations have resulted in cystic fibrosis

Front 36

Sex-limited

Back 36

Phenotype that is autosomally transmitted but expressed only in one sex. E.g., autosomal dominant male precocious puberty

Front 37

Sex-influenced

Back 37

Autosomally inherited traits that are expressed differently, in either degree or frequency, in males and females. Eg., hemochromatosis (increased iron)